Donna Flake, MSLS, MSAS

Evidence summary

There is some evidence demonstrating that antifungals effectively treat angular cheilitis. A prospective, double-blind, placebo-controlled study of 8 patients compared the efficacy of nystatin with placebo ointment. These patients were referred to a Department of Oral Diagnosis for sore lips with detected Candida albicans lesions located bilaterally.¹ All of the patients were instructed to use one ointment on the right side and the other on the left side. Contamination was prevented by the use of gloves changed between applications. All 8 patients demonstrated complete healing after 1 to 4 weeks of treatment by nystatin, whereas only 1 patient had complete healing after the placebo, giving a number needed to treat (NNT) of 1.14 (P<.001).

A second study compared antifungal treatments with placebo. This randomized-controlled trial from 1975 studied lozenge use of nystatin or amphotericin B in 52 patients with red palate, angular cheilitis, or both.² These patients were identified through screening of 600 consecutive patients attending the prosthetic clinic for examination or treatment. Patients were randomly given a 1-month supply of nystatin, amphotericin B, or placebo and instructed to dissolve 4 lozenges a day in their mouth. The study did not describe any blinding procedure. Both nystatin and amphotericin B had statistically significant cures rates at 1 month compared with placebo (P=.05 and P=0.01, respectively). The NNT was 2.7 for the nystatin group and 2.0 for the amphotericin B group at 1 month. A comparison of the 2 anti-fungals found no difference in cure rate. Recurrence rates at 2 months after discontinuing therapy were the same. The only adverse effect reported was the unpleasant taste of the lozenges, especially nystatin.

Improving oral health is another method proposed to treat angular cheilitis. Many modalities have been suggested including emphasis on denture cleaning, mouthwashes, or medicated chewing gums.

A randomized controlled, double-blind study, performed in 21 English nursing facilities, enrolled 164 patients aged 60 years and older with some natural teeth and evaluated the effects of medicated chewing gum on oral health.³ At the end of 1 year, the 111 patients (67%) completed the study. Fifty-seven percent of the participants wore dentures.

Several aspects were measured including the presence of angular cheilitis. There were 3 arms: no gum, xylitol gum, and chlorhexidine acetate/xylitol gum. The gums were used after breakfast and the evening meal and consisted of 2 pellets to be chewed for 15 minutes. Adherence was described as chewing gum at least 12 times per week for 12 months. A blinded investigator examined patients at baseline, 3, 6, 9, and 12 months.

The results demonstrated a decrease in angular cheilitis in both the xylitol and chlorhexidine acetate/xylitol group at 12 months when compared to the no gum group (P<.01). Cheilitis was found in 14% of the xylitol group (compared with 27% at baseline), 7% of the chlorhexidine acetate/xylitol group (a reduction from 28%), and 32% of the no gum group (no change). The NNT was 7.7 for the xylitol group and 4.8 for the chlorhexidine acetate/xylitol group. This effect size may be exaggerated as the study randomized by nursing home not individual patients, and there was no statistical adjustment for the cluster randomization.

Chewing gum impregnated with chlorhexidine is not readily available in the United States, whereas xylitol-containing gums are available in many retail stores and on-line centers.

Recommendations from others

We found no clinical guidelines regarding the treatment of angular cheilitis. The American Dental Association does mention topical antifungal creams for the treatment of angular cheilitis when discussing oral health and diabetes.⁴ In addition, Taylor’s Family Medicine recommends antifungals, including nystatin pastilles, clotrimazole troches, or a single 200-mg dose of fluconazole.⁵ Geriatric Medicine also recommends topical antifungals to treat angular cheilitis.⁶

Evidence summary

There is some evidence demonstrating that antifungals effectively treat angular cheilitis. A prospective, double-blind, placebo-controlled study of 8 patients compared the efficacy of nystatin with placebo ointment. These patients were referred to a Department of Oral Diagnosis for sore lips with detected Candida albicans lesions located bilaterally.¹ All of the patients were instructed to use one ointment on the right side and the other on the left side. Contamination was prevented by the use of gloves changed between applications. All 8 patients demonstrated complete healing after 1 to 4 weeks of treatment by nystatin, whereas only 1 patient had complete healing after the placebo, giving a number needed to treat (NNT) of 1.14 (P<.001).

A second study compared antifungal treatments with placebo. This randomized-controlled trial from 1975 studied lozenge use of nystatin or amphotericin B in 52 patients with red palate, angular cheilitis, or both.² These patients were identified through screening of 600 consecutive patients attending the prosthetic clinic for examination or treatment. Patients were randomly given a 1-month supply of nystatin, amphotericin B, or placebo and instructed to dissolve 4 lozenges a day in their mouth. The study did not describe any blinding procedure. Both nystatin and amphotericin B had statistically significant cures rates at 1 month compared with placebo (P=.05 and P=0.01, respectively). The NNT was 2.7 for the nystatin group and 2.0 for the amphotericin B group at 1 month. A comparison of the 2 anti-fungals found no difference in cure rate. Recurrence rates at 2 months after discontinuing therapy were the same. The only adverse effect reported was the unpleasant taste of the lozenges, especially nystatin.

Improving oral health is another method proposed to treat angular cheilitis. Many modalities have been suggested including emphasis on denture cleaning, mouthwashes, or medicated chewing gums.

A randomized controlled, double-blind study, performed in 21 English nursing facilities, enrolled 164 patients aged 60 years and older with some natural teeth and evaluated the effects of medicated chewing gum on oral health.³ At the end of 1 year, the 111 patients (67%) completed the study. Fifty-seven percent of the participants wore dentures.

Several aspects were measured including the presence of angular cheilitis. There were 3 arms: no gum, xylitol gum, and chlorhexidine acetate/xylitol gum. The gums were used after breakfast and the evening meal and consisted of 2 pellets to be chewed for 15 minutes. Adherence was described as chewing gum at least 12 times per week for 12 months. A blinded investigator examined patients at baseline, 3, 6, 9, and 12 months.

The results demonstrated a decrease in angular cheilitis in both the xylitol and chlorhexidine acetate/xylitol group at 12 months when compared to the no gum group (P<.01). Cheilitis was found in 14% of the xylitol group (compared with 27% at baseline), 7% of the chlorhexidine acetate/xylitol group (a reduction from 28%), and 32% of the no gum group (no change). The NNT was 7.7 for the xylitol group and 4.8 for the chlorhexidine acetate/xylitol group. This effect size may be exaggerated as the study randomized by nursing home not individual patients, and there was no statistical adjustment for the cluster randomization.

Chewing gum impregnated with chlorhexidine is not readily available in the United States, whereas xylitol-containing gums are available in many retail stores and on-line centers.

Recommendations from others

We found no clinical guidelines regarding the treatment of angular cheilitis. The American Dental Association does mention topical antifungal creams for the treatment of angular cheilitis when discussing oral health and diabetes.⁴ In addition, Taylor’s Family Medicine recommends antifungals, including nystatin pastilles, clotrimazole troches, or a single 200-mg dose of fluconazole.⁵ Geriatric Medicine also recommends topical antifungals to treat angular cheilitis.⁶

Evidence summary

There is some evidence demonstrating that antifungals effectively treat angular cheilitis. A prospective, double-blind, placebo-controlled study of 8 patients compared the efficacy of nystatin with placebo ointment. These patients were referred to a Department of Oral Diagnosis for sore lips with detected Candida albicans lesions located bilaterally.¹ All of the patients were instructed to use one ointment on the right side and the other on the left side. Contamination was prevented by the use of gloves changed between applications. All 8 patients demonstrated complete healing after 1 to 4 weeks of treatment by nystatin, whereas only 1 patient had complete healing after the placebo, giving a number needed to treat (NNT) of 1.14 (P<.001).

A second study compared antifungal treatments with placebo. This randomized-controlled trial from 1975 studied lozenge use of nystatin or amphotericin B in 52 patients with red palate, angular cheilitis, or both.² These patients were identified through screening of 600 consecutive patients attending the prosthetic clinic for examination or treatment. Patients were randomly given a 1-month supply of nystatin, amphotericin B, or placebo and instructed to dissolve 4 lozenges a day in their mouth. The study did not describe any blinding procedure. Both nystatin and amphotericin B had statistically significant cures rates at 1 month compared with placebo (P=.05 and P=0.01, respectively). The NNT was 2.7 for the nystatin group and 2.0 for the amphotericin B group at 1 month. A comparison of the 2 anti-fungals found no difference in cure rate. Recurrence rates at 2 months after discontinuing therapy were the same. The only adverse effect reported was the unpleasant taste of the lozenges, especially nystatin.

Improving oral health is another method proposed to treat angular cheilitis. Many modalities have been suggested including emphasis on denture cleaning, mouthwashes, or medicated chewing gums.

A randomized controlled, double-blind study, performed in 21 English nursing facilities, enrolled 164 patients aged 60 years and older with some natural teeth and evaluated the effects of medicated chewing gum on oral health.³ At the end of 1 year, the 111 patients (67%) completed the study. Fifty-seven percent of the participants wore dentures.

Several aspects were measured including the presence of angular cheilitis. There were 3 arms: no gum, xylitol gum, and chlorhexidine acetate/xylitol gum. The gums were used after breakfast and the evening meal and consisted of 2 pellets to be chewed for 15 minutes. Adherence was described as chewing gum at least 12 times per week for 12 months. A blinded investigator examined patients at baseline, 3, 6, 9, and 12 months.

The results demonstrated a decrease in angular cheilitis in both the xylitol and chlorhexidine acetate/xylitol group at 12 months when compared to the no gum group (P<.01). Cheilitis was found in 14% of the xylitol group (compared with 27% at baseline), 7% of the chlorhexidine acetate/xylitol group (a reduction from 28%), and 32% of the no gum group (no change). The NNT was 7.7 for the xylitol group and 4.8 for the chlorhexidine acetate/xylitol group. This effect size may be exaggerated as the study randomized by nursing home not individual patients, and there was no statistical adjustment for the cluster randomization.

Chewing gum impregnated with chlorhexidine is not readily available in the United States, whereas xylitol-containing gums are available in many retail stores and on-line centers.

Recommendations from others

We found no clinical guidelines regarding the treatment of angular cheilitis. The American Dental Association does mention topical antifungal creams for the treatment of angular cheilitis when discussing oral health and diabetes.⁴ In addition, Taylor’s Family Medicine recommends antifungals, including nystatin pastilles, clotrimazole troches, or a single 200-mg dose of fluconazole.⁵ Geriatric Medicine also recommends topical antifungals to treat angular cheilitis.⁶

Evidence Summary

A common female endocrinopathy, PCOS affects 5% to 10% of women. Characterized by anovulation and hyperandrogenism, it often manifests as infertility and irregular menstruation. Metformin and thiazolidinediones are likely effective treatments for these expressions of insulin resistance, but study limitations restrict our ability to clearly define their role.

The most influential systematic review was a meta-analysis that reviewed 13 RCTs including 543 women to determine the effects of metformin on ovarian function in PCOS.^1,2By selecting RCTs, performing precise statistical analysis according to the Cochrane protocols, and clearly stating limitations, this review gives good evidence that metformin modestly increases the odds of ovulation for women with PCOS (odds ratio [OR]=3.88; 95% confidence interval [CI], 2.25–6.69 for metformin vs placebo) and that metformin with clomiphene (Clomid) effectively increases ovulation (OR=4.41; 95% CI, 2.37–8.22) and pregnancy rates (OR=4.40; 95% CI, 1.96–9.85) when compared with clomiphene use alone. When metformin is used as a sole agent, ovulation is achieved in 46% of recipients compared with 24% in the placebo arm (number needed to treat [NNT]=4.4). When metformin and clomiphene are used in combination, 76% of recipients ovulate compared with 42% receiving clomiphene alone (NNT=3.0).

Several problems with recommending metformin as first-line therapy exist: (1) equal or better ovulation rates have been described by using lifestyle interventions to achieve weight loss, (2) there are no long-term studies of the effects of metformin in PCOS patients, and (3) we cannot assess the clinically important outcome of pregnancy rates because the trials did not control for other infertility factors and did not define live births as a primary outcome. In addition, there are no head-to-head trials of metformin vs clomiphene, the standard first-line therapy for ovulation induction. Only 1 study addressed menstrual patterns specifically; they were improved with metformin (OR=12.88; 95% CI, 1.85–89.61).

An additional meta-analysis reports similar results.³ Eight RCTs addressing the use of metformin or clomiphene for treatment of PCOS were reviewed for ovulation and pregnancy rates. Metformin is 50% better than placebo for ovulation induction among infertile PCOS patients (relative risk [RR]=1.50; 95% CI, 1.31–1.99), but this benefit is not necessarily improved with longer duration (>3 months) of therapy (RR=1.37; 95% CI, 1.05–1.79). Also, metformin is beneficial in regulating cycles for fertile PCOS patients with irregular menses (RR=1.45; 95% CI, 1.11–1.90).

The conclusions regarding pregnancy rates and combined therapy with metformin and clomiphene are limited due to small samples, short follow-up time (2–6 months), and study design. An ongoing randomized trial (Pregnancy in Polycystic Ovarian Syndrome: PPOS study) of 768 infertile PCOS patients is investigating effects of metformin vs clomiphene on ovulation induction and achievement of singleton pregnancies. These outcomes should clarify remaining uncertainties regarding appropriate use of metformin.

Finally, a review of 7 RCTs describes the evidence accumulated by well-designed trials and its clinical relevance.⁴ Metformin improves ovulation and menstrual cyclicity but these improvements were variable and modest. On average, 1 additional ovulation is attained in every 5-month interval with metformin treatment; specifically, the baseline of 1 ovulation per 5-month interval increased to 2 ovulations per 5-month interval. Spontaneous ovulation and normal menstruation are achieved rapidly (within 3 months of the start of therapy). These data corroborate the benefits of metformin but place its clinical significance in perspective. For PCOS patients seeking cycle regulation but not pregnancy, oral contraceptives may remain better therapy because metformin does not normalize menses.

Less information exists on the role of TZDs and ovarian function in PCOS. Studies of the most researched drug in the class, troglitazone (Rezulin), report improvements in ovulation rates and metabolic markers of PCOS.^5,6 Troglitazone has been taken off of the market due to hepatotoxicity, but results from a RCT of 40 patients with PCOS reported that the use of pioglitazone (Actos) for 3 months increased normal regular cycles and ovulations over placebo (41.2% vs 5.6%; P<.02).⁷ No liver effects were noted, but caution must be taken since these drugs are pregnancy class C. Two small RCTs studied the use of rosiglitazone (Avandia) in combination with clomiphene and reported improvements in menstrual regularity⁸ (92% with combination therapy achieved improved menstrual cycles vs 68% with rosiglitazone alone; OR=0.185) and both spontaneous and clomiphene-induced ovulation rates (52% of clomiphene-resistant women ovulated after rosiglitazone therapy and 77% vs 33% ovulated with combination therapy vs rosiglitazone alone, P=.04).⁹ Further research is needed to determine the clinical effects of the thiazolidinediones.

Recommendations from Others

The American College of Obstetricians and Gynecologists guideline on diagnosis and management of PCOS reports that interventions that improve insulin sensitivity, including weight loss, use of metformin, and use of TZDs are useful for improving ovulatory frequency for women with PCOS.¹⁰ The recommendation is based on good and consistent scientific evidence (SOR: A). They also note that insulin-sensitizing agents may improve many risk factors for diabetes and cardiovascular disease, but this recommendation is based on limited evidence (SOR: B). Finally, they recommend, based on expert opinion (SOR: C), that caution be used with these agents because their effects on early pregnancy are unknown, even though metformin appears to be safe.

The American Association of Clinical Endocrinologists recommends using metformin 850 mg twice daily to treat the hyperandrogenic state of PCOS.¹¹ The use of TZDs is less clear due to limited evidence and risks of teratogenicity.

Evidence Summary

A common female endocrinopathy, PCOS affects 5% to 10% of women. Characterized by anovulation and hyperandrogenism, it often manifests as infertility and irregular menstruation. Metformin and thiazolidinediones are likely effective treatments for these expressions of insulin resistance, but study limitations restrict our ability to clearly define their role.

The most influential systematic review was a meta-analysis that reviewed 13 RCTs including 543 women to determine the effects of metformin on ovarian function in PCOS.^1,2By selecting RCTs, performing precise statistical analysis according to the Cochrane protocols, and clearly stating limitations, this review gives good evidence that metformin modestly increases the odds of ovulation for women with PCOS (odds ratio [OR]=3.88; 95% confidence interval [CI], 2.25–6.69 for metformin vs placebo) and that metformin with clomiphene (Clomid) effectively increases ovulation (OR=4.41; 95% CI, 2.37–8.22) and pregnancy rates (OR=4.40; 95% CI, 1.96–9.85) when compared with clomiphene use alone. When metformin is used as a sole agent, ovulation is achieved in 46% of recipients compared with 24% in the placebo arm (number needed to treat [NNT]=4.4). When metformin and clomiphene are used in combination, 76% of recipients ovulate compared with 42% receiving clomiphene alone (NNT=3.0).

Several problems with recommending metformin as first-line therapy exist: (1) equal or better ovulation rates have been described by using lifestyle interventions to achieve weight loss, (2) there are no long-term studies of the effects of metformin in PCOS patients, and (3) we cannot assess the clinically important outcome of pregnancy rates because the trials did not control for other infertility factors and did not define live births as a primary outcome. In addition, there are no head-to-head trials of metformin vs clomiphene, the standard first-line therapy for ovulation induction. Only 1 study addressed menstrual patterns specifically; they were improved with metformin (OR=12.88; 95% CI, 1.85–89.61).

An additional meta-analysis reports similar results.³ Eight RCTs addressing the use of metformin or clomiphene for treatment of PCOS were reviewed for ovulation and pregnancy rates. Metformin is 50% better than placebo for ovulation induction among infertile PCOS patients (relative risk [RR]=1.50; 95% CI, 1.31–1.99), but this benefit is not necessarily improved with longer duration (>3 months) of therapy (RR=1.37; 95% CI, 1.05–1.79). Also, metformin is beneficial in regulating cycles for fertile PCOS patients with irregular menses (RR=1.45; 95% CI, 1.11–1.90).

The conclusions regarding pregnancy rates and combined therapy with metformin and clomiphene are limited due to small samples, short follow-up time (2–6 months), and study design. An ongoing randomized trial (Pregnancy in Polycystic Ovarian Syndrome: PPOS study) of 768 infertile PCOS patients is investigating effects of metformin vs clomiphene on ovulation induction and achievement of singleton pregnancies. These outcomes should clarify remaining uncertainties regarding appropriate use of metformin.

Finally, a review of 7 RCTs describes the evidence accumulated by well-designed trials and its clinical relevance.⁴ Metformin improves ovulation and menstrual cyclicity but these improvements were variable and modest. On average, 1 additional ovulation is attained in every 5-month interval with metformin treatment; specifically, the baseline of 1 ovulation per 5-month interval increased to 2 ovulations per 5-month interval. Spontaneous ovulation and normal menstruation are achieved rapidly (within 3 months of the start of therapy). These data corroborate the benefits of metformin but place its clinical significance in perspective. For PCOS patients seeking cycle regulation but not pregnancy, oral contraceptives may remain better therapy because metformin does not normalize menses.

Less information exists on the role of TZDs and ovarian function in PCOS. Studies of the most researched drug in the class, troglitazone (Rezulin), report improvements in ovulation rates and metabolic markers of PCOS.^5,6 Troglitazone has been taken off of the market due to hepatotoxicity, but results from a RCT of 40 patients with PCOS reported that the use of pioglitazone (Actos) for 3 months increased normal regular cycles and ovulations over placebo (41.2% vs 5.6%; P<.02).⁷ No liver effects were noted, but caution must be taken since these drugs are pregnancy class C. Two small RCTs studied the use of rosiglitazone (Avandia) in combination with clomiphene and reported improvements in menstrual regularity⁸ (92% with combination therapy achieved improved menstrual cycles vs 68% with rosiglitazone alone; OR=0.185) and both spontaneous and clomiphene-induced ovulation rates (52% of clomiphene-resistant women ovulated after rosiglitazone therapy and 77% vs 33% ovulated with combination therapy vs rosiglitazone alone, P=.04).⁹ Further research is needed to determine the clinical effects of the thiazolidinediones.

Recommendations from Others

The American College of Obstetricians and Gynecologists guideline on diagnosis and management of PCOS reports that interventions that improve insulin sensitivity, including weight loss, use of metformin, and use of TZDs are useful for improving ovulatory frequency for women with PCOS.¹⁰ The recommendation is based on good and consistent scientific evidence (SOR: A). They also note that insulin-sensitizing agents may improve many risk factors for diabetes and cardiovascular disease, but this recommendation is based on limited evidence (SOR: B). Finally, they recommend, based on expert opinion (SOR: C), that caution be used with these agents because their effects on early pregnancy are unknown, even though metformin appears to be safe.

The American Association of Clinical Endocrinologists recommends using metformin 850 mg twice daily to treat the hyperandrogenic state of PCOS.¹¹ The use of TZDs is less clear due to limited evidence and risks of teratogenicity.

Evidence Summary

A common female endocrinopathy, PCOS affects 5% to 10% of women. Characterized by anovulation and hyperandrogenism, it often manifests as infertility and irregular menstruation. Metformin and thiazolidinediones are likely effective treatments for these expressions of insulin resistance, but study limitations restrict our ability to clearly define their role.

The most influential systematic review was a meta-analysis that reviewed 13 RCTs including 543 women to determine the effects of metformin on ovarian function in PCOS.^1,2By selecting RCTs, performing precise statistical analysis according to the Cochrane protocols, and clearly stating limitations, this review gives good evidence that metformin modestly increases the odds of ovulation for women with PCOS (odds ratio [OR]=3.88; 95% confidence interval [CI], 2.25–6.69 for metformin vs placebo) and that metformin with clomiphene (Clomid) effectively increases ovulation (OR=4.41; 95% CI, 2.37–8.22) and pregnancy rates (OR=4.40; 95% CI, 1.96–9.85) when compared with clomiphene use alone. When metformin is used as a sole agent, ovulation is achieved in 46% of recipients compared with 24% in the placebo arm (number needed to treat [NNT]=4.4). When metformin and clomiphene are used in combination, 76% of recipients ovulate compared with 42% receiving clomiphene alone (NNT=3.0).

Several problems with recommending metformin as first-line therapy exist: (1) equal or better ovulation rates have been described by using lifestyle interventions to achieve weight loss, (2) there are no long-term studies of the effects of metformin in PCOS patients, and (3) we cannot assess the clinically important outcome of pregnancy rates because the trials did not control for other infertility factors and did not define live births as a primary outcome. In addition, there are no head-to-head trials of metformin vs clomiphene, the standard first-line therapy for ovulation induction. Only 1 study addressed menstrual patterns specifically; they were improved with metformin (OR=12.88; 95% CI, 1.85–89.61).

An additional meta-analysis reports similar results.³ Eight RCTs addressing the use of metformin or clomiphene for treatment of PCOS were reviewed for ovulation and pregnancy rates. Metformin is 50% better than placebo for ovulation induction among infertile PCOS patients (relative risk [RR]=1.50; 95% CI, 1.31–1.99), but this benefit is not necessarily improved with longer duration (>3 months) of therapy (RR=1.37; 95% CI, 1.05–1.79). Also, metformin is beneficial in regulating cycles for fertile PCOS patients with irregular menses (RR=1.45; 95% CI, 1.11–1.90).

The conclusions regarding pregnancy rates and combined therapy with metformin and clomiphene are limited due to small samples, short follow-up time (2–6 months), and study design. An ongoing randomized trial (Pregnancy in Polycystic Ovarian Syndrome: PPOS study) of 768 infertile PCOS patients is investigating effects of metformin vs clomiphene on ovulation induction and achievement of singleton pregnancies. These outcomes should clarify remaining uncertainties regarding appropriate use of metformin.

Finally, a review of 7 RCTs describes the evidence accumulated by well-designed trials and its clinical relevance.⁴ Metformin improves ovulation and menstrual cyclicity but these improvements were variable and modest. On average, 1 additional ovulation is attained in every 5-month interval with metformin treatment; specifically, the baseline of 1 ovulation per 5-month interval increased to 2 ovulations per 5-month interval. Spontaneous ovulation and normal menstruation are achieved rapidly (within 3 months of the start of therapy). These data corroborate the benefits of metformin but place its clinical significance in perspective. For PCOS patients seeking cycle regulation but not pregnancy, oral contraceptives may remain better therapy because metformin does not normalize menses.

Less information exists on the role of TZDs and ovarian function in PCOS. Studies of the most researched drug in the class, troglitazone (Rezulin), report improvements in ovulation rates and metabolic markers of PCOS.^5,6 Troglitazone has been taken off of the market due to hepatotoxicity, but results from a RCT of 40 patients with PCOS reported that the use of pioglitazone (Actos) for 3 months increased normal regular cycles and ovulations over placebo (41.2% vs 5.6%; P<.02).⁷ No liver effects were noted, but caution must be taken since these drugs are pregnancy class C. Two small RCTs studied the use of rosiglitazone (Avandia) in combination with clomiphene and reported improvements in menstrual regularity⁸ (92% with combination therapy achieved improved menstrual cycles vs 68% with rosiglitazone alone; OR=0.185) and both spontaneous and clomiphene-induced ovulation rates (52% of clomiphene-resistant women ovulated after rosiglitazone therapy and 77% vs 33% ovulated with combination therapy vs rosiglitazone alone, P=.04).⁹ Further research is needed to determine the clinical effects of the thiazolidinediones.

Recommendations from Others

The American College of Obstetricians and Gynecologists guideline on diagnosis and management of PCOS reports that interventions that improve insulin sensitivity, including weight loss, use of metformin, and use of TZDs are useful for improving ovulatory frequency for women with PCOS.¹⁰ The recommendation is based on good and consistent scientific evidence (SOR: A). They also note that insulin-sensitizing agents may improve many risk factors for diabetes and cardiovascular disease, but this recommendation is based on limited evidence (SOR: B). Finally, they recommend, based on expert opinion (SOR: C), that caution be used with these agents because their effects on early pregnancy are unknown, even though metformin appears to be safe.

The American Association of Clinical Endocrinologists recommends using metformin 850 mg twice daily to treat the hyperandrogenic state of PCOS.¹¹ The use of TZDs is less clear due to limited evidence and risks of teratogenicity.

Evidence summary

Chronic daily headache is a heterogeneous primary headache disorder, often defined as a headache duration of more than 4 hours and a headache frequency of more than 15 per month; it affects less than 5% of the US population. Four headache subtypes included in the chronic daily headache definition are chronic (transformed) migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Each subtype may be associated with medication overuse.⁴

Chronic daily headache is challenging to categorize and difficult to manage, and scientific evidence to guide treatment is scant. Despite this, a few studies do offer some hopeful alternatives to those patients who have had conservative measures fail (Table).

A meta-analysis from 2001 reviewed 38 RCTs of antidepressants as prophylaxis for chronic headache. Nineteen studies investigated TCAs, 18 examined serotonin blockers, and 7 focused on SSRIs. Patients taking antidepressants were twice as likely to report headache improvement (rate ratio [RR]=2.0; 95% confidence interval [CI], 1.6–2.4), with the average amount of improvement considered to be large (standard mean difference=0.94; 95% CI, 0.65–1.2). Serotonin blockers, most of which are not available or commonly used in the US, and TCAs were all effective in decreasing the headache burden, while the results for SSRIs were less clear. Dosages of amitriptyline ranged from 10 to 150 mg daily; most of the studies used 60 to 100 mg daily.¹

Medication withdrawal therapy is a treatment strategy for chronic daily headaches associated with the paradoxical induction of headaches by the frequent, long-term use of immediate relief medications such as aspirin, NSAIDs, acetaminophen, caffeine, codeine, ergotamine, and sumatriptan. A retrospective study tracked 101 men and women who underwent a controlled outpatient withdrawal of their overused medications. Headache diaries kept for 1 to 3 months reflected that 56% of the patients had at least a 50% reduction in headache days after removal of overused drugs. Twenty-two patients who had no success with withdrawal and continued to have headaches were treated with amitriptyline. Subsequently, 10 of these patients experienced a 50% reduction in headache frequency.⁵

A systematic review of the therapeutic approaches to medication-induced headache looked at 18 studies from 1966 to 1998. Although most were uncontrolled small trials, medically monitored withdrawal of all symptomatic headache medications is recommended by the authors. No long-term outcome comparisons between withdrawal strategies are available.²

Other therapies for treating chronic daily headache include the skeletal muscle relaxant tizanidine (Zanaflex), which was studied in an industry-sponsored, double-blind, placebo-controlled trial of 92 patients. The medication was used as prophylaxis, titrating up to a dose of 8 mg 3 times daily. The overall headache index (a measure of headache intensity, frequency, and duration) significantly decreased. The headache index decreased in the tizanidine group from 2.6 to 1.2, and in the placebo group from 2.6 to 2.1 (P =.0025). Decreases in headache frequency and headache intensity were less dramatic but still significant. This trial lasted only 12 weeks, so longer-term outcomes are not available.⁶

Stress management, acupuncture, botulinum toxin, behavioral therapy including relaxation therapy, biofeedback, and even Internet-based self-help have all been studied, but most of these therapies do not have significant evidence-based support.

TABLE
Treatment options for chronic daily headache

Recommendations from others

Our literature search and review of major textbooks found no formally organized guidelines or recommendations on the treatment of chronic daily headache.

Evidence summary

Chronic daily headache is a heterogeneous primary headache disorder, often defined as a headache duration of more than 4 hours and a headache frequency of more than 15 per month; it affects less than 5% of the US population. Four headache subtypes included in the chronic daily headache definition are chronic (transformed) migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Each subtype may be associated with medication overuse.⁴

Chronic daily headache is challenging to categorize and difficult to manage, and scientific evidence to guide treatment is scant. Despite this, a few studies do offer some hopeful alternatives to those patients who have had conservative measures fail (Table).

A meta-analysis from 2001 reviewed 38 RCTs of antidepressants as prophylaxis for chronic headache. Nineteen studies investigated TCAs, 18 examined serotonin blockers, and 7 focused on SSRIs. Patients taking antidepressants were twice as likely to report headache improvement (rate ratio [RR]=2.0; 95% confidence interval [CI], 1.6–2.4), with the average amount of improvement considered to be large (standard mean difference=0.94; 95% CI, 0.65–1.2). Serotonin blockers, most of which are not available or commonly used in the US, and TCAs were all effective in decreasing the headache burden, while the results for SSRIs were less clear. Dosages of amitriptyline ranged from 10 to 150 mg daily; most of the studies used 60 to 100 mg daily.¹

Medication withdrawal therapy is a treatment strategy for chronic daily headaches associated with the paradoxical induction of headaches by the frequent, long-term use of immediate relief medications such as aspirin, NSAIDs, acetaminophen, caffeine, codeine, ergotamine, and sumatriptan. A retrospective study tracked 101 men and women who underwent a controlled outpatient withdrawal of their overused medications. Headache diaries kept for 1 to 3 months reflected that 56% of the patients had at least a 50% reduction in headache days after removal of overused drugs. Twenty-two patients who had no success with withdrawal and continued to have headaches were treated with amitriptyline. Subsequently, 10 of these patients experienced a 50% reduction in headache frequency.⁵

A systematic review of the therapeutic approaches to medication-induced headache looked at 18 studies from 1966 to 1998. Although most were uncontrolled small trials, medically monitored withdrawal of all symptomatic headache medications is recommended by the authors. No long-term outcome comparisons between withdrawal strategies are available.²

Other therapies for treating chronic daily headache include the skeletal muscle relaxant tizanidine (Zanaflex), which was studied in an industry-sponsored, double-blind, placebo-controlled trial of 92 patients. The medication was used as prophylaxis, titrating up to a dose of 8 mg 3 times daily. The overall headache index (a measure of headache intensity, frequency, and duration) significantly decreased. The headache index decreased in the tizanidine group from 2.6 to 1.2, and in the placebo group from 2.6 to 2.1 (P =.0025). Decreases in headache frequency and headache intensity were less dramatic but still significant. This trial lasted only 12 weeks, so longer-term outcomes are not available.⁶

Stress management, acupuncture, botulinum toxin, behavioral therapy including relaxation therapy, biofeedback, and even Internet-based self-help have all been studied, but most of these therapies do not have significant evidence-based support.

TABLE
Treatment options for chronic daily headache

Recommendations from others

Our literature search and review of major textbooks found no formally organized guidelines or recommendations on the treatment of chronic daily headache.

Evidence summary

Chronic daily headache is a heterogeneous primary headache disorder, often defined as a headache duration of more than 4 hours and a headache frequency of more than 15 per month; it affects less than 5% of the US population. Four headache subtypes included in the chronic daily headache definition are chronic (transformed) migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Each subtype may be associated with medication overuse.⁴

Chronic daily headache is challenging to categorize and difficult to manage, and scientific evidence to guide treatment is scant. Despite this, a few studies do offer some hopeful alternatives to those patients who have had conservative measures fail (Table).

A meta-analysis from 2001 reviewed 38 RCTs of antidepressants as prophylaxis for chronic headache. Nineteen studies investigated TCAs, 18 examined serotonin blockers, and 7 focused on SSRIs. Patients taking antidepressants were twice as likely to report headache improvement (rate ratio [RR]=2.0; 95% confidence interval [CI], 1.6–2.4), with the average amount of improvement considered to be large (standard mean difference=0.94; 95% CI, 0.65–1.2). Serotonin blockers, most of which are not available or commonly used in the US, and TCAs were all effective in decreasing the headache burden, while the results for SSRIs were less clear. Dosages of amitriptyline ranged from 10 to 150 mg daily; most of the studies used 60 to 100 mg daily.¹

Medication withdrawal therapy is a treatment strategy for chronic daily headaches associated with the paradoxical induction of headaches by the frequent, long-term use of immediate relief medications such as aspirin, NSAIDs, acetaminophen, caffeine, codeine, ergotamine, and sumatriptan. A retrospective study tracked 101 men and women who underwent a controlled outpatient withdrawal of their overused medications. Headache diaries kept for 1 to 3 months reflected that 56% of the patients had at least a 50% reduction in headache days after removal of overused drugs. Twenty-two patients who had no success with withdrawal and continued to have headaches were treated with amitriptyline. Subsequently, 10 of these patients experienced a 50% reduction in headache frequency.⁵

A systematic review of the therapeutic approaches to medication-induced headache looked at 18 studies from 1966 to 1998. Although most were uncontrolled small trials, medically monitored withdrawal of all symptomatic headache medications is recommended by the authors. No long-term outcome comparisons between withdrawal strategies are available.²

Other therapies for treating chronic daily headache include the skeletal muscle relaxant tizanidine (Zanaflex), which was studied in an industry-sponsored, double-blind, placebo-controlled trial of 92 patients. The medication was used as prophylaxis, titrating up to a dose of 8 mg 3 times daily. The overall headache index (a measure of headache intensity, frequency, and duration) significantly decreased. The headache index decreased in the tizanidine group from 2.6 to 1.2, and in the placebo group from 2.6 to 2.1 (P =.0025). Decreases in headache frequency and headache intensity were less dramatic but still significant. This trial lasted only 12 weeks, so longer-term outcomes are not available.⁶

Stress management, acupuncture, botulinum toxin, behavioral therapy including relaxation therapy, biofeedback, and even Internet-based self-help have all been studied, but most of these therapies do not have significant evidence-based support.

TABLE
Treatment options for chronic daily headache

Recommendations from others

Our literature search and review of major textbooks found no formally organized guidelines or recommendations on the treatment of chronic daily headache.

Evidence-based summary

Few studies of exercise treadmill testing include a significant number of women, which makes it difficult to ascertain its value for detecting CAD in women. A large meta-analysis of 19 studies looked specifically at women (n=3721) and found that noninvasive exercise tests only “moderately useful” for the detection of CAD. Exercise treadmill testing in women had a specificity of 0.70 (95% confidence interval [CI], 0.64–0.75), a sensitivity of 0.61 (95% CI, 0.54–0.68), a positive likelihood ratio of 2.25 (95% CI, 1.84–2.66) and a negative likelihood ratio of 0.55 (95% CI, 0.47–0.62). In comparison, exercise treadmill testing in men had a sensitivity of 0.70 and a specificity of 0.77.¹ The Table demonstrates how exercise treadmill testing performs for different levels of pretest probability.

Among the theoretical reasons for the diminished accuracy of the exercise treadmill testing in women are the varying catecholamine response to exercise, a higher incidence of mitral valve prolapse, and chest wall anatomy different than that in men.¹ Also, the methods used in performing exercise treadmill testing, as well as the thresholds for an abnormal test result, were established for men. Accuracy may also be affected by the subjectivity inherent in the performance and interpretation of the exercise treadmill testing, in particular, the reading of the ST segment.²

A large cohort study of 2994 asymptomatic women found that those women with a below-average peak exercise capacity and heart-rate recovery rate were 3.5 times more likely to die of cardiovascular causes than women who were above average (95% CI, 1.57–7.86).³ Another cohort study of 5721 women found that an exercise capacity of <5 metabolic equivalents (METS) tripled the risk of death as compared with those with an exercise capacity of >8 METS.⁴ These studies support the role of exercise treadmill testing for risk stratification for CAD disease in women.

TABLE
Post-test probabilities of coronary artery disease using exercise echocardiogram

Recommendations from others

The Institute for Clinical Systems Improvement states that exercise treadmill testing has application for the detection of coronary artery disease in those women with an intermediate (10%–90%) pretest probability of coronary artery disease as determined by age, gender, and symptoms. The intermediate category includes women aged 30 to 49 years with typical symptoms of angina, women aged 50 to 59 years with typical or atypical symptoms of angina, and women aged 60 to 69 years with atypical or nonanginal chest pain. All other women fall into groups with pretest probability either high enough or low enough that the exercise treadmill testing is less useful.⁵

The American College of Cardiology (ACC) and the American Heart Association concluded that the diagnosis of CAD in women presents difficulties not experienced with men, due primarily to the lower sensitivity and specificity of exercise treadmill testing. The ACC recommends exercise treadmill testing for the diagnosis of CAD in patients with an intermediate pretest probability of coronary disease based on age, gender, and symptoms. (This recommendation is described as one for which there is evidence or general agreement that a given procedure or treatment is useful and effective.)⁶

Evidence-based summary

Few studies of exercise treadmill testing include a significant number of women, which makes it difficult to ascertain its value for detecting CAD in women. A large meta-analysis of 19 studies looked specifically at women (n=3721) and found that noninvasive exercise tests only “moderately useful” for the detection of CAD. Exercise treadmill testing in women had a specificity of 0.70 (95% confidence interval [CI], 0.64–0.75), a sensitivity of 0.61 (95% CI, 0.54–0.68), a positive likelihood ratio of 2.25 (95% CI, 1.84–2.66) and a negative likelihood ratio of 0.55 (95% CI, 0.47–0.62). In comparison, exercise treadmill testing in men had a sensitivity of 0.70 and a specificity of 0.77.¹ The Table demonstrates how exercise treadmill testing performs for different levels of pretest probability.

Among the theoretical reasons for the diminished accuracy of the exercise treadmill testing in women are the varying catecholamine response to exercise, a higher incidence of mitral valve prolapse, and chest wall anatomy different than that in men.¹ Also, the methods used in performing exercise treadmill testing, as well as the thresholds for an abnormal test result, were established for men. Accuracy may also be affected by the subjectivity inherent in the performance and interpretation of the exercise treadmill testing, in particular, the reading of the ST segment.²

A large cohort study of 2994 asymptomatic women found that those women with a below-average peak exercise capacity and heart-rate recovery rate were 3.5 times more likely to die of cardiovascular causes than women who were above average (95% CI, 1.57–7.86).³ Another cohort study of 5721 women found that an exercise capacity of <5 metabolic equivalents (METS) tripled the risk of death as compared with those with an exercise capacity of >8 METS.⁴ These studies support the role of exercise treadmill testing for risk stratification for CAD disease in women.

TABLE
Post-test probabilities of coronary artery disease using exercise echocardiogram

Recommendations from others

The Institute for Clinical Systems Improvement states that exercise treadmill testing has application for the detection of coronary artery disease in those women with an intermediate (10%–90%) pretest probability of coronary artery disease as determined by age, gender, and symptoms. The intermediate category includes women aged 30 to 49 years with typical symptoms of angina, women aged 50 to 59 years with typical or atypical symptoms of angina, and women aged 60 to 69 years with atypical or nonanginal chest pain. All other women fall into groups with pretest probability either high enough or low enough that the exercise treadmill testing is less useful.⁵

The American College of Cardiology (ACC) and the American Heart Association concluded that the diagnosis of CAD in women presents difficulties not experienced with men, due primarily to the lower sensitivity and specificity of exercise treadmill testing. The ACC recommends exercise treadmill testing for the diagnosis of CAD in patients with an intermediate pretest probability of coronary disease based on age, gender, and symptoms. (This recommendation is described as one for which there is evidence or general agreement that a given procedure or treatment is useful and effective.)⁶

Evidence-based summary

Few studies of exercise treadmill testing include a significant number of women, which makes it difficult to ascertain its value for detecting CAD in women. A large meta-analysis of 19 studies looked specifically at women (n=3721) and found that noninvasive exercise tests only “moderately useful” for the detection of CAD. Exercise treadmill testing in women had a specificity of 0.70 (95% confidence interval [CI], 0.64–0.75), a sensitivity of 0.61 (95% CI, 0.54–0.68), a positive likelihood ratio of 2.25 (95% CI, 1.84–2.66) and a negative likelihood ratio of 0.55 (95% CI, 0.47–0.62). In comparison, exercise treadmill testing in men had a sensitivity of 0.70 and a specificity of 0.77.¹ The Table demonstrates how exercise treadmill testing performs for different levels of pretest probability.

Among the theoretical reasons for the diminished accuracy of the exercise treadmill testing in women are the varying catecholamine response to exercise, a higher incidence of mitral valve prolapse, and chest wall anatomy different than that in men.¹ Also, the methods used in performing exercise treadmill testing, as well as the thresholds for an abnormal test result, were established for men. Accuracy may also be affected by the subjectivity inherent in the performance and interpretation of the exercise treadmill testing, in particular, the reading of the ST segment.²

A large cohort study of 2994 asymptomatic women found that those women with a below-average peak exercise capacity and heart-rate recovery rate were 3.5 times more likely to die of cardiovascular causes than women who were above average (95% CI, 1.57–7.86).³ Another cohort study of 5721 women found that an exercise capacity of <5 metabolic equivalents (METS) tripled the risk of death as compared with those with an exercise capacity of >8 METS.⁴ These studies support the role of exercise treadmill testing for risk stratification for CAD disease in women.

TABLE
Post-test probabilities of coronary artery disease using exercise echocardiogram

Recommendations from others

The Institute for Clinical Systems Improvement states that exercise treadmill testing has application for the detection of coronary artery disease in those women with an intermediate (10%–90%) pretest probability of coronary artery disease as determined by age, gender, and symptoms. The intermediate category includes women aged 30 to 49 years with typical symptoms of angina, women aged 50 to 59 years with typical or atypical symptoms of angina, and women aged 60 to 69 years with atypical or nonanginal chest pain. All other women fall into groups with pretest probability either high enough or low enough that the exercise treadmill testing is less useful.⁵

The American College of Cardiology (ACC) and the American Heart Association concluded that the diagnosis of CAD in women presents difficulties not experienced with men, due primarily to the lower sensitivity and specificity of exercise treadmill testing. The ACC recommends exercise treadmill testing for the diagnosis of CAD in patients with an intermediate pretest probability of coronary disease based on age, gender, and symptoms. (This recommendation is described as one for which there is evidence or general agreement that a given procedure or treatment is useful and effective.)⁶

Evidence summary

Intracranial aneurysms are not rare. Based on autopsy data, prevalence has been estimated to be 0.2% to 9.9% of the population.¹ Ten to 15 million Americans may have unruptured intracranial aneurysms, most of which remain undiagnosed.²

Conditions leading to the diagnosis of unruptured intracranial aneurysms include:

• headache (in 36% of patients)
• ischemic cerebrovascular disease (17.6%)
• cranial nerve deficits (15.4 %)
• aneurysmal mass effect (5.7%)
• ill-defined “spells” (4.8%)
• convulsive disorder (4.2%)
• subdural or intracerebral hemorrhage (2.7%)
• brain tumor (1.7%)
• nervous system degenerative disease (0.5%).²

No randomized controlled trials have examined whether unruptured intracranial aneurysms should be treated surgically. In the absence of a clinical trial, the evidence to answer this question is based on observational, cohort, and case-control studies, where the risks of the natural history of the condition are weighed against the risks of surgical intervention.³

One study of the natural history of unruptured cerebral aneurysm included 130 patients with 161 unruptured intracranial aneurysms who were followed for a mean of 8.3 years.^4,5 This prospective investigation found that 15 patients suffered an intracranial hemorrhage. There were no ruptures of the 102 aneurysms that were ≤10 mm in diameter at the time of discovery.^4,5

In the largest cohort study to date, patients without a history of subarachnoid hemorrhage had an overall risk of rupture of 0.05% per year over 7.5 years. This study also found that surgery-related morbidity and mortality at 1 year among patients aged <45 years was 6.5%, compared with 14.4% for those aged 45 to 64 years, and 32% for those aged >64 years.²

Recommendations from others

The Stroke Council of the American Heart Association recommends that observation is generally appropriate for incidental, small (<10-mm) aneurysms in patients without previous subarachnoid hemorrhage. However, special consideration for treatment should be given to young patients in this group, small aneurysms approaching the 10-mm size, and aneurysms with daughter sac formation ( Figure). In addition, patients with a family history of aneurysm or aneurysmal subarachnoid hemorrhage deserve special consideration for treatment.

For patients managed conservatively, periodic follow-up imaging should be considered; imaging is necessary if a specific symptom should arise. If changes in aneurysmal size or configuration are observed, special consideration for treatment should be made.⁶

Aneurysm with daughter sac

Evidence summary

Intracranial aneurysms are not rare. Based on autopsy data, prevalence has been estimated to be 0.2% to 9.9% of the population.¹ Ten to 15 million Americans may have unruptured intracranial aneurysms, most of which remain undiagnosed.²

Conditions leading to the diagnosis of unruptured intracranial aneurysms include:

• headache (in 36% of patients)
• ischemic cerebrovascular disease (17.6%)
• cranial nerve deficits (15.4 %)
• aneurysmal mass effect (5.7%)
• ill-defined “spells” (4.8%)
• convulsive disorder (4.2%)
• subdural or intracerebral hemorrhage (2.7%)
• brain tumor (1.7%)
• nervous system degenerative disease (0.5%).²

No randomized controlled trials have examined whether unruptured intracranial aneurysms should be treated surgically. In the absence of a clinical trial, the evidence to answer this question is based on observational, cohort, and case-control studies, where the risks of the natural history of the condition are weighed against the risks of surgical intervention.³

One study of the natural history of unruptured cerebral aneurysm included 130 patients with 161 unruptured intracranial aneurysms who were followed for a mean of 8.3 years.^4,5 This prospective investigation found that 15 patients suffered an intracranial hemorrhage. There were no ruptures of the 102 aneurysms that were ≤10 mm in diameter at the time of discovery.^4,5

In the largest cohort study to date, patients without a history of subarachnoid hemorrhage had an overall risk of rupture of 0.05% per year over 7.5 years. This study also found that surgery-related morbidity and mortality at 1 year among patients aged <45 years was 6.5%, compared with 14.4% for those aged 45 to 64 years, and 32% for those aged >64 years.²

Recommendations from others

The Stroke Council of the American Heart Association recommends that observation is generally appropriate for incidental, small (<10-mm) aneurysms in patients without previous subarachnoid hemorrhage. However, special consideration for treatment should be given to young patients in this group, small aneurysms approaching the 10-mm size, and aneurysms with daughter sac formation ( Figure). In addition, patients with a family history of aneurysm or aneurysmal subarachnoid hemorrhage deserve special consideration for treatment.

For patients managed conservatively, periodic follow-up imaging should be considered; imaging is necessary if a specific symptom should arise. If changes in aneurysmal size or configuration are observed, special consideration for treatment should be made.⁶

Aneurysm with daughter sac

Evidence summary

Intracranial aneurysms are not rare. Based on autopsy data, prevalence has been estimated to be 0.2% to 9.9% of the population.¹ Ten to 15 million Americans may have unruptured intracranial aneurysms, most of which remain undiagnosed.²

Conditions leading to the diagnosis of unruptured intracranial aneurysms include:

• headache (in 36% of patients)
• ischemic cerebrovascular disease (17.6%)
• cranial nerve deficits (15.4 %)
• aneurysmal mass effect (5.7%)
• ill-defined “spells” (4.8%)
• convulsive disorder (4.2%)
• subdural or intracerebral hemorrhage (2.7%)
• brain tumor (1.7%)
• nervous system degenerative disease (0.5%).²

No randomized controlled trials have examined whether unruptured intracranial aneurysms should be treated surgically. In the absence of a clinical trial, the evidence to answer this question is based on observational, cohort, and case-control studies, where the risks of the natural history of the condition are weighed against the risks of surgical intervention.³

One study of the natural history of unruptured cerebral aneurysm included 130 patients with 161 unruptured intracranial aneurysms who were followed for a mean of 8.3 years.^4,5 This prospective investigation found that 15 patients suffered an intracranial hemorrhage. There were no ruptures of the 102 aneurysms that were ≤10 mm in diameter at the time of discovery.^4,5

In the largest cohort study to date, patients without a history of subarachnoid hemorrhage had an overall risk of rupture of 0.05% per year over 7.5 years. This study also found that surgery-related morbidity and mortality at 1 year among patients aged <45 years was 6.5%, compared with 14.4% for those aged 45 to 64 years, and 32% for those aged >64 years.²

Recommendations from others

The Stroke Council of the American Heart Association recommends that observation is generally appropriate for incidental, small (<10-mm) aneurysms in patients without previous subarachnoid hemorrhage. However, special consideration for treatment should be given to young patients in this group, small aneurysms approaching the 10-mm size, and aneurysms with daughter sac formation ( Figure). In addition, patients with a family history of aneurysm or aneurysmal subarachnoid hemorrhage deserve special consideration for treatment.

For patients managed conservatively, periodic follow-up imaging should be considered; imaging is necessary if a specific symptom should arise. If changes in aneurysmal size or configuration are observed, special consideration for treatment should be made.⁶

Aneurysm with daughter sac