Cleveland Clinic Journal of Medicine

To this day I remain impressed by the algorithmic nature of trauma management. A routine that to the internist could appear mindless and slavish was to the trauma physician a protocol designed to take no chances on missing a life-threatening complication in the heat of the moment. The trauma physician cannot afford to wait for a cognitively derived epiphany in a clinical setting that often rapidly unfolds as a series of “never-miss” scenarios. The appropriate algorithm, rigorously followed, offers the best chance of avoiding a catastrophe of omission. This was long before Atul Gawande published his Checklist Manifesto.

Reviewing the article by Sussman et al, “Eyes of the mimicker,” in this issue of the Journal got me thinking about the power of algorithmic thinking and practice in internal medicine, how the patient they describe specifically relates to my practice experiences over the years, and how important the context of where we practice and who we treat informs (and can misinform) our clinical reasoning. When I was a medical student at Bellevue Hospital in New York City (in the pre-HIV era), the rapid plasma reagin (RPR) was a routine blood test, as syphilis routinely earned its moniker as the “great imitator.” When I did my residency at the Hospital of the University of Pennsylvania, my ingrained habit of ordering this test was extinguished, along with my also previously learned habit of obtaining blood cultures in all patients who presented with new heart failure that was not explained by the electrocardiogram. These habits disappeared not because of arguments steeped in evidence-based medicine or an emphasis on Bayesian test-ordering, but because in Philadelphia at that time we were not seeing patients with occult syphilis and endocarditis with the same frequency as at Bellevue. Context can and should play a role in our diagnostic reasoning.

But I still remember the patient I saw in the Philadelphia emergency room, a second visit for a man in his 20s with a diffuse, mostly macular rash on his trunk, palms, and soles (visible when the light was turned up in his darkened room, as he felt uncomfortable with bright light), diffuse adenopathy, and enlarged doughy and minimally tender wrists and finger (metacarpophalangeal) joints. I recall wondering why no one had thought to obtain an RPR test on him the first time he had presented to the emergency room; if he had been at Bellevue, the test results would already have returned.

Without appropriate algorithms, things get missed. But using algorithms indiscriminately is cost-ineffective and can lead to cascades of inappropriate tests and interventions. Striking the appropriate balance is part of what comprises the writing of useful clinical care paths.

As I read the article by Sussman et al I wondered who first looked at the patient’s retinas and what initially prompted the testing that was ordered. The presentation was not typical of ocular syphilis, and I would guess that an ophthalmologist or infectious disease consultant evaluating the blurred vision observed the retinal findings, suspected the diagnosis, and ordered serologies, as well as other studies searching for infections and systemic autoimmune disorders that can also cause Roth spots. Gone are the days when internists (and residents) routinely examine the eyes as part of a full physical examination. I am certain an evidence-based study of this practice would find it time-ineffective and with inappropriately low sensitivity.

I don’t think the retinal examination will return to the internist’s checklist. Yet that is where the algorithm that led to this patient’s diagnosis likely began. One can “google” the causes of Roth spots, but as yet there is no app for demonstrating that they are present.

To this day I remain impressed by the algorithmic nature of trauma management. A routine that to the internist could appear mindless and slavish was to the trauma physician a protocol designed to take no chances on missing a life-threatening complication in the heat of the moment. The trauma physician cannot afford to wait for a cognitively derived epiphany in a clinical setting that often rapidly unfolds as a series of “never-miss” scenarios. The appropriate algorithm, rigorously followed, offers the best chance of avoiding a catastrophe of omission. This was long before Atul Gawande published his Checklist Manifesto.

Reviewing the article by Sussman et al, “Eyes of the mimicker,” in this issue of the Journal got me thinking about the power of algorithmic thinking and practice in internal medicine, how the patient they describe specifically relates to my practice experiences over the years, and how important the context of where we practice and who we treat informs (and can misinform) our clinical reasoning. When I was a medical student at Bellevue Hospital in New York City (in the pre-HIV era), the rapid plasma reagin (RPR) was a routine blood test, as syphilis routinely earned its moniker as the “great imitator.” When I did my residency at the Hospital of the University of Pennsylvania, my ingrained habit of ordering this test was extinguished, along with my also previously learned habit of obtaining blood cultures in all patients who presented with new heart failure that was not explained by the electrocardiogram. These habits disappeared not because of arguments steeped in evidence-based medicine or an emphasis on Bayesian test-ordering, but because in Philadelphia at that time we were not seeing patients with occult syphilis and endocarditis with the same frequency as at Bellevue. Context can and should play a role in our diagnostic reasoning.

But I still remember the patient I saw in the Philadelphia emergency room, a second visit for a man in his 20s with a diffuse, mostly macular rash on his trunk, palms, and soles (visible when the light was turned up in his darkened room, as he felt uncomfortable with bright light), diffuse adenopathy, and enlarged doughy and minimally tender wrists and finger (metacarpophalangeal) joints. I recall wondering why no one had thought to obtain an RPR test on him the first time he had presented to the emergency room; if he had been at Bellevue, the test results would already have returned.

Without appropriate algorithms, things get missed. But using algorithms indiscriminately is cost-ineffective and can lead to cascades of inappropriate tests and interventions. Striking the appropriate balance is part of what comprises the writing of useful clinical care paths.

As I read the article by Sussman et al I wondered who first looked at the patient’s retinas and what initially prompted the testing that was ordered. The presentation was not typical of ocular syphilis, and I would guess that an ophthalmologist or infectious disease consultant evaluating the blurred vision observed the retinal findings, suspected the diagnosis, and ordered serologies, as well as other studies searching for infections and systemic autoimmune disorders that can also cause Roth spots. Gone are the days when internists (and residents) routinely examine the eyes as part of a full physical examination. I am certain an evidence-based study of this practice would find it time-ineffective and with inappropriately low sensitivity.

I don’t think the retinal examination will return to the internist’s checklist. Yet that is where the algorithm that led to this patient’s diagnosis likely began. One can “google” the causes of Roth spots, but as yet there is no app for demonstrating that they are present.

To this day I remain impressed by the algorithmic nature of trauma management. A routine that to the internist could appear mindless and slavish was to the trauma physician a protocol designed to take no chances on missing a life-threatening complication in the heat of the moment. The trauma physician cannot afford to wait for a cognitively derived epiphany in a clinical setting that often rapidly unfolds as a series of “never-miss” scenarios. The appropriate algorithm, rigorously followed, offers the best chance of avoiding a catastrophe of omission. This was long before Atul Gawande published his Checklist Manifesto.

Reviewing the article by Sussman et al, “Eyes of the mimicker,” in this issue of the Journal got me thinking about the power of algorithmic thinking and practice in internal medicine, how the patient they describe specifically relates to my practice experiences over the years, and how important the context of where we practice and who we treat informs (and can misinform) our clinical reasoning. When I was a medical student at Bellevue Hospital in New York City (in the pre-HIV era), the rapid plasma reagin (RPR) was a routine blood test, as syphilis routinely earned its moniker as the “great imitator.” When I did my residency at the Hospital of the University of Pennsylvania, my ingrained habit of ordering this test was extinguished, along with my also previously learned habit of obtaining blood cultures in all patients who presented with new heart failure that was not explained by the electrocardiogram. These habits disappeared not because of arguments steeped in evidence-based medicine or an emphasis on Bayesian test-ordering, but because in Philadelphia at that time we were not seeing patients with occult syphilis and endocarditis with the same frequency as at Bellevue. Context can and should play a role in our diagnostic reasoning.

But I still remember the patient I saw in the Philadelphia emergency room, a second visit for a man in his 20s with a diffuse, mostly macular rash on his trunk, palms, and soles (visible when the light was turned up in his darkened room, as he felt uncomfortable with bright light), diffuse adenopathy, and enlarged doughy and minimally tender wrists and finger (metacarpophalangeal) joints. I recall wondering why no one had thought to obtain an RPR test on him the first time he had presented to the emergency room; if he had been at Bellevue, the test results would already have returned.

Without appropriate algorithms, things get missed. But using algorithms indiscriminately is cost-ineffective and can lead to cascades of inappropriate tests and interventions. Striking the appropriate balance is part of what comprises the writing of useful clinical care paths.

As I read the article by Sussman et al I wondered who first looked at the patient’s retinas and what initially prompted the testing that was ordered. The presentation was not typical of ocular syphilis, and I would guess that an ophthalmologist or infectious disease consultant evaluating the blurred vision observed the retinal findings, suspected the diagnosis, and ordered serologies, as well as other studies searching for infections and systemic autoimmune disorders that can also cause Roth spots. Gone are the days when internists (and residents) routinely examine the eyes as part of a full physical examination. I am certain an evidence-based study of this practice would find it time-ineffective and with inappropriately low sensitivity.

I don’t think the retinal examination will return to the internist’s checklist. Yet that is where the algorithm that led to this patient’s diagnosis likely began. One can “google” the causes of Roth spots, but as yet there is no app for demonstrating that they are present.

For many women, the postmenopausal loss of estrogen is associated with uncomfortable genitourinary symptoms, collectively referred to as the genitourinary syndrome of menopause (GSM). But despite the prevalence of GSM and the availability of treatments, most women do not seek relief.

This article reviews the syndrome and offers advice on how to talk about it with patients and what treatment options to consider.

A SYNDROME RECENTLY DEFINED

The term GSM and its definition were approved by the North American Menopause Society and the International Society for the Study of Women’s Sexual Health in 2014.¹ It replaces older terms such as vulvovaginal atrophy, urogenital atrophy, and atrophic vaginitis.

GSM refers collectively to the symptoms associated with estrogen loss after menopause that adversely affect the vulvovaginal area and lower urinary tract. The most common symptoms are vulvovaginal dryness, burning, or irritation; sexual pain from inadequate lubrication; and urinary urgency, dysuria, or recurrent urinary tract infection.^1,2

The definition notes that symptoms are self-reported as bothersome and are not the result of another disorder. Symptoms may be chronic and progressive, are not likely to resolve without treatment (pharmacologic or nonpharmacologic), and can have a significant negative impact on a woman’s quality of life and sexual health.^1,2

COMMON BUT UNDERTREATED

From 40% to 60% of postmenopausal women experience GSM, but few seek treatment.³ Nevertheless, most postmenopausal women remain sexually active. In a 2008 survey of 94,000 postmenopausal women ages 50 to 79, 52% reported that they had been sexually active with a partner in the past year.⁴ However, 45% of postmenopausal women experienced unpleasant vaginal symptoms, according to a 2012 international survey of 3,520 postmenopausal women ages 55 to 65.⁵ In this survey, most respondents (75%) felt that vaginal symptoms had a negative impact on their life, but only 4% connected their symptoms to the vulvovaginal atrophy that resulted from loss of estrogen after menopause. Moreover, almost half were unaware of management options.⁵ 

These findings were supported by a 2013 survey of more than 3,000 US women who reported unpleasant vulvar and vaginal symptoms.⁶ From 60% to 85% noted negative sexual consequences from vulvovaginal symptoms, 47% felt their relationship suffered, and 27% felt it had a negative impact on their general enjoyment of life. In this study, 24% attributed their symptoms to menopause and 12% to hormonal changes. Although 56% had discussed GSM symptoms with a healthcare provider, only 40% were using GSM-specific topical treatments, mostly over-the-counter preparations.

Male partners of symptomatic women also note adverse emotional and physical effects.⁷ In an online survey of 4,100 men and 4,100 women ages 55 to 65, 52% to 78% of men and 58% to 64% of women expressed the negative effects of vulvovaginal symptoms on intimacy, libido, and sexual pain.

GSM is a progressive disorder. Women may note symptoms many years before menopause or have no symptoms until several years after menopause. One study found the prevalence of GSM to be 4% during perimenopause, rising after menopause to 25% after 1 year and to 47% after 3 years.⁸

Although distressing symptoms occur mostly after menopause, they may be seen in women of any age who experience a hypo­estrogenic state, even if it is transient. Causes of this include premature ovarian failure, hypothalamic amenorrhea, and hyperprolactinemia. In addition, some treatments such as gonadotropin-releasing hormone agonists and aromatase inhibitors may cause vulvovaginal and lower urinary tract symptoms. Chemotherapy, radiation, and surgical removal of ovaries may also precipitate symptoms. The abrupt onset of menopause that may occur with these treatments is often associated with significantly greater sexual dysfunction and negative impact on quality of life. Cigarette smoking also leads to lower estrogen levels, which may contribute to GSM.

WHAT CAUSES GSM?

The genitourinary system develops from common embryologic tissue, the basis for the functional and clinical connection. Estrogen maintains the epithelium of the vagina, vulva, urethra, and bladder trigone via estrogen receptors present throughout these tissues.⁹

Premenopausal changes

Histologically, the estrogen-exposed vagina of a premenopausal woman is lined by glycogen-rich, stratified squamous epithelium, with underlying supportive fibromuscular layers. The epithelium is composed of superficial, intermediate, and parabasal cellular layers. In the presence of estrogen, the superficial and intermediate cellular levels predominate, with few parabasal cells.

Glycogen acts as a substrate for lactobacilli, producing organic acids, primarily lactate, that help maintain an acidic pH of 2.8 to 4.0. The low pH helps protect against pathologic shifts in the microbiome. Estrogen also maintains the collagen content of the epithelium, maintains acid mucopolysaccharides and hyaluronic acid, and optimizes vaginal blood flow. These effects result in optimal epithelial thickness and elasticity, moisture, vaginal secretions, and lubrication.¹⁰

Postmenopausal changes

Low levels of estrogen after menopause result in adverse anatomic, physiologic, and clinical changes in vaginal tissue. Effects of hypoestrogenism include the loss of collagen and adipose, leading to decreased elasticity and vaginal mucosal thinning. Vascular flow is decreased. The epithelial cytology transitions to a predominance of parabasal cells and a decrease in superficial and intermediate cells. Eccrine and apocrine glands become attenuated. These changes result in decreased vaginal secretions, diminished or delayed lubrication with sexual stimulation, friability of the vaginal vault, and vaginal dryness.¹¹

Additionally, without estrogen, glycogen content is diminished, leading to decreased lactic acid production and a rise in vaginal pH to greater than 5. As the pH rises, Lactobacillus colonization decreases, leading to a further decrease in glycogen metabolism and to propagation of an elevated vaginal pH. The loss of vaginal acidity makes the vagina more susceptible to pathologic bacteria, including those found in the bowel and skin, sexually transmitted infections, and bacterial vaginosis.¹²

Other affected tissues. Anatomic effects of estrogen loss are not limited to the vagina. The epithelium, connective tissue, and smooth muscle of the vulva, vagina, urethra, and bladder trigone are also affected. The labia minora become thinner and regress, the introitus retracts, and narrowing and stricture of the vaginal canal and introitus may result. In some women, the urethral meatus becomes prominent relative to the introitus and more vulnerable to physical irritation, infection, and trauma.

Clinically, estrogen-related changes are usually responsible for vaginal dryness, irritation, burning, and superficial or deep dyspareunia. Urinary frequency, urgency, and incontinence also may develop.

The diagnosis of GSM is based on the history and physical examination. Standardized diagnostic tools for GSM are lacking, but some tools are available.

In 2006, the US Food and Drug Administration (FDA) published guidelines for industry to better define patient-reported outcome measures in clinical trials.¹³ The most significant addition was having the patient define the symptoms and rate how “bothersome” the symptoms are. Although this measure does not help diagnose GSM, it can be used effectively to follow response to treatment.

The Vaginal Symptom Questionnaire¹⁴ can be useful for assessing symptoms. It is a validated 21-item questionnaire that measures the quality-of-life impact of genital, but not urinary, symptoms of menopause.

Ask patients about symptoms

Healthcare providers should ask about GSM symptoms (Table 1) during routine clinical visits with women who are peri- or postmenopausal or who have hypoestrogenism from other causes, as many women are reluctant to initiate this discussion. Conversely, in women who present with sexual problems, such as difficulty with arousal or dyspareunia, GSM should be considered as a possible cause.

Specifically, ask women if they have any of the following symptoms:

• Vaginal itching, burning, discomfort, or irritation
• Malodorous or irritating vaginal discharge
• Urinary frequency, urgency, dysuria, urethral discomfort, or recurrent urinary tract infections
• Sexual symptoms of entry dyspareunia, vaginal pain, or irritation with sexual activity, which may be complicated by postcoital bleeding, spotting, or fissuring.

Vulvovaginal pain or irritation may be constant or may be present in the absence of sexual activity, such as with exercise, wearing tight clothing, or sitting for long periods.

Physical examination

Characteristic physical findings of GSM include scarce pubic hair, thinning of the labia from loss of labial fat, resorption of the labia minora, or fusion of the labia minora and majora (Table 2).^15,16 The vulvar skin is pale and thin. The clitoral hood may retract, exposing the glans (which may lead to increased pain with sexual stimulation), or clitoral hood fusion may occur. The vagina is pale, dry, smooth, and shiny with loss of rugae; shortening or stricturing may be present. Vaginal elasticity decreases. Inflammation and petechiae (pinpoint, nonraised, round purple-red spots) may be present. The cervix may be flush with the vaginal fornices.

Prolonged atrophy may result in introital narrowing and friability, which may cause tearing with sexual activity or insertion of a speculum during pelvic examination. In addition, the epithelium of the lower urinary tract thins, and the muscular and fibrous layers atrophy—changes that may not be obvious during examination. A urethral caruncle may form, presenting as proliferative red tissue at the entrance of the urethra. Prolapse may become more prominent.

In women with severe genitourinary atrophy, pelvic examination may cause significant discomfort. Reassuring the patient that she can ask the clinician to stop at any time due to extreme discomfort is the first step in a successful pelvic examination.

In some situations, initial examination of the pelvic area may not include insertion of a speculum. Use of a hand-held mirror so the patient can observe the examination may help her relax during the examination.

Vaginal pH and cultures, if indicated, may be obtained by gently inserting a cotton-tipped swab into the vagina without a speculum and before applying lubricant. Lubricant should be used generously; in some instances, topical lidocaine gel (diluted, as it may burn) may be placed against the perineum on a gauze pad for 3 to 5 minutes before insertion of the speculum.

When an internal pelvic examination is necessary in a timely manner, such as with postmenopausal bleeding or a history of an abnormal Papanicolaou smear, but is too painful for the patient, the examination should be done under anesthesia.

Additional considerations

The history should review current medical conditions, medication use, nongenital skin disorders (eg, eczema), and systemic menopausal symptoms, such as hot flashes.

Also, consider other potential causes of GSM during the evaluation (Table 3).^17,18 Review the use of detergents, soaps, douches, or over-the-counter topical products that could cause genitourinary symptoms secondary to contact irritation or allergy.

Any isolated, ulcerated, or nonhealing lesion should be biopsied. Reevaluate patients who have not responded to previous topical therapy or consider referral to a specialist.

Assess the personal, interpersonal, social, and sexual impact of the symptoms: if they do not cause distress, GSM does not require treatment. Nevertheless, potential treatment options should be discussed as symptoms may progress, making intervention necessary.

Laboratory tests: Helpful, not essential

Laboratory tests are unnecessary for the diagnosis of GSM. However, office-based objective evaluations such as vaginal pH testing and the maturation index can support the diagnosis.

The pH of the estrogenized vagina ranges from 3.8 to 4.2, whereas in women with GSM, the pH may reach 5.5 or higher. The pH can be obtained by placing a pH-sensitive paper against the lateral vaginal wall, avoiding any discharge or cervical mucus. A vaginal pH of 5 or greater in the absence of blood, semen, or infection suggests vulvovaginal atrophy.¹⁹

The vaginal maturation index is determined by a vaginal smear using Rakoff staining, in which 100 cells are counted and the number of parabasal, intermediate, and superficial cells is determined. In general, a well-estrogenized vagina has mostly superficial and intermediate cells, which shifts to a predominance of parabasal cells as estrogen levels decline.²⁰

A recent review of vaginal atrophy suggests that after a diagnosis of GSM, healthcare providers can consider the most bothersome symptom along with the vaginal pH to assess the response to treatment.²¹ In general, schedule a follow-up appointment at 8 to 12 weeks to review treatment response. If treatment has not resulted in adequate symptom relief, consider a pelvic examination and further testing.

Symptomatic women with GSM who desire intervention should be offered over-the-counter nonhormonal products as the first line of therapy.

If nonhormonal products are ineffective and there are no contraindications, locally applied estrogen in cream, tablet, or a ring delivery system may be offered. Local dehydro­epiandrosterone (DHEA) inserts or ospemifene, an oral selective estrogen-receptor modulator, are FDA-approved for moderate to severe dyspareunia secondary to GSM.

Oral estrogen therapy is not indicated for vulvovaginal symptoms, but some women taking systemic estrogen for vasomotor symptoms may need additional local estrogen application to relieve vaginal symptoms.

Nonhormonal treatments

Nonhormonal over-the-counter therapies provide sufficient relief for most women with mild symptoms. There is a plethora of products, so practitioners need to offer guidance to help women with their individual choices.

Vaginal lubricants are intended for use with sexual or penetrative activity (including pelvic examination). They provide short-term relief of symptoms, but there is no evidence of any impact on histologic changes of atrophy. They are meant to relieve friction. Lubricants may be water-based, oil-based, silicone-based, or a combination. Individual products have different effects on condom integrity. Perfumed, warming, or stimulating products may be irritating to some women and should be tried initially in small amounts.

Vaginal moisturizers are intended to treat GSM. They are applied regularly, not just with vaginal activity, usually once or twice a week. Some vaginal lubricants can maintain an acidic pH in the vagina and may reverse the histologic changes of atrophy. Symptomatic improvement over placebo or estrogen has been shown in clinical trials.^22–24

Women should be advised that trial and error in choosing products may be necessary to establish a successful regimen. Products should be tried in succession, not simultaneously, with a “wash-out” period between, to be able to evaluate response.

Vaginal dilators and pelvic floor physical therapy

Sexual activity, either by self-stimulation or with a partner, helps maintain vaginal health by contributing to increased vascularity and elasticity of tissue. Women who resume sexual activity after a long period of inactivity may benefit from the use of vaginal dilators, which aid both in mechanical distention and progressive relaxation of the vaginal musculature.

In some women, long-term dyspareunia may result in vaginismus, an involuntary contraction of the vaginal musculature. For these women, dilators may be effective. Additional options focus on pelvic floor physical therapy, which can isolate trigger points, using biofeedback to teach relaxation and home exercises such as vaginal massage.

HORMONAL THERAPIES

If nonhormonal lubricants and moisturizers do not achieve satisfactory symptomatic relief, FDA-approved hormonal therapies (Table 4) include estrogen-containing vaginal creams, rings, and a tablet; a vaginal tablet containing DHEA; and an oral tablet containing ospemifene.

Estrogen products

For patients whose symptoms do not respond to nonhormonal therapies, low-dose, locally applied estrogen therapy is the first treatment recommended.² Locally applied estrogens can reverse the atrophic changes of estrogen deprivation, resulting in an increase in blood flow, elasticity, and vaginal wall thickness. This therapy also can normalize pH levels with subsequent restoration of a healthy lactobacilli-based flora. Locally applied estrogens also have been shown to decrease the frequency of recurrent urinary tract infection.²⁵

Estrogen-containing vaginal creams, rings, and a tablet are available, and each has been shown to be effective for GSM. Locally applied estrogens at recommended dosages tend to have fewer adverse events and risks than systemic estrogens.²⁶ Estradiol levels generally do not exceed levels found in the untreated menopausal population, although a dose- and duration-dependent increase in systemic levels may occur.²⁷

Dosing considerations

The vaginal ring and the vaginal tablet provide the lowest prefixed daily dose of estradiol (7.5 and 10 µg daily, respectively). Estrogen creams (estradiol, conjugated equine estrogens) are more readily absorbed, and dosing should be tapered to the lowest, most effective dose for symptom relief.

The FDA-approved doses for vaginal creams containing 17-beta estradiol are higher than the dose found to be effective in clinical practice (0.5 g twice a week). Most practitioners start with the lower dose, reserving the FDA-approved higher doses for patients who do not obtain adequate relief over 6 to 8 weeks of treatment. The conjugated-estrogen vaginal cream Premarin is the only locally applied estrogen approved by the FDA to treat dyspareunia. It is dosed at 0.5 g intravaginally for 21 days and is then either withdrawn for 7 days or, more commonly, administered at 0.5 g twice a week.

Initial treatment with vaginal cream may require more frequent vulvovaginal application, such as daily for 1 to 2 weeks. Women with vaginal fissures or tearing will benefit from externally applied creams in addition to internal applications. Response to therapy is usually seen within 4 to 6 weeks from onset of treatment. Once symptom relief is obtained, treatment should continue indefinitely. Although long-term safety studies are lacking, risks are believed to be minimal.

Endometrial impact. Women with contraindications to systemic estrogen should be counseled about possible small increases in serum levels of estradiol associated with locally applied estrogens and the potential risks and benefits those increases incur. Endometrial surveillance with either transvaginal ultrasonography or endometrial sampling is not required, even with long-term use, but it should be considered with higher doses or more frequent applications.

Similarly, progesterone replacement for endometrial protection is not recommended but can be considered in women with an intact uterus at high risk of endometrial cancer, such as obese patients. If a systemic progestational agent is considered, the risks and benefits should be weighed carefully. Even in women at high risk, endometrial surveillance may be the most appropriate option.²⁸ Uterine bleeding that occurs should be considered abnormal and should be investigated.

DHEA (prasterone)

In 2016, the FDA approved intravaginal prasterone, a DHEA-containing product for the treatment of dyspareunia secondary to moderate to severe vulvovaginal atrophy caused by menopause. DHEA is an endogenous steroid that is converted by aromatase activity into testosterone and estradiol.

Clinical trials have found that 12 weeks of vaginal DHEA supplementation (0.25%, 0.5%, and 1% DHEA ovules) was more effective than placebo in improving vaginal dryness and dyspareunia in women with GSM.^29–31 In these studies, locally applied DHEA decreased parabasal cells, decreased vaginal pH, increased vaginal secretions, and improved epithelial surface thickness and integrity without any significant impact on serum levels of DHEA, DHEA-sulfate, estradiol, testosterone, or their metabolites. Importantly, transvaginal DHEA had negligible endometrial effect.

The breast cancer risk associated with vaginal DHEA has not been fully evaluated. However, labeling lists breast cancer as a warning, not a contraindication.

In 2013, the FDA approved ospemifene for the treatment of dyspareunia caused by GSM. Ospemifene, an estrogen agonist in the vagina, is taken daily as a 60-mg oral dose. Long-term safety studies suggested no adverse effects on the endometrium or breast for at least 52 weeks.³²

These studies also noted that ospemifene improved the vaginal maturation index (decreased parabasal cells and increased superficial cells) and decreased vaginal pH. It has further been shown to decrease severity of the self-identified most bothersome symptom—dyspareunia or vaginal dryness—compared with placebo.³³

Potential increases in hot flashes, which may occur in up to 7% of patients, and the risk of blood clots should be considered. Additionally, the safety of ospemifene in women with a history of breast cancer has not been established. Although early studies suggest it either has no effect or possibly a protective effect on breast tissue, the FDA does not recommend its use in women at risk for breast cancer. Long-term effects on bone are unknown.

The labeling for ospemifene includes a boxed warning about the risk of stroke, blood clots, and cancer of the lining of the uterus. Patients should be counseled about worrisome signs or symptoms that require medical attention.

ALTERNATIVE THERAPIES

Treatments for GSM not approved by the FDA include laser and radiofrequency therapies, testosterone, isoflavones, and bioidentical hormones.

Laser and radiofrequency therapies

Both of these therapies aim to promote tissue remodeling with increased collagen and elastin production and increased vascularity. This, in turn, increases muscle support and tone.

Laser therapies act by ablating and coagulating vaginal tissues; radiofrequency therapies directly heat the tissue. Both treatments are office-based, require up to 3 initial treatments, and are followed by retreatment at approximately 1-year intervals.

Studies have reported high patient satisfaction rates (91% to 100%), improved sexual functioning, and decreased GSM symptoms of vaginal dryness, burning, itching, and dyspareunia.^34–36 Data, however, are from observational studies, not placebo-controlled trials.

Although laser and radiofrequency therapies are FDA-approved for several indications, laser treatment for symptoms of vulvovaginal atrophy is not currently an approved indication. Patients should be advised of this.

Testosterone

Locally applied testosterone was shown in a small study to improve dyspareunia and vaginal dryness associated with aromatase inhibitor use in breast cancer patients.³⁷ However, due to the lack of safety and efficacy data from larger, controlled trials, testosterone therapy is not currently recommended.

Isoflavones

Isoflavones are phytoestrogens found in soy. In a 12-week, double-blind placebo-controlled study of vaginally applied 4% soy isoflavone gel, improvements in vaginal atrophy symptoms, maturation values, and vaginal pH were found in 60 postmenopausal women.³⁸ Additional data on efficacy and safety are needed before isoflavones should be considered as a treatment for GSM.

Bioidentical hormones

Bioidentical hormones are plant-derived hormones that are chemically similar or identical to those produced by the body. Although there are FDA-approved bioidentical hormones (eg, micronized progesterone, estradiol, DHEA), the term bioidentical usually refers to non-FDA-approved, commercially available hormones produced and compounded by specialty pharmacies.

Patients often view these substances as being better, safer, and more acceptable for use, and healthcare practitioners need to be prepared to address these beliefs. The FDA and the American College of Obstetricians and Gynecologists consider bioidentical hormones to be a marketing term and not an alternative treatment based on scientific evidence.³⁹ Patients should be informed that bioidentical hormones have the same risks as any similar hormone preparation along with additional risks related to potential lack of purity and potency. Further, they have not been adequately studied in controlled clinical trials.

FOLLOW-UP CARE

Healthcare providers caring for women should assume a proactive role in diagnosing and treating the symptoms of GSM. And once diagnosis of GSM is established and treatment is under way, practitioners can use symptom questionnaires and vaginal pH testing as easy and reliable means of measuring clinical response to therapy.

For many women, the postmenopausal loss of estrogen is associated with uncomfortable genitourinary symptoms, collectively referred to as the genitourinary syndrome of menopause (GSM). But despite the prevalence of GSM and the availability of treatments, most women do not seek relief.

This article reviews the syndrome and offers advice on how to talk about it with patients and what treatment options to consider.

A SYNDROME RECENTLY DEFINED

The term GSM and its definition were approved by the North American Menopause Society and the International Society for the Study of Women’s Sexual Health in 2014.¹ It replaces older terms such as vulvovaginal atrophy, urogenital atrophy, and atrophic vaginitis.

GSM refers collectively to the symptoms associated with estrogen loss after menopause that adversely affect the vulvovaginal area and lower urinary tract. The most common symptoms are vulvovaginal dryness, burning, or irritation; sexual pain from inadequate lubrication; and urinary urgency, dysuria, or recurrent urinary tract infection.^1,2

The definition notes that symptoms are self-reported as bothersome and are not the result of another disorder. Symptoms may be chronic and progressive, are not likely to resolve without treatment (pharmacologic or nonpharmacologic), and can have a significant negative impact on a woman’s quality of life and sexual health.^1,2

COMMON BUT UNDERTREATED

From 40% to 60% of postmenopausal women experience GSM, but few seek treatment.³ Nevertheless, most postmenopausal women remain sexually active. In a 2008 survey of 94,000 postmenopausal women ages 50 to 79, 52% reported that they had been sexually active with a partner in the past year.⁴ However, 45% of postmenopausal women experienced unpleasant vaginal symptoms, according to a 2012 international survey of 3,520 postmenopausal women ages 55 to 65.⁵ In this survey, most respondents (75%) felt that vaginal symptoms had a negative impact on their life, but only 4% connected their symptoms to the vulvovaginal atrophy that resulted from loss of estrogen after menopause. Moreover, almost half were unaware of management options.⁵ 

These findings were supported by a 2013 survey of more than 3,000 US women who reported unpleasant vulvar and vaginal symptoms.⁶ From 60% to 85% noted negative sexual consequences from vulvovaginal symptoms, 47% felt their relationship suffered, and 27% felt it had a negative impact on their general enjoyment of life. In this study, 24% attributed their symptoms to menopause and 12% to hormonal changes. Although 56% had discussed GSM symptoms with a healthcare provider, only 40% were using GSM-specific topical treatments, mostly over-the-counter preparations.

Male partners of symptomatic women also note adverse emotional and physical effects.⁷ In an online survey of 4,100 men and 4,100 women ages 55 to 65, 52% to 78% of men and 58% to 64% of women expressed the negative effects of vulvovaginal symptoms on intimacy, libido, and sexual pain.

GSM is a progressive disorder. Women may note symptoms many years before menopause or have no symptoms until several years after menopause. One study found the prevalence of GSM to be 4% during perimenopause, rising after menopause to 25% after 1 year and to 47% after 3 years.⁸

Although distressing symptoms occur mostly after menopause, they may be seen in women of any age who experience a hypo­estrogenic state, even if it is transient. Causes of this include premature ovarian failure, hypothalamic amenorrhea, and hyperprolactinemia. In addition, some treatments such as gonadotropin-releasing hormone agonists and aromatase inhibitors may cause vulvovaginal and lower urinary tract symptoms. Chemotherapy, radiation, and surgical removal of ovaries may also precipitate symptoms. The abrupt onset of menopause that may occur with these treatments is often associated with significantly greater sexual dysfunction and negative impact on quality of life. Cigarette smoking also leads to lower estrogen levels, which may contribute to GSM.

WHAT CAUSES GSM?

The genitourinary system develops from common embryologic tissue, the basis for the functional and clinical connection. Estrogen maintains the epithelium of the vagina, vulva, urethra, and bladder trigone via estrogen receptors present throughout these tissues.⁹

Premenopausal changes

Histologically, the estrogen-exposed vagina of a premenopausal woman is lined by glycogen-rich, stratified squamous epithelium, with underlying supportive fibromuscular layers. The epithelium is composed of superficial, intermediate, and parabasal cellular layers. In the presence of estrogen, the superficial and intermediate cellular levels predominate, with few parabasal cells.

Glycogen acts as a substrate for lactobacilli, producing organic acids, primarily lactate, that help maintain an acidic pH of 2.8 to 4.0. The low pH helps protect against pathologic shifts in the microbiome. Estrogen also maintains the collagen content of the epithelium, maintains acid mucopolysaccharides and hyaluronic acid, and optimizes vaginal blood flow. These effects result in optimal epithelial thickness and elasticity, moisture, vaginal secretions, and lubrication.¹⁰

Postmenopausal changes

Low levels of estrogen after menopause result in adverse anatomic, physiologic, and clinical changes in vaginal tissue. Effects of hypoestrogenism include the loss of collagen and adipose, leading to decreased elasticity and vaginal mucosal thinning. Vascular flow is decreased. The epithelial cytology transitions to a predominance of parabasal cells and a decrease in superficial and intermediate cells. Eccrine and apocrine glands become attenuated. These changes result in decreased vaginal secretions, diminished or delayed lubrication with sexual stimulation, friability of the vaginal vault, and vaginal dryness.¹¹

Additionally, without estrogen, glycogen content is diminished, leading to decreased lactic acid production and a rise in vaginal pH to greater than 5. As the pH rises, Lactobacillus colonization decreases, leading to a further decrease in glycogen metabolism and to propagation of an elevated vaginal pH. The loss of vaginal acidity makes the vagina more susceptible to pathologic bacteria, including those found in the bowel and skin, sexually transmitted infections, and bacterial vaginosis.¹²

Other affected tissues. Anatomic effects of estrogen loss are not limited to the vagina. The epithelium, connective tissue, and smooth muscle of the vulva, vagina, urethra, and bladder trigone are also affected. The labia minora become thinner and regress, the introitus retracts, and narrowing and stricture of the vaginal canal and introitus may result. In some women, the urethral meatus becomes prominent relative to the introitus and more vulnerable to physical irritation, infection, and trauma.

Clinically, estrogen-related changes are usually responsible for vaginal dryness, irritation, burning, and superficial or deep dyspareunia. Urinary frequency, urgency, and incontinence also may develop.

The diagnosis of GSM is based on the history and physical examination. Standardized diagnostic tools for GSM are lacking, but some tools are available.

In 2006, the US Food and Drug Administration (FDA) published guidelines for industry to better define patient-reported outcome measures in clinical trials.¹³ The most significant addition was having the patient define the symptoms and rate how “bothersome” the symptoms are. Although this measure does not help diagnose GSM, it can be used effectively to follow response to treatment.

The Vaginal Symptom Questionnaire¹⁴ can be useful for assessing symptoms. It is a validated 21-item questionnaire that measures the quality-of-life impact of genital, but not urinary, symptoms of menopause.

Ask patients about symptoms

Healthcare providers should ask about GSM symptoms (Table 1) during routine clinical visits with women who are peri- or postmenopausal or who have hypoestrogenism from other causes, as many women are reluctant to initiate this discussion. Conversely, in women who present with sexual problems, such as difficulty with arousal or dyspareunia, GSM should be considered as a possible cause.

Specifically, ask women if they have any of the following symptoms:

• Vaginal itching, burning, discomfort, or irritation
• Malodorous or irritating vaginal discharge
• Urinary frequency, urgency, dysuria, urethral discomfort, or recurrent urinary tract infections
• Sexual symptoms of entry dyspareunia, vaginal pain, or irritation with sexual activity, which may be complicated by postcoital bleeding, spotting, or fissuring.

Vulvovaginal pain or irritation may be constant or may be present in the absence of sexual activity, such as with exercise, wearing tight clothing, or sitting for long periods.

Physical examination

Characteristic physical findings of GSM include scarce pubic hair, thinning of the labia from loss of labial fat, resorption of the labia minora, or fusion of the labia minora and majora (Table 2).^15,16 The vulvar skin is pale and thin. The clitoral hood may retract, exposing the glans (which may lead to increased pain with sexual stimulation), or clitoral hood fusion may occur. The vagina is pale, dry, smooth, and shiny with loss of rugae; shortening or stricturing may be present. Vaginal elasticity decreases. Inflammation and petechiae (pinpoint, nonraised, round purple-red spots) may be present. The cervix may be flush with the vaginal fornices.

Prolonged atrophy may result in introital narrowing and friability, which may cause tearing with sexual activity or insertion of a speculum during pelvic examination. In addition, the epithelium of the lower urinary tract thins, and the muscular and fibrous layers atrophy—changes that may not be obvious during examination. A urethral caruncle may form, presenting as proliferative red tissue at the entrance of the urethra. Prolapse may become more prominent.

In women with severe genitourinary atrophy, pelvic examination may cause significant discomfort. Reassuring the patient that she can ask the clinician to stop at any time due to extreme discomfort is the first step in a successful pelvic examination.

In some situations, initial examination of the pelvic area may not include insertion of a speculum. Use of a hand-held mirror so the patient can observe the examination may help her relax during the examination.

Vaginal pH and cultures, if indicated, may be obtained by gently inserting a cotton-tipped swab into the vagina without a speculum and before applying lubricant. Lubricant should be used generously; in some instances, topical lidocaine gel (diluted, as it may burn) may be placed against the perineum on a gauze pad for 3 to 5 minutes before insertion of the speculum.

When an internal pelvic examination is necessary in a timely manner, such as with postmenopausal bleeding or a history of an abnormal Papanicolaou smear, but is too painful for the patient, the examination should be done under anesthesia.

Additional considerations

The history should review current medical conditions, medication use, nongenital skin disorders (eg, eczema), and systemic menopausal symptoms, such as hot flashes.

Also, consider other potential causes of GSM during the evaluation (Table 3).^17,18 Review the use of detergents, soaps, douches, or over-the-counter topical products that could cause genitourinary symptoms secondary to contact irritation or allergy.

Any isolated, ulcerated, or nonhealing lesion should be biopsied. Reevaluate patients who have not responded to previous topical therapy or consider referral to a specialist.

Assess the personal, interpersonal, social, and sexual impact of the symptoms: if they do not cause distress, GSM does not require treatment. Nevertheless, potential treatment options should be discussed as symptoms may progress, making intervention necessary.

Laboratory tests: Helpful, not essential

Laboratory tests are unnecessary for the diagnosis of GSM. However, office-based objective evaluations such as vaginal pH testing and the maturation index can support the diagnosis.

The pH of the estrogenized vagina ranges from 3.8 to 4.2, whereas in women with GSM, the pH may reach 5.5 or higher. The pH can be obtained by placing a pH-sensitive paper against the lateral vaginal wall, avoiding any discharge or cervical mucus. A vaginal pH of 5 or greater in the absence of blood, semen, or infection suggests vulvovaginal atrophy.¹⁹

The vaginal maturation index is determined by a vaginal smear using Rakoff staining, in which 100 cells are counted and the number of parabasal, intermediate, and superficial cells is determined. In general, a well-estrogenized vagina has mostly superficial and intermediate cells, which shifts to a predominance of parabasal cells as estrogen levels decline.²⁰

A recent review of vaginal atrophy suggests that after a diagnosis of GSM, healthcare providers can consider the most bothersome symptom along with the vaginal pH to assess the response to treatment.²¹ In general, schedule a follow-up appointment at 8 to 12 weeks to review treatment response. If treatment has not resulted in adequate symptom relief, consider a pelvic examination and further testing.

Symptomatic women with GSM who desire intervention should be offered over-the-counter nonhormonal products as the first line of therapy.

If nonhormonal products are ineffective and there are no contraindications, locally applied estrogen in cream, tablet, or a ring delivery system may be offered. Local dehydro­epiandrosterone (DHEA) inserts or ospemifene, an oral selective estrogen-receptor modulator, are FDA-approved for moderate to severe dyspareunia secondary to GSM.

Oral estrogen therapy is not indicated for vulvovaginal symptoms, but some women taking systemic estrogen for vasomotor symptoms may need additional local estrogen application to relieve vaginal symptoms.

Nonhormonal treatments

Nonhormonal over-the-counter therapies provide sufficient relief for most women with mild symptoms. There is a plethora of products, so practitioners need to offer guidance to help women with their individual choices.

Vaginal lubricants are intended for use with sexual or penetrative activity (including pelvic examination). They provide short-term relief of symptoms, but there is no evidence of any impact on histologic changes of atrophy. They are meant to relieve friction. Lubricants may be water-based, oil-based, silicone-based, or a combination. Individual products have different effects on condom integrity. Perfumed, warming, or stimulating products may be irritating to some women and should be tried initially in small amounts.

Vaginal moisturizers are intended to treat GSM. They are applied regularly, not just with vaginal activity, usually once or twice a week. Some vaginal lubricants can maintain an acidic pH in the vagina and may reverse the histologic changes of atrophy. Symptomatic improvement over placebo or estrogen has been shown in clinical trials.^22–24

Women should be advised that trial and error in choosing products may be necessary to establish a successful regimen. Products should be tried in succession, not simultaneously, with a “wash-out” period between, to be able to evaluate response.

Vaginal dilators and pelvic floor physical therapy

Sexual activity, either by self-stimulation or with a partner, helps maintain vaginal health by contributing to increased vascularity and elasticity of tissue. Women who resume sexual activity after a long period of inactivity may benefit from the use of vaginal dilators, which aid both in mechanical distention and progressive relaxation of the vaginal musculature.

In some women, long-term dyspareunia may result in vaginismus, an involuntary contraction of the vaginal musculature. For these women, dilators may be effective. Additional options focus on pelvic floor physical therapy, which can isolate trigger points, using biofeedback to teach relaxation and home exercises such as vaginal massage.

HORMONAL THERAPIES

If nonhormonal lubricants and moisturizers do not achieve satisfactory symptomatic relief, FDA-approved hormonal therapies (Table 4) include estrogen-containing vaginal creams, rings, and a tablet; a vaginal tablet containing DHEA; and an oral tablet containing ospemifene.

Estrogen products

For patients whose symptoms do not respond to nonhormonal therapies, low-dose, locally applied estrogen therapy is the first treatment recommended.² Locally applied estrogens can reverse the atrophic changes of estrogen deprivation, resulting in an increase in blood flow, elasticity, and vaginal wall thickness. This therapy also can normalize pH levels with subsequent restoration of a healthy lactobacilli-based flora. Locally applied estrogens also have been shown to decrease the frequency of recurrent urinary tract infection.²⁵

Estrogen-containing vaginal creams, rings, and a tablet are available, and each has been shown to be effective for GSM. Locally applied estrogens at recommended dosages tend to have fewer adverse events and risks than systemic estrogens.²⁶ Estradiol levels generally do not exceed levels found in the untreated menopausal population, although a dose- and duration-dependent increase in systemic levels may occur.²⁷

Dosing considerations

The vaginal ring and the vaginal tablet provide the lowest prefixed daily dose of estradiol (7.5 and 10 µg daily, respectively). Estrogen creams (estradiol, conjugated equine estrogens) are more readily absorbed, and dosing should be tapered to the lowest, most effective dose for symptom relief.

The FDA-approved doses for vaginal creams containing 17-beta estradiol are higher than the dose found to be effective in clinical practice (0.5 g twice a week). Most practitioners start with the lower dose, reserving the FDA-approved higher doses for patients who do not obtain adequate relief over 6 to 8 weeks of treatment. The conjugated-estrogen vaginal cream Premarin is the only locally applied estrogen approved by the FDA to treat dyspareunia. It is dosed at 0.5 g intravaginally for 21 days and is then either withdrawn for 7 days or, more commonly, administered at 0.5 g twice a week.

Initial treatment with vaginal cream may require more frequent vulvovaginal application, such as daily for 1 to 2 weeks. Women with vaginal fissures or tearing will benefit from externally applied creams in addition to internal applications. Response to therapy is usually seen within 4 to 6 weeks from onset of treatment. Once symptom relief is obtained, treatment should continue indefinitely. Although long-term safety studies are lacking, risks are believed to be minimal.

Endometrial impact. Women with contraindications to systemic estrogen should be counseled about possible small increases in serum levels of estradiol associated with locally applied estrogens and the potential risks and benefits those increases incur. Endometrial surveillance with either transvaginal ultrasonography or endometrial sampling is not required, even with long-term use, but it should be considered with higher doses or more frequent applications.

Similarly, progesterone replacement for endometrial protection is not recommended but can be considered in women with an intact uterus at high risk of endometrial cancer, such as obese patients. If a systemic progestational agent is considered, the risks and benefits should be weighed carefully. Even in women at high risk, endometrial surveillance may be the most appropriate option.²⁸ Uterine bleeding that occurs should be considered abnormal and should be investigated.

DHEA (prasterone)

In 2016, the FDA approved intravaginal prasterone, a DHEA-containing product for the treatment of dyspareunia secondary to moderate to severe vulvovaginal atrophy caused by menopause. DHEA is an endogenous steroid that is converted by aromatase activity into testosterone and estradiol.

Clinical trials have found that 12 weeks of vaginal DHEA supplementation (0.25%, 0.5%, and 1% DHEA ovules) was more effective than placebo in improving vaginal dryness and dyspareunia in women with GSM.^29–31 In these studies, locally applied DHEA decreased parabasal cells, decreased vaginal pH, increased vaginal secretions, and improved epithelial surface thickness and integrity without any significant impact on serum levels of DHEA, DHEA-sulfate, estradiol, testosterone, or their metabolites. Importantly, transvaginal DHEA had negligible endometrial effect.

The breast cancer risk associated with vaginal DHEA has not been fully evaluated. However, labeling lists breast cancer as a warning, not a contraindication.

In 2013, the FDA approved ospemifene for the treatment of dyspareunia caused by GSM. Ospemifene, an estrogen agonist in the vagina, is taken daily as a 60-mg oral dose. Long-term safety studies suggested no adverse effects on the endometrium or breast for at least 52 weeks.³²

These studies also noted that ospemifene improved the vaginal maturation index (decreased parabasal cells and increased superficial cells) and decreased vaginal pH. It has further been shown to decrease severity of the self-identified most bothersome symptom—dyspareunia or vaginal dryness—compared with placebo.³³

Potential increases in hot flashes, which may occur in up to 7% of patients, and the risk of blood clots should be considered. Additionally, the safety of ospemifene in women with a history of breast cancer has not been established. Although early studies suggest it either has no effect or possibly a protective effect on breast tissue, the FDA does not recommend its use in women at risk for breast cancer. Long-term effects on bone are unknown.

The labeling for ospemifene includes a boxed warning about the risk of stroke, blood clots, and cancer of the lining of the uterus. Patients should be counseled about worrisome signs or symptoms that require medical attention.

ALTERNATIVE THERAPIES

Treatments for GSM not approved by the FDA include laser and radiofrequency therapies, testosterone, isoflavones, and bioidentical hormones.

Laser and radiofrequency therapies

Both of these therapies aim to promote tissue remodeling with increased collagen and elastin production and increased vascularity. This, in turn, increases muscle support and tone.

Laser therapies act by ablating and coagulating vaginal tissues; radiofrequency therapies directly heat the tissue. Both treatments are office-based, require up to 3 initial treatments, and are followed by retreatment at approximately 1-year intervals.

Studies have reported high patient satisfaction rates (91% to 100%), improved sexual functioning, and decreased GSM symptoms of vaginal dryness, burning, itching, and dyspareunia.^34–36 Data, however, are from observational studies, not placebo-controlled trials.

Although laser and radiofrequency therapies are FDA-approved for several indications, laser treatment for symptoms of vulvovaginal atrophy is not currently an approved indication. Patients should be advised of this.

Testosterone

Locally applied testosterone was shown in a small study to improve dyspareunia and vaginal dryness associated with aromatase inhibitor use in breast cancer patients.³⁷ However, due to the lack of safety and efficacy data from larger, controlled trials, testosterone therapy is not currently recommended.

Isoflavones

Isoflavones are phytoestrogens found in soy. In a 12-week, double-blind placebo-controlled study of vaginally applied 4% soy isoflavone gel, improvements in vaginal atrophy symptoms, maturation values, and vaginal pH were found in 60 postmenopausal women.³⁸ Additional data on efficacy and safety are needed before isoflavones should be considered as a treatment for GSM.

Bioidentical hormones

Bioidentical hormones are plant-derived hormones that are chemically similar or identical to those produced by the body. Although there are FDA-approved bioidentical hormones (eg, micronized progesterone, estradiol, DHEA), the term bioidentical usually refers to non-FDA-approved, commercially available hormones produced and compounded by specialty pharmacies.

Patients often view these substances as being better, safer, and more acceptable for use, and healthcare practitioners need to be prepared to address these beliefs. The FDA and the American College of Obstetricians and Gynecologists consider bioidentical hormones to be a marketing term and not an alternative treatment based on scientific evidence.³⁹ Patients should be informed that bioidentical hormones have the same risks as any similar hormone preparation along with additional risks related to potential lack of purity and potency. Further, they have not been adequately studied in controlled clinical trials.

FOLLOW-UP CARE

Healthcare providers caring for women should assume a proactive role in diagnosing and treating the symptoms of GSM. And once diagnosis of GSM is established and treatment is under way, practitioners can use symptom questionnaires and vaginal pH testing as easy and reliable means of measuring clinical response to therapy.

For many women, the postmenopausal loss of estrogen is associated with uncomfortable genitourinary symptoms, collectively referred to as the genitourinary syndrome of menopause (GSM). But despite the prevalence of GSM and the availability of treatments, most women do not seek relief.

This article reviews the syndrome and offers advice on how to talk about it with patients and what treatment options to consider.

A SYNDROME RECENTLY DEFINED

The term GSM and its definition were approved by the North American Menopause Society and the International Society for the Study of Women’s Sexual Health in 2014.¹ It replaces older terms such as vulvovaginal atrophy, urogenital atrophy, and atrophic vaginitis.

GSM refers collectively to the symptoms associated with estrogen loss after menopause that adversely affect the vulvovaginal area and lower urinary tract. The most common symptoms are vulvovaginal dryness, burning, or irritation; sexual pain from inadequate lubrication; and urinary urgency, dysuria, or recurrent urinary tract infection.^1,2

The definition notes that symptoms are self-reported as bothersome and are not the result of another disorder. Symptoms may be chronic and progressive, are not likely to resolve without treatment (pharmacologic or nonpharmacologic), and can have a significant negative impact on a woman’s quality of life and sexual health.^1,2

COMMON BUT UNDERTREATED

From 40% to 60% of postmenopausal women experience GSM, but few seek treatment.³ Nevertheless, most postmenopausal women remain sexually active. In a 2008 survey of 94,000 postmenopausal women ages 50 to 79, 52% reported that they had been sexually active with a partner in the past year.⁴ However, 45% of postmenopausal women experienced unpleasant vaginal symptoms, according to a 2012 international survey of 3,520 postmenopausal women ages 55 to 65.⁵ In this survey, most respondents (75%) felt that vaginal symptoms had a negative impact on their life, but only 4% connected their symptoms to the vulvovaginal atrophy that resulted from loss of estrogen after menopause. Moreover, almost half were unaware of management options.⁵ 

These findings were supported by a 2013 survey of more than 3,000 US women who reported unpleasant vulvar and vaginal symptoms.⁶ From 60% to 85% noted negative sexual consequences from vulvovaginal symptoms, 47% felt their relationship suffered, and 27% felt it had a negative impact on their general enjoyment of life. In this study, 24% attributed their symptoms to menopause and 12% to hormonal changes. Although 56% had discussed GSM symptoms with a healthcare provider, only 40% were using GSM-specific topical treatments, mostly over-the-counter preparations.

Male partners of symptomatic women also note adverse emotional and physical effects.⁷ In an online survey of 4,100 men and 4,100 women ages 55 to 65, 52% to 78% of men and 58% to 64% of women expressed the negative effects of vulvovaginal symptoms on intimacy, libido, and sexual pain.

GSM is a progressive disorder. Women may note symptoms many years before menopause or have no symptoms until several years after menopause. One study found the prevalence of GSM to be 4% during perimenopause, rising after menopause to 25% after 1 year and to 47% after 3 years.⁸

Although distressing symptoms occur mostly after menopause, they may be seen in women of any age who experience a hypo­estrogenic state, even if it is transient. Causes of this include premature ovarian failure, hypothalamic amenorrhea, and hyperprolactinemia. In addition, some treatments such as gonadotropin-releasing hormone agonists and aromatase inhibitors may cause vulvovaginal and lower urinary tract symptoms. Chemotherapy, radiation, and surgical removal of ovaries may also precipitate symptoms. The abrupt onset of menopause that may occur with these treatments is often associated with significantly greater sexual dysfunction and negative impact on quality of life. Cigarette smoking also leads to lower estrogen levels, which may contribute to GSM.

WHAT CAUSES GSM?

The genitourinary system develops from common embryologic tissue, the basis for the functional and clinical connection. Estrogen maintains the epithelium of the vagina, vulva, urethra, and bladder trigone via estrogen receptors present throughout these tissues.⁹

Premenopausal changes

Histologically, the estrogen-exposed vagina of a premenopausal woman is lined by glycogen-rich, stratified squamous epithelium, with underlying supportive fibromuscular layers. The epithelium is composed of superficial, intermediate, and parabasal cellular layers. In the presence of estrogen, the superficial and intermediate cellular levels predominate, with few parabasal cells.

Glycogen acts as a substrate for lactobacilli, producing organic acids, primarily lactate, that help maintain an acidic pH of 2.8 to 4.0. The low pH helps protect against pathologic shifts in the microbiome. Estrogen also maintains the collagen content of the epithelium, maintains acid mucopolysaccharides and hyaluronic acid, and optimizes vaginal blood flow. These effects result in optimal epithelial thickness and elasticity, moisture, vaginal secretions, and lubrication.¹⁰

Postmenopausal changes

Low levels of estrogen after menopause result in adverse anatomic, physiologic, and clinical changes in vaginal tissue. Effects of hypoestrogenism include the loss of collagen and adipose, leading to decreased elasticity and vaginal mucosal thinning. Vascular flow is decreased. The epithelial cytology transitions to a predominance of parabasal cells and a decrease in superficial and intermediate cells. Eccrine and apocrine glands become attenuated. These changes result in decreased vaginal secretions, diminished or delayed lubrication with sexual stimulation, friability of the vaginal vault, and vaginal dryness.¹¹

Additionally, without estrogen, glycogen content is diminished, leading to decreased lactic acid production and a rise in vaginal pH to greater than 5. As the pH rises, Lactobacillus colonization decreases, leading to a further decrease in glycogen metabolism and to propagation of an elevated vaginal pH. The loss of vaginal acidity makes the vagina more susceptible to pathologic bacteria, including those found in the bowel and skin, sexually transmitted infections, and bacterial vaginosis.¹²

Other affected tissues. Anatomic effects of estrogen loss are not limited to the vagina. The epithelium, connective tissue, and smooth muscle of the vulva, vagina, urethra, and bladder trigone are also affected. The labia minora become thinner and regress, the introitus retracts, and narrowing and stricture of the vaginal canal and introitus may result. In some women, the urethral meatus becomes prominent relative to the introitus and more vulnerable to physical irritation, infection, and trauma.

Clinically, estrogen-related changes are usually responsible for vaginal dryness, irritation, burning, and superficial or deep dyspareunia. Urinary frequency, urgency, and incontinence also may develop.

The diagnosis of GSM is based on the history and physical examination. Standardized diagnostic tools for GSM are lacking, but some tools are available.

In 2006, the US Food and Drug Administration (FDA) published guidelines for industry to better define patient-reported outcome measures in clinical trials.¹³ The most significant addition was having the patient define the symptoms and rate how “bothersome” the symptoms are. Although this measure does not help diagnose GSM, it can be used effectively to follow response to treatment.

The Vaginal Symptom Questionnaire¹⁴ can be useful for assessing symptoms. It is a validated 21-item questionnaire that measures the quality-of-life impact of genital, but not urinary, symptoms of menopause.

Ask patients about symptoms

Healthcare providers should ask about GSM symptoms (Table 1) during routine clinical visits with women who are peri- or postmenopausal or who have hypoestrogenism from other causes, as many women are reluctant to initiate this discussion. Conversely, in women who present with sexual problems, such as difficulty with arousal or dyspareunia, GSM should be considered as a possible cause.

Specifically, ask women if they have any of the following symptoms:

• Vaginal itching, burning, discomfort, or irritation
• Malodorous or irritating vaginal discharge
• Urinary frequency, urgency, dysuria, urethral discomfort, or recurrent urinary tract infections
• Sexual symptoms of entry dyspareunia, vaginal pain, or irritation with sexual activity, which may be complicated by postcoital bleeding, spotting, or fissuring.

Vulvovaginal pain or irritation may be constant or may be present in the absence of sexual activity, such as with exercise, wearing tight clothing, or sitting for long periods.

Physical examination

Characteristic physical findings of GSM include scarce pubic hair, thinning of the labia from loss of labial fat, resorption of the labia minora, or fusion of the labia minora and majora (Table 2).^15,16 The vulvar skin is pale and thin. The clitoral hood may retract, exposing the glans (which may lead to increased pain with sexual stimulation), or clitoral hood fusion may occur. The vagina is pale, dry, smooth, and shiny with loss of rugae; shortening or stricturing may be present. Vaginal elasticity decreases. Inflammation and petechiae (pinpoint, nonraised, round purple-red spots) may be present. The cervix may be flush with the vaginal fornices.

Prolonged atrophy may result in introital narrowing and friability, which may cause tearing with sexual activity or insertion of a speculum during pelvic examination. In addition, the epithelium of the lower urinary tract thins, and the muscular and fibrous layers atrophy—changes that may not be obvious during examination. A urethral caruncle may form, presenting as proliferative red tissue at the entrance of the urethra. Prolapse may become more prominent.

In women with severe genitourinary atrophy, pelvic examination may cause significant discomfort. Reassuring the patient that she can ask the clinician to stop at any time due to extreme discomfort is the first step in a successful pelvic examination.

In some situations, initial examination of the pelvic area may not include insertion of a speculum. Use of a hand-held mirror so the patient can observe the examination may help her relax during the examination.

Vaginal pH and cultures, if indicated, may be obtained by gently inserting a cotton-tipped swab into the vagina without a speculum and before applying lubricant. Lubricant should be used generously; in some instances, topical lidocaine gel (diluted, as it may burn) may be placed against the perineum on a gauze pad for 3 to 5 minutes before insertion of the speculum.

When an internal pelvic examination is necessary in a timely manner, such as with postmenopausal bleeding or a history of an abnormal Papanicolaou smear, but is too painful for the patient, the examination should be done under anesthesia.

Additional considerations

The history should review current medical conditions, medication use, nongenital skin disorders (eg, eczema), and systemic menopausal symptoms, such as hot flashes.

Also, consider other potential causes of GSM during the evaluation (Table 3).^17,18 Review the use of detergents, soaps, douches, or over-the-counter topical products that could cause genitourinary symptoms secondary to contact irritation or allergy.

Any isolated, ulcerated, or nonhealing lesion should be biopsied. Reevaluate patients who have not responded to previous topical therapy or consider referral to a specialist.

Assess the personal, interpersonal, social, and sexual impact of the symptoms: if they do not cause distress, GSM does not require treatment. Nevertheless, potential treatment options should be discussed as symptoms may progress, making intervention necessary.

Laboratory tests: Helpful, not essential

Laboratory tests are unnecessary for the diagnosis of GSM. However, office-based objective evaluations such as vaginal pH testing and the maturation index can support the diagnosis.

The pH of the estrogenized vagina ranges from 3.8 to 4.2, whereas in women with GSM, the pH may reach 5.5 or higher. The pH can be obtained by placing a pH-sensitive paper against the lateral vaginal wall, avoiding any discharge or cervical mucus. A vaginal pH of 5 or greater in the absence of blood, semen, or infection suggests vulvovaginal atrophy.¹⁹

The vaginal maturation index is determined by a vaginal smear using Rakoff staining, in which 100 cells are counted and the number of parabasal, intermediate, and superficial cells is determined. In general, a well-estrogenized vagina has mostly superficial and intermediate cells, which shifts to a predominance of parabasal cells as estrogen levels decline.²⁰

A recent review of vaginal atrophy suggests that after a diagnosis of GSM, healthcare providers can consider the most bothersome symptom along with the vaginal pH to assess the response to treatment.²¹ In general, schedule a follow-up appointment at 8 to 12 weeks to review treatment response. If treatment has not resulted in adequate symptom relief, consider a pelvic examination and further testing.

Symptomatic women with GSM who desire intervention should be offered over-the-counter nonhormonal products as the first line of therapy.

If nonhormonal products are ineffective and there are no contraindications, locally applied estrogen in cream, tablet, or a ring delivery system may be offered. Local dehydro­epiandrosterone (DHEA) inserts or ospemifene, an oral selective estrogen-receptor modulator, are FDA-approved for moderate to severe dyspareunia secondary to GSM.

Oral estrogen therapy is not indicated for vulvovaginal symptoms, but some women taking systemic estrogen for vasomotor symptoms may need additional local estrogen application to relieve vaginal symptoms.

Nonhormonal treatments

Nonhormonal over-the-counter therapies provide sufficient relief for most women with mild symptoms. There is a plethora of products, so practitioners need to offer guidance to help women with their individual choices.

Vaginal lubricants are intended for use with sexual or penetrative activity (including pelvic examination). They provide short-term relief of symptoms, but there is no evidence of any impact on histologic changes of atrophy. They are meant to relieve friction. Lubricants may be water-based, oil-based, silicone-based, or a combination. Individual products have different effects on condom integrity. Perfumed, warming, or stimulating products may be irritating to some women and should be tried initially in small amounts.

Vaginal moisturizers are intended to treat GSM. They are applied regularly, not just with vaginal activity, usually once or twice a week. Some vaginal lubricants can maintain an acidic pH in the vagina and may reverse the histologic changes of atrophy. Symptomatic improvement over placebo or estrogen has been shown in clinical trials.^22–24

Women should be advised that trial and error in choosing products may be necessary to establish a successful regimen. Products should be tried in succession, not simultaneously, with a “wash-out” period between, to be able to evaluate response.

Vaginal dilators and pelvic floor physical therapy

Sexual activity, either by self-stimulation or with a partner, helps maintain vaginal health by contributing to increased vascularity and elasticity of tissue. Women who resume sexual activity after a long period of inactivity may benefit from the use of vaginal dilators, which aid both in mechanical distention and progressive relaxation of the vaginal musculature.

In some women, long-term dyspareunia may result in vaginismus, an involuntary contraction of the vaginal musculature. For these women, dilators may be effective. Additional options focus on pelvic floor physical therapy, which can isolate trigger points, using biofeedback to teach relaxation and home exercises such as vaginal massage.

HORMONAL THERAPIES

If nonhormonal lubricants and moisturizers do not achieve satisfactory symptomatic relief, FDA-approved hormonal therapies (Table 4) include estrogen-containing vaginal creams, rings, and a tablet; a vaginal tablet containing DHEA; and an oral tablet containing ospemifene.

Estrogen products

For patients whose symptoms do not respond to nonhormonal therapies, low-dose, locally applied estrogen therapy is the first treatment recommended.² Locally applied estrogens can reverse the atrophic changes of estrogen deprivation, resulting in an increase in blood flow, elasticity, and vaginal wall thickness. This therapy also can normalize pH levels with subsequent restoration of a healthy lactobacilli-based flora. Locally applied estrogens also have been shown to decrease the frequency of recurrent urinary tract infection.²⁵

Estrogen-containing vaginal creams, rings, and a tablet are available, and each has been shown to be effective for GSM. Locally applied estrogens at recommended dosages tend to have fewer adverse events and risks than systemic estrogens.²⁶ Estradiol levels generally do not exceed levels found in the untreated menopausal population, although a dose- and duration-dependent increase in systemic levels may occur.²⁷

Dosing considerations

The vaginal ring and the vaginal tablet provide the lowest prefixed daily dose of estradiol (7.5 and 10 µg daily, respectively). Estrogen creams (estradiol, conjugated equine estrogens) are more readily absorbed, and dosing should be tapered to the lowest, most effective dose for symptom relief.

The FDA-approved doses for vaginal creams containing 17-beta estradiol are higher than the dose found to be effective in clinical practice (0.5 g twice a week). Most practitioners start with the lower dose, reserving the FDA-approved higher doses for patients who do not obtain adequate relief over 6 to 8 weeks of treatment. The conjugated-estrogen vaginal cream Premarin is the only locally applied estrogen approved by the FDA to treat dyspareunia. It is dosed at 0.5 g intravaginally for 21 days and is then either withdrawn for 7 days or, more commonly, administered at 0.5 g twice a week.

Initial treatment with vaginal cream may require more frequent vulvovaginal application, such as daily for 1 to 2 weeks. Women with vaginal fissures or tearing will benefit from externally applied creams in addition to internal applications. Response to therapy is usually seen within 4 to 6 weeks from onset of treatment. Once symptom relief is obtained, treatment should continue indefinitely. Although long-term safety studies are lacking, risks are believed to be minimal.

Endometrial impact. Women with contraindications to systemic estrogen should be counseled about possible small increases in serum levels of estradiol associated with locally applied estrogens and the potential risks and benefits those increases incur. Endometrial surveillance with either transvaginal ultrasonography or endometrial sampling is not required, even with long-term use, but it should be considered with higher doses or more frequent applications.

Similarly, progesterone replacement for endometrial protection is not recommended but can be considered in women with an intact uterus at high risk of endometrial cancer, such as obese patients. If a systemic progestational agent is considered, the risks and benefits should be weighed carefully. Even in women at high risk, endometrial surveillance may be the most appropriate option.²⁸ Uterine bleeding that occurs should be considered abnormal and should be investigated.

DHEA (prasterone)

In 2016, the FDA approved intravaginal prasterone, a DHEA-containing product for the treatment of dyspareunia secondary to moderate to severe vulvovaginal atrophy caused by menopause. DHEA is an endogenous steroid that is converted by aromatase activity into testosterone and estradiol.

Clinical trials have found that 12 weeks of vaginal DHEA supplementation (0.25%, 0.5%, and 1% DHEA ovules) was more effective than placebo in improving vaginal dryness and dyspareunia in women with GSM.^29–31 In these studies, locally applied DHEA decreased parabasal cells, decreased vaginal pH, increased vaginal secretions, and improved epithelial surface thickness and integrity without any significant impact on serum levels of DHEA, DHEA-sulfate, estradiol, testosterone, or their metabolites. Importantly, transvaginal DHEA had negligible endometrial effect.

The breast cancer risk associated with vaginal DHEA has not been fully evaluated. However, labeling lists breast cancer as a warning, not a contraindication.

In 2013, the FDA approved ospemifene for the treatment of dyspareunia caused by GSM. Ospemifene, an estrogen agonist in the vagina, is taken daily as a 60-mg oral dose. Long-term safety studies suggested no adverse effects on the endometrium or breast for at least 52 weeks.³²

These studies also noted that ospemifene improved the vaginal maturation index (decreased parabasal cells and increased superficial cells) and decreased vaginal pH. It has further been shown to decrease severity of the self-identified most bothersome symptom—dyspareunia or vaginal dryness—compared with placebo.³³

Potential increases in hot flashes, which may occur in up to 7% of patients, and the risk of blood clots should be considered. Additionally, the safety of ospemifene in women with a history of breast cancer has not been established. Although early studies suggest it either has no effect or possibly a protective effect on breast tissue, the FDA does not recommend its use in women at risk for breast cancer. Long-term effects on bone are unknown.

The labeling for ospemifene includes a boxed warning about the risk of stroke, blood clots, and cancer of the lining of the uterus. Patients should be counseled about worrisome signs or symptoms that require medical attention.

ALTERNATIVE THERAPIES

Treatments for GSM not approved by the FDA include laser and radiofrequency therapies, testosterone, isoflavones, and bioidentical hormones.

Laser and radiofrequency therapies

Both of these therapies aim to promote tissue remodeling with increased collagen and elastin production and increased vascularity. This, in turn, increases muscle support and tone.

Laser therapies act by ablating and coagulating vaginal tissues; radiofrequency therapies directly heat the tissue. Both treatments are office-based, require up to 3 initial treatments, and are followed by retreatment at approximately 1-year intervals.

Studies have reported high patient satisfaction rates (91% to 100%), improved sexual functioning, and decreased GSM symptoms of vaginal dryness, burning, itching, and dyspareunia.^34–36 Data, however, are from observational studies, not placebo-controlled trials.

Although laser and radiofrequency therapies are FDA-approved for several indications, laser treatment for symptoms of vulvovaginal atrophy is not currently an approved indication. Patients should be advised of this.

Testosterone

Locally applied testosterone was shown in a small study to improve dyspareunia and vaginal dryness associated with aromatase inhibitor use in breast cancer patients.³⁷ However, due to the lack of safety and efficacy data from larger, controlled trials, testosterone therapy is not currently recommended.

Isoflavones

Isoflavones are phytoestrogens found in soy. In a 12-week, double-blind placebo-controlled study of vaginally applied 4% soy isoflavone gel, improvements in vaginal atrophy symptoms, maturation values, and vaginal pH were found in 60 postmenopausal women.³⁸ Additional data on efficacy and safety are needed before isoflavones should be considered as a treatment for GSM.

Bioidentical hormones

Bioidentical hormones are plant-derived hormones that are chemically similar or identical to those produced by the body. Although there are FDA-approved bioidentical hormones (eg, micronized progesterone, estradiol, DHEA), the term bioidentical usually refers to non-FDA-approved, commercially available hormones produced and compounded by specialty pharmacies.

Patients often view these substances as being better, safer, and more acceptable for use, and healthcare practitioners need to be prepared to address these beliefs. The FDA and the American College of Obstetricians and Gynecologists consider bioidentical hormones to be a marketing term and not an alternative treatment based on scientific evidence.³⁹ Patients should be informed that bioidentical hormones have the same risks as any similar hormone preparation along with additional risks related to potential lack of purity and potency. Further, they have not been adequately studied in controlled clinical trials.

FOLLOW-UP CARE

Healthcare providers caring for women should assume a proactive role in diagnosing and treating the symptoms of GSM. And once diagnosis of GSM is established and treatment is under way, practitioners can use symptom questionnaires and vaginal pH testing as easy and reliable means of measuring clinical response to therapy.

See related editorial

WHAT IS ‘EARLY’ SURGERY?

More than 50% of patients with infective endocarditis undergo cardiac surgery during their initial presentation.¹

The 2017 guidelines of the American Association for Thoracic Surgery (AATS) recommend surgery once a surgical indication has been established and effective antimicrobial therapy has been started.²

The American Heart Association/American College of Cardiology (ACC/AHA) guidelines recommend surgery during the initial hospitalization before completion of a full course of antibiotics.³

The European Society of Cardiology guidelines define surgery according to the time since the patient received intravenous antibiotic therapy: emergency surgery is performed within 24 hours of therapy, urgent surgery is performed within a few days, and elective surgery is performed after at least 1 to 2 weeks.⁴

These slight differences are due to the dearth of large randomized trials addressing this question.

INDICATIONS FOR EARLY SURGERY

Left ventricular dysfunction and heart failure

Of all the complications of infectious endocarditis, concomitant heart failure has the greatest impact on prognosis⁵ and is one of the most frequent indications for surgery.⁶

The guidelines recommend emergency surgery during the initial hospitalization for all patients with infective endocarditis who present with refractory pulmonary edema, worsening left ventricular dysfunction, or cardiogenic shock, regardless of whether they have completed a full course of antibiotics. This applies to both native valve endocarditis and prosthetic valve endocarditis.

Uncontrolled persistent infection

Persistent infection is defined as fever and positive cultures persisting after 1 week of appropriate antibiotic treatment.⁴ However, 1 week is a long time. Persistence of positive blood cultures more than 48 to 72 hours after starting antibiotic therapy is associated with poor outcome and is an independent predictor of in-hospital mortality.⁷

The ACC/AHA guidelines recommend early surgery in patients with left-sided infective endocarditis caused by fungi or highly resistant organisms such as vancomycin-resistant enterococci or multidrug-resistant gram-negative bacilli.³ Nonetheless, antibiotic resistance is an unusual reason for expediting surgery unless there are additional indications for it.

Extension of the infection beyond the valve annulus, which occurs in about 30% of cases of native valve endocarditis and 50% of cases of prosthetic valve endocarditis,⁸ is considered a more valid reason to expedite surgery. Similarly, urgent surgery should be considered if there is any evidence of locally uncontrolled infection causing perivalvular abscess, fistula, pseudoaneurysm, or conduction system abnormalities causing atrioventricular nodal block.^2–4

Some authors suggest reviewing the surgical pathology and microbial sequencing of excised cardiac valves after surgery to confirm the diagnosis and identify the culprit pathogen.^9,10

Right-sided infective endocarditis has a more favorable prognosis than left-sided infective endocarditis and usually responds well to medical therapy.¹¹

Nevertheless, surgery for right-sided infective endocarditis should be expedited in patients with right heart failure secondary to severe tricuspid regurgitation with poor response to medical therapy or in the case of large tricuspid valve vegetations.¹² Likewise, recurrent septic pulmonary emboli can be encountered in the setting of right-sided infective endocarditis and are an indication for early surgery.^4,12

Since many patients with right-sided infective endocarditis acquire the infection by intravenous drug use, there is often a reluctance to recommend surgery, given the risk of prosthetic valve infection if they continue to use intravenous drugs.^4,12 One study showed that the risk of death or reoperation between 3 and 6 months after surgery for infective endocarditis was 10 times higher in intravenous drug users. Yet their survival after surgery beyond this period was similar to that of patients with endocarditis who did not inject drugs.¹³ Therefore, the AATS guidelines recommend applying normal indications for surgery to those patients, with emphasis on the need for strict follow-up aimed at addiction treatment.²

Prevention of embolic events

Neurologic embolic events are a frequent complication of infective endocarditis, with the highest risk during the first few days after antibiotics are started. However, this risk decreases significantly after 2 weeks.¹⁴

The timing of surgery largely depends on whether the patient has had previous neurologic embolic events and on the size and mobility of the vegetation. The current guidelines recommend early surgery for recurrent emboli and persistent or enlarging vegetations despite appropriate antibiotic therapy, or in case of large vegetations (> 10 mm) on a native valve even in the absence of embolic events.⁴

A randomized trial by Kang et al¹⁵ demonstrated that, compared with conventional care, early surgery (within 48 hours of diagnosis) in patients with native valve endocarditis with large vegetations (> 10 mm) and severe valve dysfunction was associated with a significant reduction in the risk of death and embolic events.

Timing of surgery after a neurologic complication

Determining the right time for surgery is challenging in patients with infective endocarditis who have had neurologic complications, given the risk of hemorrhagic conversion of existing stroke with anticoagulation or exacerbation of cerebral ischemia in case of intraoperative hypotension. The decision should take into account the severity of cardiac decompensation, weighed against the severity of neurologic symptoms.

In general, surgery should be postponed for at least 4 weeks after intracerebral hemorrhage. However, it should be expedited in the event of silent cerebral embolism or transient ischemic attack, or in patients with infective endocarditis with stroke who have other indications for early surgery, as long as cerebral hemorrhage has been excluded by appropriate imaging.⁴

Early surgery for prosthetic valve endocarditis

The timing of surgery for prosthetic valve endocarditis follows the same general principles as for native valve endocarditis.^2–4,12

One study showed that early surgery for prosthetic valve endocarditis was not associated with lower in-hospital and 1-year mortality rates compared with medical therapy.¹⁶ On the other hand, a subgroup analysis demonstrated surgery to be significantly beneficial in those with the strongest indications for surgery, including severe valve regurgitation, heart failure, paravalvular abscess, fistula, or prosthetic valve dehiscence.

The decision to proceed with surgery in prosthetic valve endocarditis should be weighed carefully, taking into consideration the patient’s overall clinical condition and estimated surgical risk.¹⁶

COLLABORATION IS HELPFUL

Early surgery is indicated for infective endocarditis patients presenting with:

• Refractory heart failure symptoms
• Persistent infection
• Large vegetations with a high risk of embolism.

Expeditious and successful treatment entails multidisciplinary collaboration among experts in cardiology and infectious diseases with access to cardiac surgery input early in the evaluation.

See related editorial

WHAT IS ‘EARLY’ SURGERY?

More than 50% of patients with infective endocarditis undergo cardiac surgery during their initial presentation.¹

The 2017 guidelines of the American Association for Thoracic Surgery (AATS) recommend surgery once a surgical indication has been established and effective antimicrobial therapy has been started.²

The American Heart Association/American College of Cardiology (ACC/AHA) guidelines recommend surgery during the initial hospitalization before completion of a full course of antibiotics.³

The European Society of Cardiology guidelines define surgery according to the time since the patient received intravenous antibiotic therapy: emergency surgery is performed within 24 hours of therapy, urgent surgery is performed within a few days, and elective surgery is performed after at least 1 to 2 weeks.⁴

These slight differences are due to the dearth of large randomized trials addressing this question.

INDICATIONS FOR EARLY SURGERY

Left ventricular dysfunction and heart failure

Of all the complications of infectious endocarditis, concomitant heart failure has the greatest impact on prognosis⁵ and is one of the most frequent indications for surgery.⁶

The guidelines recommend emergency surgery during the initial hospitalization for all patients with infective endocarditis who present with refractory pulmonary edema, worsening left ventricular dysfunction, or cardiogenic shock, regardless of whether they have completed a full course of antibiotics. This applies to both native valve endocarditis and prosthetic valve endocarditis.

Uncontrolled persistent infection

Persistent infection is defined as fever and positive cultures persisting after 1 week of appropriate antibiotic treatment.⁴ However, 1 week is a long time. Persistence of positive blood cultures more than 48 to 72 hours after starting antibiotic therapy is associated with poor outcome and is an independent predictor of in-hospital mortality.⁷

The ACC/AHA guidelines recommend early surgery in patients with left-sided infective endocarditis caused by fungi or highly resistant organisms such as vancomycin-resistant enterococci or multidrug-resistant gram-negative bacilli.³ Nonetheless, antibiotic resistance is an unusual reason for expediting surgery unless there are additional indications for it.

Extension of the infection beyond the valve annulus, which occurs in about 30% of cases of native valve endocarditis and 50% of cases of prosthetic valve endocarditis,⁸ is considered a more valid reason to expedite surgery. Similarly, urgent surgery should be considered if there is any evidence of locally uncontrolled infection causing perivalvular abscess, fistula, pseudoaneurysm, or conduction system abnormalities causing atrioventricular nodal block.^2–4

Some authors suggest reviewing the surgical pathology and microbial sequencing of excised cardiac valves after surgery to confirm the diagnosis and identify the culprit pathogen.^9,10

Right-sided infective endocarditis has a more favorable prognosis than left-sided infective endocarditis and usually responds well to medical therapy.¹¹

Nevertheless, surgery for right-sided infective endocarditis should be expedited in patients with right heart failure secondary to severe tricuspid regurgitation with poor response to medical therapy or in the case of large tricuspid valve vegetations.¹² Likewise, recurrent septic pulmonary emboli can be encountered in the setting of right-sided infective endocarditis and are an indication for early surgery.^4,12

Since many patients with right-sided infective endocarditis acquire the infection by intravenous drug use, there is often a reluctance to recommend surgery, given the risk of prosthetic valve infection if they continue to use intravenous drugs.^4,12 One study showed that the risk of death or reoperation between 3 and 6 months after surgery for infective endocarditis was 10 times higher in intravenous drug users. Yet their survival after surgery beyond this period was similar to that of patients with endocarditis who did not inject drugs.¹³ Therefore, the AATS guidelines recommend applying normal indications for surgery to those patients, with emphasis on the need for strict follow-up aimed at addiction treatment.²

Prevention of embolic events

Neurologic embolic events are a frequent complication of infective endocarditis, with the highest risk during the first few days after antibiotics are started. However, this risk decreases significantly after 2 weeks.¹⁴

The timing of surgery largely depends on whether the patient has had previous neurologic embolic events and on the size and mobility of the vegetation. The current guidelines recommend early surgery for recurrent emboli and persistent or enlarging vegetations despite appropriate antibiotic therapy, or in case of large vegetations (> 10 mm) on a native valve even in the absence of embolic events.⁴

A randomized trial by Kang et al¹⁵ demonstrated that, compared with conventional care, early surgery (within 48 hours of diagnosis) in patients with native valve endocarditis with large vegetations (> 10 mm) and severe valve dysfunction was associated with a significant reduction in the risk of death and embolic events.

Timing of surgery after a neurologic complication

Determining the right time for surgery is challenging in patients with infective endocarditis who have had neurologic complications, given the risk of hemorrhagic conversion of existing stroke with anticoagulation or exacerbation of cerebral ischemia in case of intraoperative hypotension. The decision should take into account the severity of cardiac decompensation, weighed against the severity of neurologic symptoms.

In general, surgery should be postponed for at least 4 weeks after intracerebral hemorrhage. However, it should be expedited in the event of silent cerebral embolism or transient ischemic attack, or in patients with infective endocarditis with stroke who have other indications for early surgery, as long as cerebral hemorrhage has been excluded by appropriate imaging.⁴

Early surgery for prosthetic valve endocarditis

The timing of surgery for prosthetic valve endocarditis follows the same general principles as for native valve endocarditis.^2–4,12

One study showed that early surgery for prosthetic valve endocarditis was not associated with lower in-hospital and 1-year mortality rates compared with medical therapy.¹⁶ On the other hand, a subgroup analysis demonstrated surgery to be significantly beneficial in those with the strongest indications for surgery, including severe valve regurgitation, heart failure, paravalvular abscess, fistula, or prosthetic valve dehiscence.

The decision to proceed with surgery in prosthetic valve endocarditis should be weighed carefully, taking into consideration the patient’s overall clinical condition and estimated surgical risk.¹⁶

COLLABORATION IS HELPFUL

Early surgery is indicated for infective endocarditis patients presenting with:

• Refractory heart failure symptoms
• Persistent infection
• Large vegetations with a high risk of embolism.

Expeditious and successful treatment entails multidisciplinary collaboration among experts in cardiology and infectious diseases with access to cardiac surgery input early in the evaluation.

See related editorial

WHAT IS ‘EARLY’ SURGERY?

More than 50% of patients with infective endocarditis undergo cardiac surgery during their initial presentation.¹

The 2017 guidelines of the American Association for Thoracic Surgery (AATS) recommend surgery once a surgical indication has been established and effective antimicrobial therapy has been started.²

The American Heart Association/American College of Cardiology (ACC/AHA) guidelines recommend surgery during the initial hospitalization before completion of a full course of antibiotics.³

The European Society of Cardiology guidelines define surgery according to the time since the patient received intravenous antibiotic therapy: emergency surgery is performed within 24 hours of therapy, urgent surgery is performed within a few days, and elective surgery is performed after at least 1 to 2 weeks.⁴

These slight differences are due to the dearth of large randomized trials addressing this question.

INDICATIONS FOR EARLY SURGERY

Left ventricular dysfunction and heart failure

Of all the complications of infectious endocarditis, concomitant heart failure has the greatest impact on prognosis⁵ and is one of the most frequent indications for surgery.⁶

The guidelines recommend emergency surgery during the initial hospitalization for all patients with infective endocarditis who present with refractory pulmonary edema, worsening left ventricular dysfunction, or cardiogenic shock, regardless of whether they have completed a full course of antibiotics. This applies to both native valve endocarditis and prosthetic valve endocarditis.

Uncontrolled persistent infection

Persistent infection is defined as fever and positive cultures persisting after 1 week of appropriate antibiotic treatment.⁴ However, 1 week is a long time. Persistence of positive blood cultures more than 48 to 72 hours after starting antibiotic therapy is associated with poor outcome and is an independent predictor of in-hospital mortality.⁷

The ACC/AHA guidelines recommend early surgery in patients with left-sided infective endocarditis caused by fungi or highly resistant organisms such as vancomycin-resistant enterococci or multidrug-resistant gram-negative bacilli.³ Nonetheless, antibiotic resistance is an unusual reason for expediting surgery unless there are additional indications for it.

Extension of the infection beyond the valve annulus, which occurs in about 30% of cases of native valve endocarditis and 50% of cases of prosthetic valve endocarditis,⁸ is considered a more valid reason to expedite surgery. Similarly, urgent surgery should be considered if there is any evidence of locally uncontrolled infection causing perivalvular abscess, fistula, pseudoaneurysm, or conduction system abnormalities causing atrioventricular nodal block.^2–4

Some authors suggest reviewing the surgical pathology and microbial sequencing of excised cardiac valves after surgery to confirm the diagnosis and identify the culprit pathogen.^9,10

Right-sided infective endocarditis has a more favorable prognosis than left-sided infective endocarditis and usually responds well to medical therapy.¹¹

Nevertheless, surgery for right-sided infective endocarditis should be expedited in patients with right heart failure secondary to severe tricuspid regurgitation with poor response to medical therapy or in the case of large tricuspid valve vegetations.¹² Likewise, recurrent septic pulmonary emboli can be encountered in the setting of right-sided infective endocarditis and are an indication for early surgery.^4,12

Since many patients with right-sided infective endocarditis acquire the infection by intravenous drug use, there is often a reluctance to recommend surgery, given the risk of prosthetic valve infection if they continue to use intravenous drugs.^4,12 One study showed that the risk of death or reoperation between 3 and 6 months after surgery for infective endocarditis was 10 times higher in intravenous drug users. Yet their survival after surgery beyond this period was similar to that of patients with endocarditis who did not inject drugs.¹³ Therefore, the AATS guidelines recommend applying normal indications for surgery to those patients, with emphasis on the need for strict follow-up aimed at addiction treatment.²

Prevention of embolic events

Neurologic embolic events are a frequent complication of infective endocarditis, with the highest risk during the first few days after antibiotics are started. However, this risk decreases significantly after 2 weeks.¹⁴

The timing of surgery largely depends on whether the patient has had previous neurologic embolic events and on the size and mobility of the vegetation. The current guidelines recommend early surgery for recurrent emboli and persistent or enlarging vegetations despite appropriate antibiotic therapy, or in case of large vegetations (> 10 mm) on a native valve even in the absence of embolic events.⁴

A randomized trial by Kang et al¹⁵ demonstrated that, compared with conventional care, early surgery (within 48 hours of diagnosis) in patients with native valve endocarditis with large vegetations (> 10 mm) and severe valve dysfunction was associated with a significant reduction in the risk of death and embolic events.

Timing of surgery after a neurologic complication

Determining the right time for surgery is challenging in patients with infective endocarditis who have had neurologic complications, given the risk of hemorrhagic conversion of existing stroke with anticoagulation or exacerbation of cerebral ischemia in case of intraoperative hypotension. The decision should take into account the severity of cardiac decompensation, weighed against the severity of neurologic symptoms.

In general, surgery should be postponed for at least 4 weeks after intracerebral hemorrhage. However, it should be expedited in the event of silent cerebral embolism or transient ischemic attack, or in patients with infective endocarditis with stroke who have other indications for early surgery, as long as cerebral hemorrhage has been excluded by appropriate imaging.⁴

Early surgery for prosthetic valve endocarditis

The timing of surgery for prosthetic valve endocarditis follows the same general principles as for native valve endocarditis.^2–4,12

One study showed that early surgery for prosthetic valve endocarditis was not associated with lower in-hospital and 1-year mortality rates compared with medical therapy.¹⁶ On the other hand, a subgroup analysis demonstrated surgery to be significantly beneficial in those with the strongest indications for surgery, including severe valve regurgitation, heart failure, paravalvular abscess, fistula, or prosthetic valve dehiscence.

The decision to proceed with surgery in prosthetic valve endocarditis should be weighed carefully, taking into consideration the patient’s overall clinical condition and estimated surgical risk.¹⁶

COLLABORATION IS HELPFUL

Early surgery is indicated for infective endocarditis patients presenting with:

• Refractory heart failure symptoms
• Persistent infection
• Large vegetations with a high risk of embolism.

Expeditious and successful treatment entails multidisciplinary collaboration among experts in cardiology and infectious diseases with access to cardiac surgery input early in the evaluation.

In this issue of the Journal, Soud et al discuss the timing of referral of patients with infective endocarditis to surgery.¹ When having this discussion, it is important to understand the nature of the disease and the role of surgery in its treatment.

See related article

Unless successfully treated and cured, infective endocarditis is fatal. It is associated with septic embolism (systemic with left-sided infective endocarditis and pulmonary with right-sided infective endocarditis), destruction of valve tissue, and invasion outside the aortic root or into the atrioventricular groove. Antimicrobials kill sensitive and exposed organisms but cannot reach those hiding in vegetations or biofilm, on foreign material, or in invaded extravascular tissue.

The objectives of surgery are to eliminate the source of embolism, debride and remove infected tissue and foreign material, expose and make residual organisms vulnerable to antimicrobials, and restore functional valves and cardiac integrity. Surgery to treat infective endocarditis is difficult and high-risk and requires an experienced surgeon. But final cure of the infection is still by antimicrobial treatment.

INFECTIVE ENDOCARDITIS NEEDS MULTIDISCIPLINARY CARE

Every aspect of infective endocarditis—diagnosis, medical management, management of complications, and surgery—is difficult. Recent guidelines^2–6 therefore favor care by a multidisciplinary team that includes an infectious disease specialist, cardiologist, and cardiac surgeon from the very beginning, with access to any other needed discipline, often including neurology, neurosurgery, nephrology, and dependence specialists. Patients with infective endocarditis should be referred early to a center with access to a full endocarditis treatment team. The need for surgery and the optimal timing of it are team decisions. The American Association for Thoracic Surgery infective endocarditis guidelines are question-based and address most aspects that surgeons must consider before, during, and after operation.²

IF SURGERY IS INDICATED, IT IS BEST DONE SOONER

Once there is an indication to operate, the operation should be expedited. Delays mean continued risk of disease progression, invasion, heart block, and embolic events. Determining the timing of surgery is difficult in patients who have suffered an embolic stroke—nonhemorrhagic or hemorrhagic—or who have suffered brain bleeding; management of these issues has recently triggered expert opinion and review articles.^7,8 The recommendation for early surgery is based on the conviction that once the patient has been stabilized (or has overwhelming mechanical hemodynamic problems requiring emergency surgery) and adequate antimicrobial coverage is on board, there are no additional benefits to delaying surgery.⁹ When the indication to operate is large mobile vegetations associated with a high risk of stroke, surgery before another event can make all the difference.

In the operating room, the first aspect addressed is adequate debridement. There is wide agreement that repair is preferable to replacement for the mitral and tricuspid valves, but there is no agreement that an allograft (although favored by our team) is the best replacement alternative for a destroyed aortic root. The key is that surgeons and their surgical teams must have the experience and tools that work for them.

Our recommendation is to refer all patients with infective endocarditis to a center with access to a full team of experienced experts able to address all aspects of the disease and its complications.

In this issue of the Journal, Soud et al discuss the timing of referral of patients with infective endocarditis to surgery.¹ When having this discussion, it is important to understand the nature of the disease and the role of surgery in its treatment.

See related article

Unless successfully treated and cured, infective endocarditis is fatal. It is associated with septic embolism (systemic with left-sided infective endocarditis and pulmonary with right-sided infective endocarditis), destruction of valve tissue, and invasion outside the aortic root or into the atrioventricular groove. Antimicrobials kill sensitive and exposed organisms but cannot reach those hiding in vegetations or biofilm, on foreign material, or in invaded extravascular tissue.

The objectives of surgery are to eliminate the source of embolism, debride and remove infected tissue and foreign material, expose and make residual organisms vulnerable to antimicrobials, and restore functional valves and cardiac integrity. Surgery to treat infective endocarditis is difficult and high-risk and requires an experienced surgeon. But final cure of the infection is still by antimicrobial treatment.

INFECTIVE ENDOCARDITIS NEEDS MULTIDISCIPLINARY CARE

Every aspect of infective endocarditis—diagnosis, medical management, management of complications, and surgery—is difficult. Recent guidelines^2–6 therefore favor care by a multidisciplinary team that includes an infectious disease specialist, cardiologist, and cardiac surgeon from the very beginning, with access to any other needed discipline, often including neurology, neurosurgery, nephrology, and dependence specialists. Patients with infective endocarditis should be referred early to a center with access to a full endocarditis treatment team. The need for surgery and the optimal timing of it are team decisions. The American Association for Thoracic Surgery infective endocarditis guidelines are question-based and address most aspects that surgeons must consider before, during, and after operation.²

IF SURGERY IS INDICATED, IT IS BEST DONE SOONER

Once there is an indication to operate, the operation should be expedited. Delays mean continued risk of disease progression, invasion, heart block, and embolic events. Determining the timing of surgery is difficult in patients who have suffered an embolic stroke—nonhemorrhagic or hemorrhagic—or who have suffered brain bleeding; management of these issues has recently triggered expert opinion and review articles.^7,8 The recommendation for early surgery is based on the conviction that once the patient has been stabilized (or has overwhelming mechanical hemodynamic problems requiring emergency surgery) and adequate antimicrobial coverage is on board, there are no additional benefits to delaying surgery.⁹ When the indication to operate is large mobile vegetations associated with a high risk of stroke, surgery before another event can make all the difference.

In the operating room, the first aspect addressed is adequate debridement. There is wide agreement that repair is preferable to replacement for the mitral and tricuspid valves, but there is no agreement that an allograft (although favored by our team) is the best replacement alternative for a destroyed aortic root. The key is that surgeons and their surgical teams must have the experience and tools that work for them.

Our recommendation is to refer all patients with infective endocarditis to a center with access to a full team of experienced experts able to address all aspects of the disease and its complications.

In this issue of the Journal, Soud et al discuss the timing of referral of patients with infective endocarditis to surgery.¹ When having this discussion, it is important to understand the nature of the disease and the role of surgery in its treatment.

See related article

Unless successfully treated and cured, infective endocarditis is fatal. It is associated with septic embolism (systemic with left-sided infective endocarditis and pulmonary with right-sided infective endocarditis), destruction of valve tissue, and invasion outside the aortic root or into the atrioventricular groove. Antimicrobials kill sensitive and exposed organisms but cannot reach those hiding in vegetations or biofilm, on foreign material, or in invaded extravascular tissue.

The objectives of surgery are to eliminate the source of embolism, debride and remove infected tissue and foreign material, expose and make residual organisms vulnerable to antimicrobials, and restore functional valves and cardiac integrity. Surgery to treat infective endocarditis is difficult and high-risk and requires an experienced surgeon. But final cure of the infection is still by antimicrobial treatment.

INFECTIVE ENDOCARDITIS NEEDS MULTIDISCIPLINARY CARE

Every aspect of infective endocarditis—diagnosis, medical management, management of complications, and surgery—is difficult. Recent guidelines^2–6 therefore favor care by a multidisciplinary team that includes an infectious disease specialist, cardiologist, and cardiac surgeon from the very beginning, with access to any other needed discipline, often including neurology, neurosurgery, nephrology, and dependence specialists. Patients with infective endocarditis should be referred early to a center with access to a full endocarditis treatment team. The need for surgery and the optimal timing of it are team decisions. The American Association for Thoracic Surgery infective endocarditis guidelines are question-based and address most aspects that surgeons must consider before, during, and after operation.²

IF SURGERY IS INDICATED, IT IS BEST DONE SOONER

Once there is an indication to operate, the operation should be expedited. Delays mean continued risk of disease progression, invasion, heart block, and embolic events. Determining the timing of surgery is difficult in patients who have suffered an embolic stroke—nonhemorrhagic or hemorrhagic—or who have suffered brain bleeding; management of these issues has recently triggered expert opinion and review articles.^7,8 The recommendation for early surgery is based on the conviction that once the patient has been stabilized (or has overwhelming mechanical hemodynamic problems requiring emergency surgery) and adequate antimicrobial coverage is on board, there are no additional benefits to delaying surgery.⁹ When the indication to operate is large mobile vegetations associated with a high risk of stroke, surgery before another event can make all the difference.

In the operating room, the first aspect addressed is adequate debridement. There is wide agreement that repair is preferable to replacement for the mitral and tricuspid valves, but there is no agreement that an allograft (although favored by our team) is the best replacement alternative for a destroyed aortic root. The key is that surgeons and their surgical teams must have the experience and tools that work for them.

Our recommendation is to refer all patients with infective endocarditis to a center with access to a full team of experienced experts able to address all aspects of the disease and its complications.

A 45-year-old man with end-stage renal disease secondary to hypertension presented with abdominal pain, nausea, vomiting, and fever. He had been on peritoneal dialysis for 15 years.

Results of initial laboratory testing were as follows:

• Sodium 137 mmol/L (reference range 136–144)
• Potassium 3.7 mmol/L (3.5–5.0)
• Bicarbonate 31 mmol/L (22–30)
• Creatinine 17.5 mg/dL (0.58–0.96)
• Blood urea nitrogen 57 mg/dL (7–21)
• Lactic acid 1.7 mmol/L (0.5–2.2)
• White blood cell count 14.34 × 10⁹/L (3.70–11.0).

Blood cultures were negative. Peritoneal fluid analysis showed a white blood cell count of 1.2 × 10⁹/L (reference range < 0.5 × 10⁹/L) with 89% neutrophils, and an amylase level less than 3 U/L (reference range < 100). Fluid cultures were positive for coagulase-negative staphylococci and Staphylococcus epidermidis.

CAUSES AND CLINICAL FEATURES

Encapsulating peritoneal sclerosis is a devastating complication of peritoneal dialysis, occurring in 3% of patients on peritoneal dialysis. The mortality rate is above 40%.^1,2 It is characterized by an initial inflammatory phase followed by extensive intraperitoneal fibrosis and encasement of bowel. Causes include prolonged exposure to peritoneal dialysis or glucose degradation products, a history of severe peritonitis, use of acetate as a dialysate buffer, and reaction to medications such as beta-blockers.³

Clinical features result from inflammation, ileus, and peritoneal adhesions and include abdominal pain, nausea, and vomiting. A high peritoneal transport rate, which often heralds development of encapsulating peritoneal sclerosis, leads to failure of ultrafiltration and to fluid retention.

CT is recommended for diagnosis and demonstrates peritoneal calcification with bowel thickening and dilation.

TREATMENT

Treatment entails stopping peritoneal dialysis, changing to hemodialysis, bowel rest, and corticosteroids. Successful treatment has been reported with a combination of corticosteroids and azathioprine.^4,5 A retrospective study showed that adding the antifibrotic agent tamoxifen was associated with a decrease in the mortality rate.⁶ Bowel obstruction is a common complication, and surgery may be indicated. Enterolysis is a new surgical technique that has shown improved outcomes.⁷         

A 45-year-old man with end-stage renal disease secondary to hypertension presented with abdominal pain, nausea, vomiting, and fever. He had been on peritoneal dialysis for 15 years.

Results of initial laboratory testing were as follows:

• Sodium 137 mmol/L (reference range 136–144)
• Potassium 3.7 mmol/L (3.5–5.0)
• Bicarbonate 31 mmol/L (22–30)
• Creatinine 17.5 mg/dL (0.58–0.96)
• Blood urea nitrogen 57 mg/dL (7–21)
• Lactic acid 1.7 mmol/L (0.5–2.2)
• White blood cell count 14.34 × 10⁹/L (3.70–11.0).

Blood cultures were negative. Peritoneal fluid analysis showed a white blood cell count of 1.2 × 10⁹/L (reference range < 0.5 × 10⁹/L) with 89% neutrophils, and an amylase level less than 3 U/L (reference range < 100). Fluid cultures were positive for coagulase-negative staphylococci and Staphylococcus epidermidis.

CAUSES AND CLINICAL FEATURES

Encapsulating peritoneal sclerosis is a devastating complication of peritoneal dialysis, occurring in 3% of patients on peritoneal dialysis. The mortality rate is above 40%.^1,2 It is characterized by an initial inflammatory phase followed by extensive intraperitoneal fibrosis and encasement of bowel. Causes include prolonged exposure to peritoneal dialysis or glucose degradation products, a history of severe peritonitis, use of acetate as a dialysate buffer, and reaction to medications such as beta-blockers.³

Clinical features result from inflammation, ileus, and peritoneal adhesions and include abdominal pain, nausea, and vomiting. A high peritoneal transport rate, which often heralds development of encapsulating peritoneal sclerosis, leads to failure of ultrafiltration and to fluid retention.

CT is recommended for diagnosis and demonstrates peritoneal calcification with bowel thickening and dilation.

TREATMENT

Treatment entails stopping peritoneal dialysis, changing to hemodialysis, bowel rest, and corticosteroids. Successful treatment has been reported with a combination of corticosteroids and azathioprine.^4,5 A retrospective study showed that adding the antifibrotic agent tamoxifen was associated with a decrease in the mortality rate.⁶ Bowel obstruction is a common complication, and surgery may be indicated. Enterolysis is a new surgical technique that has shown improved outcomes.⁷         

A 45-year-old man with end-stage renal disease secondary to hypertension presented with abdominal pain, nausea, vomiting, and fever. He had been on peritoneal dialysis for 15 years.

Results of initial laboratory testing were as follows:

• Sodium 137 mmol/L (reference range 136–144)
• Potassium 3.7 mmol/L (3.5–5.0)
• Bicarbonate 31 mmol/L (22–30)
• Creatinine 17.5 mg/dL (0.58–0.96)
• Blood urea nitrogen 57 mg/dL (7–21)
• Lactic acid 1.7 mmol/L (0.5–2.2)
• White blood cell count 14.34 × 10⁹/L (3.70–11.0).

Blood cultures were negative. Peritoneal fluid analysis showed a white blood cell count of 1.2 × 10⁹/L (reference range < 0.5 × 10⁹/L) with 89% neutrophils, and an amylase level less than 3 U/L (reference range < 100). Fluid cultures were positive for coagulase-negative staphylococci and Staphylococcus epidermidis.

CAUSES AND CLINICAL FEATURES

Encapsulating peritoneal sclerosis is a devastating complication of peritoneal dialysis, occurring in 3% of patients on peritoneal dialysis. The mortality rate is above 40%.^1,2 It is characterized by an initial inflammatory phase followed by extensive intraperitoneal fibrosis and encasement of bowel. Causes include prolonged exposure to peritoneal dialysis or glucose degradation products, a history of severe peritonitis, use of acetate as a dialysate buffer, and reaction to medications such as beta-blockers.³

Clinical features result from inflammation, ileus, and peritoneal adhesions and include abdominal pain, nausea, and vomiting. A high peritoneal transport rate, which often heralds development of encapsulating peritoneal sclerosis, leads to failure of ultrafiltration and to fluid retention.

CT is recommended for diagnosis and demonstrates peritoneal calcification with bowel thickening and dilation.

TREATMENT

Treatment entails stopping peritoneal dialysis, changing to hemodialysis, bowel rest, and corticosteroids. Successful treatment has been reported with a combination of corticosteroids and azathioprine.^4,5 A retrospective study showed that adding the antifibrotic agent tamoxifen was associated with a decrease in the mortality rate.⁶ Bowel obstruction is a common complication, and surgery may be indicated. Enterolysis is a new surgical technique that has shown improved outcomes.⁷         

Fibromyalgia may seem like a nebulous diagnosis, with its array of symptoms and pain refractory to medications. But fibromyalgia is a defined syndrome of neuronal dysregulation. It can be diagnosed from the history and physical examination and managed in a primary care setting.

CASE 1: MANY SYMPTOMS

A 43-year-old woman presents to her primary care physician with multiple complaints: pain in all joints and in her back and hips, swelling of her hands and feet, morning stiffness, chest pain and shortness of breath (not necessarily related to exertion), fatigue, generalized weakness, headaches, difficulty with memory and concentration, dry mouth and dry eyes, feeling weak and faint in the sun, cold intolerance with purple discoloration of her extremities, a self-described “butterfly” rash on the face, and hair that is thinning and falling out in clumps.

Because many of her symptoms could reflect an inflammatory process or an autoimmune disease,¹ her primary care physician orders multiple tests. Her C-reactive protein level, Westergren sedimentation rate, complete blood cell count, and comprehensive metabolic panel are normal. Urinalysis shows trace leukocyte esterase. Indirect immunofluorescence assay on human laryngeal tumor (HEp-2) cells is positive for antinuclear antibody (ANA), with a titer of 1:320 (reference range ≤ 1:40) and a nuclear dense fine-speckled pattern. 

In view of the positive ANA test, the patient is informed that she may have systemic lupus erythematosus (SLE) and will be referred to a rheumatologist. In the days before her rheumatology appointment, she becomes extremely anxious. Obsessively researching SLE online, she becomes convinced that SLE is the correct diagnosis.

Rheumatology evaluation

The rheumatologist assesses the patient’s pain and reports the following:

Location and duration: Hands, wrists, elbows, shoulders, upper and lower back, sides of hips, knees, and feet; has been ongoing for 10 years, but worse in the past 3 months.

Character: The patient describes her pain as “like an ice pick being driven through my joints,” “sometimes unbearable,” and “like being hit by a truck.” She also reports numb, tingly, burning pain in her upper neck and back.

Variation with time, activity, and weather: Worse at night, causing her to wake and toss and turn all night; better with exertion, but after activity or exercise, she is exhausted for the rest of the day and sometimes for up to a week; worse with weather changes, especially during cold or humid weather.

Associated symptoms: Occasional perceived swelling of hands and feet, especially upon wakening in the morning, and 2 to 3 hours of stiffness in the morning that sometimes lasts all day.

Physical examination. Her findings are inconsistent with her symptoms.

The patient exhibits limited range of motion. When asked to bend forward, rotate her neck, or flex and extend her neck and back, she does so only slightly. However, passive range of motion is normal in all joints.

When her joints are examined, she anticipates pain and withdraws her hands. But when she is distracted, examination reveals no evidence of swollen joints or synovitis. She has tenderness in 12 of 18 tender points. Her peripheral pulses are good, strength is normal, and reflexes are brisk.

Her facial rash looks more like rosacea than the butterfly rash of SLE. There is no indication of patchy hair loss. Heart and lung examinations are normal. She appears to have a good salivary pool without glossitis.

History reveals long-standing psychological issues

The patient reports a history of panic attacks and a prior diagnosis of anxiety. She is tested with the Generalized Anxiety Disorder 7-item scale (www.mdcalc.com/gad-7-general-anxiety-disorder-7) and scores 17 out of 21, indicating severe anxiety.

DISCUSSION: CHARACTERIZING PAIN

Understanding categories of pain syndromes can help us understand fibromyalgia. Pain can be categorized into 3 types that sometimes overlap²:

Nociceptive or peripheral pain is related to damage of tissue by trauma or inflammation. Syndromes include osteoarthritis, rheumatoid arthritis, and SLE.

Neuropathic pain is associated with damage of peripheral or central nerves. Examples are neuropathy from herpes, diabetes, or spinal stenosis.

Centralized pain has no identifiable nerve or tissue damage and is thought to result from persistent neuronal dysregulation, overactive ascending pain pathways, and a deficiency of descending inhibitory pain pathways. There is evidence of biochemical changes in muscles, possibly related to chronic ischemia and an overactive sympathetic nervous system. Dysregulation of the sympathoadrenal system and hypothalamic-pituitary axis has also been implicated. And genetic predisposition is possible. Examples of centralized pain syndromes include fibromyalgia, irritable bowel syndrome, pelvic pain syndrome, neurogenic bladder, and interstitial cystitis.

Clues to a centralized pain syndrome

For patients with suspected fibromyalgia, distinguishing peripheral pain from centralized pain can be a challenge (Table 1). For example, SLE does not cause inflammation of the spine, so neck or back pain is not typical. Although both nociceptive and centralized pain syndromes improve with exertion, only patients with centralized pain are typically exhausted and bedbound for days after activity. Patients with centralized pain tend to describe their pain in much more dramatic language than do patients with inflammatory pain. Centralized pain tends to be intermittent; inflammatory pain tends to be constant. Patients with centralized pain often have had pain for many years without a diagnosis, but this is rare for patients with an inflammatory condition.

A patient with fibromyalgia typically has a normal physical examination, although allodynia (experiencing pain from normally nonpainful stimulation), hyperalgesia (increased pain perception), and brisk reflexes may be present. Fibromyalgia may involve discoloration of the fingertips resulting from an overactive sympathetic nervous system. Laboratory results are typically normal with fibromyalgia.

Patients with either nociceptive or centralized pain report stiffness, but the cause likely differs. We typically think of stiffness as arising from swollen joints caused by inflammation, but stiffness can also be caused by abnormally tight muscles, as occurs in fibromyalgia.

FIBROMYALGIA IS A CLINICAL DIAGNOSIS

Diagnosing fibromyalgia does not require multiple laboratory and imaging tests. The key indicators are derived from the patient history and physical examination.

Diagnostic criteria for fibromyalgia published by the American College of Rheumatology have evolved over the years. The 2011 criteria, in the form of a self-reported patient questionnaire, have 2 components³:

• The Widespread Pain Index measures the extent of pain in 19 areas.
• The Symptom Severity scale assesses 3 key symptoms associated with fibromyalgia, ie, fatigue, cognitive problems, and nonrestorative sleep (scale of 0–3 for each symptom).

There are also questions about symptoms of irritable bowel syndrome, depression, and headache.

Fibromyalgia is diagnosed if a patient reports at least 7 painful areas and has a symptom severity score of at least 5. A patient may also meet the 2011³ and the 2016 criteria⁴ if he or she has 4 painful areas and the pain is perceived in 4 of 5 areas and the Symptom Severity Scale score is 9 or higher.⁴ This questionnaire is not only a rapid diagnostic tool for fibromyalgia, it also helps identify and focus on specific issues—for example, having severe pain in a few localized areas, or having headache as a predominant problem.

These criteria are useful for a variety of patients, eg, a patient with hip arthritis may score high on the questionnaire, indicating that a component of centralized pain is also present. Also, people who have undergone orthopedic surgery who score high tend to require more narcotics to meet the goals of pain improvement.

The 2016 criteria,⁴ the most recent, maintain that pain must be generalized, ie, present in at least 4 of 5 body areas. They also emphasize that fibromyalgia is a valid diagnosis irrespective of other conditions.

CASE 1 CONTINUED: THE PATIENT REJECTS THE DIAGNOSIS

Our patient meets the definition of fibromyalgia by each iteration of the American College of Rheumatology clinical criteria. She also has generalized anxiety disorder and a positive ANA test. She is advised to participate in a fibromyalgia educational program, start an aerobic exercise program, and consider taking an antidepressant medication with anxiolytic effects.

However, the patient rejects the diagnosis of fibromyalgia. She believes that the diagnosis of SLE has been overlooked and that her symptom severity is being discounted.

In response, the rheumatologist orders additional tests to evaluate for an autoimmune disorder: extractable nuclear antigen panel, complement C3 and C4, double-stranded DNA antibodies, and protein electrophoresis. Results are all in the normal range. The patient is still concerned that she has SLE or another autoimmune disease because of her abnormal ANA test result and remains dissatisfied with her evaluation. She states that she will complain to the clinic ombudsman.

SIGNIFICANCE OF ANA TESTING

Patients with positive test results increasingly go online to get information. The significance of ANA testing can be confusing, and it is critical to understand and be able to explain abnormal results to worried patients. Following are answers to some common questions about ANA testing:

Is ANA positivity specific for SLE or another autoimmune disease?

No. ANA is usually tested by indirect immunofluorescence assay on HEp-2 cells. The test can identify about 150 antigens targeted by antibodies, but only a small percentage are associated with an autoimmune disease, and the others do not have a known clinical association. Enzyme-linked immunosorbent assay (ELISA) ANA testing is also available but is considered less sensitive.

Abeles and Abeles⁵ retrospectively assessed 232 patients between 2007 and 2009 who were referred to rheumatologists for evaluation because of an elevated ANA test result. No ANA-associated rheumatic disease was found in patients who had a result of less than 1:160, and more than 90% of referrals for a positive ANA test had no evidence of ANA-associated disease. The positive predictive value was 9% for any connective tissue disease, and only 2% for SLE. The most common reason for ordering the test was widespread pain (23%). The authors concluded that ANA testing is often ordered inappropriately for patients with a low pretest probability of an ANA-associated rheumatic disease.

Screening with ANA testing generates many false-positive results and unnecessary anxiety for patients. The prevalence of SLE in the general population is about 0.1%, and other autoimmune diseases total about 5% to 7%. By indirect immunofluorescence assay, using a cutoff of 1:80 (the standard at Cleveland Clinic), about 15% of the general population test positive. By ELISA, with a cutoff of 20 ELISA units, 25% of healthy controls test positive.

It is true that ANA positivity may precede the onset of SLE.^6,7 Arbuckle et al⁸ evaluated serum samples from the US Department of Defense Serum Repository obtained from 130 people before they received a diagnosis of SLE; in 115 (88%), at least 1 SLE-related autoantibody was present before diagnosis (up to 9.4 years earlier). However, in those who test positive for ANA, the percentage who eventually develop autoimmune disease is small.⁵ 

The likelihood of autoimmune disease increases with increasing titer. But high titers can be seen in healthy people. Mariz et al⁹ examined ANA test results from 918 healthy controls and 153 patients with an autoimmune rheumatic disease. Of these, ANA was positive in 13% of healthy people and 90% of patients with an autoimmune disease. High titers were more likely in patients with an autoimmune disease, but also occurred in healthy controls.

Does the immunofluorescence pattern provide diagnostic information?

It can. There are 28 identified patterns of ANA, including nuclear, cytoplasmic, and mitotic patterns. The most common, the nuclear fine-speckled pattern, is seen in healthy controls and patients with an autoimmune disease. But other patterns are either characteristic of an autoimmune disease or, conversely, of not having an autoimmune disease (Table 2).⁹

Our patient has a nuclear dense fine-speckled pattern, further reducing the likelihood that she has an autoimmune disease.

CASE 2: POORLY CONTROLLED,
LONG-STANDING FIBROMYALGIA

A 43-year-old woman who has had fibromyalgia for 15 years is referred to a new primary care provider. She reports severe pain all over, low back pain, fatigue, nonrefreshing sleep, chronic migraine, constipation alternating with diarrhea, heartburn, intermittent numbness and tingling in her hands and feet, and depression. At this time, she rates her pain on a visual analog scale as 9 out of 10, and her fatigue as 8 out of 10.

During the past 6 months, she has made 25 visits to specialists in 8 departments: spine, pain management, anesthesia, neurology, headache clinic, gastroenterology, sleep medicine, and physical therapy.

Her daily medications are duloxetine 120 mg, bupropion 300 mg, pregabalin 450 mg, cyclobenzaprine 30 mg, tramadol 200 mg, zolpidem 10 mg, nortriptyline 50 mg, acetaminophen 3,000 mg, and oxycodone 30 mg. She has also tried gabapentin and milnaci­pran without success. She reported previously taking different selective serotonin reuptake inhibitors and tricyclic antidepressants but cannot remember why they were stopped.

How should this complex patient be managed?

BIOPSYCHOSOCIAL MANAGEMENT

Managing the pain of fibromyalgia requires a different model than used for peripheral pain from injury, in which the source of pain can be identified and treated with injections or oral therapy.

Neuronal dysregulation is not amenable to clinical measurement or treatment by medications at this time. But fortunately, many factors associated with fibromyalgia can be addressed: stressful life events, sleep disturbance, physical deconditioning, mood disorders, and maladaptive pain responses, including “catastrophizing” behavior (coping with pain in a highly dramatic and obsessive way). Modifying these factors can be much more productive than focusing on treating pain.

The goal for care providers is to change the focus from reducing pain to a biopsychosocial model of pain control aimed at increasing function.¹⁰

Mood modification

Not only are mood disorders common in patients with fibromyalgia, but the prevalence of  complex psychiatric conditions is also elevated. Up to 80% of patients with fibromyalgia meet criteria for axis I (clinical psychological) disorders, and up to about 30% of patients meet criteria for axis II (personality) disorders. About 22% of patients have existing major depression, and about 58% develop it during their lifetime. In a study of 678 patients with fibromyalgia, 21% had bipolar disorder.^11–15

The severity of fibromyalgia increases linearly with the severity of depression.¹⁶ Patients with fibromyalgia and a “depressive affect balance style” have worse outcomes across all Outcome Measures in Rheumatology (OMERACT) core symptom domains, reporting more pain, fatigue, insomnia, anxiety, depression, and function.^17,18

Fibromyalgia combined with mood disorders can also be costly. In one study, the mean annual employer payments (direct and indirect costs) per patient were $5,200 for patients with fibromyalgia only, $8,100 for patients with depression only, and $11,900 for patients with both.¹⁹

Obtaining a psychiatric history is important when evaluating a patient with fibromyalgia symptoms. Patients should be asked if they have a history of depression, anxiety, posttraumatic stress disorder, or other conditions. The Patient Health Questionnaire – Depression 9 and the Generalized Anxiety Disorder Assessment (GAD-7) (both available at www.mdcalc.com) can be useful for evaluating mood disorders.

Patients with moderate depression and fibromyalgia who have not yet been treated should be prescribed duloxetine for its potential benefits for both conditions.

Patients who have already been treated with multiple drugs at high doses without benefit, such as our patient, should be referred to a psychiatrist. There is no additional benefit to referring this patient to a rheumatologist or spine clinic.

Addressing sleep problems

Sleep problems are not easy to manage but can often be helped. Epidemiologic studies indicate that poor sleep quality leads to chronic widespread pain in otherwise healthy people.^20–22 In addition, experimental sleep deprivation leads to fatigue, cognitive difficulty, and a reduced pain threshold.²³ In our patients with fibromyalgia, we have observed an inverse relationship between the number of hours slept and the severity of depression.

Sleep quantity and quality can be assessed by asking patients whether they have trouble sleeping, how many hours they sleep, and whether they have been diagnosed with a sleep disorder.

Because many patients with fibromyalgia are overweight or obese, they should also be evaluated for sleep apnea, narcolepsy, and restless leg syndrome.^24,25

Medications shown to improve sleep include pregabalin or gabapentin (taken at bedtime), low-dose amitriptyline, trazodone, cyclobenzaprine, melatonin, and nabilone.^26–29

Patients should be counseled about sleep hygiene.³⁰ Exercise can also help sleep.

Targeting maladaptive pain responses

Patients who catastrophize tend to have higher tender point counts, a hyperalgesic response, more depression and anxiety, and more self-reported disability. They are also less likely to return to work.³¹ They usually respond poorly to medications and are good candidates for cognitive behavioral therapy.

A high score on a self-reported Pain Catas­trophizing Scale³² can help determine whether a multidisciplinary approach is advisable, although no threshold defines an abnormal score.

Educating patients about the neurobiology underlying their pain can be therapeutic.^33–37 Cognitive behavioral therapy can help patients recognize their faulty thought processes and the relationship between pain and stress, and learn better coping mechanisms.^38,39 Patients who achieve the highest improvements in pain catastrophizing tend to derive the greatest benefit from cognitive behavioral therapy.⁴⁰

Exercise improves fibromyalgia on many fronts and is associated with a host of positive effects in the brain and peripheral muscles. Exercise improves Fibromyalgia Impact Questionnaire scores, increases physical function and fitness, and reduces tender point counts, depression, and catastrophizing.^41–52 There is no consensus on the best type of exercise, but both strengthening and aerobic exercises appear to be important.

I tell patients that fibromyalgia is an exercise-deprivation syndrome. Many are afraid to exercise because they associate it with pain and exhaustion afterwards. Patients should be encouraged to start with something very low-impact, such as gentle exercise in a warm-water pool. It should be emphasized that exercise is a lifelong treatment.

Drug therapy

The US Food and Drug Administration has approved 3 drugs for fibromyalgia management: 2 serotonin-norepinephrine reuptake inhibitors (duloxetine and milnacipran) and 1 gabapentinoid (pregabalin). Our patient in Case 2 is taking 2 of them without apparent benefit and has previously had no success with the third. This is not surprising. A summary of published treatment research on these drugs found that only 50% to 60% of patients tested reported more than 30% pain reduction.⁵³ The studies also showed a placebo response of 30% to 40%. Depending on the study, the number needed to treat to see a benefit from these drugs is 8 to 14.⁵³

EVALUATING THE SEVERITY OF FIBROMYALGIA

Focusing on key characteristics of the patient’s history can help evaluate fibromyalgia and determine a treatment strategy (Table 3). The Fibromyalgia Impact Questionnaire is also a useful evaluation tool.

It is important to assess the severity of fibromyalgia because patients with severe fibromyalgia are not good candidates for further referral to other specialists. They instead need chronic rehabilitation services, where they can learn to better function with a chronic pain syndrome.

In general, patients with the following features have conditions with high severity:

Symptoms: High burden and intensity

Function: Disabled, unemployed, interference with activities of daily living

Mood: Severe depression, bipolar disorder, axis II disorder, posttraumatic stress disorder

Medications: Polypharmacy, opioid drugs, multiple failed interventions

Maladaptive attitudes: High catastrophizing, refusal to accept diagnosis

Fibromyalgia Impact Questionnaire score: 60 or above.

The fibromyalgia of our patient in Case 2 would be categorized as severe.

MULTIFACETED MANAGEMENT

Patients with fibromyalgia are a heterogeneous group, and the syndrome does not lend itself to a single management strategy.⁵⁴ Multiple guidelines have been published for managing fibromyalgia.^55–57 Thieme et al⁵⁸ reviewed existing guidelines and the strength of their recommendations. The guidelines unanimously strongly favor exercise, and most also strongly favor cognitive behavioral therapy. Most favor treating with amitriptyline and duloxetine; recommendations for other antidepressants vary. Nonsteroidal anti-inflammatory drugs, opioid drugs, and benzodiazepines are not recommended.

We offer a monthly 1-day clinic for patients and family members to provide education about fibromyalgia, discuss the importance of exercise, counsel on maladaptive responses, and demonstrate mindfulness techniques. We focus on function rather than pain. Interactive online-based interventions using cognitive behavioral techniques, such as FibroGuide: A Symptom Management Program for People Living With Fibromyalgia, developed at the University of Michigan, have proven helpful.⁵⁹

RECOMMENDATIONS

For most patients, do not focus on pain reduction, as that is ineffective. Instead, target reversible factors, eg, mood, sleep, exercise status, stressors, and maladaptive attitudes toward pain. Possible treatment combinations include:

• A serotonin and norepinephrine reuptake inhibitor (eg, duloxetine)
• A low-dose tricyclic antidepressant at bedtime (eg, amitriptyline)
• A gabapentinoid (pregabalin or gabapentin).

If a medication within a class does not work, stop it and try another rather than add on.

Treat mild to moderate fibromyalgia with multidisciplinary interventions, with or without centrally acting medications. Treat severe fibromyalgia with more intensive psychiatric or psychologic interventions, multidisciplinary care, and medications targeted at comorbidities. Provide all patients with education and advice on exercise.

Keep laboratory tests and imaging studies to a minimum: a complete blood cell count with differential, comprehensive metabolic panel, thyroid-stimulating hormone, C-reactive protein, and Westergren sedimentation rate. Do not test for ANA unless the patient has objective features suggesting SLE.

Fibromyalgia may seem like a nebulous diagnosis, with its array of symptoms and pain refractory to medications. But fibromyalgia is a defined syndrome of neuronal dysregulation. It can be diagnosed from the history and physical examination and managed in a primary care setting.

CASE 1: MANY SYMPTOMS

A 43-year-old woman presents to her primary care physician with multiple complaints: pain in all joints and in her back and hips, swelling of her hands and feet, morning stiffness, chest pain and shortness of breath (not necessarily related to exertion), fatigue, generalized weakness, headaches, difficulty with memory and concentration, dry mouth and dry eyes, feeling weak and faint in the sun, cold intolerance with purple discoloration of her extremities, a self-described “butterfly” rash on the face, and hair that is thinning and falling out in clumps.

Because many of her symptoms could reflect an inflammatory process or an autoimmune disease,¹ her primary care physician orders multiple tests. Her C-reactive protein level, Westergren sedimentation rate, complete blood cell count, and comprehensive metabolic panel are normal. Urinalysis shows trace leukocyte esterase. Indirect immunofluorescence assay on human laryngeal tumor (HEp-2) cells is positive for antinuclear antibody (ANA), with a titer of 1:320 (reference range ≤ 1:40) and a nuclear dense fine-speckled pattern. 

In view of the positive ANA test, the patient is informed that she may have systemic lupus erythematosus (SLE) and will be referred to a rheumatologist. In the days before her rheumatology appointment, she becomes extremely anxious. Obsessively researching SLE online, she becomes convinced that SLE is the correct diagnosis.

Rheumatology evaluation

The rheumatologist assesses the patient’s pain and reports the following:

Location and duration: Hands, wrists, elbows, shoulders, upper and lower back, sides of hips, knees, and feet; has been ongoing for 10 years, but worse in the past 3 months.

Character: The patient describes her pain as “like an ice pick being driven through my joints,” “sometimes unbearable,” and “like being hit by a truck.” She also reports numb, tingly, burning pain in her upper neck and back.

Variation with time, activity, and weather: Worse at night, causing her to wake and toss and turn all night; better with exertion, but after activity or exercise, she is exhausted for the rest of the day and sometimes for up to a week; worse with weather changes, especially during cold or humid weather.

Associated symptoms: Occasional perceived swelling of hands and feet, especially upon wakening in the morning, and 2 to 3 hours of stiffness in the morning that sometimes lasts all day.

Physical examination. Her findings are inconsistent with her symptoms.

The patient exhibits limited range of motion. When asked to bend forward, rotate her neck, or flex and extend her neck and back, she does so only slightly. However, passive range of motion is normal in all joints.

When her joints are examined, she anticipates pain and withdraws her hands. But when she is distracted, examination reveals no evidence of swollen joints or synovitis. She has tenderness in 12 of 18 tender points. Her peripheral pulses are good, strength is normal, and reflexes are brisk.

Her facial rash looks more like rosacea than the butterfly rash of SLE. There is no indication of patchy hair loss. Heart and lung examinations are normal. She appears to have a good salivary pool without glossitis.

History reveals long-standing psychological issues

The patient reports a history of panic attacks and a prior diagnosis of anxiety. She is tested with the Generalized Anxiety Disorder 7-item scale (www.mdcalc.com/gad-7-general-anxiety-disorder-7) and scores 17 out of 21, indicating severe anxiety.

DISCUSSION: CHARACTERIZING PAIN

Understanding categories of pain syndromes can help us understand fibromyalgia. Pain can be categorized into 3 types that sometimes overlap²:

Nociceptive or peripheral pain is related to damage of tissue by trauma or inflammation. Syndromes include osteoarthritis, rheumatoid arthritis, and SLE.

Neuropathic pain is associated with damage of peripheral or central nerves. Examples are neuropathy from herpes, diabetes, or spinal stenosis.

Centralized pain has no identifiable nerve or tissue damage and is thought to result from persistent neuronal dysregulation, overactive ascending pain pathways, and a deficiency of descending inhibitory pain pathways. There is evidence of biochemical changes in muscles, possibly related to chronic ischemia and an overactive sympathetic nervous system. Dysregulation of the sympathoadrenal system and hypothalamic-pituitary axis has also been implicated. And genetic predisposition is possible. Examples of centralized pain syndromes include fibromyalgia, irritable bowel syndrome, pelvic pain syndrome, neurogenic bladder, and interstitial cystitis.

Clues to a centralized pain syndrome

For patients with suspected fibromyalgia, distinguishing peripheral pain from centralized pain can be a challenge (Table 1). For example, SLE does not cause inflammation of the spine, so neck or back pain is not typical. Although both nociceptive and centralized pain syndromes improve with exertion, only patients with centralized pain are typically exhausted and bedbound for days after activity. Patients with centralized pain tend to describe their pain in much more dramatic language than do patients with inflammatory pain. Centralized pain tends to be intermittent; inflammatory pain tends to be constant. Patients with centralized pain often have had pain for many years without a diagnosis, but this is rare for patients with an inflammatory condition.

A patient with fibromyalgia typically has a normal physical examination, although allodynia (experiencing pain from normally nonpainful stimulation), hyperalgesia (increased pain perception), and brisk reflexes may be present. Fibromyalgia may involve discoloration of the fingertips resulting from an overactive sympathetic nervous system. Laboratory results are typically normal with fibromyalgia.

Patients with either nociceptive or centralized pain report stiffness, but the cause likely differs. We typically think of stiffness as arising from swollen joints caused by inflammation, but stiffness can also be caused by abnormally tight muscles, as occurs in fibromyalgia.

FIBROMYALGIA IS A CLINICAL DIAGNOSIS

Diagnosing fibromyalgia does not require multiple laboratory and imaging tests. The key indicators are derived from the patient history and physical examination.

Diagnostic criteria for fibromyalgia published by the American College of Rheumatology have evolved over the years. The 2011 criteria, in the form of a self-reported patient questionnaire, have 2 components³:

• The Widespread Pain Index measures the extent of pain in 19 areas.
• The Symptom Severity scale assesses 3 key symptoms associated with fibromyalgia, ie, fatigue, cognitive problems, and nonrestorative sleep (scale of 0–3 for each symptom).

There are also questions about symptoms of irritable bowel syndrome, depression, and headache.

Fibromyalgia is diagnosed if a patient reports at least 7 painful areas and has a symptom severity score of at least 5. A patient may also meet the 2011³ and the 2016 criteria⁴ if he or she has 4 painful areas and the pain is perceived in 4 of 5 areas and the Symptom Severity Scale score is 9 or higher.⁴ This questionnaire is not only a rapid diagnostic tool for fibromyalgia, it also helps identify and focus on specific issues—for example, having severe pain in a few localized areas, or having headache as a predominant problem.