Meaidi A, Mascolo A, Sessa M, et al. Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study. BMJ. 2023;382:e074450. doi:10.1136/bmj-2022-074450

EXPERT COMMENTARY

Combination (estrogen plus progestin) hormonal contraceptives as well as non–aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk of VTE events, including lower extremity clots and pulmonary embolism. Taking contraceptives formulated with ethinyl estradiol increases hepatic production of clotting factors on a dose-related basis. Newer progestins, including desogestrel and drospirenone, also may contribute to an elevated VTE risk, although this association is controversial.¹ NSAIDs promote platelet aggregation, thereby activating the clotting system and formation of clots. Although studies that assessed the association between NSAID use and thrombosis have focused on arterial clots, a substantial literature suggests that NSAIDs, including older NSAIDs (such as ibuprofen, diclofenac, and naproxen), also increase VTE risk.²

Although combination contraceptives (oral contraceptives, patches, vaginal rings) and NSAIDs are both commonly used by reproductive-age women, little data have assessed the impact of concomitant use of these medications on VTE risk. Accordingly, investigators in Denmark, using national databases, conducted a retrospective cohort study to assess the impact that independent as well as concomitant use of these medications have on VTE risk.

Details of the study

Meaidi and colleagues included in the cohort reproductive-age women living in Denmark between 1996 and 2017 with no history of thrombosis, thrombophilia, cancer, tubal sterilization, hysterectomy, bilateral oophorectomy, or infertility treatment. National prescription data were used to assess exposure to hormonal contraception.

The investigators classified hormonal contraception into 3 VTE risk categories:

1. high risk—estrogen-progestin patches and vaginal rings; oral contraceptives containing 50 µg of ethinyl estradiol; or the progestins desogestrel, drospirenone, gestodene, or cyproterone (with the latter 2 progestins not available in the United States)
2. medium risk—all other combination oral contraceptives, including those formulated with the progestins norethindrone, norethindrone acetate, norgestrel, and levonorgestrel, as well as depot medroxyprogesterone acetate
3. low/no risk—progestin-only pills, implants, and progestin-containing intrauterine devices (IUDs).

Because in Denmark NSAIDs are prescribed as a single package containing no more than 30 tablets, time exposed to non–aspirin NSAIDs was assumed to last 1 week from the prescription date.

The authors considered first-time diagnoses of lower limb venous thrombosis or pulmonary embolism that were made in hospitals to represent VTE. They also constructed a subgroup of VTE patients in whom the diagnosis was either confirmed with imaging or followed by prescription of an anticoagulant.

To address potential confounding, the authors adjusted their analysis based on age, calendar year, educational attainment, occurrence of pregnancy, surgery, hypertension, diabetes, polycystic ovary syndrome, endometriosis, migraine, systemic connective tissue diseases, inflammatory polyarthropathies, and use of tranexamic acid (a medication that may increase VTE risk). They also censored (temporarily excluded women from analysis) episodes associated with a transiently elevated risk of VTE: pregnancy and 6 months following delivery, 12 weeks after other pregnancy terminations, 8 weeks following any surgery involving hospital admission, and 8 weeks following prescription of tranexamic acid.

Continue to: VTEs associated with risk category of hormonal contraception used...

Results. The overall cohort included more than 2 million women who were followed for a median of 10 years. During 21.0 million person-years, 8,710 VTE events were diagnosed; almost one-third of these were pulmonary embolisms, with the remainder diagnosed as lower extremity VTE. Of these 8,710 women diagnosed with VTE, 7,043 (81%) were confirmed with either diagnostic imaging or prescription of an anticoagulant. Unfortunately, 228 women (2.6%) died within 30 days of the diagnosis of VTE.

The investigators identified concomitant use of hormonal contraception and NSAIDs in more than 500,000 women. Among women with such concomitant use, 58% were using contraceptives that were high risk while 23% used medium-risk and 19% used low/no-risk contraceptives. Ibuprofen (60%) was the most commonly used NSAID, followed by diclofenac (20%) and naproxen (6%). Between 97% and 98% of high-risk and medium-risk contraceptives were combination pills; 89% of low/no-risk contraceptives were progestin IUDs.

Compared with nonuse of both hormonal contraceptives and NSAIDs, incidence rate ratios of VTE adjusted for age, calendar year, and education were 8.1 (95% confidence interval [CI], 6.9–9.6) for use of NSAIDs only, 4.2 (95% CI, 4.0–4.4) for use of high-risk contraceptives only, 3.0 (95% CI, 2.8–3.2) for medium-risk contraceptive use, and 1.1 (95% CI, 1.0–1.3) for use of low/no-risk hormonal contraception. Risk of VTE was approximately twice as high with the use of diclofenac only compared with the risks associated with ibuprofen or naproxen use only.

With respect to concomitant use of NSAIDs and hormonal contraception, incidence rate ratios of VTE were 50.6 (95% CI, 44.2–57.8), 26.1 (95% CI, 19.6–34.7), and 5.7 (95% CI, 3.3–10.1), respectively, with use of high-risk, medium-risk, and low/no-risk hormonal contraceptives. Adjusting for time updated information on occurrences of migraine, connective tissue disorder, inflammatory polyarthropathies, endometriosis, polycystic ovary syndrome, hypertension, and diabetes did not materially affect these associations.

When analysis was limited to women without these occurring conditions, rate ratios were somewhat higher (5.7 and 4.1) for use of high-risk and medium-risk contraceptives only. Incidence rate ratios in this subcohort of healthier women were substantially higher for NSAID use only (15.0), and 111.7, 43.2, and 13.0, respectively, for concomitant use of NSAIDs with high-risk, medium-risk, and low/no-risk contraceptives. In this analysis of healthier women, diclofenac continued to be associated with substantially higher risks of VTE than ibuprofen or naproxen. When the stricter definition of VTE (confirmed cases) was used, adjusted rate ratios remained similar.

Absolute risks of VTE

Although some of the elevated rate ratios noted in this study might appear alarming, it is important to keep in mind that the baseline incidence of VTE in healthy reproductive-age women is low. Accordingly, as the authors pointed out, even among women who used NSAIDs concomitantly with high-risk combination hormonal contraceptives, the absolute risk of VTE was 2/10,000.

Study strengths and limitations

Strengths of this analysis by Meaidi and colleagues include the use of large, essentially all-inclusive national registries. In addition, nationwide Danish registry data that indicate a diagnosis of VTE have been found to have a high positive predictive value.³ Another strength is the large number of potentially confounding factors that the authors controlled for.

One potential limitation of their analysis is that the use of only prescribed NSAIDs was considered. Fortunately, however, the prevalence of over-the-counter ibuprofen use in Denmark is not high enough to materially affect the authors’ findings.⁴ Another potential limitation was that information on smoking and body mass index was not available for most of the women included in the study cohort. The authors countered this limitation by pointing out that, in Denmark, smoking and obesity are highly correlated with educational status, and that all analyses were adjusted for educational status. ●

Meaidi A, Mascolo A, Sessa M, et al. Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study. BMJ. 2023;382:e074450. doi:10.1136/bmj-2022-074450

EXPERT COMMENTARY

Combination (estrogen plus progestin) hormonal contraceptives as well as non–aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk of VTE events, including lower extremity clots and pulmonary embolism. Taking contraceptives formulated with ethinyl estradiol increases hepatic production of clotting factors on a dose-related basis. Newer progestins, including desogestrel and drospirenone, also may contribute to an elevated VTE risk, although this association is controversial.¹ NSAIDs promote platelet aggregation, thereby activating the clotting system and formation of clots. Although studies that assessed the association between NSAID use and thrombosis have focused on arterial clots, a substantial literature suggests that NSAIDs, including older NSAIDs (such as ibuprofen, diclofenac, and naproxen), also increase VTE risk.²

Although combination contraceptives (oral contraceptives, patches, vaginal rings) and NSAIDs are both commonly used by reproductive-age women, little data have assessed the impact of concomitant use of these medications on VTE risk. Accordingly, investigators in Denmark, using national databases, conducted a retrospective cohort study to assess the impact that independent as well as concomitant use of these medications have on VTE risk.

Details of the study

Meaidi and colleagues included in the cohort reproductive-age women living in Denmark between 1996 and 2017 with no history of thrombosis, thrombophilia, cancer, tubal sterilization, hysterectomy, bilateral oophorectomy, or infertility treatment. National prescription data were used to assess exposure to hormonal contraception.

The investigators classified hormonal contraception into 3 VTE risk categories:

1. high risk—estrogen-progestin patches and vaginal rings; oral contraceptives containing 50 µg of ethinyl estradiol; or the progestins desogestrel, drospirenone, gestodene, or cyproterone (with the latter 2 progestins not available in the United States)
2. medium risk—all other combination oral contraceptives, including those formulated with the progestins norethindrone, norethindrone acetate, norgestrel, and levonorgestrel, as well as depot medroxyprogesterone acetate
3. low/no risk—progestin-only pills, implants, and progestin-containing intrauterine devices (IUDs).

Because in Denmark NSAIDs are prescribed as a single package containing no more than 30 tablets, time exposed to non–aspirin NSAIDs was assumed to last 1 week from the prescription date.

The authors considered first-time diagnoses of lower limb venous thrombosis or pulmonary embolism that were made in hospitals to represent VTE. They also constructed a subgroup of VTE patients in whom the diagnosis was either confirmed with imaging or followed by prescription of an anticoagulant.

To address potential confounding, the authors adjusted their analysis based on age, calendar year, educational attainment, occurrence of pregnancy, surgery, hypertension, diabetes, polycystic ovary syndrome, endometriosis, migraine, systemic connective tissue diseases, inflammatory polyarthropathies, and use of tranexamic acid (a medication that may increase VTE risk). They also censored (temporarily excluded women from analysis) episodes associated with a transiently elevated risk of VTE: pregnancy and 6 months following delivery, 12 weeks after other pregnancy terminations, 8 weeks following any surgery involving hospital admission, and 8 weeks following prescription of tranexamic acid.

Continue to: VTEs associated with risk category of hormonal contraception used...

Results. The overall cohort included more than 2 million women who were followed for a median of 10 years. During 21.0 million person-years, 8,710 VTE events were diagnosed; almost one-third of these were pulmonary embolisms, with the remainder diagnosed as lower extremity VTE. Of these 8,710 women diagnosed with VTE, 7,043 (81%) were confirmed with either diagnostic imaging or prescription of an anticoagulant. Unfortunately, 228 women (2.6%) died within 30 days of the diagnosis of VTE.

The investigators identified concomitant use of hormonal contraception and NSAIDs in more than 500,000 women. Among women with such concomitant use, 58% were using contraceptives that were high risk while 23% used medium-risk and 19% used low/no-risk contraceptives. Ibuprofen (60%) was the most commonly used NSAID, followed by diclofenac (20%) and naproxen (6%). Between 97% and 98% of high-risk and medium-risk contraceptives were combination pills; 89% of low/no-risk contraceptives were progestin IUDs.

Compared with nonuse of both hormonal contraceptives and NSAIDs, incidence rate ratios of VTE adjusted for age, calendar year, and education were 8.1 (95% confidence interval [CI], 6.9–9.6) for use of NSAIDs only, 4.2 (95% CI, 4.0–4.4) for use of high-risk contraceptives only, 3.0 (95% CI, 2.8–3.2) for medium-risk contraceptive use, and 1.1 (95% CI, 1.0–1.3) for use of low/no-risk hormonal contraception. Risk of VTE was approximately twice as high with the use of diclofenac only compared with the risks associated with ibuprofen or naproxen use only.

With respect to concomitant use of NSAIDs and hormonal contraception, incidence rate ratios of VTE were 50.6 (95% CI, 44.2–57.8), 26.1 (95% CI, 19.6–34.7), and 5.7 (95% CI, 3.3–10.1), respectively, with use of high-risk, medium-risk, and low/no-risk hormonal contraceptives. Adjusting for time updated information on occurrences of migraine, connective tissue disorder, inflammatory polyarthropathies, endometriosis, polycystic ovary syndrome, hypertension, and diabetes did not materially affect these associations.

When analysis was limited to women without these occurring conditions, rate ratios were somewhat higher (5.7 and 4.1) for use of high-risk and medium-risk contraceptives only. Incidence rate ratios in this subcohort of healthier women were substantially higher for NSAID use only (15.0), and 111.7, 43.2, and 13.0, respectively, for concomitant use of NSAIDs with high-risk, medium-risk, and low/no-risk contraceptives. In this analysis of healthier women, diclofenac continued to be associated with substantially higher risks of VTE than ibuprofen or naproxen. When the stricter definition of VTE (confirmed cases) was used, adjusted rate ratios remained similar.

Absolute risks of VTE

Although some of the elevated rate ratios noted in this study might appear alarming, it is important to keep in mind that the baseline incidence of VTE in healthy reproductive-age women is low. Accordingly, as the authors pointed out, even among women who used NSAIDs concomitantly with high-risk combination hormonal contraceptives, the absolute risk of VTE was 2/10,000.

Study strengths and limitations

Strengths of this analysis by Meaidi and colleagues include the use of large, essentially all-inclusive national registries. In addition, nationwide Danish registry data that indicate a diagnosis of VTE have been found to have a high positive predictive value.³ Another strength is the large number of potentially confounding factors that the authors controlled for.

One potential limitation of their analysis is that the use of only prescribed NSAIDs was considered. Fortunately, however, the prevalence of over-the-counter ibuprofen use in Denmark is not high enough to materially affect the authors’ findings.⁴ Another potential limitation was that information on smoking and body mass index was not available for most of the women included in the study cohort. The authors countered this limitation by pointing out that, in Denmark, smoking and obesity are highly correlated with educational status, and that all analyses were adjusted for educational status. ●

Meaidi A, Mascolo A, Sessa M, et al. Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study. BMJ. 2023;382:e074450. doi:10.1136/bmj-2022-074450

EXPERT COMMENTARY

Combination (estrogen plus progestin) hormonal contraceptives as well as non–aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk of VTE events, including lower extremity clots and pulmonary embolism. Taking contraceptives formulated with ethinyl estradiol increases hepatic production of clotting factors on a dose-related basis. Newer progestins, including desogestrel and drospirenone, also may contribute to an elevated VTE risk, although this association is controversial.¹ NSAIDs promote platelet aggregation, thereby activating the clotting system and formation of clots. Although studies that assessed the association between NSAID use and thrombosis have focused on arterial clots, a substantial literature suggests that NSAIDs, including older NSAIDs (such as ibuprofen, diclofenac, and naproxen), also increase VTE risk.²

Although combination contraceptives (oral contraceptives, patches, vaginal rings) and NSAIDs are both commonly used by reproductive-age women, little data have assessed the impact of concomitant use of these medications on VTE risk. Accordingly, investigators in Denmark, using national databases, conducted a retrospective cohort study to assess the impact that independent as well as concomitant use of these medications have on VTE risk.

Details of the study

Meaidi and colleagues included in the cohort reproductive-age women living in Denmark between 1996 and 2017 with no history of thrombosis, thrombophilia, cancer, tubal sterilization, hysterectomy, bilateral oophorectomy, or infertility treatment. National prescription data were used to assess exposure to hormonal contraception.

The investigators classified hormonal contraception into 3 VTE risk categories:

1. high risk—estrogen-progestin patches and vaginal rings; oral contraceptives containing 50 µg of ethinyl estradiol; or the progestins desogestrel, drospirenone, gestodene, or cyproterone (with the latter 2 progestins not available in the United States)
2. medium risk—all other combination oral contraceptives, including those formulated with the progestins norethindrone, norethindrone acetate, norgestrel, and levonorgestrel, as well as depot medroxyprogesterone acetate
3. low/no risk—progestin-only pills, implants, and progestin-containing intrauterine devices (IUDs).

Because in Denmark NSAIDs are prescribed as a single package containing no more than 30 tablets, time exposed to non–aspirin NSAIDs was assumed to last 1 week from the prescription date.

The authors considered first-time diagnoses of lower limb venous thrombosis or pulmonary embolism that were made in hospitals to represent VTE. They also constructed a subgroup of VTE patients in whom the diagnosis was either confirmed with imaging or followed by prescription of an anticoagulant.

To address potential confounding, the authors adjusted their analysis based on age, calendar year, educational attainment, occurrence of pregnancy, surgery, hypertension, diabetes, polycystic ovary syndrome, endometriosis, migraine, systemic connective tissue diseases, inflammatory polyarthropathies, and use of tranexamic acid (a medication that may increase VTE risk). They also censored (temporarily excluded women from analysis) episodes associated with a transiently elevated risk of VTE: pregnancy and 6 months following delivery, 12 weeks after other pregnancy terminations, 8 weeks following any surgery involving hospital admission, and 8 weeks following prescription of tranexamic acid.

Continue to: VTEs associated with risk category of hormonal contraception used...

Results. The overall cohort included more than 2 million women who were followed for a median of 10 years. During 21.0 million person-years, 8,710 VTE events were diagnosed; almost one-third of these were pulmonary embolisms, with the remainder diagnosed as lower extremity VTE. Of these 8,710 women diagnosed with VTE, 7,043 (81%) were confirmed with either diagnostic imaging or prescription of an anticoagulant. Unfortunately, 228 women (2.6%) died within 30 days of the diagnosis of VTE.

The investigators identified concomitant use of hormonal contraception and NSAIDs in more than 500,000 women. Among women with such concomitant use, 58% were using contraceptives that were high risk while 23% used medium-risk and 19% used low/no-risk contraceptives. Ibuprofen (60%) was the most commonly used NSAID, followed by diclofenac (20%) and naproxen (6%). Between 97% and 98% of high-risk and medium-risk contraceptives were combination pills; 89% of low/no-risk contraceptives were progestin IUDs.

Compared with nonuse of both hormonal contraceptives and NSAIDs, incidence rate ratios of VTE adjusted for age, calendar year, and education were 8.1 (95% confidence interval [CI], 6.9–9.6) for use of NSAIDs only, 4.2 (95% CI, 4.0–4.4) for use of high-risk contraceptives only, 3.0 (95% CI, 2.8–3.2) for medium-risk contraceptive use, and 1.1 (95% CI, 1.0–1.3) for use of low/no-risk hormonal contraception. Risk of VTE was approximately twice as high with the use of diclofenac only compared with the risks associated with ibuprofen or naproxen use only.

With respect to concomitant use of NSAIDs and hormonal contraception, incidence rate ratios of VTE were 50.6 (95% CI, 44.2–57.8), 26.1 (95% CI, 19.6–34.7), and 5.7 (95% CI, 3.3–10.1), respectively, with use of high-risk, medium-risk, and low/no-risk hormonal contraceptives. Adjusting for time updated information on occurrences of migraine, connective tissue disorder, inflammatory polyarthropathies, endometriosis, polycystic ovary syndrome, hypertension, and diabetes did not materially affect these associations.

When analysis was limited to women without these occurring conditions, rate ratios were somewhat higher (5.7 and 4.1) for use of high-risk and medium-risk contraceptives only. Incidence rate ratios in this subcohort of healthier women were substantially higher for NSAID use only (15.0), and 111.7, 43.2, and 13.0, respectively, for concomitant use of NSAIDs with high-risk, medium-risk, and low/no-risk contraceptives. In this analysis of healthier women, diclofenac continued to be associated with substantially higher risks of VTE than ibuprofen or naproxen. When the stricter definition of VTE (confirmed cases) was used, adjusted rate ratios remained similar.

Absolute risks of VTE

Although some of the elevated rate ratios noted in this study might appear alarming, it is important to keep in mind that the baseline incidence of VTE in healthy reproductive-age women is low. Accordingly, as the authors pointed out, even among women who used NSAIDs concomitantly with high-risk combination hormonal contraceptives, the absolute risk of VTE was 2/10,000.

Study strengths and limitations

Strengths of this analysis by Meaidi and colleagues include the use of large, essentially all-inclusive national registries. In addition, nationwide Danish registry data that indicate a diagnosis of VTE have been found to have a high positive predictive value.³ Another strength is the large number of potentially confounding factors that the authors controlled for.

One potential limitation of their analysis is that the use of only prescribed NSAIDs was considered. Fortunately, however, the prevalence of over-the-counter ibuprofen use in Denmark is not high enough to materially affect the authors’ findings.⁴ Another potential limitation was that information on smoking and body mass index was not available for most of the women included in the study cohort. The authors countered this limitation by pointing out that, in Denmark, smoking and obesity are highly correlated with educational status, and that all analyses were adjusted for educational status. ●

Restrepo J, Herrera T, Samakoses R, et al. Ten-year follow-up of 9-valent human papillomavirus vaccine: immunogenicity, effectiveness, and safety. Pediatrics. 2023;152:e2022060993. doi:10.1542/peds.2022-060993

EXPERT COMMENTARY

Infection with human papillomavirus (HPV) is associated with nearly all cases of cervical cancer. Long-term safety and efficacy of the bivalent (Cervarix) and quadrivalent (Gardasil) vaccines have been demonstrated for up to 10 to 14 years.^1-6 It is estimated that the 9-valent vaccine (Gardasil 9), which was licensed in 2014 and protects against HPV 16/18/31/33/45/52/58 and HPV 6/11, could prevent up to 90% of cervical cancer cases. The bivalent and quadrivalent vaccines could ideally prevent 70% of cases of cervical cancer. In a recent study, authors compared the efficacy and safety of the newer 9-valent vaccine at 10 years with long-term outcomes of previous vaccine studies.⁷

Details of the study

Study V503-002 conducted by Luxembourg and colleagues originally enrolled 1,935 boys and girls from 66 sites in Africa, Asia, Europe, Latin America, and North America to receive 3 doses of the 9-valent HPV vaccine, with follow-up for 12 to 36 months to monitor safety and immunogenicity.⁸ In an extension of this investigation, Restrepo and colleagues revisited 40 of these sites in 13 countries to gather 10 years of long-term follow-up data.⁷

The final long-term follow-up cohort included 971 girls and 301 boys aged 9 to 15 at vaccination.

Results. At month 126, participants continued to have very high seropositive rates (81%–100%, depending on assay sensitivity and HPV type). There were no cases of high-grade cervical, vaginal, or vulvar dysplasia related to HPV strains covered in the vaccine. Rates of infection in women with the vaccine-targeted HPV types were very low—54.6 per 10,000 person-years—compared with 927.4 per 10,000 person-years for HPV types not included in the vaccine. No adverse events attributable to the vaccine were reported.

Study strengths and limitations

Strengths of this study included the use of rigorous end points similar to those used in the initial efficacy studies for easy comparison. Limitations included the relatively small size, which precluded a robust assessment of adverse events, as well as the lack of controls. Furthermore, this study looked at children receiving 3 doses of HPV vaccine prior to the age of 15 and may not be generalizable to people who receive the vaccine at an older age or in fewer doses. ●

Restrepo J, Herrera T, Samakoses R, et al. Ten-year follow-up of 9-valent human papillomavirus vaccine: immunogenicity, effectiveness, and safety. Pediatrics. 2023;152:e2022060993. doi:10.1542/peds.2022-060993

EXPERT COMMENTARY

Infection with human papillomavirus (HPV) is associated with nearly all cases of cervical cancer. Long-term safety and efficacy of the bivalent (Cervarix) and quadrivalent (Gardasil) vaccines have been demonstrated for up to 10 to 14 years.^1-6 It is estimated that the 9-valent vaccine (Gardasil 9), which was licensed in 2014 and protects against HPV 16/18/31/33/45/52/58 and HPV 6/11, could prevent up to 90% of cervical cancer cases. The bivalent and quadrivalent vaccines could ideally prevent 70% of cases of cervical cancer. In a recent study, authors compared the efficacy and safety of the newer 9-valent vaccine at 10 years with long-term outcomes of previous vaccine studies.⁷

Details of the study

Study V503-002 conducted by Luxembourg and colleagues originally enrolled 1,935 boys and girls from 66 sites in Africa, Asia, Europe, Latin America, and North America to receive 3 doses of the 9-valent HPV vaccine, with follow-up for 12 to 36 months to monitor safety and immunogenicity.⁸ In an extension of this investigation, Restrepo and colleagues revisited 40 of these sites in 13 countries to gather 10 years of long-term follow-up data.⁷

The final long-term follow-up cohort included 971 girls and 301 boys aged 9 to 15 at vaccination.

Results. At month 126, participants continued to have very high seropositive rates (81%–100%, depending on assay sensitivity and HPV type). There were no cases of high-grade cervical, vaginal, or vulvar dysplasia related to HPV strains covered in the vaccine. Rates of infection in women with the vaccine-targeted HPV types were very low—54.6 per 10,000 person-years—compared with 927.4 per 10,000 person-years for HPV types not included in the vaccine. No adverse events attributable to the vaccine were reported.

Study strengths and limitations

Strengths of this study included the use of rigorous end points similar to those used in the initial efficacy studies for easy comparison. Limitations included the relatively small size, which precluded a robust assessment of adverse events, as well as the lack of controls. Furthermore, this study looked at children receiving 3 doses of HPV vaccine prior to the age of 15 and may not be generalizable to people who receive the vaccine at an older age or in fewer doses. ●

Restrepo J, Herrera T, Samakoses R, et al. Ten-year follow-up of 9-valent human papillomavirus vaccine: immunogenicity, effectiveness, and safety. Pediatrics. 2023;152:e2022060993. doi:10.1542/peds.2022-060993

EXPERT COMMENTARY

Infection with human papillomavirus (HPV) is associated with nearly all cases of cervical cancer. Long-term safety and efficacy of the bivalent (Cervarix) and quadrivalent (Gardasil) vaccines have been demonstrated for up to 10 to 14 years.^1-6 It is estimated that the 9-valent vaccine (Gardasil 9), which was licensed in 2014 and protects against HPV 16/18/31/33/45/52/58 and HPV 6/11, could prevent up to 90% of cervical cancer cases. The bivalent and quadrivalent vaccines could ideally prevent 70% of cases of cervical cancer. In a recent study, authors compared the efficacy and safety of the newer 9-valent vaccine at 10 years with long-term outcomes of previous vaccine studies.⁷

Details of the study

Study V503-002 conducted by Luxembourg and colleagues originally enrolled 1,935 boys and girls from 66 sites in Africa, Asia, Europe, Latin America, and North America to receive 3 doses of the 9-valent HPV vaccine, with follow-up for 12 to 36 months to monitor safety and immunogenicity.⁸ In an extension of this investigation, Restrepo and colleagues revisited 40 of these sites in 13 countries to gather 10 years of long-term follow-up data.⁷

The final long-term follow-up cohort included 971 girls and 301 boys aged 9 to 15 at vaccination.

Results. At month 126, participants continued to have very high seropositive rates (81%–100%, depending on assay sensitivity and HPV type). There were no cases of high-grade cervical, vaginal, or vulvar dysplasia related to HPV strains covered in the vaccine. Rates of infection in women with the vaccine-targeted HPV types were very low—54.6 per 10,000 person-years—compared with 927.4 per 10,000 person-years for HPV types not included in the vaccine. No adverse events attributable to the vaccine were reported.

Study strengths and limitations

Strengths of this study included the use of rigorous end points similar to those used in the initial efficacy studies for easy comparison. Limitations included the relatively small size, which precluded a robust assessment of adverse events, as well as the lack of controls. Furthermore, this study looked at children receiving 3 doses of HPV vaccine prior to the age of 15 and may not be generalizable to people who receive the vaccine at an older age or in fewer doses. ●

Long COVID can exacerbate existing mental health disorders or cause new-onset psychiatric symptoms, but mental illness does not cause long COVID, experts say.

The consensus guidance statement on the assessment and treatment of mental health symptoms in patients with post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID, was published online in Physical Medicine and Rehabilitation, the journal of the American Academy of Physical Medicine and Rehabilitation (AAPM&R).

The statement was developed by a task force that included experts from physical medicine, neurology, neuropsychiatry, neuropsychology, rehabilitation psychology, and primary care. It is the eighth guidance statement on long COVID published by AAPM&R).

“Many of our patients have reported experiences in which their symptoms of long COVID have been dismissed either by loved ones in the community, or also amongst health care providers, and they’ve been told their symptoms are in their head or due to a mental health condition, but that’s simply not true,” Abby L. Cheng, MD, a physiatrist at Barnes Jewish Hospital in St. Louis and a coauthor of the new guidance, said in a press briefing.

“Long COVID is real, and mental health conditions do not cause long COVID,” Dr. Cheng added.
 

Millions of Americans affected

Anxiety and depression have been reported as the second and third most common symptoms of long COVID, according to the guidance statement.

There is some evidence that the body’s inflammatory response – specifically, circulating cytokines – may contribute to the worsening of mental health symptoms or may bring on new symptoms of anxiety or depression, said Dr. Cheng. Cytokines may also affect levels of brain chemicals, such as serotonin, she said.

Researchers are also exploring whether the persistence of virus in the body, miniature blood clots in the body and brain, and changes to the gut microbiome affect the mental health of people with long COVID.

Some mental health symptoms – such as fatigue, brain fog, sleep disturbances, and tachycardia – can mimic long COVID symptoms, said Dr. Cheng.

The treatment is the same for someone with or without long COVID who has anxiety, depression, posttraumatic stress disorder, or other mental health conditions and includes treatment of coexisting medical conditions, supportive therapy and cognitive-behavioral therapy, and pharmacologic interventions, she said.

“Group therapy may have a particular role in the long COVID population because it really provides that social connection and awareness of additional resources in addition to validation of their experiences,” Dr. Cheng said.

The guidance suggests that primary care practitioners – if it’s within their comfort zone and they have the training – can be the first line for managing mental health symptoms.

But for patients whose symptoms are interfering with functioning and their ability to interact with the community, the guidance urges primary care clinicians to refer the patient to a specialist.

“It leaves the door open to them to practice within their scope but also gives guidance as to how, why, and who should be referred to the next level of care,” said Dr. Cheng.

Coauthor Monica Verduzco-Gutierrez, MD, chair of rehabilitation medicine at UT Health San Antonio, Texas, said that although fewer people are now getting long COVID, “it’s still an impactful number.”

The Centers for Disease Control and Prevention recently estimated that about 7% of American adults (18 million) and 1.3% of children had experienced long COVID.

Dr. Gutierrez said that it’s an evolving number, as some patients who have a second or third or fourth SARS-CoV-2 infection experience exacerbations of previous bouts of long COVID or develop long COVID for the first time.

“We are still getting new patients on a regular basis with long COVID,” said AAPM&R President Steven R. Flanagan, MD, a physical medicine specialist.

“This is a problem that really is not going away. It is still real and still ever-present,” said Dr. Flanagan, chair of rehabilitation medicine at NYU Langone Health.
 

A version of this article first appeared on Medscape.com.

Long COVID can exacerbate existing mental health disorders or cause new-onset psychiatric symptoms, but mental illness does not cause long COVID, experts say.

The consensus guidance statement on the assessment and treatment of mental health symptoms in patients with post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID, was published online in Physical Medicine and Rehabilitation, the journal of the American Academy of Physical Medicine and Rehabilitation (AAPM&R).

The statement was developed by a task force that included experts from physical medicine, neurology, neuropsychiatry, neuropsychology, rehabilitation psychology, and primary care. It is the eighth guidance statement on long COVID published by AAPM&R).

“Many of our patients have reported experiences in which their symptoms of long COVID have been dismissed either by loved ones in the community, or also amongst health care providers, and they’ve been told their symptoms are in their head or due to a mental health condition, but that’s simply not true,” Abby L. Cheng, MD, a physiatrist at Barnes Jewish Hospital in St. Louis and a coauthor of the new guidance, said in a press briefing.

“Long COVID is real, and mental health conditions do not cause long COVID,” Dr. Cheng added.
 

Millions of Americans affected

Anxiety and depression have been reported as the second and third most common symptoms of long COVID, according to the guidance statement.

There is some evidence that the body’s inflammatory response – specifically, circulating cytokines – may contribute to the worsening of mental health symptoms or may bring on new symptoms of anxiety or depression, said Dr. Cheng. Cytokines may also affect levels of brain chemicals, such as serotonin, she said.

Researchers are also exploring whether the persistence of virus in the body, miniature blood clots in the body and brain, and changes to the gut microbiome affect the mental health of people with long COVID.

Some mental health symptoms – such as fatigue, brain fog, sleep disturbances, and tachycardia – can mimic long COVID symptoms, said Dr. Cheng.

The treatment is the same for someone with or without long COVID who has anxiety, depression, posttraumatic stress disorder, or other mental health conditions and includes treatment of coexisting medical conditions, supportive therapy and cognitive-behavioral therapy, and pharmacologic interventions, she said.

“Group therapy may have a particular role in the long COVID population because it really provides that social connection and awareness of additional resources in addition to validation of their experiences,” Dr. Cheng said.

The guidance suggests that primary care practitioners – if it’s within their comfort zone and they have the training – can be the first line for managing mental health symptoms.

But for patients whose symptoms are interfering with functioning and their ability to interact with the community, the guidance urges primary care clinicians to refer the patient to a specialist.

“It leaves the door open to them to practice within their scope but also gives guidance as to how, why, and who should be referred to the next level of care,” said Dr. Cheng.

Coauthor Monica Verduzco-Gutierrez, MD, chair of rehabilitation medicine at UT Health San Antonio, Texas, said that although fewer people are now getting long COVID, “it’s still an impactful number.”

The Centers for Disease Control and Prevention recently estimated that about 7% of American adults (18 million) and 1.3% of children had experienced long COVID.

Dr. Gutierrez said that it’s an evolving number, as some patients who have a second or third or fourth SARS-CoV-2 infection experience exacerbations of previous bouts of long COVID or develop long COVID for the first time.

“We are still getting new patients on a regular basis with long COVID,” said AAPM&R President Steven R. Flanagan, MD, a physical medicine specialist.

“This is a problem that really is not going away. It is still real and still ever-present,” said Dr. Flanagan, chair of rehabilitation medicine at NYU Langone Health.
 

A version of this article first appeared on Medscape.com.

Long COVID can exacerbate existing mental health disorders or cause new-onset psychiatric symptoms, but mental illness does not cause long COVID, experts say.

The consensus guidance statement on the assessment and treatment of mental health symptoms in patients with post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID, was published online in Physical Medicine and Rehabilitation, the journal of the American Academy of Physical Medicine and Rehabilitation (AAPM&R).

The statement was developed by a task force that included experts from physical medicine, neurology, neuropsychiatry, neuropsychology, rehabilitation psychology, and primary care. It is the eighth guidance statement on long COVID published by AAPM&R).

“Many of our patients have reported experiences in which their symptoms of long COVID have been dismissed either by loved ones in the community, or also amongst health care providers, and they’ve been told their symptoms are in their head or due to a mental health condition, but that’s simply not true,” Abby L. Cheng, MD, a physiatrist at Barnes Jewish Hospital in St. Louis and a coauthor of the new guidance, said in a press briefing.

“Long COVID is real, and mental health conditions do not cause long COVID,” Dr. Cheng added.
 

Millions of Americans affected

Anxiety and depression have been reported as the second and third most common symptoms of long COVID, according to the guidance statement.

There is some evidence that the body’s inflammatory response – specifically, circulating cytokines – may contribute to the worsening of mental health symptoms or may bring on new symptoms of anxiety or depression, said Dr. Cheng. Cytokines may also affect levels of brain chemicals, such as serotonin, she said.

Researchers are also exploring whether the persistence of virus in the body, miniature blood clots in the body and brain, and changes to the gut microbiome affect the mental health of people with long COVID.

Some mental health symptoms – such as fatigue, brain fog, sleep disturbances, and tachycardia – can mimic long COVID symptoms, said Dr. Cheng.

The treatment is the same for someone with or without long COVID who has anxiety, depression, posttraumatic stress disorder, or other mental health conditions and includes treatment of coexisting medical conditions, supportive therapy and cognitive-behavioral therapy, and pharmacologic interventions, she said.

“Group therapy may have a particular role in the long COVID population because it really provides that social connection and awareness of additional resources in addition to validation of their experiences,” Dr. Cheng said.

The guidance suggests that primary care practitioners – if it’s within their comfort zone and they have the training – can be the first line for managing mental health symptoms.

But for patients whose symptoms are interfering with functioning and their ability to interact with the community, the guidance urges primary care clinicians to refer the patient to a specialist.

“It leaves the door open to them to practice within their scope but also gives guidance as to how, why, and who should be referred to the next level of care,” said Dr. Cheng.

Coauthor Monica Verduzco-Gutierrez, MD, chair of rehabilitation medicine at UT Health San Antonio, Texas, said that although fewer people are now getting long COVID, “it’s still an impactful number.”

The Centers for Disease Control and Prevention recently estimated that about 7% of American adults (18 million) and 1.3% of children had experienced long COVID.

Dr. Gutierrez said that it’s an evolving number, as some patients who have a second or third or fourth SARS-CoV-2 infection experience exacerbations of previous bouts of long COVID or develop long COVID for the first time.

“We are still getting new patients on a regular basis with long COVID,” said AAPM&R President Steven R. Flanagan, MD, a physical medicine specialist.

“This is a problem that really is not going away. It is still real and still ever-present,” said Dr. Flanagan, chair of rehabilitation medicine at NYU Langone Health.
 

A version of this article first appeared on Medscape.com.

A, B, C, D, E: It’s a short, menacing alphabet representing the five types of virus causing viral hepatitis, a sickness afflicting some 400 million people around the world today.

Hepatitis viruses are a set of very different pathogens that kill 1.4 million people annually and infect more than HIV and the malaria pathogen do combined. Most of the deaths are from cirrhosis of the liver or hepatic cancer due to chronic infections with hepatitis viruses B or C, picked up through contact with contaminated blood.

Hepatitis B was the first of the five to be discovered, in the 1960s, by biochemist Baruch S. Blumberg, MD. Hepatitis A, which is most commonly spread through contaminated food and water, was next, discovered in 1973 by researchers Stephen Mark Feinstone, MD, Albert Kapikian, MD, and Robert Purcell, MD.

Screening tests for those two types of viruses paved the way to discovering a third. In the 1970s, hematologist Harvey J. Alter, MD, examined unexplained cases of hepatitis in patients after blood transfusions and found that only 25% of such cases were caused by the hepatitis B virus, and none were linked to the hepatitis A virus. The rest were caused by an unidentified transmissible agent that could persist in the body as a chronic infection and lead to liver cirrhosis and liver cancer.

The agent behind this disease, named non-A, non-B hepatitis, remained a mystery for a decade until Michael Houghton, PhD, a microbiologist working at the biotechnology company Chiron Corporation, and his team sequenced the agent’s genome in 1989 after years of intensive investigation. They identified it as a novel virus of the family to which yellow fever virus belongs: the flaviviruses, a group of RNA viruses often transmitted through the bite of infected arthropods.

But there was more to the story. Scientists needed to show that this new virus could, indeed, cause hepatitis C on its own – a feat achieved in 1997, when Charles M. Rice, PhD, then a virologist at Washington University in St. Louis, and others succeeded in creating a form of the virus in the lab that could replicate in the only animal model for hepatitis C, the chimpanzee. When they injected the virus into the liver of chimpanzees, it triggered clinical hepatitis, demonstrating the direct connection between hepatitis C and non-A, non-B hepatitis.

The findings led to lifesaving hepatitis C tests to avert infections through transfusions with contaminated blood, as well as for the development of effective antiviral medications to treat the disease. In 2020, in the thick of the SARS-CoV-2 pandemic, Dr. Alter, Dr. Houghton, and Dr. Rice received a Nobel Prize in Medicine for their work on identifying the virus.

To learn more about hepatitis C history and the treatment and prevention challenges that remain, Knowable Magazine spoke with Dr. Rice, now at the Rockefeller University, at the 72nd Lindau Nobel Laureate Meeting in Germany in June 2023. This conversation has been edited for length and clarity.
 

What were the challenges at the time you began your research on hepatitis C?

The realization that an agent was behind non-A, non-B hepatitis had initiated a virus hunt to try to figure out what the causative agent was. Dr. Houghton and his group at Chiron won that race and reported the partial sequence of the virus in 1989 in Science.

It was an interesting kind of a dilemma for me as an early-stage assistant professor at Washington University in St. Louis, where I’d been working on yellow fever. All of a sudden, we had this new human virus that dropped into our laps and joined the flavivirus family; we had to decide if we were going to shift some of our attention to work on this virus. Initially, people in the viral hepatitis field invited us to meetings, but because we were doing work on the related virus, yellow fever, not because we were considered majors player in the field.

The main challenge was that we could not grow the virus in cell culture. And the only experimental model was the chimpanzee, so it was really difficult for laboratories to study this virus.

There were two major goals. One was to establish a cell culture system where you could replicate the virus and study it. And the other was try to create a system where we could do genetics on the virus. It was shown to be an RNA virus, and the collection of tools available for modifying RNA at that time, in the early 1990s, was not the same as it was for DNA. Now that’s changed to some extent, with modern editing technologies.

If there’s one lesson to be learned from this hepatitis C story, it’s that persistence pays off.
 

This journey started with an unknown virus and ended up with treatment in a relatively short period of time.

I don’t think it was a short period of time, between all of the failures to actually get a cell culture system and to show that we had a functional clone. From 1989, when the virus sequence was reported, to 2011, when the first antiviral compounds were produced, was 22 years.

And then, that initial generation of treatment compounds was not the greatest, and they were combined with the treatment that we were trying to get rid of – interferon – that made people quite ill and didn’t always cure them. They only had about a 50% cure rate.

It was 2014 when the interferon-free cocktails came about. And that was really amazing.

There were people who thought, “You are not going to be able to develop a drug cocktail that can eliminate this virus.” It was presumptuous to think that one could, but it was accomplished by biotech and the pharmaceutical industry. So it is really quite a success story, but I wish it could have been faster.

Over the last 50 years, researchers have identified five types of viruses that cause different forms of viral hepatitis. Each virus has its own mode of transmission and health impacts. Scientists around the world have worked to develop treatments and vaccines.
 

What are the current challenges in combating hepatitis C?

One thing that was a little sobering and disappointing for me was that when these medical advances are made and shown to be efficacious, it is not possible to get these drugs to everybody who needs them and successfully treat them. It’s a lot more complicated, in part because of the economics – how much the companies decide to charge for the drugs.

Also, it’s difficult to identify people who are infected with hepatitis C, because it’s often asymptomatic. Even when identified, getting people into treatment is challenging given differences in public health capabilities which vary at the local, national, and global levels. So we have wonderful drugs that can basically cure anybody, but I think we still could use a vaccine for hepatitis C.
 

During the first year of the COVID-19 pandemic, you won the Nobel Prize for the discovery of the hepatitis C virus. What was that experience like?

It was December 2020, and we were working on SARS-CoV-2 in the peak of the pandemic in New York City. My spouse and the dogs were off at our house in Connecticut, and I was living in the apartment in Manhattan. And I got this call at 4:30 in the morning. It was pretty shocking.

The pandemic made people more aware of what a highly infectious, disease-causing virus can do to our world. It encouraged the rapid dissemination of research results and more open publications. It also really made us appreciate how the same virus does different things depending upon who’s infected: In the case of COVID-19, it’s not good to be old, for example.
 

After many decades working with viruses, what would you say is the next frontier in virology?

There’s a lot that we don’t understand about these viruses. The more we study them, the more we understand about ourselves, our cells and our antiviral defense systems.

And there’s also great power in terms of being able to diagnose new viruses. The sequencing technology, the functional genomics technologies, all of those things, when applied to virology, give us a much richer picture of how these viruses interact with cells. I think it’s a golden age.

The five known types of viral hepatitis afflict hundreds of millions of people around the world, causing both acute and chronic liver diseases. Among them, types B and C are the most severe, and diagnosis often remains a challenge.
 

You have been working with flaviviruses (dengue, Zika, yellow fever, and hepatitis C) for many decades. Zika and dengue pose an ongoing threat worldwide and, in particular, Latin America. Based on the successful example of hepatitis C, what can scientific research do to mitigate the impact of these viruses?

For viruses like Zika, developing a vaccine is probably going to be fairly straightforward – except that since Zika is so transient, it makes it hard to prove that your vaccine works. You would have to do a human challenge study, in which volunteers are deliberately exposed to an infection in a safe way with health-care support.

For dengue, it’s much more difficult, because there are four different serotypes – different versions of the same virus – and infection with one serotype can put you at increased risk of more severe disease if you get infected with a second serotype. Eliciting a balanced response that would protect you against all four dengue serotypes is the holy grail of trying to develop a dengue vaccine.

People are using various approaches to accomplish that. The classic one is to take live attenuated versions – weakened forms of viruses that have been modified so they can’t cause severe illness but can still stimulate the immune system – of each of the four serotypes and mix them together. Another is to make chimeric viruses: a combination of genetic material from different viruses, resulting in new viruses that have features of each of the four dengue serotypes, engineered into the backbone of the yellow fever vaccine. But this hasn’t worked as well as people have hoped. I think the cocktail of live, attenuated dengue variants is probably the most advanced approach. But I would guess that given the success of COVID-19 mRNA vaccines, the mRNA approach will also be tried out.

These diseases are not going to go away. You can’t eradicate every mosquito. And you can’t really immunize every susceptible vertebrate host. So occasionally there’s going to be spillover into the human population. We need to keep working on these because they are big problems.
 

You began your career at the California Institute of Technology studying RNA viruses, such as the mosquito-borne Sindbis virus, and then flaviviruses that cause encephalitis, polyarthritis, yellow fever, and dengue fever. Later on, you also studied hepatitis C virus. Is there any advantage for virologists in changing the viruses they study throughout their careers?

They’re all interesting, right? And they are all different in their own ways. I say that my career has been a downward spiral of tackling increasingly intricate viruses. Initially, the alphaviruses – a viral family that includes chikungunya virus, for example – were easy. The classical flaviviruses – like yellow fever, dengue fever, West Nile viruses, and Zika virus, among others – were a little more difficult, but the hepatitis C virus was impossible for 15 years, until we, and others, finally achieved a complete replication system in the laboratory.

We coexist daily with viruses, but the pandemic may have given people the idea that all these microorganisms are invariably life-threatening.

We have to treat them with respect. We’ve seen what can happen with the emergence of a novel coronavirus that can spread during an asymptomatic phase of infection. You can’t be prepared for everything, but in some respects our response was a lot slower and less effective than it could have been.

If there’s anything that we’ve learned over the last 10 years with the new nucleic acid sequencing technologies, it’s that our past view of the virosphere was very narrow. And if you really look at what’s out there, the estimated virus diversity is a staggering number, like 1,031 types. Although most of them are not pathogenic to humans, some are. We have to take this threat seriously.
 

Is science prepared?

I think so, but there has to be an investment, a societal investment. And that investment has to not only be an investment in infrastructure that can react quickly to something new, but also to establish a repository of protective antibodies and small molecules against viruses that we know could be future threats.

Often, these things go in cycles. There’s a disaster, like the COVID-19 pandemic, people are changed by the experience, but then they think “Oh, well, the virus has faded into the background, the threat is over.” And that’s just not the case. We need a more sustained plan rather than a reactive stance. And that’s hard to do when resources and money are limited.
 

What is the effect of science illiteracy, conspiracy theories, and lack of science information on the battle against viruses?

These are huge issues, and I don’t know the best way to combat them and educate people. Any combative, confrontational kind of response – it’s just not going to work. People will get more resolute in their entrenched beliefs and not hear or believe compelling evidence to the contrary.

It’s frustrating. I think that we have amazing tools and the power to make really significant advances to help people. It is more than a little discouraging for scientists when there’s a substantial fraction of people who don’t believe in things that are well-supported by facts.

It’s in large part an educational problem. I think we don’t put enough money into education, particularly early education. A lot of people don’t understand how much of what we take for granted today is underpinned by science. All this technology – good, bad or ugly – is all science.
 

This article originally appeared in Knowable Magazine on Oct. 30, 2023. Knowable Magazine is an independent journalistic endeavor from Annual Reviews, a nonprofit publisher dedicated to synthesizing and integrating knowledge for the progress of science and the benefit of society. Sign up for Knowable Magazine’s newsletter.

A, B, C, D, E: It’s a short, menacing alphabet representing the five types of virus causing viral hepatitis, a sickness afflicting some 400 million people around the world today.

Hepatitis viruses are a set of very different pathogens that kill 1.4 million people annually and infect more than HIV and the malaria pathogen do combined. Most of the deaths are from cirrhosis of the liver or hepatic cancer due to chronic infections with hepatitis viruses B or C, picked up through contact with contaminated blood.

Hepatitis B was the first of the five to be discovered, in the 1960s, by biochemist Baruch S. Blumberg, MD. Hepatitis A, which is most commonly spread through contaminated food and water, was next, discovered in 1973 by researchers Stephen Mark Feinstone, MD, Albert Kapikian, MD, and Robert Purcell, MD.

Screening tests for those two types of viruses paved the way to discovering a third. In the 1970s, hematologist Harvey J. Alter, MD, examined unexplained cases of hepatitis in patients after blood transfusions and found that only 25% of such cases were caused by the hepatitis B virus, and none were linked to the hepatitis A virus. The rest were caused by an unidentified transmissible agent that could persist in the body as a chronic infection and lead to liver cirrhosis and liver cancer.

The agent behind this disease, named non-A, non-B hepatitis, remained a mystery for a decade until Michael Houghton, PhD, a microbiologist working at the biotechnology company Chiron Corporation, and his team sequenced the agent’s genome in 1989 after years of intensive investigation. They identified it as a novel virus of the family to which yellow fever virus belongs: the flaviviruses, a group of RNA viruses often transmitted through the bite of infected arthropods.

But there was more to the story. Scientists needed to show that this new virus could, indeed, cause hepatitis C on its own – a feat achieved in 1997, when Charles M. Rice, PhD, then a virologist at Washington University in St. Louis, and others succeeded in creating a form of the virus in the lab that could replicate in the only animal model for hepatitis C, the chimpanzee. When they injected the virus into the liver of chimpanzees, it triggered clinical hepatitis, demonstrating the direct connection between hepatitis C and non-A, non-B hepatitis.

The findings led to lifesaving hepatitis C tests to avert infections through transfusions with contaminated blood, as well as for the development of effective antiviral medications to treat the disease. In 2020, in the thick of the SARS-CoV-2 pandemic, Dr. Alter, Dr. Houghton, and Dr. Rice received a Nobel Prize in Medicine for their work on identifying the virus.

To learn more about hepatitis C history and the treatment and prevention challenges that remain, Knowable Magazine spoke with Dr. Rice, now at the Rockefeller University, at the 72nd Lindau Nobel Laureate Meeting in Germany in June 2023. This conversation has been edited for length and clarity.
 

What were the challenges at the time you began your research on hepatitis C?

The realization that an agent was behind non-A, non-B hepatitis had initiated a virus hunt to try to figure out what the causative agent was. Dr. Houghton and his group at Chiron won that race and reported the partial sequence of the virus in 1989 in Science.

It was an interesting kind of a dilemma for me as an early-stage assistant professor at Washington University in St. Louis, where I’d been working on yellow fever. All of a sudden, we had this new human virus that dropped into our laps and joined the flavivirus family; we had to decide if we were going to shift some of our attention to work on this virus. Initially, people in the viral hepatitis field invited us to meetings, but because we were doing work on the related virus, yellow fever, not because we were considered majors player in the field.

The main challenge was that we could not grow the virus in cell culture. And the only experimental model was the chimpanzee, so it was really difficult for laboratories to study this virus.

There were two major goals. One was to establish a cell culture system where you could replicate the virus and study it. And the other was try to create a system where we could do genetics on the virus. It was shown to be an RNA virus, and the collection of tools available for modifying RNA at that time, in the early 1990s, was not the same as it was for DNA. Now that’s changed to some extent, with modern editing technologies.

If there’s one lesson to be learned from this hepatitis C story, it’s that persistence pays off.
 

This journey started with an unknown virus and ended up with treatment in a relatively short period of time.

I don’t think it was a short period of time, between all of the failures to actually get a cell culture system and to show that we had a functional clone. From 1989, when the virus sequence was reported, to 2011, when the first antiviral compounds were produced, was 22 years.

And then, that initial generation of treatment compounds was not the greatest, and they were combined with the treatment that we were trying to get rid of – interferon – that made people quite ill and didn’t always cure them. They only had about a 50% cure rate.

It was 2014 when the interferon-free cocktails came about. And that was really amazing.

There were people who thought, “You are not going to be able to develop a drug cocktail that can eliminate this virus.” It was presumptuous to think that one could, but it was accomplished by biotech and the pharmaceutical industry. So it is really quite a success story, but I wish it could have been faster.

Over the last 50 years, researchers have identified five types of viruses that cause different forms of viral hepatitis. Each virus has its own mode of transmission and health impacts. Scientists around the world have worked to develop treatments and vaccines.
 

What are the current challenges in combating hepatitis C?

One thing that was a little sobering and disappointing for me was that when these medical advances are made and shown to be efficacious, it is not possible to get these drugs to everybody who needs them and successfully treat them. It’s a lot more complicated, in part because of the economics – how much the companies decide to charge for the drugs.

Also, it’s difficult to identify people who are infected with hepatitis C, because it’s often asymptomatic. Even when identified, getting people into treatment is challenging given differences in public health capabilities which vary at the local, national, and global levels. So we have wonderful drugs that can basically cure anybody, but I think we still could use a vaccine for hepatitis C.
 

During the first year of the COVID-19 pandemic, you won the Nobel Prize for the discovery of the hepatitis C virus. What was that experience like?

It was December 2020, and we were working on SARS-CoV-2 in the peak of the pandemic in New York City. My spouse and the dogs were off at our house in Connecticut, and I was living in the apartment in Manhattan. And I got this call at 4:30 in the morning. It was pretty shocking.

The pandemic made people more aware of what a highly infectious, disease-causing virus can do to our world. It encouraged the rapid dissemination of research results and more open publications. It also really made us appreciate how the same virus does different things depending upon who’s infected: In the case of COVID-19, it’s not good to be old, for example.
 

After many decades working with viruses, what would you say is the next frontier in virology?

There’s a lot that we don’t understand about these viruses. The more we study them, the more we understand about ourselves, our cells and our antiviral defense systems.

And there’s also great power in terms of being able to diagnose new viruses. The sequencing technology, the functional genomics technologies, all of those things, when applied to virology, give us a much richer picture of how these viruses interact with cells. I think it’s a golden age.

The five known types of viral hepatitis afflict hundreds of millions of people around the world, causing both acute and chronic liver diseases. Among them, types B and C are the most severe, and diagnosis often remains a challenge.
 

You have been working with flaviviruses (dengue, Zika, yellow fever, and hepatitis C) for many decades. Zika and dengue pose an ongoing threat worldwide and, in particular, Latin America. Based on the successful example of hepatitis C, what can scientific research do to mitigate the impact of these viruses?

For viruses like Zika, developing a vaccine is probably going to be fairly straightforward – except that since Zika is so transient, it makes it hard to prove that your vaccine works. You would have to do a human challenge study, in which volunteers are deliberately exposed to an infection in a safe way with health-care support.

For dengue, it’s much more difficult, because there are four different serotypes – different versions of the same virus – and infection with one serotype can put you at increased risk of more severe disease if you get infected with a second serotype. Eliciting a balanced response that would protect you against all four dengue serotypes is the holy grail of trying to develop a dengue vaccine.

People are using various approaches to accomplish that. The classic one is to take live attenuated versions – weakened forms of viruses that have been modified so they can’t cause severe illness but can still stimulate the immune system – of each of the four serotypes and mix them together. Another is to make chimeric viruses: a combination of genetic material from different viruses, resulting in new viruses that have features of each of the four dengue serotypes, engineered into the backbone of the yellow fever vaccine. But this hasn’t worked as well as people have hoped. I think the cocktail of live, attenuated dengue variants is probably the most advanced approach. But I would guess that given the success of COVID-19 mRNA vaccines, the mRNA approach will also be tried out.

These diseases are not going to go away. You can’t eradicate every mosquito. And you can’t really immunize every susceptible vertebrate host. So occasionally there’s going to be spillover into the human population. We need to keep working on these because they are big problems.
 

You began your career at the California Institute of Technology studying RNA viruses, such as the mosquito-borne Sindbis virus, and then flaviviruses that cause encephalitis, polyarthritis, yellow fever, and dengue fever. Later on, you also studied hepatitis C virus. Is there any advantage for virologists in changing the viruses they study throughout their careers?

They’re all interesting, right? And they are all different in their own ways. I say that my career has been a downward spiral of tackling increasingly intricate viruses. Initially, the alphaviruses – a viral family that includes chikungunya virus, for example – were easy. The classical flaviviruses – like yellow fever, dengue fever, West Nile viruses, and Zika virus, among others – were a little more difficult, but the hepatitis C virus was impossible for 15 years, until we, and others, finally achieved a complete replication system in the laboratory.

We coexist daily with viruses, but the pandemic may have given people the idea that all these microorganisms are invariably life-threatening.

We have to treat them with respect. We’ve seen what can happen with the emergence of a novel coronavirus that can spread during an asymptomatic phase of infection. You can’t be prepared for everything, but in some respects our response was a lot slower and less effective than it could have been.

If there’s anything that we’ve learned over the last 10 years with the new nucleic acid sequencing technologies, it’s that our past view of the virosphere was very narrow. And if you really look at what’s out there, the estimated virus diversity is a staggering number, like 1,031 types. Although most of them are not pathogenic to humans, some are. We have to take this threat seriously.
 

Is science prepared?

I think so, but there has to be an investment, a societal investment. And that investment has to not only be an investment in infrastructure that can react quickly to something new, but also to establish a repository of protective antibodies and small molecules against viruses that we know could be future threats.

Often, these things go in cycles. There’s a disaster, like the COVID-19 pandemic, people are changed by the experience, but then they think “Oh, well, the virus has faded into the background, the threat is over.” And that’s just not the case. We need a more sustained plan rather than a reactive stance. And that’s hard to do when resources and money are limited.
 

What is the effect of science illiteracy, conspiracy theories, and lack of science information on the battle against viruses?

These are huge issues, and I don’t know the best way to combat them and educate people. Any combative, confrontational kind of response – it’s just not going to work. People will get more resolute in their entrenched beliefs and not hear or believe compelling evidence to the contrary.

It’s frustrating. I think that we have amazing tools and the power to make really significant advances to help people. It is more than a little discouraging for scientists when there’s a substantial fraction of people who don’t believe in things that are well-supported by facts.

It’s in large part an educational problem. I think we don’t put enough money into education, particularly early education. A lot of people don’t understand how much of what we take for granted today is underpinned by science. All this technology – good, bad or ugly – is all science.
 

This article originally appeared in Knowable Magazine on Oct. 30, 2023. Knowable Magazine is an independent journalistic endeavor from Annual Reviews, a nonprofit publisher dedicated to synthesizing and integrating knowledge for the progress of science and the benefit of society. Sign up for Knowable Magazine’s newsletter.

A, B, C, D, E: It’s a short, menacing alphabet representing the five types of virus causing viral hepatitis, a sickness afflicting some 400 million people around the world today.

Hepatitis viruses are a set of very different pathogens that kill 1.4 million people annually and infect more than HIV and the malaria pathogen do combined. Most of the deaths are from cirrhosis of the liver or hepatic cancer due to chronic infections with hepatitis viruses B or C, picked up through contact with contaminated blood.

Hepatitis B was the first of the five to be discovered, in the 1960s, by biochemist Baruch S. Blumberg, MD. Hepatitis A, which is most commonly spread through contaminated food and water, was next, discovered in 1973 by researchers Stephen Mark Feinstone, MD, Albert Kapikian, MD, and Robert Purcell, MD.

Screening tests for those two types of viruses paved the way to discovering a third. In the 1970s, hematologist Harvey J. Alter, MD, examined unexplained cases of hepatitis in patients after blood transfusions and found that only 25% of such cases were caused by the hepatitis B virus, and none were linked to the hepatitis A virus. The rest were caused by an unidentified transmissible agent that could persist in the body as a chronic infection and lead to liver cirrhosis and liver cancer.

The agent behind this disease, named non-A, non-B hepatitis, remained a mystery for a decade until Michael Houghton, PhD, a microbiologist working at the biotechnology company Chiron Corporation, and his team sequenced the agent’s genome in 1989 after years of intensive investigation. They identified it as a novel virus of the family to which yellow fever virus belongs: the flaviviruses, a group of RNA viruses often transmitted through the bite of infected arthropods.

But there was more to the story. Scientists needed to show that this new virus could, indeed, cause hepatitis C on its own – a feat achieved in 1997, when Charles M. Rice, PhD, then a virologist at Washington University in St. Louis, and others succeeded in creating a form of the virus in the lab that could replicate in the only animal model for hepatitis C, the chimpanzee. When they injected the virus into the liver of chimpanzees, it triggered clinical hepatitis, demonstrating the direct connection between hepatitis C and non-A, non-B hepatitis.

The findings led to lifesaving hepatitis C tests to avert infections through transfusions with contaminated blood, as well as for the development of effective antiviral medications to treat the disease. In 2020, in the thick of the SARS-CoV-2 pandemic, Dr. Alter, Dr. Houghton, and Dr. Rice received a Nobel Prize in Medicine for their work on identifying the virus.

To learn more about hepatitis C history and the treatment and prevention challenges that remain, Knowable Magazine spoke with Dr. Rice, now at the Rockefeller University, at the 72nd Lindau Nobel Laureate Meeting in Germany in June 2023. This conversation has been edited for length and clarity.
 

What were the challenges at the time you began your research on hepatitis C?

The realization that an agent was behind non-A, non-B hepatitis had initiated a virus hunt to try to figure out what the causative agent was. Dr. Houghton and his group at Chiron won that race and reported the partial sequence of the virus in 1989 in Science.

It was an interesting kind of a dilemma for me as an early-stage assistant professor at Washington University in St. Louis, where I’d been working on yellow fever. All of a sudden, we had this new human virus that dropped into our laps and joined the flavivirus family; we had to decide if we were going to shift some of our attention to work on this virus. Initially, people in the viral hepatitis field invited us to meetings, but because we were doing work on the related virus, yellow fever, not because we were considered majors player in the field.

The main challenge was that we could not grow the virus in cell culture. And the only experimental model was the chimpanzee, so it was really difficult for laboratories to study this virus.

There were two major goals. One was to establish a cell culture system where you could replicate the virus and study it. And the other was try to create a system where we could do genetics on the virus. It was shown to be an RNA virus, and the collection of tools available for modifying RNA at that time, in the early 1990s, was not the same as it was for DNA. Now that’s changed to some extent, with modern editing technologies.

If there’s one lesson to be learned from this hepatitis C story, it’s that persistence pays off.
 

This journey started with an unknown virus and ended up with treatment in a relatively short period of time.

I don’t think it was a short period of time, between all of the failures to actually get a cell culture system and to show that we had a functional clone. From 1989, when the virus sequence was reported, to 2011, when the first antiviral compounds were produced, was 22 years.

And then, that initial generation of treatment compounds was not the greatest, and they were combined with the treatment that we were trying to get rid of – interferon – that made people quite ill and didn’t always cure them. They only had about a 50% cure rate.

It was 2014 when the interferon-free cocktails came about. And that was really amazing.

There were people who thought, “You are not going to be able to develop a drug cocktail that can eliminate this virus.” It was presumptuous to think that one could, but it was accomplished by biotech and the pharmaceutical industry. So it is really quite a success story, but I wish it could have been faster.

Over the last 50 years, researchers have identified five types of viruses that cause different forms of viral hepatitis. Each virus has its own mode of transmission and health impacts. Scientists around the world have worked to develop treatments and vaccines.
 

What are the current challenges in combating hepatitis C?

One thing that was a little sobering and disappointing for me was that when these medical advances are made and shown to be efficacious, it is not possible to get these drugs to everybody who needs them and successfully treat them. It’s a lot more complicated, in part because of the economics – how much the companies decide to charge for the drugs.

Also, it’s difficult to identify people who are infected with hepatitis C, because it’s often asymptomatic. Even when identified, getting people into treatment is challenging given differences in public health capabilities which vary at the local, national, and global levels. So we have wonderful drugs that can basically cure anybody, but I think we still could use a vaccine for hepatitis C.
 

During the first year of the COVID-19 pandemic, you won the Nobel Prize for the discovery of the hepatitis C virus. What was that experience like?

It was December 2020, and we were working on SARS-CoV-2 in the peak of the pandemic in New York City. My spouse and the dogs were off at our house in Connecticut, and I was living in the apartment in Manhattan. And I got this call at 4:30 in the morning. It was pretty shocking.

The pandemic made people more aware of what a highly infectious, disease-causing virus can do to our world. It encouraged the rapid dissemination of research results and more open publications. It also really made us appreciate how the same virus does different things depending upon who’s infected: In the case of COVID-19, it’s not good to be old, for example.
 

After many decades working with viruses, what would you say is the next frontier in virology?

There’s a lot that we don’t understand about these viruses. The more we study them, the more we understand about ourselves, our cells and our antiviral defense systems.

And there’s also great power in terms of being able to diagnose new viruses. The sequencing technology, the functional genomics technologies, all of those things, when applied to virology, give us a much richer picture of how these viruses interact with cells. I think it’s a golden age.

The five known types of viral hepatitis afflict hundreds of millions of people around the world, causing both acute and chronic liver diseases. Among them, types B and C are the most severe, and diagnosis often remains a challenge.
 

You have been working with flaviviruses (dengue, Zika, yellow fever, and hepatitis C) for many decades. Zika and dengue pose an ongoing threat worldwide and, in particular, Latin America. Based on the successful example of hepatitis C, what can scientific research do to mitigate the impact of these viruses?

For viruses like Zika, developing a vaccine is probably going to be fairly straightforward – except that since Zika is so transient, it makes it hard to prove that your vaccine works. You would have to do a human challenge study, in which volunteers are deliberately exposed to an infection in a safe way with health-care support.

For dengue, it’s much more difficult, because there are four different serotypes – different versions of the same virus – and infection with one serotype can put you at increased risk of more severe disease if you get infected with a second serotype. Eliciting a balanced response that would protect you against all four dengue serotypes is the holy grail of trying to develop a dengue vaccine.

People are using various approaches to accomplish that. The classic one is to take live attenuated versions – weakened forms of viruses that have been modified so they can’t cause severe illness but can still stimulate the immune system – of each of the four serotypes and mix them together. Another is to make chimeric viruses: a combination of genetic material from different viruses, resulting in new viruses that have features of each of the four dengue serotypes, engineered into the backbone of the yellow fever vaccine. But this hasn’t worked as well as people have hoped. I think the cocktail of live, attenuated dengue variants is probably the most advanced approach. But I would guess that given the success of COVID-19 mRNA vaccines, the mRNA approach will also be tried out.

These diseases are not going to go away. You can’t eradicate every mosquito. And you can’t really immunize every susceptible vertebrate host. So occasionally there’s going to be spillover into the human population. We need to keep working on these because they are big problems.
 

You began your career at the California Institute of Technology studying RNA viruses, such as the mosquito-borne Sindbis virus, and then flaviviruses that cause encephalitis, polyarthritis, yellow fever, and dengue fever. Later on, you also studied hepatitis C virus. Is there any advantage for virologists in changing the viruses they study throughout their careers?

They’re all interesting, right? And they are all different in their own ways. I say that my career has been a downward spiral of tackling increasingly intricate viruses. Initially, the alphaviruses – a viral family that includes chikungunya virus, for example – were easy. The classical flaviviruses – like yellow fever, dengue fever, West Nile viruses, and Zika virus, among others – were a little more difficult, but the hepatitis C virus was impossible for 15 years, until we, and others, finally achieved a complete replication system in the laboratory.

We coexist daily with viruses, but the pandemic may have given people the idea that all these microorganisms are invariably life-threatening.

We have to treat them with respect. We’ve seen what can happen with the emergence of a novel coronavirus that can spread during an asymptomatic phase of infection. You can’t be prepared for everything, but in some respects our response was a lot slower and less effective than it could have been.

If there’s anything that we’ve learned over the last 10 years with the new nucleic acid sequencing technologies, it’s that our past view of the virosphere was very narrow. And if you really look at what’s out there, the estimated virus diversity is a staggering number, like 1,031 types. Although most of them are not pathogenic to humans, some are. We have to take this threat seriously.
 

Is science prepared?

I think so, but there has to be an investment, a societal investment. And that investment has to not only be an investment in infrastructure that can react quickly to something new, but also to establish a repository of protective antibodies and small molecules against viruses that we know could be future threats.

Often, these things go in cycles. There’s a disaster, like the COVID-19 pandemic, people are changed by the experience, but then they think “Oh, well, the virus has faded into the background, the threat is over.” And that’s just not the case. We need a more sustained plan rather than a reactive stance. And that’s hard to do when resources and money are limited.
 

What is the effect of science illiteracy, conspiracy theories, and lack of science information on the battle against viruses?

These are huge issues, and I don’t know the best way to combat them and educate people. Any combative, confrontational kind of response – it’s just not going to work. People will get more resolute in their entrenched beliefs and not hear or believe compelling evidence to the contrary.

It’s frustrating. I think that we have amazing tools and the power to make really significant advances to help people. It is more than a little discouraging for scientists when there’s a substantial fraction of people who don’t believe in things that are well-supported by facts.

It’s in large part an educational problem. I think we don’t put enough money into education, particularly early education. A lot of people don’t understand how much of what we take for granted today is underpinned by science. All this technology – good, bad or ugly – is all science.
 

This article originally appeared in Knowable Magazine on Oct. 30, 2023. Knowable Magazine is an independent journalistic endeavor from Annual Reviews, a nonprofit publisher dedicated to synthesizing and integrating knowledge for the progress of science and the benefit of society. Sign up for Knowable Magazine’s newsletter.

Final results of the SELECT trial have shown that the antiobesity drug semaglutide (Wegovy) produced a consistent reduction of around 20% versus placebo across major cardiovascular event endpoints over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.

“This is a very exciting set of results. I think it is going to have a big impact on a large number of people,” lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, said in an interview. 

“And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity,” he added.

The trial involved 17,604 patients with a history of cardiovascular disease and a body mass index of 27 kg/m² or above (mean BMI was 33), who were randomly assigned to the glucagonlike peptide–1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.

Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.

The primary cardiovascular endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was reduced significantly, with a hazard ratio of 0.80 (95% confidence interval, 0.72-0.90; P < .001).  

Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.

However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.

The HR for the heart failure composite endpoint was 0.82 (95% CI, 0.71-0.96), and the HR for death from any cause was 0.81 (95% CI, 0.71-0.93). Nonfatal MI was reduced by 28% (HR 0.72; 95% CI, 0.61-0.85).

The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.

Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal effects, and in 8.2% in the placebo group.

The trial results were presented by Dr. Lincoff at the annual scientific sessions of the American Heart Association . They were also simultaneously published online in the New England Journal of Medicine.

Dr. Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events – and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity. 

“Patients in the trial were already taking standard of care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit,” he said.

Dr. Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.

“There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness – at least in the population with a history of cardiovascular disease,” he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.

On the outcome data, Dr. Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.

“The cardiovascular death curves separated, then merged, then separated again. We don’t really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that.”

But he added: “The all-cause mortality is more reassuring, as it doesn’t depend on classifying cause of death. Because of the design of the trial, we can’t formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring.”
 

‘A new era’ for patients with obesity

Outside experts in the field were also impressed with the data.

Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale University, New Haven, Conn., said the SELECT trial was “a turning point in the treatment of obesity and a call to action.

“Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease,” she said.

Dr. Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two-thirds of which were caused by cardiovascular disease. And she presented data showing that U.S. individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.

She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.

Deepak L. Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York, described the SELECT results as “altogether a compelling package of data.”

“These results are even better than I had expected,” Dr. Bhatt said in an interview. “There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding,” he noted.

“Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced,” he said. “To me, apart from the GI side effects, this counts as a home run.”

Steve Nissen, MD, chief academic officer at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute, was similarly upbeat.

“These data prove what many of us have long suspected – that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control,” he added. “We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity.”

Michelle O’Donoghue, MD, associate professor of medicine at Harvard Medical School, Boston, called the results of SELECT “both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity.”

Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, described the SELECT study as “a landmark trial which will change the practice of medicine in regard to how we treat obesity.”

He compared it with the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and “began a drastic change in the way that physicians approached treatment of cholesterol.”

On the more robust reduction in all-cause death, compared with cardiovascular death,

Dr. Ballantyne pointed out: “Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths.”
 

Gastrointestinal adverse effects

On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”

“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”

He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.

Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”  

Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”

He noted that the semaglutide dose used in this study was larger than that used in diabetes.

“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
 

Just weight loss or other actions too?

Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.

“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”

In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.

Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.

Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”

She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”
 

Effect on clinical practice

With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.

Dr. Bhatt noted that semaglutide is already very popular. “Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it’s going to cause weight loss and they come in asking for it even if they don’t strictly need it. I think it’s good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it.”

He agreed with Dr. Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream health care costs.

“It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the health care system to fund this drug,” he said. “I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs.”

Dr. Lincoff said it would not be easy to prioritize certain groups. “We couldn’t identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available.”
 

‘A welcome treatment option’

In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell-Wiley, MD, MPH, National Institutes of Health, Bethesda, noted that baseline risk factors such as LDL cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that the benefits of semaglutide may be attenuated when these measures are better controlled.

But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they said that, even in the context of well-controlled risk factors and very low LDL cholesterol levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. “Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients.”

However, the editorialists cautioned that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many. 

They added that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.

The SELECT trial was supported by Novo Nordisk, and several coauthors are employees of the company. Dr. Lincoff is a consultant for Novo Nordisk. Dr. Bhatt and Dr. Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Dr. Bhatt and Dr. Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.

Final results of the SELECT trial have shown that the antiobesity drug semaglutide (Wegovy) produced a consistent reduction of around 20% versus placebo across major cardiovascular event endpoints over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.

“This is a very exciting set of results. I think it is going to have a big impact on a large number of people,” lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, said in an interview. 

“And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity,” he added.

The trial involved 17,604 patients with a history of cardiovascular disease and a body mass index of 27 kg/m² or above (mean BMI was 33), who were randomly assigned to the glucagonlike peptide–1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.

Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.

The primary cardiovascular endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was reduced significantly, with a hazard ratio of 0.80 (95% confidence interval, 0.72-0.90; P < .001).  

Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.

However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.

The HR for the heart failure composite endpoint was 0.82 (95% CI, 0.71-0.96), and the HR for death from any cause was 0.81 (95% CI, 0.71-0.93). Nonfatal MI was reduced by 28% (HR 0.72; 95% CI, 0.61-0.85).

The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.

Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal effects, and in 8.2% in the placebo group.

The trial results were presented by Dr. Lincoff at the annual scientific sessions of the American Heart Association . They were also simultaneously published online in the New England Journal of Medicine.

Dr. Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events – and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity. 

“Patients in the trial were already taking standard of care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit,” he said.

Dr. Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.

“There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness – at least in the population with a history of cardiovascular disease,” he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.

On the outcome data, Dr. Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.

“The cardiovascular death curves separated, then merged, then separated again. We don’t really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that.”

But he added: “The all-cause mortality is more reassuring, as it doesn’t depend on classifying cause of death. Because of the design of the trial, we can’t formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring.”
 

‘A new era’ for patients with obesity

Outside experts in the field were also impressed with the data.

Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale University, New Haven, Conn., said the SELECT trial was “a turning point in the treatment of obesity and a call to action.

“Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease,” she said.

Dr. Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two-thirds of which were caused by cardiovascular disease. And she presented data showing that U.S. individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.

She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.

Deepak L. Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York, described the SELECT results as “altogether a compelling package of data.”

“These results are even better than I had expected,” Dr. Bhatt said in an interview. “There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding,” he noted.

“Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced,” he said. “To me, apart from the GI side effects, this counts as a home run.”

Steve Nissen, MD, chief academic officer at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute, was similarly upbeat.

“These data prove what many of us have long suspected – that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control,” he added. “We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity.”

Michelle O’Donoghue, MD, associate professor of medicine at Harvard Medical School, Boston, called the results of SELECT “both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity.”

Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, described the SELECT study as “a landmark trial which will change the practice of medicine in regard to how we treat obesity.”

He compared it with the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and “began a drastic change in the way that physicians approached treatment of cholesterol.”

On the more robust reduction in all-cause death, compared with cardiovascular death,

Dr. Ballantyne pointed out: “Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths.”
 

Gastrointestinal adverse effects

On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”

“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”

He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.

Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”  

Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”

He noted that the semaglutide dose used in this study was larger than that used in diabetes.

“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
 

Just weight loss or other actions too?

Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.

“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”

In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.

Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.

Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”

She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”
 

Effect on clinical practice

With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.

Dr. Bhatt noted that semaglutide is already very popular. “Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it’s going to cause weight loss and they come in asking for it even if they don’t strictly need it. I think it’s good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it.”

He agreed with Dr. Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream health care costs.

“It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the health care system to fund this drug,” he said. “I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs.”

Dr. Lincoff said it would not be easy to prioritize certain groups. “We couldn’t identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available.”
 

‘A welcome treatment option’

In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell-Wiley, MD, MPH, National Institutes of Health, Bethesda, noted that baseline risk factors such as LDL cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that the benefits of semaglutide may be attenuated when these measures are better controlled.

But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they said that, even in the context of well-controlled risk factors and very low LDL cholesterol levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. “Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients.”

However, the editorialists cautioned that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many. 

They added that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.

The SELECT trial was supported by Novo Nordisk, and several coauthors are employees of the company. Dr. Lincoff is a consultant for Novo Nordisk. Dr. Bhatt and Dr. Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Dr. Bhatt and Dr. Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.

Final results of the SELECT trial have shown that the antiobesity drug semaglutide (Wegovy) produced a consistent reduction of around 20% versus placebo across major cardiovascular event endpoints over the approximately 3-year follow-up in patients with overweight or obesity and cardiovascular disease but not diabetes.

“This is a very exciting set of results. I think it is going to have a big impact on a large number of people,” lead investigator A. Michael Lincoff, MD, vice chair for research in the department of cardiovascular medicine at the Cleveland Clinic, said in an interview. 

“And from a scientific standpoint, these data show that we now have a new pathway or a new modifiable risk factor for cardiovascular disease that we can use in our patients who have overweight or obesity,” he added.

The trial involved 17,604 patients with a history of cardiovascular disease and a body mass index of 27 kg/m² or above (mean BMI was 33), who were randomly assigned to the glucagonlike peptide–1 (GLP-1) agonist semaglutide, given by subcutaneous injection once weekly at a gradually escalating dose up to 2.4 mg daily by week 16, or placebo. The mean baseline glycated hemoglobin level was 5.8% and 66.4% of patients met the criteria for prediabetes.

Patients lost a mean of 9.4% of body weight over the first 2 years with semaglutide versus 0.88% with placebo.

The primary cardiovascular endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – was reduced significantly, with a hazard ratio of 0.80 (95% confidence interval, 0.72-0.90; P < .001).  

Death from cardiovascular causes, the first confirmatory secondary endpoint, showed a 15% reduction (HR, 0.85; P = .07) but this missed meeting criteria for statistical significance, and because of the hierarchical design of the trial, this meant that superiority testing was not performed for the remaining confirmatory secondary endpoints.

However, results showed reductions of around 20% for the heart failure composite endpoint and for all-cause mortality, with confidence intervals that did not cross 1.0, and directionally consistent effects were observed for all supportive secondary endpoints.

The HR for the heart failure composite endpoint was 0.82 (95% CI, 0.71-0.96), and the HR for death from any cause was 0.81 (95% CI, 0.71-0.93). Nonfatal MI was reduced by 28% (HR 0.72; 95% CI, 0.61-0.85).

The effects of semaglutide on the primary endpoint appeared to be similar across all prespecified subgroups.

Adverse events leading to discontinuation of treatment occurred in 16.6% in the semaglutide group, mostly gastrointestinal effects, and in 8.2% in the placebo group.

The trial results were presented by Dr. Lincoff at the annual scientific sessions of the American Heart Association . They were also simultaneously published online in the New England Journal of Medicine.

Dr. Lincoff explained that there is a growing pandemic of overweight and obesity worldwide with clear evidence for years that these conditions increase the risk of cardiovascular events – and yet there has been no evidence, until now, that any pharmacologic or lifestyle therapy can reduce the increased risk conferred by overweight/obesity. 

“Patients in the trial were already taking standard of care therapies for other risk factors, such as hypertension and cholesterol, so this drug is giving additional benefit,” he said.

Dr. Lincoff believes these data will lead to a large increase in use of semaglutide, which is already available for the treatment of obesity and diabetes but can be difficult to get reimbursed.

“There is a lot of difficulty getting payors to pay for this drug for weight management. But with this new data from the SELECT trial there should be more willingness – at least in the population with a history of cardiovascular disease,” he commented. In diabetes, where it is already established that there is a cardiovascular risk reduction, it is easier to get these drugs reimbursed, he noted.

On the outcome data, Dr. Lincoff said he could not explain why cardiovascular death was not significantly reduced while all-cause mortality appeared to be cut more definitively.

“The cardiovascular death curves separated, then merged, then separated again. We don’t really know what is going on there. It may be that some deaths were misclassified. This trial was conducted through the COVID era and there may have been less information available on some patients because of that.”

But he added: “The all-cause mortality is more reassuring, as it doesn’t depend on classifying cause of death. Because of the design of the trial, we can’t formally claim a reduction in all-cause mortality, but the results do suggest there is an effect on this endpoint. And all the different types of cardiovascular events were similarly reduced in a consistent way, with similar effects seen across all subgroups. That is very reassuring.”
 

‘A new era’ for patients with obesity

Outside experts in the field were also impressed with the data.

Designated discussant of the trial at the AHA meeting, Ania Jastreboff, MD, associate professor medicine (endocrinology) at Yale University, New Haven, Conn., said the SELECT trial was “a turning point in the treatment of obesity and a call to action.

“Now is the time to treat obesity to improve health outcomes in people with cardiovascular disease,” she said.

Dr. Jastreboff noted that high BMI was estimated to have accounted for 4 million deaths worldwide in 2015, two-thirds of which were caused by cardiovascular disease. And she presented data showing that U.S. individuals meeting the SELECT criteria increased from 4.3 million in 2011-12 to 6.6 million in 2017-18.

She highlighted one major limitation of the SELECT trial: it enrolled a low number of women (38%) and ethnic minorities, with only 12% of the trial population being Black.

Deepak L. Bhatt, MD, director of Mount Sinai Fuster Heart Hospital, New York, described the SELECT results as “altogether a compelling package of data.”

“These results are even better than I had expected,” Dr. Bhatt said in an interview. “There is a significant reduction in MI as I had anticipated, but additionally, there is a reduction in all-cause death. One can debate the statistics, though on a common-sense level, I think it is a real finding,” he noted.

“Given that MI, heart failure, nephropathy, and revascularization are all reduced, and even stroke is numerically lower, it makes sense that all-cause mortality would be reduced,” he said. “To me, apart from the GI side effects, this counts as a home run.”

Steve Nissen, MD, chief academic officer at the Cleveland Clinic’s Heart, Vascular and Thoracic Institute, was similarly upbeat.

“These data prove what many of us have long suspected – that losing weight can reduce cardiovascular morbidity and mortality. This is great news for patients living with obesity. The obesity epidemic is out of control,” he added. “We need to have therapies that improve cardiovascular outcomes caused by obesity and this shows that semaglutide can do that. I think this is the beginning of a whole new era for patients with obesity.”

Michelle O’Donoghue, MD, associate professor of medicine at Harvard Medical School, Boston, called the results of SELECT “both intriguing and compelling. Certainly, these findings lend further support to the use of semaglutide in a much broader secondary prevention population of individuals with obesity.”

Christie Ballantyne, MD, director of the center for cardiometabolic disease prevention at Baylor College of Medicine, Houston, described the SELECT study as “a landmark trial which will change the practice of medicine in regard to how we treat obesity.”

He compared it with the landmark 4S trial in 1994, the first study in the area of cholesterol lowering therapy to show a clear benefit in reducing cardiovascular events and total mortality, and “began a drastic change in the way that physicians approached treatment of cholesterol.”

On the more robust reduction in all-cause death, compared with cardiovascular death,

Dr. Ballantyne pointed out: “Adjudication of dead or alive is something that everyone gets right. In contrast, the cause of death is sometime difficult to ascertain. Most importantly, the benefit on total mortality also provides assurance that this therapy does not have some adverse effect on increasing noncardiovascular deaths.”
 

Gastrointestinal adverse effects

On the side effects seen with semaglutide, Dr. Lincoff reported that 10% of patients in the semaglutide group discontinued treatment because of GI side effects versus 2% in the placebo arm. He said this was “an expected issue.”

“GI effects, such as nausea, vomiting and diarrhea, are known side effects of this whole class of drugs. The dose is slowly escalated to manage these adverse effects but there will be a proportion of patients who can’t tolerate it, although the vast majority are able to continue.”

He noted that, while dose reduction was allowed, of the patients who were still on the drug at 2 years, 77% were on the full dose, and 23% were on a reduced dose.

Dr. Lincoff pointed out that there were no serious adverse events with semaglutide. “This is the largest database by far now on the drug with a long-term follow up and we didn’t see the emergence of any new safety signals, which is very reassuring.”  

Dr. Nissen said the 16% rate of patients stopping the drug because of tolerability “is not a trivial number.”

He noted that the semaglutide dose used in this study was larger than that used in diabetes.

“They did this to try to achieve more weight loss but then you get more issues with tolerability. It’s a trade-off. If patients are experiencing adverse effects, the dose can be reduced, but then you will lose some effect. All the GLP-1 agonists have GI side effects – it’s part of the way that they work.”
 

Just weight loss or other actions too?

Speculating on the mechanism behind the reduction in cardiovascular events with semaglutide, Dr. Lincoff does not think it is just weight reduction.

“The event curves start to diverge very soon after the start of the trial and yet the maximum weight loss doesn’t occur until about 65 weeks. I think something else is going on.”

In the paper, the researchers noted that GLP-1 agonists have been shown in animal studies to reduce inflammation, improve endothelial and left ventricular function, promote plaque stability, and decrease platelet aggregation. In this trial, semaglutide was associated with changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and C-reactive protein.

Dr. Lincoff also pointed out that similar benefits were seen in patients with different levels of overweight, and in those who were prediabetic and those who weren’t, so benefit was not dependent on baseline BMI or glycated hemoglobin levels.

Dr. O’Donoghue agreed that other effects, as well as weight loss, could be involved. “The reduction in events with semaglutide appeared very early after initiation and far preceded the drug’s maximal effects on weight reduction. This might suggest that the drug offers other cardioprotective effects through pathways independent of weight loss. Certainly, semaglutide and the other GLP-1 agonists appear to attenuate inflammation, and the patterns of redistribution of adipose tissue may also be of interest.”

She also pointed out that the reduction in cardiovascular events appeared even earlier in this population of obese nondiabetic patients with cardiovascular disease than in prior studies of patients with diabetes. “It may suggest that there is particular benefit for this type of therapy in patients with an inflammatory milieu. I look forward to seeing further analyses to help tease apart the correlation between changes in inflammation, observed weight loss and cardiovascular benefit.”
 

Effect on clinical practice

With the majority of patients with cardiovascular disease being overweight, these results are obviously going to increase demand for semaglutide, but cost and availability are going to be an issue.

Dr. Bhatt noted that semaglutide is already very popular. “Weight loss drugs are somewhat different from other medications. I can spend 30 minutes trying to convince a patient to take a statin, but here people realize it’s going to cause weight loss and they come in asking for it even if they don’t strictly need it. I think it’s good to have cardiovascular outcome data because now at least for this population of patients, we have evidence to prescribe it.”

He agreed with Dr. Lincoff that these new data should encourage insurance companies to cover the drug, because in reducing cardiovascular events it should also improve downstream health care costs.

“It is providing clear cardiovascular and kidney benefit, so it is in the best interest to the health care system to fund this drug,” he said. “I hope insurers look at it rationally in this way, but they may also be frightened of the explosion of patients wanting this drug and now doctors wanting to prescribe it and how that would affect their shorter-term costs.”

Dr. Lincoff said it would not be easy to prioritize certain groups. “We couldn’t identify any subgroup who showed particularly more benefit than any others. But in the evolution of any therapy, there is a time period where it is in short supply and prohibitively expensive, then over time when there is some competition and pricing deals occur as more people are advocating for it, they become more available.”
 

‘A welcome treatment option’

In an editorial accompanying publication of the trial, Amit Khera, MD, University of Texas Southwestern Medical Center, Dallas, and Tiffany Powell-Wiley, MD, MPH, National Institutes of Health, Bethesda, noted that baseline risk factors such as LDL cholesterol (78 mg/dL) and systolic blood pressure (131 mm Hg) were not ideal in the semaglutide group in this trial, and they suggest that the benefits of semaglutide may be attenuated when these measures are better controlled.

But given that more than 20 million people in the United States have coronary artery disease, with the majority having overweight or obesity and only approximately 30% having concomitant diabetes, they said that, even in the context of well-controlled risk factors and very low LDL cholesterol levels, the residual risk of atherosclerotic cardiovascular disease in these persons is unacceptably high. “Thus, the SELECT trial provides a welcome treatment option that can be extended to millions of additional patients.”

However, the editorialists cautioned that semaglutide at current pricing comes with a significant cost to both patients and society, which makes this treatment inaccessible for many. 

They added that intensive lifestyle interventions and bariatric surgery remain effective but underutilized options for obesity, and that the prevention of obesity before it develops should be the primary goal.

The SELECT trial was supported by Novo Nordisk, and several coauthors are employees of the company. Dr. Lincoff is a consultant for Novo Nordisk. Dr. Bhatt and Dr. Nissen are involved in a cardiovascular outcomes trial with a new investigational weight loss drug from Lilly. Dr. Bhatt and Dr. Ballantyne are also investigators in a Novo Nordisk trial of a new anti-inflammatory drug.

ILLUSTRATIVE CASE

A 9-year-old girl presents to your urgent care clinic after a fall while snowboarding for the first time. She reports falling forward onto her outstretched right hand and describes pain in her distal right forearm. She denies paresthesias, weakness, or lacerations. Physical examination reveals mild edema of the dorsal aspect of her distal right forearm and tenderness to palpation of the dorsal aspect of her distal radius. She denies tenderness to palpation of her ulna, anatomic snuffbox, hand, and elbow. Range of motion of the wrist is full on passive testing, but she declines active testing due to pain. Wrist radiographs reveal an uncomplicated torus fracture of the distal radius. Can immobilization with a soft bandage alone sufficiently treat this fracture?

Fractures of the distal radius are among the most common fractures of the upper extremity and commonly occur from a fall onto an outstretched hand.² In the pediatric population, torus fractures, also known as buckle fractures, are the most common type of distal radius fracture, comprising an estimated 50% of pediatric wrist fractures.^3,4 This is due to the presence of a physeal growth plate, thicker periosteum, and softer underlying bone in pediatric patients.^4,5 When an axial load is applied, as in a fall onto an outstretched hand, the force can lead to plastic deformation, with or without cortical disruption of the bone.^4,5

Pediatric torus fractures of the distal radius generally are treated with immobilization,² traditionally through a short arm cast or a removable, rigid wrist splint.^2,6 The wrist often is immobilized for 3 to 4 weeks, with routine follow-up and potential repeat plain film radiography to ensure stability.^2,6

Despite common use of immobilization, torus fractures of the distal radius are anatomically stable, and displacement is unlikely to occur.^7,8 As such, many studies have suggested that treatment of torus fractures with rigid immobilization in a cast or splint may not be necessary.^9,10 However, a 2018 Cochrane review concluded that the quality of evidence illustrating similar recovery between treatments was low, leaving uncertainty as to the most appropriate management strategy.⁶ Less casting and follow-up imaging could have positive implications for patient satisfaction, health care–associated costs, and radiation exposure.¹⁰

This study, the Forearm Fracture Recovery in Children Evaluation (FORCE) trial, compared the traditional treatment of distal radius torus fractures with rigid immobilization to soft immobilization and immediate discharge.

STUDY SUMMARY

Providing quality evidence for a standard of care

FORCE was a randomized controlled equivalence trial (N = 965) across 23 emergency departments (EDs) in the United Kingdom that compared pain and function in pediatric patients with distal radius torus fractures treated with a soft bandage and immediate discharge vs rigid immobilization and routine follow-up.¹ Patients included children ages 4 to 15 years presenting to the ED with a distal radius torus fracture, which was confirmed radiologically.

At 3 days, pain scores improved by 3.2 points in the soft bandage group and 3.1 points in the rigid immobilization group.

Patients with concomitant ipsilateral ulnar fractures were included in the study. Researchers excluded patients with injuries older than 36 hours, evidence of cortical disruption on radiograph (eg, greenstick fracture), or additional fractures other than the wrist, or those who were deemed unable to follow up with the full study protocol (eg, having insufficient English comprehension).

Continue to: Patients were randomly assigned...

Patients were randomly assigned in a 1:1 ratio to receive treatment with either a soft bandage such as a gauze roller bandage (n = 489) or rigid immobilization (n = 476). For patients in the bandage group, a soft bandage was applied in the ED or provided for home application without planned clinical follow-up. Patients in the rigid immobilization group were treated in the ED with either a removable manufactured splint or a molded splint or cast, followed by the standard follow-up practice of the treating center. Patients in the soft bandage group were advised not to wear the bandage for more than 3 weeks. Blinding was not possible, but the treatment team did not take part in patient follow-up.

The primary outcome was change in pain 3 days after treatment, measured on the Wong-Baker FACES Pain Rating Scale (an ordinal assessment using 6 illustrated facial expressions translated to a numeric rating on a scale of 0-10, with higher scores indicating worse pain). This scale has an established minimum clinically important difference (MCID) value of 1 face (2 points).¹¹ Per standard practice in equivalence trials, the equivalence margin was defined as half the MCID, with a value of 1.0 used in this study.

Secondary outcomes measured over the 6-week follow-up period included additional pain measurements using the Wong-Baker scale, measures of function and health-­related quality of life, analgesia use, days of absence from school or childcare, complication rates, and patient satisfaction. This study used modified intention-to-treat and per-protocol analyses.

The mean age of participants was 9.6 years; 39% were girls and 61% were boys. In the bandage group, 94% opted to have the soft bandage applied in the ED, and 95% of the rigid immobilization group were treated with a removable wrist splint in the ED. At 3 days, pain scores improved by 3.2 points (standard deviation [SD] = 2.1) in the soft bandage group and 3.1 points (SD = 2.1) in the rigid immobilization group. The adjusted difference was –0.1 (95% CI, –0.37 to 0.17) in the intention-to-treat analysis and –0.06 (95% CI, –0.34 to 0.21) in the per-protocol analysis, which were both less than the predetermined equivalence margin. This equivalence margin also was met at all secondary time points (1 day, 7 days, 3 weeks, and 6 weeks after treatment) and in subgroup analysis of those 4 to 7 years and 8 to 15 years.

Use of any analgesia in the prior 24 hours was slightly higher in the soft bandage group on Day 1 (83% vs 78%; P = .04) and Day 3 (57% vs 51%; P = .05), but this difference was not seen on Day 7. Satisfaction, measured via a 7-point Likert scale (range from “extremely satisfied” to “extremely unsatisfied”), was slightly lower in the soft bandage group on Day 1 (median 2 [interquartile range = 1, 2] vs median 1 [interquartile range = 1, 2]; P < .0001) but was not different after 6 weeks. There were no measured differences in any other secondary outcomes, including function, quality of life, and complication rates.

Continue to: By the primary end point...

De-escalation of treatment offers an equivalent, resource-sparing alternative to traditional treatment of pediatric torus fractures of the distal radius.

By the primary end point of 3 days, 36 patients (7%) in the soft bandage group returned to medical care requesting a change to rigid immobilization, compared with 1 patient (0.2%) in the rigid immobilization group declining intervention.

WHAT’S NEW

Equivalence in pain and function scores

This trial showed equivalence in pain at 3 days’ follow-up in children with distal radius torus fractures who were offered bandaging and then immediately discharged from the ED, compared with rigid immobilization and clinical follow-up. There were no significant differences in pain or function between groups during the 6 weeks following the initial injury. De-escalation of treatment offers an equivalent, resource-sparing alternative to traditional treatment of these fractures.

CAVEATS

Lack of masking likely introduced bias

There are no major caveats associated with managing distal radius torus fractures with a soft bandage and discharge from the ED, compared with the traditional treatment of rigid immobilization. However, bias was likely introduced in patient-reported outcomes due to the inability to mask patients and families to the treatment allocation. This may have led to overstating the severity of outcomes in the bandage group, given the strong preference for rigid immobilization, although equivalence was illustrated despite this potential bias.

CHALLENGES TO IMPLEMENTATION

Preferences may be difficult to change

Parents and clinicians demonstrated a preference for rigid immobilization, as shown in the imbalance in treatment crossovers, with 7% of children changing to the rigid immobilization group by the primary study end point of 3 days. The study authors hypothesized that crossovers may have been due to the perception by some parents that rigid immobilization is the gold standard of treatment, as well as clinicians’ seeking to escalate care for patients returning for follow-up. Policy and guideline changes, as well as physician efforts to educate patients on outcomes with soft bandage treatment, are likely to improve these misconceptions.

ILLUSTRATIVE CASE

A 9-year-old girl presents to your urgent care clinic after a fall while snowboarding for the first time. She reports falling forward onto her outstretched right hand and describes pain in her distal right forearm. She denies paresthesias, weakness, or lacerations. Physical examination reveals mild edema of the dorsal aspect of her distal right forearm and tenderness to palpation of the dorsal aspect of her distal radius. She denies tenderness to palpation of her ulna, anatomic snuffbox, hand, and elbow. Range of motion of the wrist is full on passive testing, but she declines active testing due to pain. Wrist radiographs reveal an uncomplicated torus fracture of the distal radius. Can immobilization with a soft bandage alone sufficiently treat this fracture?

Fractures of the distal radius are among the most common fractures of the upper extremity and commonly occur from a fall onto an outstretched hand.² In the pediatric population, torus fractures, also known as buckle fractures, are the most common type of distal radius fracture, comprising an estimated 50% of pediatric wrist fractures.^3,4 This is due to the presence of a physeal growth plate, thicker periosteum, and softer underlying bone in pediatric patients.^4,5 When an axial load is applied, as in a fall onto an outstretched hand, the force can lead to plastic deformation, with or without cortical disruption of the bone.^4,5

Pediatric torus fractures of the distal radius generally are treated with immobilization,² traditionally through a short arm cast or a removable, rigid wrist splint.^2,6 The wrist often is immobilized for 3 to 4 weeks, with routine follow-up and potential repeat plain film radiography to ensure stability.^2,6

Despite common use of immobilization, torus fractures of the distal radius are anatomically stable, and displacement is unlikely to occur.^7,8 As such, many studies have suggested that treatment of torus fractures with rigid immobilization in a cast or splint may not be necessary.^9,10 However, a 2018 Cochrane review concluded that the quality of evidence illustrating similar recovery between treatments was low, leaving uncertainty as to the most appropriate management strategy.⁶ Less casting and follow-up imaging could have positive implications for patient satisfaction, health care–associated costs, and radiation exposure.¹⁰

This study, the Forearm Fracture Recovery in Children Evaluation (FORCE) trial, compared the traditional treatment of distal radius torus fractures with rigid immobilization to soft immobilization and immediate discharge.

STUDY SUMMARY

Providing quality evidence for a standard of care

FORCE was a randomized controlled equivalence trial (N = 965) across 23 emergency departments (EDs) in the United Kingdom that compared pain and function in pediatric patients with distal radius torus fractures treated with a soft bandage and immediate discharge vs rigid immobilization and routine follow-up.¹ Patients included children ages 4 to 15 years presenting to the ED with a distal radius torus fracture, which was confirmed radiologically.

At 3 days, pain scores improved by 3.2 points in the soft bandage group and 3.1 points in the rigid immobilization group.

Patients with concomitant ipsilateral ulnar fractures were included in the study. Researchers excluded patients with injuries older than 36 hours, evidence of cortical disruption on radiograph (eg, greenstick fracture), or additional fractures other than the wrist, or those who were deemed unable to follow up with the full study protocol (eg, having insufficient English comprehension).

Continue to: Patients were randomly assigned...

Patients were randomly assigned in a 1:1 ratio to receive treatment with either a soft bandage such as a gauze roller bandage (n = 489) or rigid immobilization (n = 476). For patients in the bandage group, a soft bandage was applied in the ED or provided for home application without planned clinical follow-up. Patients in the rigid immobilization group were treated in the ED with either a removable manufactured splint or a molded splint or cast, followed by the standard follow-up practice of the treating center. Patients in the soft bandage group were advised not to wear the bandage for more than 3 weeks. Blinding was not possible, but the treatment team did not take part in patient follow-up.

The primary outcome was change in pain 3 days after treatment, measured on the Wong-Baker FACES Pain Rating Scale (an ordinal assessment using 6 illustrated facial expressions translated to a numeric rating on a scale of 0-10, with higher scores indicating worse pain). This scale has an established minimum clinically important difference (MCID) value of 1 face (2 points).¹¹ Per standard practice in equivalence trials, the equivalence margin was defined as half the MCID, with a value of 1.0 used in this study.

Secondary outcomes measured over the 6-week follow-up period included additional pain measurements using the Wong-Baker scale, measures of function and health-­related quality of life, analgesia use, days of absence from school or childcare, complication rates, and patient satisfaction. This study used modified intention-to-treat and per-protocol analyses.

The mean age of participants was 9.6 years; 39% were girls and 61% were boys. In the bandage group, 94% opted to have the soft bandage applied in the ED, and 95% of the rigid immobilization group were treated with a removable wrist splint in the ED. At 3 days, pain scores improved by 3.2 points (standard deviation [SD] = 2.1) in the soft bandage group and 3.1 points (SD = 2.1) in the rigid immobilization group. The adjusted difference was –0.1 (95% CI, –0.37 to 0.17) in the intention-to-treat analysis and –0.06 (95% CI, –0.34 to 0.21) in the per-protocol analysis, which were both less than the predetermined equivalence margin. This equivalence margin also was met at all secondary time points (1 day, 7 days, 3 weeks, and 6 weeks after treatment) and in subgroup analysis of those 4 to 7 years and 8 to 15 years.

Use of any analgesia in the prior 24 hours was slightly higher in the soft bandage group on Day 1 (83% vs 78%; P = .04) and Day 3 (57% vs 51%; P = .05), but this difference was not seen on Day 7. Satisfaction, measured via a 7-point Likert scale (range from “extremely satisfied” to “extremely unsatisfied”), was slightly lower in the soft bandage group on Day 1 (median 2 [interquartile range = 1, 2] vs median 1 [interquartile range = 1, 2]; P < .0001) but was not different after 6 weeks. There were no measured differences in any other secondary outcomes, including function, quality of life, and complication rates.

Continue to: By the primary end point...

De-escalation of treatment offers an equivalent, resource-sparing alternative to traditional treatment of pediatric torus fractures of the distal radius.

By the primary end point of 3 days, 36 patients (7%) in the soft bandage group returned to medical care requesting a change to rigid immobilization, compared with 1 patient (0.2%) in the rigid immobilization group declining intervention.

WHAT’S NEW

Equivalence in pain and function scores

This trial showed equivalence in pain at 3 days’ follow-up in children with distal radius torus fractures who were offered bandaging and then immediately discharged from the ED, compared with rigid immobilization and clinical follow-up. There were no significant differences in pain or function between groups during the 6 weeks following the initial injury. De-escalation of treatment offers an equivalent, resource-sparing alternative to traditional treatment of these fractures.

CAVEATS

Lack of masking likely introduced bias

There are no major caveats associated with managing distal radius torus fractures with a soft bandage and discharge from the ED, compared with the traditional treatment of rigid immobilization. However, bias was likely introduced in patient-reported outcomes due to the inability to mask patients and families to the treatment allocation. This may have led to overstating the severity of outcomes in the bandage group, given the strong preference for rigid immobilization, although equivalence was illustrated despite this potential bias.

CHALLENGES TO IMPLEMENTATION

Preferences may be difficult to change

Parents and clinicians demonstrated a preference for rigid immobilization, as shown in the imbalance in treatment crossovers, with 7% of children changing to the rigid immobilization group by the primary study end point of 3 days. The study authors hypothesized that crossovers may have been due to the perception by some parents that rigid immobilization is the gold standard of treatment, as well as clinicians’ seeking to escalate care for patients returning for follow-up. Policy and guideline changes, as well as physician efforts to educate patients on outcomes with soft bandage treatment, are likely to improve these misconceptions.

ILLUSTRATIVE CASE

A 9-year-old girl presents to your urgent care clinic after a fall while snowboarding for the first time. She reports falling forward onto her outstretched right hand and describes pain in her distal right forearm. She denies paresthesias, weakness, or lacerations. Physical examination reveals mild edema of the dorsal aspect of her distal right forearm and tenderness to palpation of the dorsal aspect of her distal radius. She denies tenderness to palpation of her ulna, anatomic snuffbox, hand, and elbow. Range of motion of the wrist is full on passive testing, but she declines active testing due to pain. Wrist radiographs reveal an uncomplicated torus fracture of the distal radius. Can immobilization with a soft bandage alone sufficiently treat this fracture?

Fractures of the distal radius are among the most common fractures of the upper extremity and commonly occur from a fall onto an outstretched hand.² In the pediatric population, torus fractures, also known as buckle fractures, are the most common type of distal radius fracture, comprising an estimated 50% of pediatric wrist fractures.^3,4 This is due to the presence of a physeal growth plate, thicker periosteum, and softer underlying bone in pediatric patients.^4,5 When an axial load is applied, as in a fall onto an outstretched hand, the force can lead to plastic deformation, with or without cortical disruption of the bone.^4,5

Pediatric torus fractures of the distal radius generally are treated with immobilization,² traditionally through a short arm cast or a removable, rigid wrist splint.^2,6 The wrist often is immobilized for 3 to 4 weeks, with routine follow-up and potential repeat plain film radiography to ensure stability.^2,6

Despite common use of immobilization, torus fractures of the distal radius are anatomically stable, and displacement is unlikely to occur.^7,8 As such, many studies have suggested that treatment of torus fractures with rigid immobilization in a cast or splint may not be necessary.^9,10 However, a 2018 Cochrane review concluded that the quality of evidence illustrating similar recovery between treatments was low, leaving uncertainty as to the most appropriate management strategy.⁶ Less casting and follow-up imaging could have positive implications for patient satisfaction, health care–associated costs, and radiation exposure.¹⁰

This study, the Forearm Fracture Recovery in Children Evaluation (FORCE) trial, compared the traditional treatment of distal radius torus fractures with rigid immobilization to soft immobilization and immediate discharge.

STUDY SUMMARY

Providing quality evidence for a standard of care

FORCE was a randomized controlled equivalence trial (N = 965) across 23 emergency departments (EDs) in the United Kingdom that compared pain and function in pediatric patients with distal radius torus fractures treated with a soft bandage and immediate discharge vs rigid immobilization and routine follow-up.¹ Patients included children ages 4 to 15 years presenting to the ED with a distal radius torus fracture, which was confirmed radiologically.

At 3 days, pain scores improved by 3.2 points in the soft bandage group and 3.1 points in the rigid immobilization group.

Patients with concomitant ipsilateral ulnar fractures were included in the study. Researchers excluded patients with injuries older than 36 hours, evidence of cortical disruption on radiograph (eg, greenstick fracture), or additional fractures other than the wrist, or those who were deemed unable to follow up with the full study protocol (eg, having insufficient English comprehension).

Continue to: Patients were randomly assigned...

Patients were randomly assigned in a 1:1 ratio to receive treatment with either a soft bandage such as a gauze roller bandage (n = 489) or rigid immobilization (n = 476). For patients in the bandage group, a soft bandage was applied in the ED or provided for home application without planned clinical follow-up. Patients in the rigid immobilization group were treated in the ED with either a removable manufactured splint or a molded splint or cast, followed by the standard follow-up practice of the treating center. Patients in the soft bandage group were advised not to wear the bandage for more than 3 weeks. Blinding was not possible, but the treatment team did not take part in patient follow-up.

The primary outcome was change in pain 3 days after treatment, measured on the Wong-Baker FACES Pain Rating Scale (an ordinal assessment using 6 illustrated facial expressions translated to a numeric rating on a scale of 0-10, with higher scores indicating worse pain). This scale has an established minimum clinically important difference (MCID) value of 1 face (2 points).¹¹ Per standard practice in equivalence trials, the equivalence margin was defined as half the MCID, with a value of 1.0 used in this study.

Secondary outcomes measured over the 6-week follow-up period included additional pain measurements using the Wong-Baker scale, measures of function and health-­related quality of life, analgesia use, days of absence from school or childcare, complication rates, and patient satisfaction. This study used modified intention-to-treat and per-protocol analyses.

The mean age of participants was 9.6 years; 39% were girls and 61% were boys. In the bandage group, 94% opted to have the soft bandage applied in the ED, and 95% of the rigid immobilization group were treated with a removable wrist splint in the ED. At 3 days, pain scores improved by 3.2 points (standard deviation [SD] = 2.1) in the soft bandage group and 3.1 points (SD = 2.1) in the rigid immobilization group. The adjusted difference was –0.1 (95% CI, –0.37 to 0.17) in the intention-to-treat analysis and –0.06 (95% CI, –0.34 to 0.21) in the per-protocol analysis, which were both less than the predetermined equivalence margin. This equivalence margin also was met at all secondary time points (1 day, 7 days, 3 weeks, and 6 weeks after treatment) and in subgroup analysis of those 4 to 7 years and 8 to 15 years.

Use of any analgesia in the prior 24 hours was slightly higher in the soft bandage group on Day 1 (83% vs 78%; P = .04) and Day 3 (57% vs 51%; P = .05), but this difference was not seen on Day 7. Satisfaction, measured via a 7-point Likert scale (range from “extremely satisfied” to “extremely unsatisfied”), was slightly lower in the soft bandage group on Day 1 (median 2 [interquartile range = 1, 2] vs median 1 [interquartile range = 1, 2]; P < .0001) but was not different after 6 weeks. There were no measured differences in any other secondary outcomes, including function, quality of life, and complication rates.

Continue to: By the primary end point...

De-escalation of treatment offers an equivalent, resource-sparing alternative to traditional treatment of pediatric torus fractures of the distal radius.

By the primary end point of 3 days, 36 patients (7%) in the soft bandage group returned to medical care requesting a change to rigid immobilization, compared with 1 patient (0.2%) in the rigid immobilization group declining intervention.

WHAT’S NEW

Equivalence in pain and function scores

This trial showed equivalence in pain at 3 days’ follow-up in children with distal radius torus fractures who were offered bandaging and then immediately discharged from the ED, compared with rigid immobilization and clinical follow-up. There were no significant differences in pain or function between groups during the 6 weeks following the initial injury. De-escalation of treatment offers an equivalent, resource-sparing alternative to traditional treatment of these fractures.

CAVEATS

Lack of masking likely introduced bias

There are no major caveats associated with managing distal radius torus fractures with a soft bandage and discharge from the ED, compared with the traditional treatment of rigid immobilization. However, bias was likely introduced in patient-reported outcomes due to the inability to mask patients and families to the treatment allocation. This may have led to overstating the severity of outcomes in the bandage group, given the strong preference for rigid immobilization, although equivalence was illustrated despite this potential bias.

CHALLENGES TO IMPLEMENTATION

Preferences may be difficult to change

Parents and clinicians demonstrated a preference for rigid immobilization, as shown in the imbalance in treatment crossovers, with 7% of children changing to the rigid immobilization group by the primary study end point of 3 days. The study authors hypothesized that crossovers may have been due to the perception by some parents that rigid immobilization is the gold standard of treatment, as well as clinicians’ seeking to escalate care for patients returning for follow-up. Policy and guideline changes, as well as physician efforts to educate patients on outcomes with soft bandage treatment, are likely to improve these misconceptions.

PHILADELPHIA – Percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) reduces angina frequency, increases exercise capacity, and improves quality of life, results of a placebo-controlled, randomized trial show, confirming advantages that have never before been proven.

“The effect of PCI was immediate, sustained over 12 weeks, and consistent across all endpoints,” reported Christopher A. Rajkumar, MBBS, an interventional cardiology registrar at the Imperial College Healthcare Trust, London.

Results of the trial, ORBITA-2, were presented at the annual scientific sessions of the American Heart Association and simultaneously published online in the New England Journal of Medicine.

Symptom relief has long been a justification for PCI in patients with stable CAD, but the evidence has been derived from uncontrolled studies, Dr. Rajkumar said. However, the first ORBITA trial, which was also placebo controlled and randomized, failed to show benefit.

Dr. Rajkumar acknowledged that the benefit of PCI in ORBITA-2 was lower than previously reported in nonrandomized trials. He also noted that 59% of patients still had at least some angina symptoms following PCI.

Even though ORBITA-2 proves that PCI is better than no PCI, he agreed that well-informed patients, such as those who wish to avoid an invasive procedure, might still reasonably select antianginal medication over PCI. Current guidelines recommend PCI for patients with refractory angina despite medical therapy.

While Dr. Rajkumar was unwilling to speculate on how these data might change guidelines, he did say that patients with stable CAD and angina “now have a choice of two first-line evidence-based pathways.”
 

‘Remarkable’ trial

“ORBITA 2 is a rather remarkable trial because my surgical colleagues have been asking me for many decades whether PCI actually works,” said Martin B. Leon, MD, professor of medicine, Columbia University Irving Medical Center, New York. “Now I can say with confidence on the basis of a placebo-controlled trial that PCI certainly does have a favorable impact in patients with documented angina, severe coronary stenosis, and demonstrated ischemia.”

The key enrollment criteria for ORBITA-2 were angina, severe coronary stenosis in at least one vessel, and ischemia on stress imaging or invasive physiology. Unlike the previous ORBITA trial, which was limited to single-vessel disease and did not require objective evidence of ischemia, ORBITA 2 employed change in angina, rather than improved exercise capacity, as its primary endpoint.

Relative to sham PCI, patients randomly assigned to an interventional procedure had a more than twofold increase in the odds ratio of improved angina control (OR, 2.2; P < .001) based on a patient scoring system that captured angina symptoms as well as angina medication use on a smartphone application.  

The advantage of PCI over sham PCI was also significant for all secondary outcomes. These included a nearly fourfold greater (OR, 3.76; P < .001) likelihood of improvement in the Canadian Cardiovascular Society angina grade and a 1-minute increase (from 10 min. 40 seconds to 11 min. 40 seconds) in treadmill exercise time (P = .008).

On quality of life measured with the self-assessment questionnaire and the EQ-5D-5L, almost all endpoints were highly statistically significant in favor of PCI (typically on the level of P < .001).

The study had a bold design: At enrollment patients stopped all antianginal medications to undergo dobutamine echocardiography and other baseline tests. They were stopped again 2 weeks later, when patients were randomized.  

With a study protocol that enrolled patients off medication, “we intentionally diverged from the clinical guidelines,” Dr. Rajkumar said.

Of the 439 patients enrolled, 301 were randomly assigned at the end of the 2-week period, when patients were already sedated. Control patients remained sedated for at least 15 minutes. All 151 of those randomized to PCI and the 150 control patients were available for the intent-to-treat analysis at the end of 12 weeks.

The novel angina symptom burden score was created from daily angina episodes and units of daily antianginal medication captured on the smartphone app. On an ordinal scale, a score of 0 on any given day represented no anginal symptoms and no antianginal medication.

As angina severity or medication use increased, it raised the daily scores. If there was unacceptable angina (requiring the patient to be removed from the blind), acute coronary syndrome, or death, it produced the highest scores, which reached a maximum of 79.

The favorable OR for a lower symptom burden in the PCI group reflected a relative reduction in angina observed the first day after the procedure. Over the entire follow-up, more patients in the PCI group had an angina score of 0 and more of those who had angina did not take antianginal medications.

This objective evidence that PCI reduces symptoms and improves quality of life in patients with angina and stable CAD was met at the AHA late-breaking session with a sustained ovation.
 

ORBITA-2 addresses ORBITA criticisms

Connie N. Hess, MD, the AHA-invited discussant and an interventional cardiologist at the University of Colorado Medicine, Aurora, provided perspective on the differences between ORBITA 2 and ORBITA, which she said “addressed a fundamentally different hypothesis” by focusing on angina rather than exercise capacity.

Of the criticisms of the original ORBITA, which Dr. Hess noted was the first sham-controlled PCI trial ever conducted in stable CAD, one is that patients with multivessel disease were excluded, another was that objectively proven ischemia was not required, and a third was that the study of 6 weeks had a short duration.

“ORBITA 2 addressed many of these concerns,” Dr. Hess said, but, when noting that 80% of patients in the newer trial still had single vessel disease, she questioned whether the true effect of PCI for improving symptoms might still be underestimated.

ORBITA-2 was supported by the National Institute for Health and Care Research Imperial Biomedical Research Centre, the Medical Research Council, NIHR, the British Heart Foundation, Philips, and St. Mary’s Coronary Flow Trust. Dr. Rajkumar reported relevant financial relationships. Dr. Leon reported financial relationships with Abbott Vascular, Anteris, Boston Scientific, Edwards Lifesciences, Foldax, and Medtronic. Dr. Hess has financial relationships with more than 20 pharmaceutical companies, but none related specifically to this presentation.

PHILADELPHIA – Percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) reduces angina frequency, increases exercise capacity, and improves quality of life, results of a placebo-controlled, randomized trial show, confirming advantages that have never before been proven.

“The effect of PCI was immediate, sustained over 12 weeks, and consistent across all endpoints,” reported Christopher A. Rajkumar, MBBS, an interventional cardiology registrar at the Imperial College Healthcare Trust, London.

Results of the trial, ORBITA-2, were presented at the annual scientific sessions of the American Heart Association and simultaneously published online in the New England Journal of Medicine.

Symptom relief has long been a justification for PCI in patients with stable CAD, but the evidence has been derived from uncontrolled studies, Dr. Rajkumar said. However, the first ORBITA trial, which was also placebo controlled and randomized, failed to show benefit.

Dr. Rajkumar acknowledged that the benefit of PCI in ORBITA-2 was lower than previously reported in nonrandomized trials. He also noted that 59% of patients still had at least some angina symptoms following PCI.

Even though ORBITA-2 proves that PCI is better than no PCI, he agreed that well-informed patients, such as those who wish to avoid an invasive procedure, might still reasonably select antianginal medication over PCI. Current guidelines recommend PCI for patients with refractory angina despite medical therapy.

While Dr. Rajkumar was unwilling to speculate on how these data might change guidelines, he did say that patients with stable CAD and angina “now have a choice of two first-line evidence-based pathways.”
 

‘Remarkable’ trial

“ORBITA 2 is a rather remarkable trial because my surgical colleagues have been asking me for many decades whether PCI actually works,” said Martin B. Leon, MD, professor of medicine, Columbia University Irving Medical Center, New York. “Now I can say with confidence on the basis of a placebo-controlled trial that PCI certainly does have a favorable impact in patients with documented angina, severe coronary stenosis, and demonstrated ischemia.”

The key enrollment criteria for ORBITA-2 were angina, severe coronary stenosis in at least one vessel, and ischemia on stress imaging or invasive physiology. Unlike the previous ORBITA trial, which was limited to single-vessel disease and did not require objective evidence of ischemia, ORBITA 2 employed change in angina, rather than improved exercise capacity, as its primary endpoint.

Relative to sham PCI, patients randomly assigned to an interventional procedure had a more than twofold increase in the odds ratio of improved angina control (OR, 2.2; P < .001) based on a patient scoring system that captured angina symptoms as well as angina medication use on a smartphone application.  

The advantage of PCI over sham PCI was also significant for all secondary outcomes. These included a nearly fourfold greater (OR, 3.76; P < .001) likelihood of improvement in the Canadian Cardiovascular Society angina grade and a 1-minute increase (from 10 min. 40 seconds to 11 min. 40 seconds) in treadmill exercise time (P = .008).

On quality of life measured with the self-assessment questionnaire and the EQ-5D-5L, almost all endpoints were highly statistically significant in favor of PCI (typically on the level of P < .001).

The study had a bold design: At enrollment patients stopped all antianginal medications to undergo dobutamine echocardiography and other baseline tests. They were stopped again 2 weeks later, when patients were randomized.  

With a study protocol that enrolled patients off medication, “we intentionally diverged from the clinical guidelines,” Dr. Rajkumar said.

Of the 439 patients enrolled, 301 were randomly assigned at the end of the 2-week period, when patients were already sedated. Control patients remained sedated for at least 15 minutes. All 151 of those randomized to PCI and the 150 control patients were available for the intent-to-treat analysis at the end of 12 weeks.

The novel angina symptom burden score was created from daily angina episodes and units of daily antianginal medication captured on the smartphone app. On an ordinal scale, a score of 0 on any given day represented no anginal symptoms and no antianginal medication.

As angina severity or medication use increased, it raised the daily scores. If there was unacceptable angina (requiring the patient to be removed from the blind), acute coronary syndrome, or death, it produced the highest scores, which reached a maximum of 79.

The favorable OR for a lower symptom burden in the PCI group reflected a relative reduction in angina observed the first day after the procedure. Over the entire follow-up, more patients in the PCI group had an angina score of 0 and more of those who had angina did not take antianginal medications.

This objective evidence that PCI reduces symptoms and improves quality of life in patients with angina and stable CAD was met at the AHA late-breaking session with a sustained ovation.
 

ORBITA-2 addresses ORBITA criticisms

Connie N. Hess, MD, the AHA-invited discussant and an interventional cardiologist at the University of Colorado Medicine, Aurora, provided perspective on the differences between ORBITA 2 and ORBITA, which she said “addressed a fundamentally different hypothesis” by focusing on angina rather than exercise capacity.

Of the criticisms of the original ORBITA, which Dr. Hess noted was the first sham-controlled PCI trial ever conducted in stable CAD, one is that patients with multivessel disease were excluded, another was that objectively proven ischemia was not required, and a third was that the study of 6 weeks had a short duration.

“ORBITA 2 addressed many of these concerns,” Dr. Hess said, but, when noting that 80% of patients in the newer trial still had single vessel disease, she questioned whether the true effect of PCI for improving symptoms might still be underestimated.

ORBITA-2 was supported by the National Institute for Health and Care Research Imperial Biomedical Research Centre, the Medical Research Council, NIHR, the British Heart Foundation, Philips, and St. Mary’s Coronary Flow Trust. Dr. Rajkumar reported relevant financial relationships. Dr. Leon reported financial relationships with Abbott Vascular, Anteris, Boston Scientific, Edwards Lifesciences, Foldax, and Medtronic. Dr. Hess has financial relationships with more than 20 pharmaceutical companies, but none related specifically to this presentation.

PHILADELPHIA – Percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) reduces angina frequency, increases exercise capacity, and improves quality of life, results of a placebo-controlled, randomized trial show, confirming advantages that have never before been proven.

“The effect of PCI was immediate, sustained over 12 weeks, and consistent across all endpoints,” reported Christopher A. Rajkumar, MBBS, an interventional cardiology registrar at the Imperial College Healthcare Trust, London.

Results of the trial, ORBITA-2, were presented at the annual scientific sessions of the American Heart Association and simultaneously published online in the New England Journal of Medicine.

Symptom relief has long been a justification for PCI in patients with stable CAD, but the evidence has been derived from uncontrolled studies, Dr. Rajkumar said. However, the first ORBITA trial, which was also placebo controlled and randomized, failed to show benefit.

Dr. Rajkumar acknowledged that the benefit of PCI in ORBITA-2 was lower than previously reported in nonrandomized trials. He also noted that 59% of patients still had at least some angina symptoms following PCI.

Even though ORBITA-2 proves that PCI is better than no PCI, he agreed that well-informed patients, such as those who wish to avoid an invasive procedure, might still reasonably select antianginal medication over PCI. Current guidelines recommend PCI for patients with refractory angina despite medical therapy.

While Dr. Rajkumar was unwilling to speculate on how these data might change guidelines, he did say that patients with stable CAD and angina “now have a choice of two first-line evidence-based pathways.”
 

‘Remarkable’ trial

“ORBITA 2 is a rather remarkable trial because my surgical colleagues have been asking me for many decades whether PCI actually works,” said Martin B. Leon, MD, professor of medicine, Columbia University Irving Medical Center, New York. “Now I can say with confidence on the basis of a placebo-controlled trial that PCI certainly does have a favorable impact in patients with documented angina, severe coronary stenosis, and demonstrated ischemia.”

The key enrollment criteria for ORBITA-2 were angina, severe coronary stenosis in at least one vessel, and ischemia on stress imaging or invasive physiology. Unlike the previous ORBITA trial, which was limited to single-vessel disease and did not require objective evidence of ischemia, ORBITA 2 employed change in angina, rather than improved exercise capacity, as its primary endpoint.

Relative to sham PCI, patients randomly assigned to an interventional procedure had a more than twofold increase in the odds ratio of improved angina control (OR, 2.2; P < .001) based on a patient scoring system that captured angina symptoms as well as angina medication use on a smartphone application.  

The advantage of PCI over sham PCI was also significant for all secondary outcomes. These included a nearly fourfold greater (OR, 3.76; P < .001) likelihood of improvement in the Canadian Cardiovascular Society angina grade and a 1-minute increase (from 10 min. 40 seconds to 11 min. 40 seconds) in treadmill exercise time (P = .008).

On quality of life measured with the self-assessment questionnaire and the EQ-5D-5L, almost all endpoints were highly statistically significant in favor of PCI (typically on the level of P < .001).

The study had a bold design: At enrollment patients stopped all antianginal medications to undergo dobutamine echocardiography and other baseline tests. They were stopped again 2 weeks later, when patients were randomized.  

With a study protocol that enrolled patients off medication, “we intentionally diverged from the clinical guidelines,” Dr. Rajkumar said.

Of the 439 patients enrolled, 301 were randomly assigned at the end of the 2-week period, when patients were already sedated. Control patients remained sedated for at least 15 minutes. All 151 of those randomized to PCI and the 150 control patients were available for the intent-to-treat analysis at the end of 12 weeks.

The novel angina symptom burden score was created from daily angina episodes and units of daily antianginal medication captured on the smartphone app. On an ordinal scale, a score of 0 on any given day represented no anginal symptoms and no antianginal medication.

As angina severity or medication use increased, it raised the daily scores. If there was unacceptable angina (requiring the patient to be removed from the blind), acute coronary syndrome, or death, it produced the highest scores, which reached a maximum of 79.

The favorable OR for a lower symptom burden in the PCI group reflected a relative reduction in angina observed the first day after the procedure. Over the entire follow-up, more patients in the PCI group had an angina score of 0 and more of those who had angina did not take antianginal medications.

This objective evidence that PCI reduces symptoms and improves quality of life in patients with angina and stable CAD was met at the AHA late-breaking session with a sustained ovation.
 

ORBITA-2 addresses ORBITA criticisms

Connie N. Hess, MD, the AHA-invited discussant and an interventional cardiologist at the University of Colorado Medicine, Aurora, provided perspective on the differences between ORBITA 2 and ORBITA, which she said “addressed a fundamentally different hypothesis” by focusing on angina rather than exercise capacity.

Of the criticisms of the original ORBITA, which Dr. Hess noted was the first sham-controlled PCI trial ever conducted in stable CAD, one is that patients with multivessel disease were excluded, another was that objectively proven ischemia was not required, and a third was that the study of 6 weeks had a short duration.

“ORBITA 2 addressed many of these concerns,” Dr. Hess said, but, when noting that 80% of patients in the newer trial still had single vessel disease, she questioned whether the true effect of PCI for improving symptoms might still be underestimated.

ORBITA-2 was supported by the National Institute for Health and Care Research Imperial Biomedical Research Centre, the Medical Research Council, NIHR, the British Heart Foundation, Philips, and St. Mary’s Coronary Flow Trust. Dr. Rajkumar reported relevant financial relationships. Dr. Leon reported financial relationships with Abbott Vascular, Anteris, Boston Scientific, Edwards Lifesciences, Foldax, and Medtronic. Dr. Hess has financial relationships with more than 20 pharmaceutical companies, but none related specifically to this presentation.

Liver-resident gamma delta T cells that produce interleukin(IL)-17 coordinate with hepatic macrophages to offer early protection against Listeria monocytogenes infection, according to investigators.

These finding suggest that gamma delta T17 cells could be a target for novel cell-based therapies against liver diseases, reported lead author Yanan Wang, PhD, of Shandong University, Jinan, China, and colleagues.

“Gamma delta T cells are located in mucosal tissues and other peripheral lymphoid tissues and are considered to act as the first line of defense within the immune system,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “Several studies have reported that IL-17A produced by gamma delta T cells plays a critical role in host defense after Listeria monocytogenes [infection] in the liver. However, in those studies, the details of the phenotypes, dynamic changes, proliferation activity, and cytokine production of the responding gamma delta T cell populations in the overall process of hepatic infection are unclear, and how they accumulated into the infection sites has not been elucidated.”

To address this knowledge gap, Dr. Wang and colleagues conducted a series of experiments involving gamma delta T cells from murine liver samples.

First, using single-cell RNA-sequencing (scRNA-seq), the investigators identified six clusters of hepatic gamma delta T cells.

“[This first step] revealed the unique gene expression characteristics and indicated the possible important roles in immune responses of hepatic gamma delta T17 cells,” they noted.

Next, the investigators measured expression of CD44 and CD27 in liver gamma delta cells.

“Expression of CD44 and CD27 has been used to distinguish IL-17A–, interferon gamma–producing, and other subsets of gamma delta T cells in the thymus, lymph nodes, lungs, and other peripheral lymphoid tissues,” they wrote.

These efforts revealed three subsets of hepatic gamma delta T cells, of which CD44hiCD27– gamma delta T cells were most abundant. Further analysis revealed expression profiles consistent with liver residency.

The next phases of the study characterized the immune roles of hepatic gamma delta T cells.

A comparison of Listeria monocytogenes infection in wild-type versus T-cell antigen receptor knockout mice, for example, showed that knockout mice had significantly more weight loss than did wild-type mice, greater bacterial load in the liver, and shorter survival times.

“As expected, the proportion and absolute numbers of gamma delta T cells in the liver of wild-type mice increased at day 3 and reached a peak at day 7 after infection,” the investigators wrote. “These data suggested that hepatic gamma delta T cells proliferated after infection and contributed to Lm clearance.”

Parabiosis experiments showed that the increased number of CD44hiCD27– gamma delta T cells in the livers of Listeria monocytogenes-infected mice were due to migration and proliferation of liver-resident gamma delta T cells instead of circulating gamma delta T cells. A transwell assay revealed that Kupffer cells and monocyte-derived macrophages promoted migration of CD44hiCD27– gamma delta T cells upon infection.

“Our study provides additional insight into liver-resident lymphocytes and will aid in targeting such tissue-resident lymphocyte populations to promote local immune surveillance,” the investigators concluded.

The study was supported by grants from the National Natural Science Foundation of China and the Shandong Provincial Natural Science Foundation. The investigators disclosed no conflicts of interest.

Liver-resident gamma delta T cells that produce interleukin(IL)-17 coordinate with hepatic macrophages to offer early protection against Listeria monocytogenes infection, according to investigators.

These finding suggest that gamma delta T17 cells could be a target for novel cell-based therapies against liver diseases, reported lead author Yanan Wang, PhD, of Shandong University, Jinan, China, and colleagues.

“Gamma delta T cells are located in mucosal tissues and other peripheral lymphoid tissues and are considered to act as the first line of defense within the immune system,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “Several studies have reported that IL-17A produced by gamma delta T cells plays a critical role in host defense after Listeria monocytogenes [infection] in the liver. However, in those studies, the details of the phenotypes, dynamic changes, proliferation activity, and cytokine production of the responding gamma delta T cell populations in the overall process of hepatic infection are unclear, and how they accumulated into the infection sites has not been elucidated.”

To address this knowledge gap, Dr. Wang and colleagues conducted a series of experiments involving gamma delta T cells from murine liver samples.

First, using single-cell RNA-sequencing (scRNA-seq), the investigators identified six clusters of hepatic gamma delta T cells.

“[This first step] revealed the unique gene expression characteristics and indicated the possible important roles in immune responses of hepatic gamma delta T17 cells,” they noted.

Next, the investigators measured expression of CD44 and CD27 in liver gamma delta cells.

“Expression of CD44 and CD27 has been used to distinguish IL-17A–, interferon gamma–producing, and other subsets of gamma delta T cells in the thymus, lymph nodes, lungs, and other peripheral lymphoid tissues,” they wrote.

These efforts revealed three subsets of hepatic gamma delta T cells, of which CD44hiCD27– gamma delta T cells were most abundant. Further analysis revealed expression profiles consistent with liver residency.

The next phases of the study characterized the immune roles of hepatic gamma delta T cells.

A comparison of Listeria monocytogenes infection in wild-type versus T-cell antigen receptor knockout mice, for example, showed that knockout mice had significantly more weight loss than did wild-type mice, greater bacterial load in the liver, and shorter survival times.

“As expected, the proportion and absolute numbers of gamma delta T cells in the liver of wild-type mice increased at day 3 and reached a peak at day 7 after infection,” the investigators wrote. “These data suggested that hepatic gamma delta T cells proliferated after infection and contributed to Lm clearance.”

Parabiosis experiments showed that the increased number of CD44hiCD27– gamma delta T cells in the livers of Listeria monocytogenes-infected mice were due to migration and proliferation of liver-resident gamma delta T cells instead of circulating gamma delta T cells. A transwell assay revealed that Kupffer cells and monocyte-derived macrophages promoted migration of CD44hiCD27– gamma delta T cells upon infection.

“Our study provides additional insight into liver-resident lymphocytes and will aid in targeting such tissue-resident lymphocyte populations to promote local immune surveillance,” the investigators concluded.

The study was supported by grants from the National Natural Science Foundation of China and the Shandong Provincial Natural Science Foundation. The investigators disclosed no conflicts of interest.

Liver-resident gamma delta T cells that produce interleukin(IL)-17 coordinate with hepatic macrophages to offer early protection against Listeria monocytogenes infection, according to investigators.

These finding suggest that gamma delta T17 cells could be a target for novel cell-based therapies against liver diseases, reported lead author Yanan Wang, PhD, of Shandong University, Jinan, China, and colleagues.

“Gamma delta T cells are located in mucosal tissues and other peripheral lymphoid tissues and are considered to act as the first line of defense within the immune system,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “Several studies have reported that IL-17A produced by gamma delta T cells plays a critical role in host defense after Listeria monocytogenes [infection] in the liver. However, in those studies, the details of the phenotypes, dynamic changes, proliferation activity, and cytokine production of the responding gamma delta T cell populations in the overall process of hepatic infection are unclear, and how they accumulated into the infection sites has not been elucidated.”

To address this knowledge gap, Dr. Wang and colleagues conducted a series of experiments involving gamma delta T cells from murine liver samples.

First, using single-cell RNA-sequencing (scRNA-seq), the investigators identified six clusters of hepatic gamma delta T cells.

“[This first step] revealed the unique gene expression characteristics and indicated the possible important roles in immune responses of hepatic gamma delta T17 cells,” they noted.

Next, the investigators measured expression of CD44 and CD27 in liver gamma delta cells.

“Expression of CD44 and CD27 has been used to distinguish IL-17A–, interferon gamma–producing, and other subsets of gamma delta T cells in the thymus, lymph nodes, lungs, and other peripheral lymphoid tissues,” they wrote.

These efforts revealed three subsets of hepatic gamma delta T cells, of which CD44hiCD27– gamma delta T cells were most abundant. Further analysis revealed expression profiles consistent with liver residency.

The next phases of the study characterized the immune roles of hepatic gamma delta T cells.

A comparison of Listeria monocytogenes infection in wild-type versus T-cell antigen receptor knockout mice, for example, showed that knockout mice had significantly more weight loss than did wild-type mice, greater bacterial load in the liver, and shorter survival times.

“As expected, the proportion and absolute numbers of gamma delta T cells in the liver of wild-type mice increased at day 3 and reached a peak at day 7 after infection,” the investigators wrote. “These data suggested that hepatic gamma delta T cells proliferated after infection and contributed to Lm clearance.”

Parabiosis experiments showed that the increased number of CD44hiCD27– gamma delta T cells in the livers of Listeria monocytogenes-infected mice were due to migration and proliferation of liver-resident gamma delta T cells instead of circulating gamma delta T cells. A transwell assay revealed that Kupffer cells and monocyte-derived macrophages promoted migration of CD44hiCD27– gamma delta T cells upon infection.

“Our study provides additional insight into liver-resident lymphocytes and will aid in targeting such tissue-resident lymphocyte populations to promote local immune surveillance,” the investigators concluded.

The study was supported by grants from the National Natural Science Foundation of China and the Shandong Provincial Natural Science Foundation. The investigators disclosed no conflicts of interest.

Evidence summary

Cohort studies demonstrate no adverse CV outcomes

A 2020 systematic review and meta-­analysis evaluated randomized controlled trials (RCTs) and observational studies to examine the association between menopausal hormone therapy and CV disease.¹ The 26 RCTs primarily evaluated oral hormone administration. The observational studies comprised 30 cohort studies, 13 case-control studies, and 5 nested case-control studies, primarily in Europe and North America; 21 reported the route of administration. The trials evaluated women ages 49 to 77 years (mean, 61 years), and follow-up ranged from 1 to 21.5 years (mean, 7 years). In subgroup analyses of the observational studies, nonoral hormone therapy was associated with a lower risk for stroke and MI compared to oral administration (see TABLE¹). Study limitations included enrollment of patients with few comorbidities, from limited geographic regions. Results in the meta-analysis were not stratified by the type of nonoral hormone therapy; only 4 studies evaluated vaginal estrogen use. 

Two large cohort studies included in the systematic review provided more specific data on vaginal estrogens. The first used data from the Women’s Health Initiative in a subset of women ages 50 to 79 years (n = 46,566) who were not already on systemic hormone therapy and who did not have prior history of breast, endometrial, or ovarian cancer.² Data were collected from self-assessment questionnaires and medical record reviews. The median duration of vaginal estrogen use was 2 years, and median follow-up duration was 7.2 years. Vaginal estrogen users had a 48% lower risk for CHD (adjusted hazard ratio [aHR] = 0.52; 95% CI, 0.31-0.85) than nonusers. Rates for all-cause mortality (aHR = 0.78; 95% CI, 0.58-1.04), stroke (aHR = 0.78; 95% CI, 0.49-1.24), and DVT/PE (aHR = 0.68; 95% CI, 0.36-1.28) were similar. In this and the other cohort studies to be discussed, outcome data for all vaginal estrogen preparations (eg, cream, ring, tablet) were combined. 

The other large cohort study in the systematic review evaluated data on postmenopausal women from the Nurses’ Health Study.³ The authors evaluated health reports on 53,797 women as they transitioned through menopause. Patients with systemic hormone therapy use, history of cancer, and self-reported CV disease were excluded. After adjusting for covariates, the authors found no statistically significant difference between users and nonusers of vaginal estrogen and risk for total MI (aHR = 0.73; 95% CI, 0.47-1.13), stroke (aHR = 0.85; 95% CI, 0.56-1.29), or DVT/PE (aHR = 1.06; 95% CI, 0.58-1.93). Study limitations included low prevalence of vaginal estrogen use (< 3%), short duration of use (mean, 37.5 months), and lack of data on the type or dose of vaginal estrogen used. The study only included health professionals, which limits generalizability. 

A Finnish cohort study (excluded from the systematic review because it used historical controls) compared rates of CHD and stroke in postmenopausal women who used vaginal estrogen against an age-matched background population. Researchers collected­ data from a nationwide prescription registry for women at least 50 years old who had purchased vaginal estrogens between 1994 and 2009 (n = 195,756).⁴ Women who purchased systemic hormone therapy at any point were excluded. After 3 to 5 years of exposure, use of vaginal estrogen was associated with a decreased risk for mortality from CHD (relative risk [RR] = 0.64; 95% CI, 0.57-0.70) and stroke (RR = 0.79; 95% CI, 0.69-0.91). However, after 10 years, these benefits were not seen (CHD: RR = 0.95; 95% CI, 0.90-1.00; stroke: RR = 0.93; 95% CI, 0.85-1.01). All confidence interval data were presented graphically. Key weaknesses of this study included use of both vaginal and systemic estrogen in the comparator background population, and the failure to collect data for other CV risk variables such as weight, tobacco exposure, and blood pressure.

Recommendations from others

In 2022, the North American Menopause Society issued a Hormone Therapy Position Statement that acknowledged the lack of clinical trials directly comparing risk for adverse CV endpoints with different estrogen administration routes.⁵ They stated nonoral routes of administration might offer advantages by bypassing first-pass hepatic metabolism.

Similarly, the 2015 Endocrine Society Clinical Practice Guideline on the Treatment of Symptoms of the Menopause also stated that the effects of low-dose vaginal estrogen therapy on CV disease or DVT/PE risk had not been adequately studied.⁶

A 2013 opinion by the American College of Obstetricians and Gynecologists stated that topical estrogen vaginal creams, tablets, and rings had low levels of systemic absorption and were not associated with an increased risk for DVT/PE.⁷ 

Editor’s takeaway

The available evidence on vaginal estrogen ­replacement reassures us of its safety. After decades spent studying hormone replacement therapy with vacillating conclusions and opinions, these cohorts—the best evidence we may ever get—along with a consensus of expert opinions, consistently demonstrate no adverse CV outcomes.

Evidence summary

Cohort studies demonstrate no adverse CV outcomes

A 2020 systematic review and meta-­analysis evaluated randomized controlled trials (RCTs) and observational studies to examine the association between menopausal hormone therapy and CV disease.¹ The 26 RCTs primarily evaluated oral hormone administration. The observational studies comprised 30 cohort studies, 13 case-control studies, and 5 nested case-control studies, primarily in Europe and North America; 21 reported the route of administration. The trials evaluated women ages 49 to 77 years (mean, 61 years), and follow-up ranged from 1 to 21.5 years (mean, 7 years). In subgroup analyses of the observational studies, nonoral hormone therapy was associated with a lower risk for stroke and MI compared to oral administration (see TABLE¹). Study limitations included enrollment of patients with few comorbidities, from limited geographic regions. Results in the meta-analysis were not stratified by the type of nonoral hormone therapy; only 4 studies evaluated vaginal estrogen use. 

Two large cohort studies included in the systematic review provided more specific data on vaginal estrogens. The first used data from the Women’s Health Initiative in a subset of women ages 50 to 79 years (n = 46,566) who were not already on systemic hormone therapy and who did not have prior history of breast, endometrial, or ovarian cancer.² Data were collected from self-assessment questionnaires and medical record reviews. The median duration of vaginal estrogen use was 2 years, and median follow-up duration was 7.2 years. Vaginal estrogen users had a 48% lower risk for CHD (adjusted hazard ratio [aHR] = 0.52; 95% CI, 0.31-0.85) than nonusers. Rates for all-cause mortality (aHR = 0.78; 95% CI, 0.58-1.04), stroke (aHR = 0.78; 95% CI, 0.49-1.24), and DVT/PE (aHR = 0.68; 95% CI, 0.36-1.28) were similar. In this and the other cohort studies to be discussed, outcome data for all vaginal estrogen preparations (eg, cream, ring, tablet) were combined. 

The other large cohort study in the systematic review evaluated data on postmenopausal women from the Nurses’ Health Study.³ The authors evaluated health reports on 53,797 women as they transitioned through menopause. Patients with systemic hormone therapy use, history of cancer, and self-reported CV disease were excluded. After adjusting for covariates, the authors found no statistically significant difference between users and nonusers of vaginal estrogen and risk for total MI (aHR = 0.73; 95% CI, 0.47-1.13), stroke (aHR = 0.85; 95% CI, 0.56-1.29), or DVT/PE (aHR = 1.06; 95% CI, 0.58-1.93). Study limitations included low prevalence of vaginal estrogen use (< 3%), short duration of use (mean, 37.5 months), and lack of data on the type or dose of vaginal estrogen used. The study only included health professionals, which limits generalizability. 

A Finnish cohort study (excluded from the systematic review because it used historical controls) compared rates of CHD and stroke in postmenopausal women who used vaginal estrogen against an age-matched background population. Researchers collected­ data from a nationwide prescription registry for women at least 50 years old who had purchased vaginal estrogens between 1994 and 2009 (n = 195,756).⁴ Women who purchased systemic hormone therapy at any point were excluded. After 3 to 5 years of exposure, use of vaginal estrogen was associated with a decreased risk for mortality from CHD (relative risk [RR] = 0.64; 95% CI, 0.57-0.70) and stroke (RR = 0.79; 95% CI, 0.69-0.91). However, after 10 years, these benefits were not seen (CHD: RR = 0.95; 95% CI, 0.90-1.00; stroke: RR = 0.93; 95% CI, 0.85-1.01). All confidence interval data were presented graphically. Key weaknesses of this study included use of both vaginal and systemic estrogen in the comparator background population, and the failure to collect data for other CV risk variables such as weight, tobacco exposure, and blood pressure.

Recommendations from others

In 2022, the North American Menopause Society issued a Hormone Therapy Position Statement that acknowledged the lack of clinical trials directly comparing risk for adverse CV endpoints with different estrogen administration routes.⁵ They stated nonoral routes of administration might offer advantages by bypassing first-pass hepatic metabolism.

Similarly, the 2015 Endocrine Society Clinical Practice Guideline on the Treatment of Symptoms of the Menopause also stated that the effects of low-dose vaginal estrogen therapy on CV disease or DVT/PE risk had not been adequately studied.⁶

A 2013 opinion by the American College of Obstetricians and Gynecologists stated that topical estrogen vaginal creams, tablets, and rings had low levels of systemic absorption and were not associated with an increased risk for DVT/PE.⁷ 

Editor’s takeaway

The available evidence on vaginal estrogen ­replacement reassures us of its safety. After decades spent studying hormone replacement therapy with vacillating conclusions and opinions, these cohorts—the best evidence we may ever get—along with a consensus of expert opinions, consistently demonstrate no adverse CV outcomes.

Evidence summary

Cohort studies demonstrate no adverse CV outcomes

A 2020 systematic review and meta-­analysis evaluated randomized controlled trials (RCTs) and observational studies to examine the association between menopausal hormone therapy and CV disease.¹ The 26 RCTs primarily evaluated oral hormone administration. The observational studies comprised 30 cohort studies, 13 case-control studies, and 5 nested case-control studies, primarily in Europe and North America; 21 reported the route of administration. The trials evaluated women ages 49 to 77 years (mean, 61 years), and follow-up ranged from 1 to 21.5 years (mean, 7 years). In subgroup analyses of the observational studies, nonoral hormone therapy was associated with a lower risk for stroke and MI compared to oral administration (see TABLE¹). Study limitations included enrollment of patients with few comorbidities, from limited geographic regions. Results in the meta-analysis were not stratified by the type of nonoral hormone therapy; only 4 studies evaluated vaginal estrogen use. 

Two large cohort studies included in the systematic review provided more specific data on vaginal estrogens. The first used data from the Women’s Health Initiative in a subset of women ages 50 to 79 years (n = 46,566) who were not already on systemic hormone therapy and who did not have prior history of breast, endometrial, or ovarian cancer.² Data were collected from self-assessment questionnaires and medical record reviews. The median duration of vaginal estrogen use was 2 years, and median follow-up duration was 7.2 years. Vaginal estrogen users had a 48% lower risk for CHD (adjusted hazard ratio [aHR] = 0.52; 95% CI, 0.31-0.85) than nonusers. Rates for all-cause mortality (aHR = 0.78; 95% CI, 0.58-1.04), stroke (aHR = 0.78; 95% CI, 0.49-1.24), and DVT/PE (aHR = 0.68; 95% CI, 0.36-1.28) were similar. In this and the other cohort studies to be discussed, outcome data for all vaginal estrogen preparations (eg, cream, ring, tablet) were combined. 

The other large cohort study in the systematic review evaluated data on postmenopausal women from the Nurses’ Health Study.³ The authors evaluated health reports on 53,797 women as they transitioned through menopause. Patients with systemic hormone therapy use, history of cancer, and self-reported CV disease were excluded. After adjusting for covariates, the authors found no statistically significant difference between users and nonusers of vaginal estrogen and risk for total MI (aHR = 0.73; 95% CI, 0.47-1.13), stroke (aHR = 0.85; 95% CI, 0.56-1.29), or DVT/PE (aHR = 1.06; 95% CI, 0.58-1.93). Study limitations included low prevalence of vaginal estrogen use (< 3%), short duration of use (mean, 37.5 months), and lack of data on the type or dose of vaginal estrogen used. The study only included health professionals, which limits generalizability. 

A Finnish cohort study (excluded from the systematic review because it used historical controls) compared rates of CHD and stroke in postmenopausal women who used vaginal estrogen against an age-matched background population. Researchers collected­ data from a nationwide prescription registry for women at least 50 years old who had purchased vaginal estrogens between 1994 and 2009 (n = 195,756).⁴ Women who purchased systemic hormone therapy at any point were excluded. After 3 to 5 years of exposure, use of vaginal estrogen was associated with a decreased risk for mortality from CHD (relative risk [RR] = 0.64; 95% CI, 0.57-0.70) and stroke (RR = 0.79; 95% CI, 0.69-0.91). However, after 10 years, these benefits were not seen (CHD: RR = 0.95; 95% CI, 0.90-1.00; stroke: RR = 0.93; 95% CI, 0.85-1.01). All confidence interval data were presented graphically. Key weaknesses of this study included use of both vaginal and systemic estrogen in the comparator background population, and the failure to collect data for other CV risk variables such as weight, tobacco exposure, and blood pressure.

Recommendations from others

In 2022, the North American Menopause Society issued a Hormone Therapy Position Statement that acknowledged the lack of clinical trials directly comparing risk for adverse CV endpoints with different estrogen administration routes.⁵ They stated nonoral routes of administration might offer advantages by bypassing first-pass hepatic metabolism.

Similarly, the 2015 Endocrine Society Clinical Practice Guideline on the Treatment of Symptoms of the Menopause also stated that the effects of low-dose vaginal estrogen therapy on CV disease or DVT/PE risk had not been adequately studied.⁶

A 2013 opinion by the American College of Obstetricians and Gynecologists stated that topical estrogen vaginal creams, tablets, and rings had low levels of systemic absorption and were not associated with an increased risk for DVT/PE.⁷ 

Editor’s takeaway

The available evidence on vaginal estrogen ­replacement reassures us of its safety. After decades spent studying hormone replacement therapy with vacillating conclusions and opinions, these cohorts—the best evidence we may ever get—along with a consensus of expert opinions, consistently demonstrate no adverse CV outcomes.

Managing first-time seizures and epilepsy often requires consultation with a neurologist or epileptologist for diagnosis and subsequent management, including when medical treatment fails or in determining whether patients may benefit from surgery. However, given the high prevalence of epilepsy and even higher incidence of a single seizure, family physicians contribute significantly to the management of these patients. The main issues are managing a first-time seizure, making the diagnosis, establishing a treatment plan, and exploring triggers and mitigating factors.

Seizure vs epilepsy

All patients with epilepsy experience seizures, but not every person who experiences a seizure has (or will develop) epilepsy. Nearly 10% of the population has one seizure during their lifetime,whereas the risk for epilepsy is just 3%.¹ Therefore, a first-time seizure may not herald epilepsy, defined as repetitive (≥ 2) unprovoked seizures more than 24 hours apart.² Seizures can be provoked (acute symptomatic) or unprovoked; a clear distinction between these 2 occurrences—as well as between single and recurrent seizures—is critical for proper management. A close look at the circumstances of a first-time seizure is imperative to define the nature of the event and the possibility of further seizures before devising a treatment plan.

Provoked seizures are due to an acute brain insult such as toxic-metabolic disorders, concussion, alcohol withdrawal, an adverse effect of a medication or its withdrawal, or photic stimulation presumably by disrupting the brain’s metabolic homeostasis or integrity. The key factor is that provoked seizures always happen in close temporal association with an acute insult. A single provoked seizure happens each year in 29 to 39 individuals per 100,000.³ While these seizures typically occur singly, there is a small risk they may recur if the triggering insult persists or repeats.¹ Therefore, more than 1 seizure per se may not indicate epilepsy.³

Unprovoked seizures reflect an underlying brain dysfunction. A single unprovoked seizure happens in 23 to 61 individuals per 100,000 per year, often in men in either younger or older age groups.³ Unprovoked seizures may occur only once or may recur (ie, evolve into epilepsy). The latter scenario happens in only about half of cases; the overall risk for a recurrent seizure within 2 years of a first seizure is estimated at 42% (24% to 65%, depending on the etiology and electroencephalogram [EEG] findings).⁴ More specifically, without treatment the relapse rate will be 36% at 1 year and 47% at 2 years.⁴ Further, a second unprovoked seizure, if untreated, would increase the risk for third and fourth seizures to 73% and 76%, respectively, within 4 years.³

Evaluating the first-time seizure

Ask the patient or observers about the circumstances of the event to differentiate provoked from unprovoked onset. For one thing, not all “spells” are seizures. The differential diagnoses may include syncope, psychogenic nonepileptic events, drug intoxication or withdrawal, migraine, panic attacks, sleep disorders (parasomnia), transient global amnesia, concussion, and transient ischemic attack. EEG, neuroimaging, and other relevant diagnostic tests often are needed (eg, electrocardiogram/echocardiogram/Holter monitoring to evaluate for syncope/cardiac arrhythmia). Clinically, syncopal episodes tend to be brief with rapid recovery and no confusion, speech problems, aura, or lateralizing signs such as hand posturing or lip smacking that are typical with focal seizures. However, cases of convulsive syncope can be challenging to assess without diagnostic tests.

Many patients have experienced prior undiagnosed seizures. Subtle prior events include episodes of deja vu, transient feelings of fear, unusual smells, and speech difficulties.

True convulsive seizures do not have the variability in clinical signs seen with psychogenic nonepileptic events (eg, alternating body parts involved or direction of movements). Transient global amnesia is a rare condition with no established diagnostic test and is considered a diagnosis of exclusion, although bitemporal hyperintensities on magnetic resonance imaging (MRI) may appear 12 to 48 hours after the clinical episode.⁵ Blood work is needed in patients with medical issues treated with multiple medications to evaluate for metabolic derangements; otherwise, routine blood work provides minimal information in stable patients.

Region-specific causes. Neurocysticercosis is common in some regions, such as Latin America; therefore, attention should be paid to this aspect of patient history.

Continue to: Is it really a first-time seizure?

Is it really a first-time seizure? A “first,” usually dramatic, generalized tonic-clonic seizure that triggers the diagnostic work-up may not be the very first seizure. Evidence suggests that many patients have experienced prior undiagnosed seizures. Subtle prior events often missed include episodes of deja vu, transient feelings of fear or unusual smells, speech difficulties, staring spells, or myoclonic jerks.¹ A routine EEG to record epileptiform discharges and a high-resolution brain MRI to rule out any intracranial pathology are indicated. However, if the EEG indicates a primary generalized (as opposed to focal-onset) epilepsy, a brain MRI may not be needed. If a routine EEG is unrevealing, long-term video-EEG monitoring may be needed to detect an abnormality.

Accuracy of EEG and MRI. Following a first unprovoked seizure, routine EEG to detect epileptiform discharges in adults has yielded a sensitivity of 17.3% and specificity of 94.7%. In evaluating children, these values are 57.8% and 69.6%, respectively.⁶ If results are equivocal, a 24-hour EEG can increase the likelihood of detecting epileptiform discharges to 89% of patients.⁷ Brain MRI may detect an abnormality in 12% to 14% of patients with newly diagnosed epilepsy, and in up to 80% of those with recurrent seizures.⁸ In confirming hippocampus sclerosis, MRI has demonstrated a sensitivity of 93% and specificity of 86%.⁹

When to treat a first-time seizure. Available data and prediction models identify risk factors that would help determine whether to start an antiseizure medication after a first unprovoked seizure: abnormal EEG with particular epileptiform activity, abnormal neurologic exam, abnormal computerized tomography or MRI results, nocturnal seizure, focal seizure, or family history of seizures. In the absence of such risk factors, chances of further unprovoked seizures are not high enough to justify treatment with antiseizure medications. However, if a second unprovoked seizure were to occur, that would meet the definition of epilepsy, and treatment is indicated due to the high risk for further seizures.^10,11

Epilepsy diagnosis

The International League Against Epilepsy (ILAE) previously defined epilepsy as 2 unprovoked seizures more than 24 hours apart. However, a more recent ILAE task force modified this definition: even a single unprovoked seizure would be enough to diagnose epilepsy if there is high probability of further seizures—eg, in the presence of definitive epileptiform discharges on EEG or presence of a brain tumor or a remote brain insult on imaging, since such conditions induce an enduring predisposition to generate epileptic seizures. ² Also, a single unprovoked seizure is enough to diagnose epilepsy if it is part of an epileptic syndrome such as juvenile myoclonic epilepsy. Further, a time limit was added to the definition—ie, epilepsy is considered resolved if a patient remains seizure free for 10 years without use of antiseizure medications during the past 5 years. However, given the multitude of variables and evidence, the task force acknowledged the need for individualized considerations. ²

Seizure classification

Classification of seizure type is based on the site of seizure onset and its spread pattern—ie, focal, generalized, or unknown onset.

Continue to: Focal-onset seizures

Focal-onset seizures originate “within networks limited to one hemisphere,” although possibly in more than 1 region (ie, multifocal, and presence or absence of loss of awareness). ¹² Focal seizures may then be further classified into “motor onset” or “nonmotor onset” (eg, autonomic, emotional, sensory). ²

Generalized seizures are those “originating at some point within, and rapidly engaging, bilaterally distributed networks.” ¹³ Unlike focal-onset seizures, generalized seizures are not classified based on awareness, as most generalized seizures involve loss of awareness (absence) or total loss of consciousness (generalized tonic-clonic). They are instead categorized based on the presence of motor vs nonmotor features (eg, tonic-clonic, myoclonic, atonic). Epilepsy classification is quite dynamic and constantly updated based on new genetic, electroencephalographic, and neuroimaging discoveries.

Treatment of epilepsy

Antiseizure medications

Treatment with antiseizure medications (ASMs; formerly known as antiepileptic drugs ) is the mainstay of epilepsy management. Achieving efficacy (seizure freedom) and tolerability (minimal adverse effects) are the primary goals of treatment. Factors that should govern the selection of an ASM include the seizure type/epilepsy syndrome, adverse effect profile of the ASM, pharmacodynamic/pharmacokinetic considerations, and patient comorbidities.

Levetiracetam and valproate (not to be used in women of childbearing potential) are considered appropriate first-line agents for generalized and unclassified epilepsies.

The Standard and New Antiepileptic Drugs (SANAD I and II) trials provide data from direct, unblinded, and longitudinal comparisons of existing and new ASMs and their utility in different seizure types. In the SANAD I cohort of patients with generalized and unclassified epilepsies, valproate was superior to lamotrigine and topiramate for 12-month remission and treatment failure rates, respectively.¹⁴ However, valproate generally is avoided in women of childbearing age due its potential adverse effects during pregnancy. In focal epilepsies, lamotrigine was superior to carbamazepine, gabapentin, and topiramate with respect to treatment failure, and noninferior to carbamazepine for 12-month remission.¹⁵ In the SANAD II trial, levetiracetam was noninferior to valproate for incidence of adverse events in patients with generalized and unclassified epilepsies although was found to be neither more clinically effective nor more cost effective.¹⁶ For patients of childbearing potential with generalized and unclassified epilepsies, there is evidence to support the safe and effective use of levetiracetam.¹⁷In focal epilepsies, lamotrigine was superior to levetiracetam and zonisamide with respect to treatment failures and adverse events and was noninferior to zonisamide for 12-month remission.¹⁸ In summary, levetiracetam and valproate (not to be used in women of childbearing potential) are considered appropriate first-line agents for generalized and unclassified epilepsies while lamotrigine is deemed an appropriate first-line agent for focal epilepsies (TABLE 1^19-28).

Drug level monitoring. It is standard practice to periodically monitor serum levels in patients taking first-generation ASMs such as phenytoin, carbamazepine, phenobarbital, and valproic acid because of their narrow therapeutic range and the potential for overdose or interaction with other medications or foods (eg, grapefruit juice may increase carbamazepine serum level by inhibiting ­CYP3A4, the enzyme that metabolizes the drug). Patients taking newer ASMs may not require regular serum level monitoring except during titration, with hepatic or renal dosing, when concomitantly used with estrogen-based oral contraceptives (eg, lamotrigine), before or during pregnancy, or when nonadherence is suspected.

Continue to: Can antiseizure treatment be stopped?

Can antiseizure treatment be stopped?

Current evidence favors continuing ASM therapy in patients whose seizures are under control, although the decision should be tailored to an individual’s circumstances. According to the 2021 American Academy of Neurology (AAN) guidelines, adults who have been seizure free for at least 2 years and discontinue ASMs are possibly still at higher risk for seizure recurrence in the long term (24-60 months), compared with those who continue treatment.²⁹ On the other hand, for adults who have been seizure free for at least 12 months, ASM withdrawal may not increase their risk for status epilepticus, and there are insufficient data to support or refute an effect on mortality or quality of life with ASM withdrawal in this population. The decision to taper or maintain ASM therapy in seizure-free patients also should take into consideration other clinically relevant outcome measures such as the patient’s lifestyle and medication adverse effects. Therefore, this decision should be made after sufficient discussion with patients and their caregivers. (Information for patients can be found at: www.epilepsy.com/treatment/medicines/stopping-medication.)

There are no reliable methods for predicting seizure other than knowing of the several potential risks and recognizing and avoiding these triggers.

For children, the AAN guideline panel recommends discussing with family the small risk (2%) for becoming medication resistant if seizures recur during or after ASM withdrawal. ²⁹ For children who have been seizure free for 18 to 24 months, there is probably not a significant long-term (24-48 months) difference in seizure recurrence in those who taper ASMs vs those who do not. However, presence of epileptiform discharges on EEG before discontinuation of an ASM indicates increased risk for seizure recurrence. ²⁹

Intractable (refractory) epilepsy

While most patients with epilepsy attain complete seizure control with appropriate drug therapy, approximately 30% continue to experience seizures (“drug-resistant” epilepsy, also termed intractable or refractory ). ³⁰ In 2010, the ILAE defined drug-resistant epilepsy as “failure of adequate trials of two tolerated, appropriately chosen and used anti-epileptic drug schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom” (defined as cessation of seizures for at least 3 times the longest pre-intervention inter-seizure interval or 12 months, whichever is longer). ^21,31 It should be noted that drug withdrawal due to adverse effects is not counted as failure of that ASM. Recognition of drug-resistant epilepsy may prompt referral to an epileptologist who can consider rational combination drug therapy or surgical resection of the seizure focus, vagus nerve stimulation, electrical stimulation of the seizure focus, or deep brain (thalamic) stimulation.

Seizure triggers and mitigating factors

Epilepsy mostly affects patients during seizure episodes; however, the unpredictability of these events adds significantly to the burden of disease. There are no reliable methods for predicting seizure other than knowing of the several potential risks and recognizing and avoiding these triggers.

Noncompliance with antiseizure medications is a common seizure trigger affecting up to one-half of patients with epilepsy.³²

Continue to: Medications

Medications may provoke seizures in susceptible individuals (TABLE 2^33-35).

Sleep deprivation is a potential seizure trigger in people with epilepsy based on observational studies, case reports, patient surveys, and EEG-based studies, although data from randomized controlled studies are limited.³⁶ The standard best practice is to encourage appropriate sleep hygiene, which involves getting at least 7 hours of sleep per night.³⁷

Alcohol is a GABAergic substance like benzodiazepines with antiseizure effects. However, it acts as a potential precipitant of seizures in cases of withdrawal or acute intoxication, or when it leads to sleep disruption or nonadherence to antiseizure medications. Therefore, advise patients with alcohol use disorder to slowly taper consumption (best done through a support program) and avoid sudden withdrawal. However, complete abstinence from alcohol use is not often recommended except in special circumstances (eg, a history of alcohol-related seizures). Several studies have demonstrated that modest alcohol use (1-2 drinks per occasion) does not increase seizure frequency or significantly alter serum concentrations of commonly used ASMs.³⁸

Cannabis and other substances. The 2 main biologically active components of marijuana are delta-9-tetrahydrocannibinol (THC), the main psychoactive constituent, and cannabidiol (CBD). Animal and human studies have demonstrated anticonvulsant properties of THC and CBD. But THC, in high amounts, can result in adverse cognitive effects and worsening seizures.³⁹ A purified 98% oil-based CBD extract (Epidiolex) has been approved as an adjunctive treatment for certain medically refractory epilepsy syndromes in children and young adults—ie, Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex syndrome.⁴⁰ There are no reliable data on the effect of recreational use of marijuana on seizure control. Other illicit substances such as cocaine may lower seizure threshold by their stimulatory and disruptive effects on sleep, diet, and healthy routines.

Special clinical cases

Pregnancy and epilepsy

Despite the potential adverse effects of ASMs on fetal health, the current global consensus is to continue treatment during pregnancy, given that the potential harm of convulsive seizures outweighs the potential risks associated with in-utero exposure to ASMs. There is not enough evidence to indicate significant harm to the fetus caused by focal, absence, or myoclonic seizures. Low-dose folic acid is used to minimize the risks of ASMs during pregnancy.

Continue to: As the fetus develops...

Illicit substances such as cocaine may lower seizure threshold by their stimulatory and disruptive effects on sleep, diet, and healthy routines.

As the fetus develops, there are changes in volume of ASM distribution, renal clearance, protein binding, and hepatic metabolism, which require checking serum levels at regular intervals and making dosage adjustments.

The ongoing study evaluating Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD)⁴¹ has led to multiple landmark studies guiding the choice of preferred ASMs during pregnancy in patients with epilepsy.^42,43 This has culminated in today’s use of lamotrigine and levetiracetam as the 2 preferred agents (while avoiding valproate) in pregnant patients with epilepsy.⁴⁴

Psychogenic nonepileptic seizures

Having epilepsy should not preclude patients from seeking employment and pursuing meaningful careers.

A form of conversion disorder, psychogenic nonepileptic seizures (PNES) manifests as abnormal motor or behavioral events mimicking seizures but without associated epileptiform discharges on EEG. This is observed in 10% of patients seen in epilepsy clinics and even more often in those admitted to epilepsy­ monitoring units (25%-40%).⁴⁵ Diagnosis of PNES requires EEG monitoring both for confirmation and for discernment from true epileptic seizures, in particular frontal lobe epilepsy that may clinically mimic PNES. PNES often is associated with underlying psychological tensions or comorbid conditions such as depression, anxiety, or traumatic life experiences. There is no treatment for PNES per se, and its management is focused on controlling any underlying psychological comorbidities that may not always be obvious. There is some evidence suggesting that these patients experience an innate inability to verbally express their emotions and instead subconsciously resort to psychosomatics to express them in a somatic dimension.^46,47

Status epilepticus

Defined as prolonged seizures (> 5 min) or 2 consecutive seizures without regaining aware ness in between, status epilepticus (SE) is a potentially fatal condition. Subclinical nonconvulsive SE, especially in comatose patients, can be diagnosed only via EEG monitoring. Untreated SE may manifest as a diagnostic dilemma in unresponsive or critically ill patients and can increase the risk for mortality. ⁴⁸

Febrile seizures

Febrile seizures affect 2% to 5% of children most often in the second year of life.⁴⁹ The use of preventive antiseizure medication is not recommended; instead, the key is to investigate the underlying febrile illness. Lumbar puncture is indicated if there are signs and symptoms of meningitis (25% of children with bacterial meningitis present with seizures).⁴⁹ Febrile seizures often are self-limited, but there is risk for SE in up to 15% of cases.⁵⁰ If convulsive febrile seizures last longer than 5 minutes, initiate benzodiazepines followed by the standard protocol used for the management of SE.⁵¹

Continue to: Epilepsy as a spectrum disorder

The higher prevalence of comorbid cognitive and psychiatric conditions in patients with epilepsy, affecting about half of patients, ⁵² suggests that seizures may constitute only one aspect of a multifaceted disease that otherwise should be considered a spectrum disorder. Among such conditions are memory deficits, depression, and anxiety. Conversely, epilepsy is more common in patients with depression than in those without. ⁵²

Social impact of epilepsy

De-escalation of treatment offers an equivalent, resource-sparing alternative to traditional treatment of pediatric torus fractures of the distal radius.

Vehicle driving regulations. Patients with epilepsy are required to follow state law regarding driving restrictions. Different states have different rules and regulations about driving restrictions and reporting requirements (by patients or their physicians). Refer patients to the Department of Motor Vehicles (DMV) in their state of residence for up-to-date instructions.⁵³ The Epilepsy Foundation (epilepsy.com) can serve as a resource for each state’s DMV website.

Employment assistance. Having epilepsy should not preclude patients from seeking employment and pursuing meaningful careers. The Americans with Disabilities Act (ADA) and the US Equal Employment Opportunity Commission (EEOC) forbid discrimination against qualified people with disabilities, including those with epilepsy, and require reasonable accommodations in the workplace (www.eeoc.gov/laws/guidance/­epilepsy-workplace-and-ada).⁵⁴

CORRESPONDENCE
Gholam K. Motamedi, MD, Department of Neurology, PHC 7, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC 20007; [email protected]

Managing first-time seizures and epilepsy often requires consultation with a neurologist or epileptologist for diagnosis and subsequent management, including when medical treatment fails or in determining whether patients may benefit from surgery. However, given the high prevalence of epilepsy and even higher incidence of a single seizure, family physicians contribute significantly to the management of these patients. The main issues are managing a first-time seizure, making the diagnosis, establishing a treatment plan, and exploring triggers and mitigating factors.

Seizure vs epilepsy

All patients with epilepsy experience seizures, but not every person who experiences a seizure has (or will develop) epilepsy. Nearly 10% of the population has one seizure during their lifetime,whereas the risk for epilepsy is just 3%.¹ Therefore, a first-time seizure may not herald epilepsy, defined as repetitive (≥ 2) unprovoked seizures more than 24 hours apart.² Seizures can be provoked (acute symptomatic) or unprovoked; a clear distinction between these 2 occurrences—as well as between single and recurrent seizures—is critical for proper management. A close look at the circumstances of a first-time seizure is imperative to define the nature of the event and the possibility of further seizures before devising a treatment plan.

Provoked seizures are due to an acute brain insult such as toxic-metabolic disorders, concussion, alcohol withdrawal, an adverse effect of a medication or its withdrawal, or photic stimulation presumably by disrupting the brain’s metabolic homeostasis or integrity. The key factor is that provoked seizures always happen in close temporal association with an acute insult. A single provoked seizure happens each year in 29 to 39 individuals per 100,000.³ While these seizures typically occur singly, there is a small risk they may recur if the triggering insult persists or repeats.¹ Therefore, more than 1 seizure per se may not indicate epilepsy.³

Unprovoked seizures reflect an underlying brain dysfunction. A single unprovoked seizure happens in 23 to 61 individuals per 100,000 per year, often in men in either younger or older age groups.³ Unprovoked seizures may occur only once or may recur (ie, evolve into epilepsy). The latter scenario happens in only about half of cases; the overall risk for a recurrent seizure within 2 years of a first seizure is estimated at 42% (24% to 65%, depending on the etiology and electroencephalogram [EEG] findings).⁴ More specifically, without treatment the relapse rate will be 36% at 1 year and 47% at 2 years.⁴ Further, a second unprovoked seizure, if untreated, would increase the risk for third and fourth seizures to 73% and 76%, respectively, within 4 years.³

Evaluating the first-time seizure

Ask the patient or observers about the circumstances of the event to differentiate provoked from unprovoked onset. For one thing, not all “spells” are seizures. The differential diagnoses may include syncope, psychogenic nonepileptic events, drug intoxication or withdrawal, migraine, panic attacks, sleep disorders (parasomnia), transient global amnesia, concussion, and transient ischemic attack. EEG, neuroimaging, and other relevant diagnostic tests often are needed (eg, electrocardiogram/echocardiogram/Holter monitoring to evaluate for syncope/cardiac arrhythmia). Clinically, syncopal episodes tend to be brief with rapid recovery and no confusion, speech problems, aura, or lateralizing signs such as hand posturing or lip smacking that are typical with focal seizures. However, cases of convulsive syncope can be challenging to assess without diagnostic tests.

Many patients have experienced prior undiagnosed seizures. Subtle prior events include episodes of deja vu, transient feelings of fear, unusual smells, and speech difficulties.

True convulsive seizures do not have the variability in clinical signs seen with psychogenic nonepileptic events (eg, alternating body parts involved or direction of movements). Transient global amnesia is a rare condition with no established diagnostic test and is considered a diagnosis of exclusion, although bitemporal hyperintensities on magnetic resonance imaging (MRI) may appear 12 to 48 hours after the clinical episode.⁵ Blood work is needed in patients with medical issues treated with multiple medications to evaluate for metabolic derangements; otherwise, routine blood work provides minimal information in stable patients.

Region-specific causes. Neurocysticercosis is common in some regions, such as Latin America; therefore, attention should be paid to this aspect of patient history.

Continue to: Is it really a first-time seizure?

Is it really a first-time seizure? A “first,” usually dramatic, generalized tonic-clonic seizure that triggers the diagnostic work-up may not be the very first seizure. Evidence suggests that many patients have experienced prior undiagnosed seizures. Subtle prior events often missed include episodes of deja vu, transient feelings of fear or unusual smells, speech difficulties, staring spells, or myoclonic jerks.¹ A routine EEG to record epileptiform discharges and a high-resolution brain MRI to rule out any intracranial pathology are indicated. However, if the EEG indicates a primary generalized (as opposed to focal-onset) epilepsy, a brain MRI may not be needed. If a routine EEG is unrevealing, long-term video-EEG monitoring may be needed to detect an abnormality.

Accuracy of EEG and MRI. Following a first unprovoked seizure, routine EEG to detect epileptiform discharges in adults has yielded a sensitivity of 17.3% and specificity of 94.7%. In evaluating children, these values are 57.8% and 69.6%, respectively.⁶ If results are equivocal, a 24-hour EEG can increase the likelihood of detecting epileptiform discharges to 89% of patients.⁷ Brain MRI may detect an abnormality in 12% to 14% of patients with newly diagnosed epilepsy, and in up to 80% of those with recurrent seizures.⁸ In confirming hippocampus sclerosis, MRI has demonstrated a sensitivity of 93% and specificity of 86%.⁹

When to treat a first-time seizure. Available data and prediction models identify risk factors that would help determine whether to start an antiseizure medication after a first unprovoked seizure: abnormal EEG with particular epileptiform activity, abnormal neurologic exam, abnormal computerized tomography or MRI results, nocturnal seizure, focal seizure, or family history of seizures. In the absence of such risk factors, chances of further unprovoked seizures are not high enough to justify treatment with antiseizure medications. However, if a second unprovoked seizure were to occur, that would meet the definition of epilepsy, and treatment is indicated due to the high risk for further seizures.^10,11

Epilepsy diagnosis

The International League Against Epilepsy (ILAE) previously defined epilepsy as 2 unprovoked seizures more than 24 hours apart. However, a more recent ILAE task force modified this definition: even a single unprovoked seizure would be enough to diagnose epilepsy if there is high probability of further seizures—eg, in the presence of definitive epileptiform discharges on EEG or presence of a brain tumor or a remote brain insult on imaging, since such conditions induce an enduring predisposition to generate epileptic seizures. ² Also, a single unprovoked seizure is enough to diagnose epilepsy if it is part of an epileptic syndrome such as juvenile myoclonic epilepsy. Further, a time limit was added to the definition—ie, epilepsy is considered resolved if a patient remains seizure free for 10 years without use of antiseizure medications during the past 5 years. However, given the multitude of variables and evidence, the task force acknowledged the need for individualized considerations. ²

Seizure classification

Classification of seizure type is based on the site of seizure onset and its spread pattern—ie, focal, generalized, or unknown onset.

Continue to: Focal-onset seizures

Focal-onset seizures originate “within networks limited to one hemisphere,” although possibly in more than 1 region (ie, multifocal, and presence or absence of loss of awareness). ¹² Focal seizures may then be further classified into “motor onset” or “nonmotor onset” (eg, autonomic, emotional, sensory). ²

Generalized seizures are those “originating at some point within, and rapidly engaging, bilaterally distributed networks.” ¹³ Unlike focal-onset seizures, generalized seizures are not classified based on awareness, as most generalized seizures involve loss of awareness (absence) or total loss of consciousness (generalized tonic-clonic). They are instead categorized based on the presence of motor vs nonmotor features (eg, tonic-clonic, myoclonic, atonic). Epilepsy classification is quite dynamic and constantly updated based on new genetic, electroencephalographic, and neuroimaging discoveries.

Treatment of epilepsy

Antiseizure medications

Treatment with antiseizure medications (ASMs; formerly known as antiepileptic drugs ) is the mainstay of epilepsy management. Achieving efficacy (seizure freedom) and tolerability (minimal adverse effects) are the primary goals of treatment. Factors that should govern the selection of an ASM include the seizure type/epilepsy syndrome, adverse effect profile of the ASM, pharmacodynamic/pharmacokinetic considerations, and patient comorbidities.

Levetiracetam and valproate (not to be used in women of childbearing potential) are considered appropriate first-line agents for generalized and unclassified epilepsies.

The Standard and New Antiepileptic Drugs (SANAD I and II) trials provide data from direct, unblinded, and longitudinal comparisons of existing and new ASMs and their utility in different seizure types. In the SANAD I cohort of patients with generalized and unclassified epilepsies, valproate was superior to lamotrigine and topiramate for 12-month remission and treatment failure rates, respectively.¹⁴ However, valproate generally is avoided in women of childbearing age due its potential adverse effects during pregnancy. In focal epilepsies, lamotrigine was superior to carbamazepine, gabapentin, and topiramate with respect to treatment failure, and noninferior to carbamazepine for 12-month remission.¹⁵ In the SANAD II trial, levetiracetam was noninferior to valproate for incidence of adverse events in patients with generalized and unclassified epilepsies although was found to be neither more clinically effective nor more cost effective.¹⁶ For patients of childbearing potential with generalized and unclassified epilepsies, there is evidence to support the safe and effective use of levetiracetam.¹⁷In focal epilepsies, lamotrigine was superior to levetiracetam and zonisamide with respect to treatment failures and adverse events and was noninferior to zonisamide for 12-month remission.¹⁸ In summary, levetiracetam and valproate (not to be used in women of childbearing potential) are considered appropriate first-line agents for generalized and unclassified epilepsies while lamotrigine is deemed an appropriate first-line agent for focal epilepsies (TABLE 1^19-28).

Drug level monitoring. It is standard practice to periodically monitor serum levels in patients taking first-generation ASMs such as phenytoin, carbamazepine, phenobarbital, and valproic acid because of their narrow therapeutic range and the potential for overdose or interaction with other medications or foods (eg, grapefruit juice may increase carbamazepine serum level by inhibiting ­CYP3A4, the enzyme that metabolizes the drug). Patients taking newer ASMs may not require regular serum level monitoring except during titration, with hepatic or renal dosing, when concomitantly used with estrogen-based oral contraceptives (eg, lamotrigine), before or during pregnancy, or when nonadherence is suspected.

Continue to: Can antiseizure treatment be stopped?

Can antiseizure treatment be stopped?

Current evidence favors continuing ASM therapy in patients whose seizures are under control, although the decision should be tailored to an individual’s circumstances. According to the 2021 American Academy of Neurology (AAN) guidelines, adults who have been seizure free for at least 2 years and discontinue ASMs are possibly still at higher risk for seizure recurrence in the long term (24-60 months), compared with those who continue treatment.²⁹ On the other hand, for adults who have been seizure free for at least 12 months, ASM withdrawal may not increase their risk for status epilepticus, and there are insufficient data to support or refute an effect on mortality or quality of life with ASM withdrawal in this population. The decision to taper or maintain ASM therapy in seizure-free patients also should take into consideration other clinically relevant outcome measures such as the patient’s lifestyle and medication adverse effects. Therefore, this decision should be made after sufficient discussion with patients and their caregivers. (Information for patients can be found at: www.epilepsy.com/treatment/medicines/stopping-medication.)

There are no reliable methods for predicting seizure other than knowing of the several potential risks and recognizing and avoiding these triggers.

For children, the AAN guideline panel recommends discussing with family the small risk (2%) for becoming medication resistant if seizures recur during or after ASM withdrawal. ²⁹ For children who have been seizure free for 18 to 24 months, there is probably not a significant long-term (24-48 months) difference in seizure recurrence in those who taper ASMs vs those who do not. However, presence of epileptiform discharges on EEG before discontinuation of an ASM indicates increased risk for seizure recurrence. ²⁹

Intractable (refractory) epilepsy

While most patients with epilepsy attain complete seizure control with appropriate drug therapy, approximately 30% continue to experience seizures (“drug-resistant” epilepsy, also termed intractable or refractory ). ³⁰ In 2010, the ILAE defined drug-resistant epilepsy as “failure of adequate trials of two tolerated, appropriately chosen and used anti-epileptic drug schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom” (defined as cessation of seizures for at least 3 times the longest pre-intervention inter-seizure interval or 12 months, whichever is longer). ^21,31 It should be noted that drug withdrawal due to adverse effects is not counted as failure of that ASM. Recognition of drug-resistant epilepsy may prompt referral to an epileptologist who can consider rational combination drug therapy or surgical resection of the seizure focus, vagus nerve stimulation, electrical stimulation of the seizure focus, or deep brain (thalamic) stimulation.

Seizure triggers and mitigating factors

Epilepsy mostly affects patients during seizure episodes; however, the unpredictability of these events adds significantly to the burden of disease. There are no reliable methods for predicting seizure other than knowing of the several potential risks and recognizing and avoiding these triggers.

Noncompliance with antiseizure medications is a common seizure trigger affecting up to one-half of patients with epilepsy.³²

Continue to: Medications

Medications may provoke seizures in susceptible individuals (TABLE 2^33-35).

Sleep deprivation is a potential seizure trigger in people with epilepsy based on observational studies, case reports, patient surveys, and EEG-based studies, although data from randomized controlled studies are limited.³⁶ The standard best practice is to encourage appropriate sleep hygiene, which involves getting at least 7 hours of sleep per night.³⁷

Alcohol is a GABAergic substance like benzodiazepines with antiseizure effects. However, it acts as a potential precipitant of seizures in cases of withdrawal or acute intoxication, or when it leads to sleep disruption or nonadherence to antiseizure medications. Therefore, advise patients with alcohol use disorder to slowly taper consumption (best done through a support program) and avoid sudden withdrawal. However, complete abstinence from alcohol use is not often recommended except in special circumstances (eg, a history of alcohol-related seizures). Several studies have demonstrated that modest alcohol use (1-2 drinks per occasion) does not increase seizure frequency or significantly alter serum concentrations of commonly used ASMs.³⁸

Cannabis and other substances. The 2 main biologically active components of marijuana are delta-9-tetrahydrocannibinol (THC), the main psychoactive constituent, and cannabidiol (CBD). Animal and human studies have demonstrated anticonvulsant properties of THC and CBD. But THC, in high amounts, can result in adverse cognitive effects and worsening seizures.³⁹ A purified 98% oil-based CBD extract (Epidiolex) has been approved as an adjunctive treatment for certain medically refractory epilepsy syndromes in children and young adults—ie, Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex syndrome.⁴⁰ There are no reliable data on the effect of recreational use of marijuana on seizure control. Other illicit substances such as cocaine may lower seizure threshold by their stimulatory and disruptive effects on sleep, diet, and healthy routines.

Special clinical cases

Pregnancy and epilepsy

Despite the potential adverse effects of ASMs on fetal health, the current global consensus is to continue treatment during pregnancy, given that the potential harm of convulsive seizures outweighs the potential risks associated with in-utero exposure to ASMs. There is not enough evidence to indicate significant harm to the fetus caused by focal, absence, or myoclonic seizures. Low-dose folic acid is used to minimize the risks of ASMs during pregnancy.

Continue to: As the fetus develops...

Illicit substances such as cocaine may lower seizure threshold by their stimulatory and disruptive effects on sleep, diet, and healthy routines.

As the fetus develops, there are changes in volume of ASM distribution, renal clearance, protein binding, and hepatic metabolism, which require checking serum levels at regular intervals and making dosage adjustments.

The ongoing study evaluating Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD)⁴¹ has led to multiple landmark studies guiding the choice of preferred ASMs during pregnancy in patients with epilepsy.^42,43 This has culminated in today’s use of lamotrigine and levetiracetam as the 2 preferred agents (while avoiding valproate) in pregnant patients with epilepsy.⁴⁴

Psychogenic nonepileptic seizures

Having epilepsy should not preclude patients from seeking employment and pursuing meaningful careers.

A form of conversion disorder, psychogenic nonepileptic seizures (PNES) manifests as abnormal motor or behavioral events mimicking seizures but without associated epileptiform discharges on EEG. This is observed in 10% of patients seen in epilepsy clinics and even more often in those admitted to epilepsy­ monitoring units (25%-40%).⁴⁵ Diagnosis of PNES requires EEG monitoring both for confirmation and for discernment from true epileptic seizures, in particular frontal lobe epilepsy that may clinically mimic PNES. PNES often is associated with underlying psychological tensions or comorbid conditions such as depression, anxiety, or traumatic life experiences. There is no treatment for PNES per se, and its management is focused on controlling any underlying psychological comorbidities that may not always be obvious. There is some evidence suggesting that these patients experience an innate inability to verbally express their emotions and instead subconsciously resort to psychosomatics to express them in a somatic dimension.^46,47

Status epilepticus

Defined as prolonged seizures (> 5 min) or 2 consecutive seizures without regaining aware ness in between, status epilepticus (SE) is a potentially fatal condition. Subclinical nonconvulsive SE, especially in comatose patients, can be diagnosed only via EEG monitoring. Untreated SE may manifest as a diagnostic dilemma in unresponsive or critically ill patients and can increase the risk for mortality. ⁴⁸

Febrile seizures

Febrile seizures affect 2% to 5% of children most often in the second year of life.⁴⁹ The use of preventive antiseizure medication is not recommended; instead, the key is to investigate the underlying febrile illness. Lumbar puncture is indicated if there are signs and symptoms of meningitis (25% of children with bacterial meningitis present with seizures).⁴⁹ Febrile seizures often are self-limited, but there is risk for SE in up to 15% of cases.⁵⁰ If convulsive febrile seizures last longer than 5 minutes, initiate benzodiazepines followed by the standard protocol used for the management of SE.⁵¹

Continue to: Epilepsy as a spectrum disorder

The higher prevalence of comorbid cognitive and psychiatric conditions in patients with epilepsy, affecting about half of patients, ⁵² suggests that seizures may constitute only one aspect of a multifaceted disease that otherwise should be considered a spectrum disorder. Among such conditions are memory deficits, depression, and anxiety. Conversely, epilepsy is more common in patients with depression than in those without. ⁵²

Social impact of epilepsy

De-escalation of treatment offers an equivalent, resource-sparing alternative to traditional treatment of pediatric torus fractures of the distal radius.

Vehicle driving regulations. Patients with epilepsy are required to follow state law regarding driving restrictions. Different states have different rules and regulations about driving restrictions and reporting requirements (by patients or their physicians). Refer patients to the Department of Motor Vehicles (DMV) in their state of residence for up-to-date instructions.⁵³ The Epilepsy Foundation (epilepsy.com) can serve as a resource for each state’s DMV website.

Employment assistance. Having epilepsy should not preclude patients from seeking employment and pursuing meaningful careers. The Americans with Disabilities Act (ADA) and the US Equal Employment Opportunity Commission (EEOC) forbid discrimination against qualified people with disabilities, including those with epilepsy, and require reasonable accommodations in the workplace (www.eeoc.gov/laws/guidance/­epilepsy-workplace-and-ada).⁵⁴

CORRESPONDENCE
Gholam K. Motamedi, MD, Department of Neurology, PHC 7, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC 20007; [email protected]

Managing first-time seizures and epilepsy often requires consultation with a neurologist or epileptologist for diagnosis and subsequent management, including when medical treatment fails or in determining whether patients may benefit from surgery. However, given the high prevalence of epilepsy and even higher incidence of a single seizure, family physicians contribute significantly to the management of these patients. The main issues are managing a first-time seizure, making the diagnosis, establishing a treatment plan, and exploring triggers and mitigating factors.

Seizure vs epilepsy

All patients with epilepsy experience seizures, but not every person who experiences a seizure has (or will develop) epilepsy. Nearly 10% of the population has one seizure during their lifetime,whereas the risk for epilepsy is just 3%.¹ Therefore, a first-time seizure may not herald epilepsy, defined as repetitive (≥ 2) unprovoked seizures more than 24 hours apart.² Seizures can be provoked (acute symptomatic) or unprovoked; a clear distinction between these 2 occurrences—as well as between single and recurrent seizures—is critical for proper management. A close look at the circumstances of a first-time seizure is imperative to define the nature of the event and the possibility of further seizures before devising a treatment plan.

Provoked seizures are due to an acute brain insult such as toxic-metabolic disorders, concussion, alcohol withdrawal, an adverse effect of a medication or its withdrawal, or photic stimulation presumably by disrupting the brain’s metabolic homeostasis or integrity. The key factor is that provoked seizures always happen in close temporal association with an acute insult. A single provoked seizure happens each year in 29 to 39 individuals per 100,000.³ While these seizures typically occur singly, there is a small risk they may recur if the triggering insult persists or repeats.¹ Therefore, more than 1 seizure per se may not indicate epilepsy.³

Unprovoked seizures reflect an underlying brain dysfunction. A single unprovoked seizure happens in 23 to 61 individuals per 100,000 per year, often in men in either younger or older age groups.³ Unprovoked seizures may occur only once or may recur (ie, evolve into epilepsy). The latter scenario happens in only about half of cases; the overall risk for a recurrent seizure within 2 years of a first seizure is estimated at 42% (24% to 65%, depending on the etiology and electroencephalogram [EEG] findings).⁴ More specifically, without treatment the relapse rate will be 36% at 1 year and 47% at 2 years.⁴ Further, a second unprovoked seizure, if untreated, would increase the risk for third and fourth seizures to 73% and 76%, respectively, within 4 years.³

Evaluating the first-time seizure

Ask the patient or observers about the circumstances of the event to differentiate provoked from unprovoked onset. For one thing, not all “spells” are seizures. The differential diagnoses may include syncope, psychogenic nonepileptic events, drug intoxication or withdrawal, migraine, panic attacks, sleep disorders (parasomnia), transient global amnesia, concussion, and transient ischemic attack. EEG, neuroimaging, and other relevant diagnostic tests often are needed (eg, electrocardiogram/echocardiogram/Holter monitoring to evaluate for syncope/cardiac arrhythmia). Clinically, syncopal episodes tend to be brief with rapid recovery and no confusion, speech problems, aura, or lateralizing signs such as hand posturing or lip smacking that are typical with focal seizures. However, cases of convulsive syncope can be challenging to assess without diagnostic tests.

Many patients have experienced prior undiagnosed seizures. Subtle prior events include episodes of deja vu, transient feelings of fear, unusual smells, and speech difficulties.

True convulsive seizures do not have the variability in clinical signs seen with psychogenic nonepileptic events (eg, alternating body parts involved or direction of movements). Transient global amnesia is a rare condition with no established diagnostic test and is considered a diagnosis of exclusion, although bitemporal hyperintensities on magnetic resonance imaging (MRI) may appear 12 to 48 hours after the clinical episode.⁵ Blood work is needed in patients with medical issues treated with multiple medications to evaluate for metabolic derangements; otherwise, routine blood work provides minimal information in stable patients.

Region-specific causes. Neurocysticercosis is common in some regions, such as Latin America; therefore, attention should be paid to this aspect of patient history.

Continue to: Is it really a first-time seizure?

Is it really a first-time seizure? A “first,” usually dramatic, generalized tonic-clonic seizure that triggers the diagnostic work-up may not be the very first seizure. Evidence suggests that many patients have experienced prior undiagnosed seizures. Subtle prior events often missed include episodes of deja vu, transient feelings of fear or unusual smells, speech difficulties, staring spells, or myoclonic jerks.¹ A routine EEG to record epileptiform discharges and a high-resolution brain MRI to rule out any intracranial pathology are indicated. However, if the EEG indicates a primary generalized (as opposed to focal-onset) epilepsy, a brain MRI may not be needed. If a routine EEG is unrevealing, long-term video-EEG monitoring may be needed to detect an abnormality.

Accuracy of EEG and MRI. Following a first unprovoked seizure, routine EEG to detect epileptiform discharges in adults has yielded a sensitivity of 17.3% and specificity of 94.7%. In evaluating children, these values are 57.8% and 69.6%, respectively.⁶ If results are equivocal, a 24-hour EEG can increase the likelihood of detecting epileptiform discharges to 89% of patients.⁷ Brain MRI may detect an abnormality in 12% to 14% of patients with newly diagnosed epilepsy, and in up to 80% of those with recurrent seizures.⁸ In confirming hippocampus sclerosis, MRI has demonstrated a sensitivity of 93% and specificity of 86%.⁹

When to treat a first-time seizure. Available data and prediction models identify risk factors that would help determine whether to start an antiseizure medication after a first unprovoked seizure: abnormal EEG with particular epileptiform activity, abnormal neurologic exam, abnormal computerized tomography or MRI results, nocturnal seizure, focal seizure, or family history of seizures. In the absence of such risk factors, chances of further unprovoked seizures are not high enough to justify treatment with antiseizure medications. However, if a second unprovoked seizure were to occur, that would meet the definition of epilepsy, and treatment is indicated due to the high risk for further seizures.^10,11

Epilepsy diagnosis

The International League Against Epilepsy (ILAE) previously defined epilepsy as 2 unprovoked seizures more than 24 hours apart. However, a more recent ILAE task force modified this definition: even a single unprovoked seizure would be enough to diagnose epilepsy if there is high probability of further seizures—eg, in the presence of definitive epileptiform discharges on EEG or presence of a brain tumor or a remote brain insult on imaging, since such conditions induce an enduring predisposition to generate epileptic seizures. ² Also, a single unprovoked seizure is enough to diagnose epilepsy if it is part of an epileptic syndrome such as juvenile myoclonic epilepsy. Further, a time limit was added to the definition—ie, epilepsy is considered resolved if a patient remains seizure free for 10 years without use of antiseizure medications during the past 5 years. However, given the multitude of variables and evidence, the task force acknowledged the need for individualized considerations. ²

Seizure classification

Classification of seizure type is based on the site of seizure onset and its spread pattern—ie, focal, generalized, or unknown onset.

Continue to: Focal-onset seizures

Focal-onset seizures originate “within networks limited to one hemisphere,” although possibly in more than 1 region (ie, multifocal, and presence or absence of loss of awareness). ¹² Focal seizures may then be further classified into “motor onset” or “nonmotor onset” (eg, autonomic, emotional, sensory). ²

Generalized seizures are those “originating at some point within, and rapidly engaging, bilaterally distributed networks.” ¹³ Unlike focal-onset seizures, generalized seizures are not classified based on awareness, as most generalized seizures involve loss of awareness (absence) or total loss of consciousness (generalized tonic-clonic). They are instead categorized based on the presence of motor vs nonmotor features (eg, tonic-clonic, myoclonic, atonic). Epilepsy classification is quite dynamic and constantly updated based on new genetic, electroencephalographic, and neuroimaging discoveries.

Treatment of epilepsy

Antiseizure medications

Treatment with antiseizure medications (ASMs; formerly known as antiepileptic drugs ) is the mainstay of epilepsy management. Achieving efficacy (seizure freedom) and tolerability (minimal adverse effects) are the primary goals of treatment. Factors that should govern the selection of an ASM include the seizure type/epilepsy syndrome, adverse effect profile of the ASM, pharmacodynamic/pharmacokinetic considerations, and patient comorbidities.

Levetiracetam and valproate (not to be used in women of childbearing potential) are considered appropriate first-line agents for generalized and unclassified epilepsies.

The Standard and New Antiepileptic Drugs (SANAD I and II) trials provide data from direct, unblinded, and longitudinal comparisons of existing and new ASMs and their utility in different seizure types. In the SANAD I cohort of patients with generalized and unclassified epilepsies, valproate was superior to lamotrigine and topiramate for 12-month remission and treatment failure rates, respectively.¹⁴ However, valproate generally is avoided in women of childbearing age due its potential adverse effects during pregnancy. In focal epilepsies, lamotrigine was superior to carbamazepine, gabapentin, and topiramate with respect to treatment failure, and noninferior to carbamazepine for 12-month remission.¹⁵ In the SANAD II trial, levetiracetam was noninferior to valproate for incidence of adverse events in patients with generalized and unclassified epilepsies although was found to be neither more clinically effective nor more cost effective.¹⁶ For patients of childbearing potential with generalized and unclassified epilepsies, there is evidence to support the safe and effective use of levetiracetam.¹⁷In focal epilepsies, lamotrigine was superior to levetiracetam and zonisamide with respect to treatment failures and adverse events and was noninferior to zonisamide for 12-month remission.¹⁸ In summary, levetiracetam and valproate (not to be used in women of childbearing potential) are considered appropriate first-line agents for generalized and unclassified epilepsies while lamotrigine is deemed an appropriate first-line agent for focal epilepsies (TABLE 1^19-28).

Drug level monitoring. It is standard practice to periodically monitor serum levels in patients taking first-generation ASMs such as phenytoin, carbamazepine, phenobarbital, and valproic acid because of their narrow therapeutic range and the potential for overdose or interaction with other medications or foods (eg, grapefruit juice may increase carbamazepine serum level by inhibiting ­CYP3A4, the enzyme that metabolizes the drug). Patients taking newer ASMs may not require regular serum level monitoring except during titration, with hepatic or renal dosing, when concomitantly used with estrogen-based oral contraceptives (eg, lamotrigine), before or during pregnancy, or when nonadherence is suspected.

Continue to: Can antiseizure treatment be stopped?

Can antiseizure treatment be stopped?

Current evidence favors continuing ASM therapy in patients whose seizures are under control, although the decision should be tailored to an individual’s circumstances. According to the 2021 American Academy of Neurology (AAN) guidelines, adults who have been seizure free for at least 2 years and discontinue ASMs are possibly still at higher risk for seizure recurrence in the long term (24-60 months), compared with those who continue treatment.²⁹ On the other hand, for adults who have been seizure free for at least 12 months, ASM withdrawal may not increase their risk for status epilepticus, and there are insufficient data to support or refute an effect on mortality or quality of life with ASM withdrawal in this population. The decision to taper or maintain ASM therapy in seizure-free patients also should take into consideration other clinically relevant outcome measures such as the patient’s lifestyle and medication adverse effects. Therefore, this decision should be made after sufficient discussion with patients and their caregivers. (Information for patients can be found at: www.epilepsy.com/treatment/medicines/stopping-medication.)

There are no reliable methods for predicting seizure other than knowing of the several potential risks and recognizing and avoiding these triggers.

For children, the AAN guideline panel recommends discussing with family the small risk (2%) for becoming medication resistant if seizures recur during or after ASM withdrawal. ²⁹ For children who have been seizure free for 18 to 24 months, there is probably not a significant long-term (24-48 months) difference in seizure recurrence in those who taper ASMs vs those who do not. However, presence of epileptiform discharges on EEG before discontinuation of an ASM indicates increased risk for seizure recurrence. ²⁹

Intractable (refractory) epilepsy

While most patients with epilepsy attain complete seizure control with appropriate drug therapy, approximately 30% continue to experience seizures (“drug-resistant” epilepsy, also termed intractable or refractory ). ³⁰ In 2010, the ILAE defined drug-resistant epilepsy as “failure of adequate trials of two tolerated, appropriately chosen and used anti-epileptic drug schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom” (defined as cessation of seizures for at least 3 times the longest pre-intervention inter-seizure interval or 12 months, whichever is longer). ^21,31 It should be noted that drug withdrawal due to adverse effects is not counted as failure of that ASM. Recognition of drug-resistant epilepsy may prompt referral to an epileptologist who can consider rational combination drug therapy or surgical resection of the seizure focus, vagus nerve stimulation, electrical stimulation of the seizure focus, or deep brain (thalamic) stimulation.

Seizure triggers and mitigating factors

Epilepsy mostly affects patients during seizure episodes; however, the unpredictability of these events adds significantly to the burden of disease. There are no reliable methods for predicting seizure other than knowing of the several potential risks and recognizing and avoiding these triggers.

Noncompliance with antiseizure medications is a common seizure trigger affecting up to one-half of patients with epilepsy.³²

Continue to: Medications

Medications may provoke seizures in susceptible individuals (TABLE 2^33-35).

Sleep deprivation is a potential seizure trigger in people with epilepsy based on observational studies, case reports, patient surveys, and EEG-based studies, although data from randomized controlled studies are limited.³⁶ The standard best practice is to encourage appropriate sleep hygiene, which involves getting at least 7 hours of sleep per night.³⁷

Alcohol is a GABAergic substance like benzodiazepines with antiseizure effects. However, it acts as a potential precipitant of seizures in cases of withdrawal or acute intoxication, or when it leads to sleep disruption or nonadherence to antiseizure medications. Therefore, advise patients with alcohol use disorder to slowly taper consumption (best done through a support program) and avoid sudden withdrawal. However, complete abstinence from alcohol use is not often recommended except in special circumstances (eg, a history of alcohol-related seizures). Several studies have demonstrated that modest alcohol use (1-2 drinks per occasion) does not increase seizure frequency or significantly alter serum concentrations of commonly used ASMs.³⁸

Cannabis and other substances. The 2 main biologically active components of marijuana are delta-9-tetrahydrocannibinol (THC), the main psychoactive constituent, and cannabidiol (CBD). Animal and human studies have demonstrated anticonvulsant properties of THC and CBD. But THC, in high amounts, can result in adverse cognitive effects and worsening seizures.³⁹ A purified 98% oil-based CBD extract (Epidiolex) has been approved as an adjunctive treatment for certain medically refractory epilepsy syndromes in children and young adults—ie, Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex syndrome.⁴⁰ There are no reliable data on the effect of recreational use of marijuana on seizure control. Other illicit substances such as cocaine may lower seizure threshold by their stimulatory and disruptive effects on sleep, diet, and healthy routines.

Special clinical cases

Pregnancy and epilepsy

Despite the potential adverse effects of ASMs on fetal health, the current global consensus is to continue treatment during pregnancy, given that the potential harm of convulsive seizures outweighs the potential risks associated with in-utero exposure to ASMs. There is not enough evidence to indicate significant harm to the fetus caused by focal, absence, or myoclonic seizures. Low-dose folic acid is used to minimize the risks of ASMs during pregnancy.

Continue to: As the fetus develops...

Illicit substances such as cocaine may lower seizure threshold by their stimulatory and disruptive effects on sleep, diet, and healthy routines.

As the fetus develops, there are changes in volume of ASM distribution, renal clearance, protein binding, and hepatic metabolism, which require checking serum levels at regular intervals and making dosage adjustments.

The ongoing study evaluating Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD)⁴¹ has led to multiple landmark studies guiding the choice of preferred ASMs during pregnancy in patients with epilepsy.^42,43 This has culminated in today’s use of lamotrigine and levetiracetam as the 2 preferred agents (while avoiding valproate) in pregnant patients with epilepsy.⁴⁴

Psychogenic nonepileptic seizures

Having epilepsy should not preclude patients from seeking employment and pursuing meaningful careers.

A form of conversion disorder, psychogenic nonepileptic seizures (PNES) manifests as abnormal motor or behavioral events mimicking seizures but without associated epileptiform discharges on EEG. This is observed in 10% of patients seen in epilepsy clinics and even more often in those admitted to epilepsy­ monitoring units (25%-40%).⁴⁵ Diagnosis of PNES requires EEG monitoring both for confirmation and for discernment from true epileptic seizures, in particular frontal lobe epilepsy that may clinically mimic PNES. PNES often is associated with underlying psychological tensions or comorbid conditions such as depression, anxiety, or traumatic life experiences. There is no treatment for PNES per se, and its management is focused on controlling any underlying psychological comorbidities that may not always be obvious. There is some evidence suggesting that these patients experience an innate inability to verbally express their emotions and instead subconsciously resort to psychosomatics to express them in a somatic dimension.^46,47

Status epilepticus

Defined as prolonged seizures (> 5 min) or 2 consecutive seizures without regaining aware ness in between, status epilepticus (SE) is a potentially fatal condition. Subclinical nonconvulsive SE, especially in comatose patients, can be diagnosed only via EEG monitoring. Untreated SE may manifest as a diagnostic dilemma in unresponsive or critically ill patients and can increase the risk for mortality. ⁴⁸

Febrile seizures

Febrile seizures affect 2% to 5% of children most often in the second year of life.⁴⁹ The use of preventive antiseizure medication is not recommended; instead, the key is to investigate the underlying febrile illness. Lumbar puncture is indicated if there are signs and symptoms of meningitis (25% of children with bacterial meningitis present with seizures).⁴⁹ Febrile seizures often are self-limited, but there is risk for SE in up to 15% of cases.⁵⁰ If convulsive febrile seizures last longer than 5 minutes, initiate benzodiazepines followed by the standard protocol used for the management of SE.⁵¹

Continue to: Epilepsy as a spectrum disorder

The higher prevalence of comorbid cognitive and psychiatric conditions in patients with epilepsy, affecting about half of patients, ⁵² suggests that seizures may constitute only one aspect of a multifaceted disease that otherwise should be considered a spectrum disorder. Among such conditions are memory deficits, depression, and anxiety. Conversely, epilepsy is more common in patients with depression than in those without. ⁵²

Social impact of epilepsy

De-escalation of treatment offers an equivalent, resource-sparing alternative to traditional treatment of pediatric torus fractures of the distal radius.

Vehicle driving regulations. Patients with epilepsy are required to follow state law regarding driving restrictions. Different states have different rules and regulations about driving restrictions and reporting requirements (by patients or their physicians). Refer patients to the Department of Motor Vehicles (DMV) in their state of residence for up-to-date instructions.⁵³ The Epilepsy Foundation (epilepsy.com) can serve as a resource for each state’s DMV website.

Employment assistance. Having epilepsy should not preclude patients from seeking employment and pursuing meaningful careers. The Americans with Disabilities Act (ADA) and the US Equal Employment Opportunity Commission (EEOC) forbid discrimination against qualified people with disabilities, including those with epilepsy, and require reasonable accommodations in the workplace (www.eeoc.gov/laws/guidance/­epilepsy-workplace-and-ada).⁵⁴

CORRESPONDENCE
Gholam K. Motamedi, MD, Department of Neurology, PHC 7, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC 20007; [email protected]