Etiology and diagnosis of sexual dysfunction in women
Author
Alan Altman, MD
Section Editor
Robert L Barbieri, MD
Deputy Editor
Kathryn A Martin, MD
Last literature review version 16.2: May 2008 | This topic last updated: October 24, 2007 (More)
INTRODUCTION — Female sexual dysfunction refers to persistent or recurring reduction in sex drive, aversion to sexual activity, difficulty becoming aroused, inability to achieve orgasm, or dyspareunia that causes distress. According to the National Health and Social Life Survey, a study of sexual behavior in a demographically representative cohort of American men and women, sexual dysfunction is more prevalent among women than men (43 versus 31 percent) [1] .
Sexual dysfunction can occur at any age in women, but "midlife" is a particularly common time for changes to occur. The transition to menopause impacts the lives of women in different ways. Many will notice little change, some may experience an improvement, while others will complain of diminished sexual function. These variations are understandable considering the multiple factors that may affect midlife sexuality:
• Erratic ovarian function and fluctuating hormone levels that define perimenopause and the more definite decline that follows the menopause
• Alterations in anatomical structure, neurologic function, vascular responsiveness, and psychosocial function that accompany the normal aging process
• Relationship dynamics and each individual's foundation of sexual beliefs, expectations, and prior sexual experiences
Caring for women at this stage of life presents a unique opportunity for the clinician to ask the appropriate questions, bring the problem out into the open, and offer counsel and guidance. This requires the ability to communicate comfortably with patients plus an understanding of the physiology of human sexual response, the normal effects of aging on sexuality, relationship dynamics, and the healthcare provider's own limitations.
The etiology and diagnosis of sexual dysfunction are discussed here, with a focus upon changes that occur in midlife. The treatment of sexual dysfunction in women and an overview of the approach to sexual dysfunction in both men and women are discussed separately. (See "Treatment of sexual dysfunction in women" and see "The sexual history and approach to the patient with sexual dysfunction").
MIDLIFE — The concept of "midlife" must be redefined as life expectancy grows longer. Women today experience "two midlives:" one is reproductive, the other chronological, and they do not necessarily coincide. In the past, with a life expectancy of 50 to 60 years, menopause generally appeared near the end of a woman's life, and midlife, chronologically, coincided with the reproductive changes in ovarian function beginning in the mid 30s.
Today life expectancy has increased and chronological midlife has been redefined as the 50s and 60s, while age at menopause remains unchanged. This discrepancy between a woman's reproductive midlife and her chronological midlife presents some problems. It is difficult for women in their 30s to think of themselves as entering midlife, even though decline in reproductive function begins at that age. In addition, when midlife occurs it will impact the kind of sexual changes that are experienced. The older midlife woman will tend to have more physiologic and anatomic problems compared with the younger midlife woman, in whom psychosocial problems might predominate. Women and men expect sexual interest and function to continue for decades beyond the point where women lose their natural reproductive capabilities. Fortunately, the clinician can do much to help patients in reproductive midlife maintain sexual function well into and beyond chronological midlife.
Midlife sexuality — While the host of hormonal and other changes that begin prior to the menopausal transition and continue beyond the menopause affect sexuality, the desire for an active sex life remains important for many men and women throughout midlife, as illustrated by the following surveys:
• One survey of 1879 women ages 45 to 55 (most of whom had partners) was designed to identify changes in sexual interest over the previous year [2] . Of the respondents, 62 percent noted no change, 31 percent reported a decline in interest, and 7 percent indicated an increase in interest; most of the last group had new partners.
• A 1999 survey asked responders ages 45 and older if they were more or equally satisfied with their current sex life when compared with their past levels of sexual activity [3] . Fifty-six percent of men and 51 percent of women were more or equally satisfied. In addition, 54 percent of the men and 38 percent of the women considered themselves "a better lover now than in the past."
Seventy percent of males and females with partners in this study had intercourse one or two times per week. Of those without regular partners, 6 percent of males had intercourse one or two times per week; women had considerably less. Women ages 45 to 59 years were more likely than men to approve of sex outside of marriage, oral sex, masturbation, and sex, as a normal part of aging. Age became a factor when the participants were asked, "What would improve your sex life?" Men and women age 45 to 59 cited less stress and more free time; men over 60, better health; women 60 to 74, better health for their partner; and women over 75 responded that just having a partner would improve their sex life.
Midlife can be a time of sexual freedom for many women; freedom from menstrual cycles, interruptions by small children, and unwanted pregnancy. These factors may enhance midlife sexuality, especially if sex was a positive experience earlier in life. On the other hand, some women see midlife as a loss of youth, femininity, and childbearing capacity, leading to a negative impact upon sexuality. Still others see midlife as a time when they can finally use these changes as a long anticipated excuse to avoid sex that was never enjoyable for them before. Absence of sexual activity is, in itself, not a problem; it should be viewed and treated as a problem only when a woman or her partner are bothered by it.
PHYSIOLOGY OF THE NORMAL HUMAN SEXUAL RESPONSE — Knowledge of the physiology of the normal sexual response can facilitate an understanding of what may go wrong. Two basic models have been proposed to illustrate the physiology of human sexual response: the Masters and Johnson model and the biopsychosocial model (see below). While they differ in many ways, both acknowledge that neurologic and vascular responses are essential to produce a sexual response.
The brain is the most important sex organ in the human body. Neurologic changes initiate the process as the brain reacts to an image, idea, fantasy, smell, or anything else that stimulates a response or triggers desire. This leads to changes in vascular blood flow. Sex hormones play key roles here. There are estrogen, androgen, and progesterone receptors in the brain [4,5] . Estrogen and androgen receptors are particularly dense in the hypothalamus, which controls sexual function and mood.
Testosterone is the primary precursor for estradiol biosynthesis in the brain; the testosterone concentration in the brain is 7 to 10 times higher than the estrogen concentration. Thus, the free circulating concentration of estrogen and testosterone does not necessarily correlate with what is occurring in the brain.
Estrogen increases blood flow to the brain. Estrogens also increase vibratory sensation peripherally and have a positive effect on neuronal growth and nerve transmission. Other hormones, including oxytocin and endorphins, influence sexuality in the brain as well, while prolactin may have a negative effect on sexual response.
Increased blood flow to the genitalia occurs with sexual stimulation. This marks the arousal phase, in which the additional blood flow produces peripheral responses that define the sexual response. Estrogens affect how blood flows: increased estrogen increases vaginal blood flow (VBF) while a decreased concentration diminishes VBF [6] . The mechanism by which this occurs is related to estrogen stimulation of the release of vasoactive substances such as nitric oxide by endothelial cells, which induces vasodilatation [7] .
Addition of androgens to estrogen increases VBF further. Testosterone may work directly in the artery or indirectly by increasing the availability of estrogen [8] . Progesterone, on the other hand, can diminish blood flow by down-regulating the estrogen receptor [9] . Blood flow can also be increased through any mechanism that provides the neurovascular stimulus, be it sexual activity, the use of sexual aids, masturbation, or fantasy.
Masters and Johnson — Masters and Johnson first detailed the phases of human sexual response as a linear progression from excitement to plateau to orgasm, followed by resolution [10] .
Excitement — Activation of the central nervous system (CNS) causes specific changes in blood flow. Ovarian hormones also play essential roles in this process, encouraging vasodilation and increased blood flow. Uterine and internal mammary arteries contain some of the highest density of estrogen receptors, hence their responsiveness in the excitement phase.
Genital vasocongestion occurs because of this increase in blood flow and smooth muscle relaxation. The vaginal wall becomes lubricated. The labia increase in size and spread open. The clitoris increases in size and the vagina expands while the uterus elevates. Other areas of the skin, including the face and breasts, demonstrate this increase in blood flow with the "sex flush."
Following Masters and Johnson, Kaplan replaced the excitement phase with two phases: desire, in which the neurologic stimulus occurs; followed by arousal, in which blood flow produces the peripheral response leading up to orgasm [11] .
Plateau — Masters and Johnson presented this as a separate phase, while Kaplan later blended it into the arousal phase. Actions associated with this phase include retraction of the clitoris and engorgement of the labia. Bartholin gland secretion occurs, as well as congestion of the outer third of the vagina and further expansion of the upper two thirds of the vagina. Muscle tension builds.
Orgasm — In the orgasm phase, 8 to 12 muscular contractions of the levator ani muscles occur at precise intervals. Vaginal and uterine contractions occur followed by massive release of muscle tension. Regularly orgasmic women will achieve orgasm 50 to 70 percent of the time and a satisfying prolonged plateau phase other times.
Resolution — The final phase, or culmination, is often characterized as a gradual, pleasant diminishment of sexual tension and response, differing in the time it lasts among individuals.
The biopsychosocial sexual response — An alternative model has also been proposed to describe the female sexual response. Proponents believe that a large component of women's sexual desire is responsive rather than spontaneous. They maintain the biopsychosocial nature of the female sexual response cycle is a result of the dynamic and mutable interaction of four components [12,13] :
• Biology
• Psychology
• Sociocultural influences
• Interpersonal relationships
If only the biological or physiological component is addressed, as with the use of pharmacotherapy, successful treatment will frequently not be achieved. In this model, emotional intimacy of some kind motivates the woman to seek out or become responsive to sexual stimuli, which in turn leads to arousal. Once arousal is achieved, sexual desire is then accessed, allowing continuation of the experience for sexual reasons. Hence, sexual desire can be responsive to arousal instead of preceding it. While spontaneous drive can occur, it is not essential. Thus, lack of spontaneous desire is not necessarily a dysfunction. In addition, satisfaction is the goal, which may or may not include orgasm.
SEXUAL CHANGES WITH AGING — Sexuality and sexual capacity evolve over a lifetime of development and change, based on personal experience, interest, cultural attitudes, interpersonal relationships, desires, behaviors, physiology, and other factors.
Epidemiology — Although many older adults remain sexually active, sexual problems become more common, and these problems are infrequently discussed with their health care providers. This was illustrated in a national probability sample study of 3005 men and women ages 57 to 85 years [14] . The prevalence of sexual activity decreased with age in both men and women, but women at all ages were less likely than men to be sexually active (62, 40, and 17 percent among women who were ages 57 to 64, 65 to 74, and 75 to 85 years, respectively). The most common sexual problems in women were low desire, vaginal dryness, and inability to achieve orgasm (43, 39, and 34 percent, respectively). Only 38 percent of men and 2 percent of women reported having discussed their sexual concerns with a health care provider since the age of 50.
Estrogen — Estrogen deficiency develops gradually as women near menopause. A more abrupt decline is seen with surgical menopause. This decline in estrogen can cause several changes that may affect sexual function.
Urogenital function — Estrogen sustains the structure and function of the cells of the vagina. Every woman with estrogen deficiency for a prolonged period of time will develop some degree of vaginal and genital atrophy. Epithelial changes in the vagina occur first within weeks to months of estrogen loss. This leads to a decrease in superficial cells, an increase in parabasal cells, and a progressive loss of elasticity and integrity of the epithelium. Along with this change comes an increase in vaginal pH, which promotes the growth of organisms and leads to more frequent vaginal infections [15] .
Later changes, over years, affect the deeper structures such as the underlying vascular, muscle, and connective tissue, leading to a decrease in vaginal blood flow, and both foreshortening and narrowing of the vagina. There is actual loss of blood vessels in the layers beneath the epithelium. This constellation of changes can lead to vaginal dryness, decreased or absent lubrication and, dyspareunia. (See "Clinical manifestations and diagnosis of menopause" and see "Approach to the woman with dyspareunia").
The bladder tissues also suffer from estrogen loss with mucosal changes that can lead to urinary frequency, urgency, nocturia, dysuria, and incontinence. Clitoral changes can occur, including a 50 percent decrease in perfusion and shrinkage of the structure [16] . Neurologic changes include decreased touch perception, a decline in vibratory sensation, and slowing of nerve impulses leading to a delay in reaction time [17] . Decreased androgen levels also affect some of these changes (see below).
Effect on sexual response — Changes in the vaginal and clitoral tissues due to estrogen deficiency can have a profound effect on sexual response. The decrease in genital blood flow will affect vasocongestion. Sexual arousal will be delayed or altered. More time and stimulation may be necessary to achieve lubrication, which may be significantly reduced or absent. The outer third of the vagina, including the labia and G-spot, demonstrate decreased or absent congestion, as does the clitoris. Vaginal expansion in length and transcervical width decreases. Elsewhere, there is a reduced incidence of skin flush, a lack of increase in breast and nipple size during stimulation, decreased tactile sensation, or worse, aversion to skin touch due to pain perception instead of pleasure in the clitoris, skin, and nipples, and a general decrease in muscle tension [18] .
Taken together, these changes can result in delayed arousal, delayed or absent orgasm, or diminished peak of orgasm. Fewer uterine contractions occur with orgasm and, in older women, particularly age 70 and older, painful uterine contractions can be associated with orgasm because of vasoconstriction that produces a reaction similar to ischemia [16] .
Androgens — All women produce some androgens, which may contribute to maintaining normal ovarian function, bone metabolism, cognition, and sexual behavior [19] . However, serum testosterone concentrations are not a good predictor of libido in women. Studies evaluating vaginal blood flow and vasocongestion of the clitoris and labia suggest that normal testosterone levels are necessary for arousal and orgasm to occur [20] . In women who undergo bilateral oophorectomy and subsequently develop hypoactive sexual desire disorder, exogenous testosterone therapy may be moderately effective for libido and sexual activity. (See "Androgen production and therapy in women").
Total testosterone and androstenedione (the major androgen in the serum of cycling women) gradually decline with increasing age in normal women. Androgen levels peak around age 25 and begin a gradual, age-related decline in the early to mid 30s, much earlier than the decline in estrogen levels [21] . There is also a midcycle testosterone surge that declines with age [22] . Some have argued that the sexual effects of reduced androgen levels can occur well before menopause and the onset of estrogen deprivation [23] .
Other suggested causes of androgen deficiency include:
• Oophorectomy (producing sudden 50 percent fall in levels within 24 hours of surgery)
• Premature ovarian failure
• GnRH agonist therapy
• Corticosteroid therapy suppressing ACTH secretion
• Adrenal insufficiency
Additional important causes include exogenous oral estrogens, such as oral contraceptives (OCs) and hormone replacement therapy (HRT), both of which increase sex hormone binding globulin (SHBG), resulting in reduced bioavailability of androgens as well as estrogens. Non-oral contraceptives, ie ring and patch, also increase SHBG, while non-oral postmenopausal therapy does not.
The menopausal transition (ie, perimenopause) results in a somewhat unique hormonal profile. Erratic ovarian function leads to estrogen levels that can be normal, elevated, or decreased at any given time, but in general, estrogen secretion is preserved. (See "Clinical manifestations and diagnosis of menopause"). Ultimately, lower estrogen levels predominate. The postmenopausal ovary is an androgen-producing organ. Ovaries continue to produce androgens well into the postmenopausal years [24] . (See "Androgen production and therapy in women").
Serum androgen concentrations — It has been proposed that serum androgen concentrations are an independent predictor of sexual desire and function in women. In a community-based, cross-sectional study of 1021 women aged 18 to 75 years, low serum concentrations of testosterone, free testosterone, or androstenedione were not significantly associated with a low score on the Profile of Female Sexual Dysfunction instrument [25] . Women with low sexual function were more likely to have a low DHEAS level, however, the majority of women with a low DHEAS level did not report low sexual function. This suggests that the measurement of serum androgens in women presenting with sexual dysfunction is not clinically useful.
Impact of male sexuality — One of the major factors that impacts female midlife sexuality is the spectrum of midlife sexual changes in men. It has been reported that 50 percent of men over 50, 60 percent of men over 60, and 70 percent of men over 70 have some degree of erectile dysfunction [26] . (See "Overview of male sexual dysfunction"). Other changes include a prolonged preorgasmic or plateau phase during which it can take considerably longer to achieve orgasm after arousal, and, as with women, orgasm may not always be achieved [27] . Finally, the ejaculate itself can be decreased or absent during sexual encounters.
Many couples adjust to these changes with more manual or oral stimulation to compensate for waning maintenance of erection and carry on normal sex lives. Sexual dysfunction occurs when either partner is bothered by the changes and the lack of successful activity. In men, however, these changes often lead to performance anxiety, one of the most significant psychosocial sexual problems. When the man experiences performance anxiety, he will frequently withdraw from intimacy at all levels of the relationship for fear of stimulating his partner to expect sexual activity that he believes he cannot provide. This withdrawal from other areas of intimacy has a most profound impact on the woman because of the major importance of intimacy to female desire and sexual response.
Decreased libido or sexual desire — Decreased libido or sexual desire, termed hypoactive sexual desire disorder (HSDD), has increasingly become one of the more common complaints of women in the menopausal transition and in midlife in general [28] . Sexual desire includes sexual appetite, drive, and fantasy. While sexual arousal leading to orgasm is predominantly a physiological event dependent upon neurovascular responses to stimuli within the appropriate hormonal milieu, libido or sexual desire is more psychosocial and behavioral, impacted by a multitude of factors in daily life and relationships.
The desire for sexual intimacy can be diminished in spite of normal levels of testosterone and estrogen. Many factors affect sexual drive and its expression in midlife and should be evaluated when patients present with decreased libido.
A number of instruments exist for the measurement of female sexual function, but only one has been validated for use in evaluation of treatment response (Profile of Female Sexual Function [PFSF]) in women with HSDD in international clinical trials [29] . Of note, androgen deficiency is not one of the criterion for the diagnosis of HSDD. Revised definitions of female sexual disorders have been proposed that reflect the importance of subjective sexual arousal and the concept of a circular sex-response cycle rather than a linear model (Masters and Johnson) [30] . In this model, a woman may access desire only after she becomes aroused by her partner, in which case lack of spontaneous desire is not a sexual dysfunction.
Partner availability — Women tend to live longer than men, resulting in a natural shortage of males ages 50 and older. At the same time, many men seek out younger partners, further affecting the availability of partners for women in midlife and beyond.
Personal well-being — A woman's sense of personal well-being is important to sexual interest and activity. Low perceived levels of physical and emotional satisfaction and a sense of unhappiness correlate with low sexual desire, resistance to arousal, and pain during sex [1] . Women who experience premenopausal physical or emotional problems, particularly disorders of sexual desire, sexual response, and sexual behavior, tend to experience a worsening of these conditions after menopause [16] .
Overall health and socioeconomic circumstances — Analysis of data from the National Health and Social Life Survey of 1749 women and 1410 men indicated that sexual dysfunction is highest in women with poor health, low income, and a history of infrequent sexual interest. Sexual dysfunction is also more common among women and men with poor physical and emotional health [1] .
Other — Other predictors of decreased libido have been described in women in their late reproductive years. In a four-year prospective cohort study of 326 women ages 35 to 47 (27 percent of whom reported a decreased libido), depression, vaginal dryness, and children living at home were associated with an increased risk of low libido [31] . Mean serum testosterone concentrations (measured every eight months in the early follicular phase) were not associated with libido. However, women with the greatest variability in serum testosterone concentrations reported the greatest declines in libido.
In a second report of 341 peri- and postmenopausal women, common menopausal symptoms, including depression, sleep disturbances, and night sweats, were associated with diminished libido [32] .
Medical issues — Chronological midlife may be associated with medical issues that impact sexuality in either the woman or her partner. These problems can diminish the physical ability to perform sexually, such as with coronary artery disease or arthritis (the most prevalent cause of sexual inactivity in the United States), or can affect arousal and orgasm capability as with neurologic disorders such as multiple sclerosis, Parkinson's disease, or sequelae of diabetes [1] . Alcohol and substance abuse may have a disabling affect on performance by altering erectile capability in the male and arousal in the female. Psychiatric or emotional problems can impact sexual function due to the particular disorder or to the treatment.
Medications — Both prescription and over-the-counter medications have the capability to alter desire, arousal, and orgasm. Any medication that alters blood flow (eg, antihypertensives), affects the CNS (eg, psychotropics), or dries the skin or mucous membranes (eg, antihistamines), may disrupt normal sexual function. As previously mentioned, both oral estrogens in HRT and oral asl well as non-oral contraceptives can adversely affect levels of bioavailable androgens. Non-oral estrogens, however, used peri or postmenopausally, do not diminish bioavailable androgens.
One of the major classes of medications that impacts sexuality is the selective serotonin reuptake inhibitors (SSRIs), frequently used to treat depression in the perimenopausal woman. (See "Antidepressant medication in adults: SSRIs and SNRIs"). The risk/benefit ratio with use of these agents is based on individual need and response. When depression is severe, SSRI's may allow for increase in sexual activity by treating the underlying process. However, in many patients, therapy can diminish sexual desire and alter or eliminate arousal and orgasm. Changing to a different antidepressant may help; the addition of bupropion to ongoing therapy also has been shown to improve sexual function [33] . (See "Sexual dysfunction associated with selective serotonin reuptake inhibitor (SSRI) antidepressants").
Surgery — Surgery related to cancers of the breast or female genital tract can have a profound effect on sexuality in midlife, as can prostate surgery in men. This occurs as a result of the extensive surgery affecting body image and function, as well as the psychological sequelae of the cancer diagnosis and prognosis on patient and partner. Many of these malignancies preclude the use of hormonal therapies, leading to even further problems involving genital function. Referral for counseling is critical in these patients.
Contrary to public perception, sexual function often improves with hysterectomy. Seriousness of pathology along with level of annoyance of bleeding, pain, or pressure preoperatively, affect satisfaction with sexual activity postoperatively. A two year prospective study assessed measures of sexual functioning in over 1000 women prior to hysterectomy and at 6, 12, 18, and 24 months, after the procedure [34] . The percentage of women who engaged in sexual relations increased from approximately 71 percent before hysterectomy to 77 percent at 12 and 24 months after hysterectomy; the rate of frequent dyspareunia dropped from 19 to 4 percent; the rate of experiencing orgasms increased from 92 to 95 percent; and libido increased. Overall, the frequency of sexual activity increased and problems with sexual functioning decreased postoperatively.
There remain, however, women who note a decrease or total absence of orgasm after hysterectomy. Preoperative counseling can help to prepare and assist the patient and partner by reviewing the risks of surgery, as well as the risks of not having the surgery, and potential sexual changes, better or worse, that might follow. Preservation of the ovaries and cervix, if not contraindicated and surgically possible, may help to avoid major changes in sexual response. (See "Abdominal hysterectomy", section on Outcome).
DIAGNOSIS OF SEXUAL DYSFUNCTION — The diagnosis of sexual dysfunction should begin with use of the non-threatening question, "Are you sexually active?" If the answer is affirmative, the second question can be, "Do you have any questions, problems, or concerns about your sexual activity that you would like to discuss?" If, instead, the patient indicates that she is not sexually active, the next and most important question should be, "Does that bother you or your partner?"
There are two common reasons that these questions are not asked. First, because the clinician may feel uncomfortable with the questions or with his or her level of knowledge of the subject and, second, the amount of time needed for discussion once the patient senses sincere interest and feels comfortable beginning a dialogue with the provider. After initiating the discussion, a separate consultation can be scheduled at a later date so that more uninterrupted time can be spent, and also to allow the patient to gather all her thoughts on the topic she now knows is open for discussion. Presence of the partner may also be useful later, once the patient has covered her own concerns. (See "The sexual history and approach to the patient with sexual dysfunction").
A teaching session should occur during the second consultation, in which the clinician describes normal sexual response as well as the physiological changes in sexuality that are common in midlife. Frequently little or no therapy is needed once patients realize so many of these changes are a normal part of the aging process and learn how to cope with them effectively.
The point at which the physiologic changes of aging become sexual dysfunction is best defined within the context of each individual relationship, based on the effect these changes have on the couple. The need for referral to a specialized counselor, therapist, or sexologist, should be made when more detailed consultation is necessary or when the clinician is unable to provide the service.
A detailed gynecologic examination is an important component of the evaluation. Careful assessment of the vulva, clitoris, introitus, and vagina, for atrophic changes, loss of elasticity, inflammation, scarring, infection, or genital prolapse, is paramount. Any tenderness to palpation, superficial or deep, must be evaluated. The pelvic structures, including the bladder, should be evaluated for pathology that might interfere with successful sexual activity, such as masses, endometriosis, or urinary incontinence. Routine breast and cervical cancer screening should be updated.
Laboratory testing is guided by the history and physical examination. No specific tests are universally recommended in all women. Assessment of the serum free and total testosterone concentrations are often done in women considering androgen therapy. However, many currently available methods for measurement of total and free testosterone lack the sensitivity and accuracy necessary for determining androgen deficiency in women [35] .
It is also important to note that the type and dose of androgen replacement therapy for women has not been well established. (See "Androgen production and therapy in women").
INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Sexual problems in women"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.
Tuesday, September 30, 2008
Monday, September 22, 2008
Patient information: Painful bladder syndrome and interstitial cystitis
Patient information: Painful bladder syndrome and interstitial cystitis
Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Leah K Moynihan, RNC, MSN
Sandy J Falk, MD
Last literature review version 16.2: May 2008 | This topic last updated: July 12, 2007 (More)
INTRODUCTION — Painful bladder syndrome/interstitial cystitis (PBS/IC) is a group of disorders with symptoms of mild to severe bladder pain and an urgent and/or frequent need to urinate. The disorder can affect women and men, but is more common in women. It can be difficult to diagnose and treat because the underlying cause is not well understood.
The symptoms and diagnosis of PBS/IC will be discussed here. Treatment of this disorder is reviewed separately. (See "Patient information: Treatment of painful bladder syndrome and interstitial cystitis").
DEFINITION — The definitions of painful bladder syndrome and interstitial cystitis have evolved over the years, and will probably continue to change as the cause is better understood.
Painful bladder syndrome — PBS is defined as a group of symptoms that include bladder pain and a frequent and/or urgent need to urinate during the day and/or night.
Interstitial cystitis — IC is the diagnosis used to describe people who have symptoms of PBS as well as changes in the bladder lining (seen during cystoscopy, see "Cystoscopy" below).
It is difficult to know for sure how many people are affected by PBS/IC; estimates range from 0.01 to 11 percent of women and 0.04 to 5 percent of men.
CAUSES — Little is known about the cause of PBS/IC. Many studies have shown that patients with IC have abnormalities in the lining of the bladder. However, it is not known if these bladder abnormalities are the cause of symptoms or develop as a result of some unknown underlying disorder that also causes painful bladder symptoms.
It is likely that the nerves in the bladder become highly sensitive to pain and pressure as PBS/IC develops. Nerves outside the bladder, including nerves of the abdomen, pelvis, and hips, and legs, may also become more sensitive.
One or more events may lead to the symptoms of PBS/IC, including:
Urinary tract infection
• An episode of vaginitis or prostatitis (eg, a yeast infection of the vagina or a bacterial infection of the prostate)
• Bladder, pelvic, back or other type of surgery
• Trauma (eg, fall onto the tailbone [coccyx] or car accident)
However, in many people, there is no clear explanation for why or how the symptoms of PBS/IC first began.
SYMPTOMS — The symptoms of PBS/IC can vary from one person to another and from time to time for each person. All patients with PBS/IC have bladder pain that is relieved at least partially by urinating. Symptoms usually include a frequent and urgent need to urinate during the day and/or night. Most, although not all, people with PBS/IC do not have urinary leakage (incontinence). Most people describe pain in the suprapubic area (in the lower abdomen, above the pubic bone) or urethral area (show figure 1). Some people describe one-sided lower abdominal pain or low back pain. The severity of pain ranges from mild burning to severe and debilitating pelvic pain.
Most people describe symptoms that begin gradually, with worsening discomfort, urgency and frequency over a period of months. A smaller subset of patients describes symptoms that are severe from the beginning. When symptoms of PBS/IC begin suddenly, some patients are able to name the exact date on which symptoms began (see "Causes" above).
Some people have chronic pelvic pain that is distinct from bladder pain, sometimes with other pain symptoms. Some people have several pain-related diagnoses, such as irritable bowel syndrome, painful menstrual periods, endometriosis, vulvar pain (vulvodynia), or fibromyalgia. PBS/IC symptoms are sometimes at their worst during times when other pain symptoms are also at their worst. (See "Patient information: Irritable bowel syndrome" and see "Patient information: Endometriosis" and see "Patient information: Fibromyalgia").
Symptoms may vary from one day to the next. Worsening of PBS/IC symptoms may occur after consuming certain foods or drinks (eg, strawberries, oranges, beer, coffee), or during the luteal phase of the menstrual cycle (14 to 28 days after the first day of the last period), during stressful times, or after activities such as exercise, sexual intercourse, or being seated for long periods of time (eg, during a plane trip).
A person with severe disease may have to urinate several times per hour, which can seriously disrupt daily activities and sleep. As a result of these symptoms, home and work life are often disrupted, interest in sex may be minimal, and difficulty coping with chronic pain and fatigue can occur. In surveys, 50 percent of patients reported being unable to work full-time, 75 percent described pain with intercourse, 70 percent reported sleep disturbance, and 90 percent reported that PBS/IC affected their daily activities [1] .
EVALUATION — The diagnosis of PBS/IC is based upon a person's symptoms and examination. A careful medical history, physical examination, and sometimes laboratory testing are needed to confirm the diagnosis and also to be sure that another condition (eg, bladder infection or kidney stone) is not the cause of symptoms. There is no single test that can definitively diagnose PBS/IC. (See "Patient information: Urinary tract infections in adolescents and adults" and see "Patient information: Kidney stones in adults").
Physical examination — The physical examination usually includes a complete pelvic examination with a brief rectal exam. Often, patients with PBS/IC have tenderness in the lower abdomen, hips, and buttocks. Women often have tenderness in the vagina and around the bladder, and men may have tenderness in the scrotum and penis. For this reason, being examined can be uncomfortable. In some individuals, it may be necessary to use ultrasound to ensure that the pelvic organs have no evidence of abnormalities.
If an examination or ultrasound is too uncomfortable, some healthcare providers will recommend that the patient begin a course of treatment for PBS/IC without further testing. If improvement is not seen, it may be necessary to perform more testing to confirm the diagnosis.
Some providers will measure the amount of urine remaining in the bladder after the patient urinates; this is called a post-void residual. This measurement can be done by inserting a small catheter into the bladder or by using ultrasound. While it is normal to have some urine in the bladder after voiding, having a large amount of urine is not normal. Urinary retention is the medical term for retaining urine in the bladder, and is not typical of PBS/IC.
Laboratory tests — Most clinicians will perform a urine test to confirm the diagnosis of PBS/IC and ensure that a person's symptoms are not related to another condition, such as a kidney stone or bladder infection. If a urinary tract infection is discovered, the person will be treated with antibiotics. If blood is detected in the urine, further urine and/or diagnostic testing (eg, cystoscopy) may be recommended. (See "Patient information: Urinary tract infections in adolescents and adults" and see "Patient information: Blood in the urine (hematuria)").
Recurrent urinary tract infection — PBS/IC is sometimes misdiagnosed as a chronic or recurrent urinary tract infection. Some people are given antibiotics to treat the pain, urgency, and frequency of PBS/IC, although there is no benefit of antibiotics unless an infection is present. The best way to determine if a urinary tract infection is present is to have a urine culture and sensitivity. (See "Patient information: Urinary tract infections in adolescents and adults").
Cystoscopy — Cystoscopy is a test that allows a doctor to examine the inside of the bladder. Cystoscopy is not required to diagnose PBS/IC, but may be recommended in certain situations. Cystoscopy can be done in the office, after a numbing gel is applied inside the urethra. It can also be done in an operating room while a patient is under anesthesia, sometimes in combination with other procedures (see "Hydrodistension" below).
To perform cystoscopy, a physician inserts a thin telescope with a camera through the urethra and into the bladder. The physician examines the inside (lining) of the bladder to determine if there are any abnormalities. A person with PBS/IC may have either a normal or abnormal-appearing bladder. If an abnormality is seen, further testing may be recommended.
Hydrodistension — Hydrodistension is a procedure that is sometimes recommended to diagnose interstitial cystitis. The procedure is done while a person is under anesthesia, after cystoscopy. The physician fills the patient's bladder with water to stretch the walls of the bladder. The water is released after a few minutes, and then filled again with a smaller amount of water. The lining of the bladder is then examined with a cystoscope to determine if there are signs of IC. Signs of IC can include glomerulations (small reddened areas) and Hunner's patches (larger red areas). Some patients with painful bladder symptoms can have a completely normal appearance during cystoscopy, however. A biopsy (small tissue sample) may be taken from any abnormal areas and later examined with a microscope.
There are conflicting opinions about the need for hydrodistension in the diagnosis of IC. Although some clinicians still perform hydrodistension, most clinicians believe is not necessary or helpful to see such evidence of IC before treating it.
TREATMENT — A topic review that discusses the treatment of painful bladder syndrome/interstitial cystitis is available separately. (See "Patient information: Treatment of painful bladder syndrome and interstitial cystitis").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable.
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Institute of Diabetes and Digestive and Kidney Diseases
(http://kidney.niddk.nih.gov/kudiseases/pubs/interstitialcystitis/)
Interstitial Cystitis Association
(www.ichelp.org)
Interstitial Cystitis Network
(www.ic-network.com)
European Society for the Study of Interstitial Cystitis
(www.essic.eu)
United States Department of Health and Human Services
(www.4woman.gov/faq/intcyst.htm)
Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Leah K Moynihan, RNC, MSN
Sandy J Falk, MD
Last literature review version 16.2: May 2008 | This topic last updated: July 12, 2007 (More)
INTRODUCTION — Painful bladder syndrome/interstitial cystitis (PBS/IC) is a group of disorders with symptoms of mild to severe bladder pain and an urgent and/or frequent need to urinate. The disorder can affect women and men, but is more common in women. It can be difficult to diagnose and treat because the underlying cause is not well understood.
The symptoms and diagnosis of PBS/IC will be discussed here. Treatment of this disorder is reviewed separately. (See "Patient information: Treatment of painful bladder syndrome and interstitial cystitis").
DEFINITION — The definitions of painful bladder syndrome and interstitial cystitis have evolved over the years, and will probably continue to change as the cause is better understood.
Painful bladder syndrome — PBS is defined as a group of symptoms that include bladder pain and a frequent and/or urgent need to urinate during the day and/or night.
Interstitial cystitis — IC is the diagnosis used to describe people who have symptoms of PBS as well as changes in the bladder lining (seen during cystoscopy, see "Cystoscopy" below).
It is difficult to know for sure how many people are affected by PBS/IC; estimates range from 0.01 to 11 percent of women and 0.04 to 5 percent of men.
CAUSES — Little is known about the cause of PBS/IC. Many studies have shown that patients with IC have abnormalities in the lining of the bladder. However, it is not known if these bladder abnormalities are the cause of symptoms or develop as a result of some unknown underlying disorder that also causes painful bladder symptoms.
It is likely that the nerves in the bladder become highly sensitive to pain and pressure as PBS/IC develops. Nerves outside the bladder, including nerves of the abdomen, pelvis, and hips, and legs, may also become more sensitive.
One or more events may lead to the symptoms of PBS/IC, including:
Urinary tract infection
• An episode of vaginitis or prostatitis (eg, a yeast infection of the vagina or a bacterial infection of the prostate)
• Bladder, pelvic, back or other type of surgery
• Trauma (eg, fall onto the tailbone [coccyx] or car accident)
However, in many people, there is no clear explanation for why or how the symptoms of PBS/IC first began.
SYMPTOMS — The symptoms of PBS/IC can vary from one person to another and from time to time for each person. All patients with PBS/IC have bladder pain that is relieved at least partially by urinating. Symptoms usually include a frequent and urgent need to urinate during the day and/or night. Most, although not all, people with PBS/IC do not have urinary leakage (incontinence). Most people describe pain in the suprapubic area (in the lower abdomen, above the pubic bone) or urethral area (show figure 1). Some people describe one-sided lower abdominal pain or low back pain. The severity of pain ranges from mild burning to severe and debilitating pelvic pain.
Most people describe symptoms that begin gradually, with worsening discomfort, urgency and frequency over a period of months. A smaller subset of patients describes symptoms that are severe from the beginning. When symptoms of PBS/IC begin suddenly, some patients are able to name the exact date on which symptoms began (see "Causes" above).
Some people have chronic pelvic pain that is distinct from bladder pain, sometimes with other pain symptoms. Some people have several pain-related diagnoses, such as irritable bowel syndrome, painful menstrual periods, endometriosis, vulvar pain (vulvodynia), or fibromyalgia. PBS/IC symptoms are sometimes at their worst during times when other pain symptoms are also at their worst. (See "Patient information: Irritable bowel syndrome" and see "Patient information: Endometriosis" and see "Patient information: Fibromyalgia").
Symptoms may vary from one day to the next. Worsening of PBS/IC symptoms may occur after consuming certain foods or drinks (eg, strawberries, oranges, beer, coffee), or during the luteal phase of the menstrual cycle (14 to 28 days after the first day of the last period), during stressful times, or after activities such as exercise, sexual intercourse, or being seated for long periods of time (eg, during a plane trip).
A person with severe disease may have to urinate several times per hour, which can seriously disrupt daily activities and sleep. As a result of these symptoms, home and work life are often disrupted, interest in sex may be minimal, and difficulty coping with chronic pain and fatigue can occur. In surveys, 50 percent of patients reported being unable to work full-time, 75 percent described pain with intercourse, 70 percent reported sleep disturbance, and 90 percent reported that PBS/IC affected their daily activities [1] .
EVALUATION — The diagnosis of PBS/IC is based upon a person's symptoms and examination. A careful medical history, physical examination, and sometimes laboratory testing are needed to confirm the diagnosis and also to be sure that another condition (eg, bladder infection or kidney stone) is not the cause of symptoms. There is no single test that can definitively diagnose PBS/IC. (See "Patient information: Urinary tract infections in adolescents and adults" and see "Patient information: Kidney stones in adults").
Physical examination — The physical examination usually includes a complete pelvic examination with a brief rectal exam. Often, patients with PBS/IC have tenderness in the lower abdomen, hips, and buttocks. Women often have tenderness in the vagina and around the bladder, and men may have tenderness in the scrotum and penis. For this reason, being examined can be uncomfortable. In some individuals, it may be necessary to use ultrasound to ensure that the pelvic organs have no evidence of abnormalities.
If an examination or ultrasound is too uncomfortable, some healthcare providers will recommend that the patient begin a course of treatment for PBS/IC without further testing. If improvement is not seen, it may be necessary to perform more testing to confirm the diagnosis.
Some providers will measure the amount of urine remaining in the bladder after the patient urinates; this is called a post-void residual. This measurement can be done by inserting a small catheter into the bladder or by using ultrasound. While it is normal to have some urine in the bladder after voiding, having a large amount of urine is not normal. Urinary retention is the medical term for retaining urine in the bladder, and is not typical of PBS/IC.
Laboratory tests — Most clinicians will perform a urine test to confirm the diagnosis of PBS/IC and ensure that a person's symptoms are not related to another condition, such as a kidney stone or bladder infection. If a urinary tract infection is discovered, the person will be treated with antibiotics. If blood is detected in the urine, further urine and/or diagnostic testing (eg, cystoscopy) may be recommended. (See "Patient information: Urinary tract infections in adolescents and adults" and see "Patient information: Blood in the urine (hematuria)").
Recurrent urinary tract infection — PBS/IC is sometimes misdiagnosed as a chronic or recurrent urinary tract infection. Some people are given antibiotics to treat the pain, urgency, and frequency of PBS/IC, although there is no benefit of antibiotics unless an infection is present. The best way to determine if a urinary tract infection is present is to have a urine culture and sensitivity. (See "Patient information: Urinary tract infections in adolescents and adults").
Cystoscopy — Cystoscopy is a test that allows a doctor to examine the inside of the bladder. Cystoscopy is not required to diagnose PBS/IC, but may be recommended in certain situations. Cystoscopy can be done in the office, after a numbing gel is applied inside the urethra. It can also be done in an operating room while a patient is under anesthesia, sometimes in combination with other procedures (see "Hydrodistension" below).
To perform cystoscopy, a physician inserts a thin telescope with a camera through the urethra and into the bladder. The physician examines the inside (lining) of the bladder to determine if there are any abnormalities. A person with PBS/IC may have either a normal or abnormal-appearing bladder. If an abnormality is seen, further testing may be recommended.
Hydrodistension — Hydrodistension is a procedure that is sometimes recommended to diagnose interstitial cystitis. The procedure is done while a person is under anesthesia, after cystoscopy. The physician fills the patient's bladder with water to stretch the walls of the bladder. The water is released after a few minutes, and then filled again with a smaller amount of water. The lining of the bladder is then examined with a cystoscope to determine if there are signs of IC. Signs of IC can include glomerulations (small reddened areas) and Hunner's patches (larger red areas). Some patients with painful bladder symptoms can have a completely normal appearance during cystoscopy, however. A biopsy (small tissue sample) may be taken from any abnormal areas and later examined with a microscope.
There are conflicting opinions about the need for hydrodistension in the diagnosis of IC. Although some clinicians still perform hydrodistension, most clinicians believe is not necessary or helpful to see such evidence of IC before treating it.
TREATMENT — A topic review that discusses the treatment of painful bladder syndrome/interstitial cystitis is available separately. (See "Patient information: Treatment of painful bladder syndrome and interstitial cystitis").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable.
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Institute of Diabetes and Digestive and Kidney Diseases
(http://kidney.niddk.nih.gov/kudiseases/pubs/interstitialcystitis/)
Interstitial Cystitis Association
(www.ichelp.org)
Interstitial Cystitis Network
(www.ic-network.com)
European Society for the Study of Interstitial Cystitis
(www.essic.eu)
United States Department of Health and Human Services
(www.4woman.gov/faq/intcyst.htm)
Treatment of painful bladder syndrome/interstitial cystitis
Treatment of painful bladder syndrome/interstitial cystitis
Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Sandy J Falk, MD
Last literature review version 16.2: May 2008 | This topic last updated: May 16, 2008 (More)
INTRODUCTION — Although painful bladder syndrome/interstitial cystitis (PBS/IC) can cause major deterioration in quality of life, there is no consensus surrounding the optimal approach to its treatment. This is due, in part, to our lack of a clear understanding of the etiology of the disorder, which precludes development of therapies targeted at the underlying pathophysiology. In addition, there have been few randomized, controlled treatment trials of PBS/IC, instead the great majority of therapeutic studies have been retrospective and/or uncontrolled. Lastly, varying definitions of the condition and outcome have been an impediment to interpretation of results and their application to clinical care [1] .
The symptoms of PBS/IC can be somewhat nonspecific; these patients probably suffer from one or more unrecognized disorders. Therefore, it is not surprising that clinically popular treatment algorithms for PBS/IC usually involve several treatment modalities or cycling through various therapies when initial treatments are unsuccessful. This was illustrated by the Interstitial Cystitis Data Base study, which recorded data on 581 women with a diagnosis of IC [2] . These women underwent 183 different types of therapy over several years follow-up. No one therapy was successful in a majority of patients.
In practice, physicians who treat patients with PBS/IC choose a model of the disease that seems to fit their clinical experience, and treat according to that model. Clinicians tend to favor one theory over others, and initiate treatment(s) in line with their favored theory. Therefore, treatment algorithms are highly empiric and vary considerably from site to site. Since treatments tend to have a low success rate, most patients try more than one therapy before finding relief. In this clinical setting, it cannot be determined whether the relief that patients experience is simply due to the passage of time and natural remission of symptoms, or whether the treatment was responsible for the improvement.
NONSPECIFIC THERAPIES — Common sense dictates that the following components are part of all treatment programs:
Psychosocial support — Psychosocial support is an integral part of treatment of any chronic pain disorder. Patients may benefit from identification of a support person within the clinical practice whom they may contact, as needed. They may wish to be in touch with local pain support groups, or with national support groups, such as the Interstitial Cystitis Society (www.ichelp.org) or the Interstitial Cystitis Network (www.ic-network.com). Some centers may have resources to refer patients for formal counseling by a psychologist with expertise in support of patients with chronic illness.
Depression is common in patients with chronic pain, and may impede treatment success. Referral for mental health evaluation may be useful when there is any suspicion that depression is present. (See "Depression: Clinical manifestations and diagnosis").
Referral to pain management specialists — Referral to specialists in pain management should be considered if the full range of pain management options is not available within the practice.
Treatment of comorbid conditions — Acute genitourinary disorders (eg, urinary tract infection, vulvovaginitis) can exacerbate PBS/IC symptoms, thus they should be addressed promptly. Other disorders associated with visceral pain should also be treated since sensitization of any viscera probably results in increased bladder sensitivity. Therefore, it is critically important to treat concomitant inflammatory bowel disease (Crohn's disease, ulcerative colitis, diverticulitis), irritable bowel syndrome, dysmenorrhea or endometriosis. Since PBS/IC patients often carry more than one of these diagnoses, treatment decisions can be complex, and collaboration with other medical professionals is usually necessary. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis").
Avoidance of activities associated with flares — Patients frequently note that some exercises or recreational activities, sexual activities, or body positions seem to worsen bladder symptoms. Others note that some foods or beverages are troublesome. Common sense suggests that these factors be avoided until symptoms are resolved, at which time they may be reintroduced. Some practitioners strongly recommend the highly restrictive interstitial cystitis diet [3] , but its benefit has never been studied, and in practice, most patients with food sensitivities are already aware of them and have already excluded them from their diet.
Behavioral therapy — Behavioral therapy forms the cornerstone of all treatment packages. It includes avoidance of exacerbating activities, and also some form of a timed voiding protocol to expand functional bladder capacity. Such protocols are critical because frequent voiding leads to diminished functional bladder capacity (possibly due to shrinkage of smooth muscle, similar to diminished stomach capacity after fasting or after chronic intake of smaller amounts of food).
A typical bladder reeducation protocol involves teaching patients to "void by the clock" rather than voiding when they feel an urge to do so. As an example, a patient who is currently voiding every half an hour is asked to void only on the hour during the daytime (drills are not typically continued through the night), whether they feel the need to void or not, and not to void more frequently than the prescribed interval. This voiding interval is continued for a full week, and if patients are successful at that voiding interval, it is increased by an appropriate amount. This might result in the prescription of a voiding interval of 90 minutes for the second week, of two hours for the third week, 2.5 hours for the fourth week, and three hours for the fifth week. Other similar bladder retraining therapies are widely used since they are cheap, without side effects, and universally available.
The only study of timed voiding in IC patients reported 15 of 21 patients experienced a 50 percent decrease in their IC symptoms [4] .
SPECIFIC THERAPIES
Correction of uroepithelial abnormalities — Proponents of the theory that urothelial abnormalities are responsible for symptoms favor use of therapies directed at the urothelium. These include:
Pentosan polysulfate sodium — Pentosan polysulfate sodium (PPS) is the only oral medication approved by the United States Food and Drug Administration (FDA) for treatment of IC. The approved dose is 100 mg three times daily, although off-label treatment using 200 mg twice daily is clinically common. The medication is a protein that is supposed to be filtered by the kidneys and appear in the urine so that it can reconstitute the deficient glycosaminoglycan (GAG) layer over the urothelium. In fact, only a tiny proportion of the drug is absorbed by the gastrointestinal tract and excreted in the urine. Urinary levels in patients who respond to treatment are not significantly different from the levels in nonresponders [5] .
A systematic review of randomized trials assessing pharmacologic treatments of PBS/IC found that PPS was more effective than placebo in overall improvement of patient-reported symptoms (pain, urgency, frequency) (RR 1.78, 95% CI 1.34-2.35), but the magnitude of effect was modest [6] . There was considerable heterogeneity in the studies that addressed this question.
Intravesical heparin and lidocaine — Some practitioners recommend intravesical instillations of heparin and/or lidocaine, PPS, and sodium bicarbonate in various nonstandardized drug cocktails. No controlled studies of these therapies exist. As an example, use of a solution consisting of 40,000 units of heparin, 8 mL of 2 percent lidocaine, and 3 mL of 8.4 percent of sodium bicarbonate to reach a total fluid volume of 15 mL instilled into the bladder has been described as effective, with over 80 percent of patients experiencing good remissions after two weeks of three treatments per week [7] . Similar solutions have been recommended for use in patients with severe symptoms as a "rescue" intervention. Patients can be taught to perform the instillations themselves at home.
Intravesical dimethyl sulfoxide (DMSO) — Dimethyl sulfoxide (DMSO) was approved by the FDA for use in IC in 1997 on the basis of data from one uncontrolled clinical trial. Its action is thought to be nonspecific, including antiinflammatory, analgesic, smooth muscle relaxing, and mast cell inhibiting effects [8] . Treatment involves bladder catheterization with instillation of 50 mL DMSO weekly for six to eight weeks, followed by 50 mL every two weeks for 3 to 12 months. Small randomized trials initially suggested benefit [9,10] , but adverse effects, including pain and significant exacerbation of symptoms, limited its use. DMSO is currently less commonly used than in the past, as other, less painful treatments have become available.
Hydrodistension — Hydrodistension is usually used as a diagnostic aid for PBS/IC. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis" section on Hydrodistension). It has also been used as a treatment because some patients report prolonged relief of symptoms after the procedure, possibly due to disruption of sensory nerves within the bladder wall [11] . An uncontrolled study reported a positive effect in 35 of 50 patients who underwent 30 minutes of hydrodistension [8] , but others have reported lower success rates [12] . Even when there is benefit, it is usually short-lived, and many patients experience worsening of their symptoms; thus, many clinicians feel that the risk-benefit ratio of hydrodistension therapy is not appropriate for their patients. It may be appropriate to reserve use of repetitive therapeutic hydrodistension for patients who generally obtain significant and prolonged relief. Risks of hydrodistension include bleeding (from ruptured vessels) and, rarely, rupture of the bladder wall.
Neuromodulating therapies — Proponents of the theory that PBS/IC represents a neurological hypersensitivity disorder tend to favor use of neuromodulating treatments. These include:
Amitriptyline — Medications used to treat other pain syndromes are commonly utilized for IC patients, as well. Amitriptyline is commonly prescribed for relief of PBS/IC symptoms. In Germany, one trial randomly assigned 50 subjects with IC to amitriptyline or placebo (IC was defined according to National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria) (show table 1) [13] . Subjects were treated for four months with a self-titration protocol that allowed them to escalate drug dosage by 25 mg increments weekly to a maximum of 100 mg. Amitriptyline use resulted in greater improvement in symptom scores than placebo. In addition, significantly more subjects prescribed amitriptyline rated their satisfaction with treatment as being "good" or "excellent" than those given placebo, 63 and 4 percent, respectively. However, only 42 percent of patients in the amitriptyline group experienced greater than 30 percent decrease in symptom score, suggesting that benefits are modest.
An open-label study of the long-term use of amitriptyline in 94 patients followed for a mean of 19 months reported similar results [14] . Almost one-half of patients rated satisfaction with treatment as "good" or "excellent" and designated themselves as being "moderately" or "markedly" improved. However, about one-third dropped out of the study after a mean treatment period of six weeks, with nonresponse to treatment being the primary reason for dropout. Side effects of amitriptyline include sedation, dry mouth and weight gain.
A National Institutes of Health-sponsored randomized trial comparing behavioral therapy to amitriptyline-plus-behavioral therapy for treatment of PBS is ongoing [15] .
Side effects of amitriptyline include anticholinergic effects, sedation, weight gain, orthostatic hypotension, and conduction abnormalities. (See "Antidepressant medication in adults: Tricyclics and tetracyclics", section on Heterocyclic antidepressants).
Gabapentin — In an uncontrolled study, 21 patients with refractory genitourinary pain were treated with gabapentin at a dose of 300 to 1200 mg/day [16] . About one-half of the patients reported improvement in pain, including five of eight patients who had a diagnosis of IC. Anecdotal reports also suggest that pregabalin can be effective for pain relief in PBS/IC, but no formal studies support its use. (See "Antiepileptic drugs in the treatment of neuropathic pain").
Electrical stimulation therapy — Several reports support treatment of PBS/IC symptoms with implanted sacral neuromodulation (eg, InterStim device, Medtronic Inc, Minneapolis, MN). This device is FDA approved for treatment of urinary urgency and frequency, but not specifically for treatment of PBS/IC. The device consists of an implanted lead that lies along a sacral nerve root (usually at S3 level) and is attached to an implanted pulse generator. An uncontrolled study from a single center described 17 patients diagnosed with IC according to NIDDK criteria (show table 1) who received InterStim implants and were followed for an average of 14 months [17] . Mean daytime and nighttime voiding frequencies decreased from 17 and 9 to 4 and 1, respectively. Average pain rating decreased from 5.8/10 at baseline to 1.6/10 [17] . Another case series documented "moderate" or "marked" improvement in pain in 20 of 21 IC patients (NIDDK criteria) during one year of follow-up [18] .
InterStim is a costly procedure, and surgical revisions are relatively common. Adverse events include surgical site infections and pain, and reoperation for revisions at the lead or pulse generator site(s) is not uncommon.
Somatic therapy — Proponents of the theory that bladder symptoms are caused or maintained by somatic (body wall) abnormalities favor somatic therapies. At present, physical therapy is the only somatic therapy in routine use.
Physical therapy — Treatment of the somatic abnormalities in PBS/IC patients is not within the scope of training of most physical therapists, even those who are skilled in treatment of urinary incontinence. Resolution of the tender points, trigger points, connective tissue restrictions, and muscular abnormalities of the soft tissues requires specialized training in pelvic soft tissue manual manipulation and rehabilitation. The therapist may also suggest that manual therapy treatments be supplemented by heat or ice treatments.
Several case series have described symptom relief from manual physical therapies. As an example, one study reported that 70 percent of IC patients who were treated with manual physical therapy to the pelvic floor tissues for 12 to 15 visits experienced moderate to marked improvement [19] . Another study of 21 women with IC and associated pelvic floor hypertonicity demonstrated decreased symptom scores after five weeks of pelvic floor massage [20] . A randomized trial of physical therapies for treatment of PBS/IC is currently ongoing [15] .
Therapies directed at mast cells — Proponents of the theory that mast cells play a critical role in the development and/or maintenance of IC symptoms favor therapies directed at mast cells and allergic phenomena. These include:
Hydroxyzine and cimetidine — Until recently, the antihistamine hydroxyzine was a mainstay of IC treatment, with initial dosing of 10 mg in the evening [21] , increasing to 50 to 100 mg daily as needed. However, a randomized controlled trial found hydroxyzine had no benefit over placebo [22] .
Two small studies suggested benefit of treatment with cimetidine, an H2-receptor blocker, but clinical experience has not generally supported these smaller studies and cimetidine is not commonly used [23,24] .
Montelukast — The presence of leukotriene D4 receptors in human detrusor myocytes and increased urinary leukotriene E4 in patients with interstitial cystitis and detrusor mastocytosis suggest cysteinyl containing leukotrienes may have a role as proinflammatory mediators in this disease [25] . One small study of 10 women with interstitial cystitis (NIDDK criteria) and detrusor mastocytosis received a single dose of montelukast daily for three months [25] . After one month of montelukast treatment, there was a statistically significant decrease in 24-hour urinary frequency, nocturia and pain which persisted during the three months of treatment. After three months, 24-hour urinary frequency decreased from 17.4 to 12 voidings, nocturia decreased from 4.5 to 2.8 voidings, and pain decreased from 46.8 to 19.6 mm on a visual analog scale. No side effects were observed during treatment. Further investigation of this modality is required.
Dimethyl sulfoxide — (see "Intravesical dimethyl sulfoxide (DMSO)" above)
Immunomodulatory treatments — There is some current interest in exploration of immunomodulatory treatments for PBS/IC. In one trial, 64 patients were randomized in a 1:1 ratio to 1.5 mg/kg cyclosporine A twice daily or 100 mg PPS three times daily for six months [26] . Cyclosporine A was superior to PPS in all clinical outcome parameters measured: micturition frequency in 24 hours was significantly reduced (-6.7 +/- 4.7 versus -2.0 +/- 5.1 times) and the clinical response rate (according to global response assessment) was significantly higher for cyclosporine than PPS (75 versus 19 percent). Adverse effects of cyclosporine A include hair growth, gingival hyperplasia, paresthesias, abdominal pain, flushing and muscle pain.
Although intravesical instillation of bacillus Calmette-Guerin (BCG) triggers a variety of local immune responses and has an acceptable safety profile, it has not provided significantly greater relief of IC symptoms than placebo in randomized trials [27,28] .
INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Painful bladder syndrome and interstitial cystitis" and see "Patient information: Treatment of painful bladder syndrome and interstitial cystitis"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.
SUMMARY AND RECOMMENDATIONS — Painful bladder syndrome/Interstitial cystitis (PBS/IC) causes significant deterioration in quality of life, and there is no consensus on the optimal treatment. Several etiologies have been proposed, and clinicians tend to treat according to their belief about the pathophysiology of the disorder. Significant advances in treatment success are likely to depend on major advances in our understanding of the etiology of these disorders, and refinements in diagnosis. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis").
Pentosan polysulfate sodium is the only oral treatment for IC approved by the FDA. Uncontrolled studies suggest modest benefit, in a minority of patients, but a randomized controlled trial suggested no benefit over placebo. (See "Pentosan polysulfate sodium" above).
Intravesical therapy with dimethyl sulfoxide is approved by the FDA, but is not in common clinical use due to associated pain and uneven clinical benefit. Intravesical therapy with heparin, lidocaine and/or pentosan polysulfate sodium is also used clinically, without strong evidence to support its use. (See "Intravesical heparin and lidocaine" above and see "Intravesical dimethyl sulfoxide (DMSO)" above).
Hydrodistension is primarily a diagnostic test, but may be considered for patients who obtain significant relief of symptoms after the procedure. (See "Hydrodistension" above).
Amitriptyline has clinical utility, probably acting as a nonspecific neuromodulatory agent that decreases the sensitivity of bladder sensory pathways. (See "Amitriptyline" above).
Sacral neuromodulation with implanted electrodes that lie along a sacral nerve root has shown significant benefit in uncontrolled studies, but is expensive and is not approved by the FDA for this indication. (See "Electrical stimulation therapy" above).
Physical therapy is directed at resolution of the tender points, trigger points, connective tissue restrictions, and muscular abnormalities of the soft tissues, but requires specialized training. (See "Physical therapy" above).
There is no good evidence showing that one treatment regimen is clearly superior to another. We suggest physical therapy for initial treatment of patients with PBS/IC (Grade 2C). We also suggest a trial of amitriptyline (Grade 2B). We start with 10 mg nightly and increase to 25 mg nightly as tolerated, in accordance with side effects and symptom relief. In our experience, it is only those women with the most severe symptoms who are willing to tolerate the side effects (eg, sedation and weight gain) that can be associated with amitriptyline use. When symptoms improve on this dual therapy, patients can usually discontinue amitriptyline while maintaining physical therapy, which is continued until their symptoms have resolved. We suggest sacral neuromodulation to patients who do not respond to physical therapy and/or amitriptyline (Grade 2C).
Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Sandy J Falk, MD
Last literature review version 16.2: May 2008 | This topic last updated: May 16, 2008 (More)
INTRODUCTION — Although painful bladder syndrome/interstitial cystitis (PBS/IC) can cause major deterioration in quality of life, there is no consensus surrounding the optimal approach to its treatment. This is due, in part, to our lack of a clear understanding of the etiology of the disorder, which precludes development of therapies targeted at the underlying pathophysiology. In addition, there have been few randomized, controlled treatment trials of PBS/IC, instead the great majority of therapeutic studies have been retrospective and/or uncontrolled. Lastly, varying definitions of the condition and outcome have been an impediment to interpretation of results and their application to clinical care [1] .
The symptoms of PBS/IC can be somewhat nonspecific; these patients probably suffer from one or more unrecognized disorders. Therefore, it is not surprising that clinically popular treatment algorithms for PBS/IC usually involve several treatment modalities or cycling through various therapies when initial treatments are unsuccessful. This was illustrated by the Interstitial Cystitis Data Base study, which recorded data on 581 women with a diagnosis of IC [2] . These women underwent 183 different types of therapy over several years follow-up. No one therapy was successful in a majority of patients.
In practice, physicians who treat patients with PBS/IC choose a model of the disease that seems to fit their clinical experience, and treat according to that model. Clinicians tend to favor one theory over others, and initiate treatment(s) in line with their favored theory. Therefore, treatment algorithms are highly empiric and vary considerably from site to site. Since treatments tend to have a low success rate, most patients try more than one therapy before finding relief. In this clinical setting, it cannot be determined whether the relief that patients experience is simply due to the passage of time and natural remission of symptoms, or whether the treatment was responsible for the improvement.
NONSPECIFIC THERAPIES — Common sense dictates that the following components are part of all treatment programs:
Psychosocial support — Psychosocial support is an integral part of treatment of any chronic pain disorder. Patients may benefit from identification of a support person within the clinical practice whom they may contact, as needed. They may wish to be in touch with local pain support groups, or with national support groups, such as the Interstitial Cystitis Society (www.ichelp.org) or the Interstitial Cystitis Network (www.ic-network.com). Some centers may have resources to refer patients for formal counseling by a psychologist with expertise in support of patients with chronic illness.
Depression is common in patients with chronic pain, and may impede treatment success. Referral for mental health evaluation may be useful when there is any suspicion that depression is present. (See "Depression: Clinical manifestations and diagnosis").
Referral to pain management specialists — Referral to specialists in pain management should be considered if the full range of pain management options is not available within the practice.
Treatment of comorbid conditions — Acute genitourinary disorders (eg, urinary tract infection, vulvovaginitis) can exacerbate PBS/IC symptoms, thus they should be addressed promptly. Other disorders associated with visceral pain should also be treated since sensitization of any viscera probably results in increased bladder sensitivity. Therefore, it is critically important to treat concomitant inflammatory bowel disease (Crohn's disease, ulcerative colitis, diverticulitis), irritable bowel syndrome, dysmenorrhea or endometriosis. Since PBS/IC patients often carry more than one of these diagnoses, treatment decisions can be complex, and collaboration with other medical professionals is usually necessary. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis").
Avoidance of activities associated with flares — Patients frequently note that some exercises or recreational activities, sexual activities, or body positions seem to worsen bladder symptoms. Others note that some foods or beverages are troublesome. Common sense suggests that these factors be avoided until symptoms are resolved, at which time they may be reintroduced. Some practitioners strongly recommend the highly restrictive interstitial cystitis diet [3] , but its benefit has never been studied, and in practice, most patients with food sensitivities are already aware of them and have already excluded them from their diet.
Behavioral therapy — Behavioral therapy forms the cornerstone of all treatment packages. It includes avoidance of exacerbating activities, and also some form of a timed voiding protocol to expand functional bladder capacity. Such protocols are critical because frequent voiding leads to diminished functional bladder capacity (possibly due to shrinkage of smooth muscle, similar to diminished stomach capacity after fasting or after chronic intake of smaller amounts of food).
A typical bladder reeducation protocol involves teaching patients to "void by the clock" rather than voiding when they feel an urge to do so. As an example, a patient who is currently voiding every half an hour is asked to void only on the hour during the daytime (drills are not typically continued through the night), whether they feel the need to void or not, and not to void more frequently than the prescribed interval. This voiding interval is continued for a full week, and if patients are successful at that voiding interval, it is increased by an appropriate amount. This might result in the prescription of a voiding interval of 90 minutes for the second week, of two hours for the third week, 2.5 hours for the fourth week, and three hours for the fifth week. Other similar bladder retraining therapies are widely used since they are cheap, without side effects, and universally available.
The only study of timed voiding in IC patients reported 15 of 21 patients experienced a 50 percent decrease in their IC symptoms [4] .
SPECIFIC THERAPIES
Correction of uroepithelial abnormalities — Proponents of the theory that urothelial abnormalities are responsible for symptoms favor use of therapies directed at the urothelium. These include:
Pentosan polysulfate sodium — Pentosan polysulfate sodium (PPS) is the only oral medication approved by the United States Food and Drug Administration (FDA) for treatment of IC. The approved dose is 100 mg three times daily, although off-label treatment using 200 mg twice daily is clinically common. The medication is a protein that is supposed to be filtered by the kidneys and appear in the urine so that it can reconstitute the deficient glycosaminoglycan (GAG) layer over the urothelium. In fact, only a tiny proportion of the drug is absorbed by the gastrointestinal tract and excreted in the urine. Urinary levels in patients who respond to treatment are not significantly different from the levels in nonresponders [5] .
A systematic review of randomized trials assessing pharmacologic treatments of PBS/IC found that PPS was more effective than placebo in overall improvement of patient-reported symptoms (pain, urgency, frequency) (RR 1.78, 95% CI 1.34-2.35), but the magnitude of effect was modest [6] . There was considerable heterogeneity in the studies that addressed this question.
Intravesical heparin and lidocaine — Some practitioners recommend intravesical instillations of heparin and/or lidocaine, PPS, and sodium bicarbonate in various nonstandardized drug cocktails. No controlled studies of these therapies exist. As an example, use of a solution consisting of 40,000 units of heparin, 8 mL of 2 percent lidocaine, and 3 mL of 8.4 percent of sodium bicarbonate to reach a total fluid volume of 15 mL instilled into the bladder has been described as effective, with over 80 percent of patients experiencing good remissions after two weeks of three treatments per week [7] . Similar solutions have been recommended for use in patients with severe symptoms as a "rescue" intervention. Patients can be taught to perform the instillations themselves at home.
Intravesical dimethyl sulfoxide (DMSO) — Dimethyl sulfoxide (DMSO) was approved by the FDA for use in IC in 1997 on the basis of data from one uncontrolled clinical trial. Its action is thought to be nonspecific, including antiinflammatory, analgesic, smooth muscle relaxing, and mast cell inhibiting effects [8] . Treatment involves bladder catheterization with instillation of 50 mL DMSO weekly for six to eight weeks, followed by 50 mL every two weeks for 3 to 12 months. Small randomized trials initially suggested benefit [9,10] , but adverse effects, including pain and significant exacerbation of symptoms, limited its use. DMSO is currently less commonly used than in the past, as other, less painful treatments have become available.
Hydrodistension — Hydrodistension is usually used as a diagnostic aid for PBS/IC. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis" section on Hydrodistension). It has also been used as a treatment because some patients report prolonged relief of symptoms after the procedure, possibly due to disruption of sensory nerves within the bladder wall [11] . An uncontrolled study reported a positive effect in 35 of 50 patients who underwent 30 minutes of hydrodistension [8] , but others have reported lower success rates [12] . Even when there is benefit, it is usually short-lived, and many patients experience worsening of their symptoms; thus, many clinicians feel that the risk-benefit ratio of hydrodistension therapy is not appropriate for their patients. It may be appropriate to reserve use of repetitive therapeutic hydrodistension for patients who generally obtain significant and prolonged relief. Risks of hydrodistension include bleeding (from ruptured vessels) and, rarely, rupture of the bladder wall.
Neuromodulating therapies — Proponents of the theory that PBS/IC represents a neurological hypersensitivity disorder tend to favor use of neuromodulating treatments. These include:
Amitriptyline — Medications used to treat other pain syndromes are commonly utilized for IC patients, as well. Amitriptyline is commonly prescribed for relief of PBS/IC symptoms. In Germany, one trial randomly assigned 50 subjects with IC to amitriptyline or placebo (IC was defined according to National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria) (show table 1) [13] . Subjects were treated for four months with a self-titration protocol that allowed them to escalate drug dosage by 25 mg increments weekly to a maximum of 100 mg. Amitriptyline use resulted in greater improvement in symptom scores than placebo. In addition, significantly more subjects prescribed amitriptyline rated their satisfaction with treatment as being "good" or "excellent" than those given placebo, 63 and 4 percent, respectively. However, only 42 percent of patients in the amitriptyline group experienced greater than 30 percent decrease in symptom score, suggesting that benefits are modest.
An open-label study of the long-term use of amitriptyline in 94 patients followed for a mean of 19 months reported similar results [14] . Almost one-half of patients rated satisfaction with treatment as "good" or "excellent" and designated themselves as being "moderately" or "markedly" improved. However, about one-third dropped out of the study after a mean treatment period of six weeks, with nonresponse to treatment being the primary reason for dropout. Side effects of amitriptyline include sedation, dry mouth and weight gain.
A National Institutes of Health-sponsored randomized trial comparing behavioral therapy to amitriptyline-plus-behavioral therapy for treatment of PBS is ongoing [15] .
Side effects of amitriptyline include anticholinergic effects, sedation, weight gain, orthostatic hypotension, and conduction abnormalities. (See "Antidepressant medication in adults: Tricyclics and tetracyclics", section on Heterocyclic antidepressants).
Gabapentin — In an uncontrolled study, 21 patients with refractory genitourinary pain were treated with gabapentin at a dose of 300 to 1200 mg/day [16] . About one-half of the patients reported improvement in pain, including five of eight patients who had a diagnosis of IC. Anecdotal reports also suggest that pregabalin can be effective for pain relief in PBS/IC, but no formal studies support its use. (See "Antiepileptic drugs in the treatment of neuropathic pain").
Electrical stimulation therapy — Several reports support treatment of PBS/IC symptoms with implanted sacral neuromodulation (eg, InterStim device, Medtronic Inc, Minneapolis, MN). This device is FDA approved for treatment of urinary urgency and frequency, but not specifically for treatment of PBS/IC. The device consists of an implanted lead that lies along a sacral nerve root (usually at S3 level) and is attached to an implanted pulse generator. An uncontrolled study from a single center described 17 patients diagnosed with IC according to NIDDK criteria (show table 1) who received InterStim implants and were followed for an average of 14 months [17] . Mean daytime and nighttime voiding frequencies decreased from 17 and 9 to 4 and 1, respectively. Average pain rating decreased from 5.8/10 at baseline to 1.6/10 [17] . Another case series documented "moderate" or "marked" improvement in pain in 20 of 21 IC patients (NIDDK criteria) during one year of follow-up [18] .
InterStim is a costly procedure, and surgical revisions are relatively common. Adverse events include surgical site infections and pain, and reoperation for revisions at the lead or pulse generator site(s) is not uncommon.
Somatic therapy — Proponents of the theory that bladder symptoms are caused or maintained by somatic (body wall) abnormalities favor somatic therapies. At present, physical therapy is the only somatic therapy in routine use.
Physical therapy — Treatment of the somatic abnormalities in PBS/IC patients is not within the scope of training of most physical therapists, even those who are skilled in treatment of urinary incontinence. Resolution of the tender points, trigger points, connective tissue restrictions, and muscular abnormalities of the soft tissues requires specialized training in pelvic soft tissue manual manipulation and rehabilitation. The therapist may also suggest that manual therapy treatments be supplemented by heat or ice treatments.
Several case series have described symptom relief from manual physical therapies. As an example, one study reported that 70 percent of IC patients who were treated with manual physical therapy to the pelvic floor tissues for 12 to 15 visits experienced moderate to marked improvement [19] . Another study of 21 women with IC and associated pelvic floor hypertonicity demonstrated decreased symptom scores after five weeks of pelvic floor massage [20] . A randomized trial of physical therapies for treatment of PBS/IC is currently ongoing [15] .
Therapies directed at mast cells — Proponents of the theory that mast cells play a critical role in the development and/or maintenance of IC symptoms favor therapies directed at mast cells and allergic phenomena. These include:
Hydroxyzine and cimetidine — Until recently, the antihistamine hydroxyzine was a mainstay of IC treatment, with initial dosing of 10 mg in the evening [21] , increasing to 50 to 100 mg daily as needed. However, a randomized controlled trial found hydroxyzine had no benefit over placebo [22] .
Two small studies suggested benefit of treatment with cimetidine, an H2-receptor blocker, but clinical experience has not generally supported these smaller studies and cimetidine is not commonly used [23,24] .
Montelukast — The presence of leukotriene D4 receptors in human detrusor myocytes and increased urinary leukotriene E4 in patients with interstitial cystitis and detrusor mastocytosis suggest cysteinyl containing leukotrienes may have a role as proinflammatory mediators in this disease [25] . One small study of 10 women with interstitial cystitis (NIDDK criteria) and detrusor mastocytosis received a single dose of montelukast daily for three months [25] . After one month of montelukast treatment, there was a statistically significant decrease in 24-hour urinary frequency, nocturia and pain which persisted during the three months of treatment. After three months, 24-hour urinary frequency decreased from 17.4 to 12 voidings, nocturia decreased from 4.5 to 2.8 voidings, and pain decreased from 46.8 to 19.6 mm on a visual analog scale. No side effects were observed during treatment. Further investigation of this modality is required.
Dimethyl sulfoxide — (see "Intravesical dimethyl sulfoxide (DMSO)" above)
Immunomodulatory treatments — There is some current interest in exploration of immunomodulatory treatments for PBS/IC. In one trial, 64 patients were randomized in a 1:1 ratio to 1.5 mg/kg cyclosporine A twice daily or 100 mg PPS three times daily for six months [26] . Cyclosporine A was superior to PPS in all clinical outcome parameters measured: micturition frequency in 24 hours was significantly reduced (-6.7 +/- 4.7 versus -2.0 +/- 5.1 times) and the clinical response rate (according to global response assessment) was significantly higher for cyclosporine than PPS (75 versus 19 percent). Adverse effects of cyclosporine A include hair growth, gingival hyperplasia, paresthesias, abdominal pain, flushing and muscle pain.
Although intravesical instillation of bacillus Calmette-Guerin (BCG) triggers a variety of local immune responses and has an acceptable safety profile, it has not provided significantly greater relief of IC symptoms than placebo in randomized trials [27,28] .
INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Painful bladder syndrome and interstitial cystitis" and see "Patient information: Treatment of painful bladder syndrome and interstitial cystitis"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.
SUMMARY AND RECOMMENDATIONS — Painful bladder syndrome/Interstitial cystitis (PBS/IC) causes significant deterioration in quality of life, and there is no consensus on the optimal treatment. Several etiologies have been proposed, and clinicians tend to treat according to their belief about the pathophysiology of the disorder. Significant advances in treatment success are likely to depend on major advances in our understanding of the etiology of these disorders, and refinements in diagnosis. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis").
Pentosan polysulfate sodium is the only oral treatment for IC approved by the FDA. Uncontrolled studies suggest modest benefit, in a minority of patients, but a randomized controlled trial suggested no benefit over placebo. (See "Pentosan polysulfate sodium" above).
Intravesical therapy with dimethyl sulfoxide is approved by the FDA, but is not in common clinical use due to associated pain and uneven clinical benefit. Intravesical therapy with heparin, lidocaine and/or pentosan polysulfate sodium is also used clinically, without strong evidence to support its use. (See "Intravesical heparin and lidocaine" above and see "Intravesical dimethyl sulfoxide (DMSO)" above).
Hydrodistension is primarily a diagnostic test, but may be considered for patients who obtain significant relief of symptoms after the procedure. (See "Hydrodistension" above).
Amitriptyline has clinical utility, probably acting as a nonspecific neuromodulatory agent that decreases the sensitivity of bladder sensory pathways. (See "Amitriptyline" above).
Sacral neuromodulation with implanted electrodes that lie along a sacral nerve root has shown significant benefit in uncontrolled studies, but is expensive and is not approved by the FDA for this indication. (See "Electrical stimulation therapy" above).
Physical therapy is directed at resolution of the tender points, trigger points, connective tissue restrictions, and muscular abnormalities of the soft tissues, but requires specialized training. (See "Physical therapy" above).
There is no good evidence showing that one treatment regimen is clearly superior to another. We suggest physical therapy for initial treatment of patients with PBS/IC (Grade 2C). We also suggest a trial of amitriptyline (Grade 2B). We start with 10 mg nightly and increase to 25 mg nightly as tolerated, in accordance with side effects and symptom relief. In our experience, it is only those women with the most severe symptoms who are willing to tolerate the side effects (eg, sedation and weight gain) that can be associated with amitriptyline use. When symptoms improve on this dual therapy, patients can usually discontinue amitriptyline while maintaining physical therapy, which is continued until their symptoms have resolved. We suggest sacral neuromodulation to patients who do not respond to physical therapy and/or amitriptyline (Grade 2C).
Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis
Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis
Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Sandy J Falk, MD
Last literature review version 16.2: May 2008 | This topic last updated: June 3, 2008 (More)
INTRODUCTION — Painful bladder syndrome/interstitial cystitis (PBS/IC) is a disorder characterized by bladder pain of variable severity, lasting over a protracted period of time. It can affect women or men, but is more common in women. The diagnosis and treatment of PBS/IC are controversial, similar to other enigmatic medical conditions of unknown origin that are difficult to treat.
The diagnosis and etiology of PBS/IC will be discussed here. Treatment of this disorder is reviewed separately. (See "Treatment of painful bladder syndrome/interstitial cystitis").
DEFINITION — Definitions of IC have widely varied over the past few decades. Before 2002, IC was defined in research settings according to the criteria of the National Institute for Diabetes and Diseases of the Kidney (NIDDK), the so-called "NIDDK criteria" (show table 1) [1] . The NIDDK criteria were soon recognized as being too restrictive for general use; therefore, in 2002 the International Continence Society (ICS) published new recommendations for definition of the painful bladder disorders (show table 1) [2] . Although this definition has been recognized as having some limitations, it is widely used. The ICS defines PBS as a clinical syndrome (ie, a complex of symptoms) consisting of "suprapubic pain related to bladder filling, accompanied by other symptoms, such as increased daytime and nighttime frequency in the absence of proven infection or other obvious pathology." By comparison, the term "interstitial cystitis (IC)" is reserved for patients who have PBS symptoms, but who also demonstrate "typical cystoscopic and histological features" during bladder hydrodistension.
In 2006, the European Society for the Study of IC/BPS (ESSIC) proposed yet another system that is likely to become popular (show table 1) [3] . The diagnosis of Bladder Pain Syndrome (BPS), distinct from PBS, is based upon the presence of pain related to the urinary bladder and accompanied by at least one other urinary symptom. Diseases that cause similar symptoms need to be excluded and cystoscopy with hydrodistension and biopsy (if indicated) should be performed. The ESSIC suggest avoiding the term IC, and instead using the term BPS, followed by a grade denoting severity of cystoscopic appearance and severity of biopsy findings (if performed).
It is likely that further refinement of terminology will occur during the coming years.
PREVALENCE — Because of variable diagnostic criteria, reported prevalence rates for PBS/IC vary widely.
Population-based studies report prevalence rates of 10 to 865 cases per 100,000 women [4,5] .
A survey of participants in the United States Nurses' Health Studies suggested a prevalence of 52 to 67 cases per 100,000 women [6] .
The prevalence of physician-diagnosed PBS/IC in a managed care population was 197 cases per 100,000 women and 41 per 100,000 men [7] , but the prevalence of PBS/IC symptoms in the same population was much higher, at 11 percent of women and 5 percent of men [8] .
A Canadian survey of the diagnostic patterns of 65 urologists found that 2.8 percent of patients seen during a two-week period were diagnosed with IC (7.9 percent of female and 0.4 percent of male patients seen in the office, female:male ratio 8:1) [9] .
The estimated clinical prevalence is highest in reports by researchers who believe that many, or even most, women with chronic pelvic pain may actually have IC; as well as those who feel that many men with lower urinary tract symptoms or prostatitis also may have IC and those who use somewhat nonspecific symptom questionnaires to make the diagnosis [10-12] . The "true prevalence" of PBS/IC will only be established when agreement is reached about diagnostic criteria, and a gold standard is available for its diagnosis.
EPIDEMIOLOGY — Studies have consistently found that PBS/IC is more common in women [12] , with a female:male ratio typically reported as 4.5 to 9 females to one male [5,9,13] . The mean age of diagnosis is probably about 42 to 45 years, although symptoms have been recognized in children [4,14,15] . A greater concordance of IC among monozygotic than dizygotic twin pairs suggests a genetic susceptibility to IC [16] .
ETIOLOGY AND PATHOGENESIS — Little is known about the etiology and pathogenesis of PBS/IC. Ongoing and future research will likely demonstrate that patients currently grouped together under the umbrella diagnosis of PBS/IC actually suffer from several distinct conditions with distinct etiologies. Several pathogenetic mechanisms have been proposed to explain the clinical phenomena, and it is accepted that any of several inciting factors may lead to the clinical manifestation of PBS/IC.
Many studies have documented that patients with IC have urothelial abnormalities present in bladder biopsies. Importantly, it is not known whether these urothelial abnormalities represent primary or secondary phenomena (ie, whether the bladder abnormalities are secondary to another process that is yet unrecognized). These abnormalities include: altered bladder epithelial expression of HLA Class I and II antigens, decreased expression of uroplakin and chondroitin sulfate, altered cytokeratin profile (towards a profile more typical of squamous cells), and altered integrity of the glycosaminoglycan (GAG) layer [17-23] . In addition, the expression of interleukin-6 and P2X3 ATP receptors is increased, and activation of the NFkB gene is enhanced.
The GAG layer normally coats the urothelial surface and renders it impermeable to solutes, thus defects in this layer may allow urinary irritants to penetrate the urothelium and activate the underlying nerve and muscle tissues [24] . This process may promote further tissue damage, pain, and hypersensitivity. Bladder mast cells may also play a role in the propagation of ongoing bladder damage after an initial insult [25,26] .
Antiproliferative factor (APF) may also have a pathogenetic role in the generation of PBS/IC symptoms. APF is a sialoglygopeptide that is produced by the urothelium of IC patients, but not by controls without IC [27] . APF may affect urothelial activity through altered production of growth factors and other proteins involved in urothelial growth and function [28] .
It is likely that neurologic upregulation with central sensitization and increased activation of bladder sensory neurons during normal bladder filling plays a role in the generation and maintenance of PBS/IC symptoms [29,30] . This increased sensitivity may be present in the bladder itself, or may be due to increased activity and new pathways within the central nervous system. Animal models suggest that hypersensitivity in bowel and other pelvic organs may be responsible for sensitization of the bladder [31] . Similar alterations in neural pathways may be responsible for the tenderness that is present in PBS/IC patients [32] . It is also possible that the increase in visceral (bladder) sensitivity is secondary to a primary somatic injury that has sensitized central pathways that overlap with afferents from the bladder.
CLINICAL MANIFESTATIONS — The presentation of PBS/IC is variable, but there are many common clinical features [33,34] . All patients with PBS/IC have pain, which is associated with bladder filling and/or emptying, and usually accompanied by urinary frequency, urgency, and nocturia. The pain that is thought to be of bladder origin is usually described as being suprapubic or urethral, although patterns such as unilateral lower abdominal pain or low back pain with bladder filling are not uncommon [35,36] . The severity of pain ranges from mild burning to severe and debilitating.
Increased urinary frequency arises because the pain of bladder filling is partially or completely relieved by voiding, so patients prefer to maintain low bladder volumes. Clinically, it is useful to ask patients why they void frequently to help distinguish PBS/IC from other causes of frequency. As an example, patients with overactive bladder syndrome void frequently to avoid urinary urge incontinence, whereas in PBS/IC they void frequently to avoid discomfort.
Affected patients may also describe chronic pelvic pain that is distinct from their bladder pain, as well as other ongoing, distinct pain symptoms. These patients often carry several diagnoses, such as irritable bowel syndrome (another visceral pain syndrome), dysmenorrhea, endometriosis, vulvodynia, or fibromyalgia [37] . They may also describe exacerbation of their PBS/IC symptoms during times when other pain symptoms are at their worst (eg, "flares" of PBS/IC when irritable bowel syndrome is symptomatic).
The character of symptoms may vary from one day to the next in a single patient. Exacerbation of PBS/IC symptoms may occur after intake of certain foods or drinks (eg, strawberries, oranges, beer, coffee), or during the luteal phase of the menstrual cycle, stressful times, or after activities such as exercise, sexual intercourse, or being seated for long periods of time (eg, a plane trip).
In severe disease, urinary frequency of as many as 60 voids daily may occur, with associated disruptions of daytime activities, and of sleep. Patients may describe sitting on the toilet for hours at a time in order to let urine dribble from their bladders more or less continuously so that bladders remain as empty as possible and pain is minimized. Associated disruption of home and work life, avoidance of sexual intimacy, chronic fatigue and pain, predictably result in some degree of worsening of quality of life in all affected patients. In surveys, 50 percent of patients reported being unable to work full-time, 75 percent described dyspareunia, 70 percent reported sleep disturbance, and 90 percent reported that PBS/IC affected their daily activities [36] .
The majority of patients describe symptoms that are of gradual onset, with worsening of discomfort, urgency and frequency over a period of months. A smaller subset of patients describes symptoms that are severe from their onset. Symptoms of PBS/IC begin suddenly, with some patients able to name the exact date on which symptoms began. In other patients, symptoms begin after an apparently uncomplicated urinary tract infection or surgical procedure, episode of vaginitis or prostatitis, or after a trauma, such as a fall onto the coccyx. In hindsight, these "sentinel events" have often been empirically diagnosed and treated, and usually are themselves somewhat enigmatic.
DIAGNOSTIC EVALUATION — The diagnosis of PBS/IC is based upon the presence of characteristic symptoms, provided that no symptoms or signs of other conditions are present. Confounding conditions, such as genitourinary cancers, urinary tract stones, urinary infection, urinary retention, or pelvic masses, should be excluded by careful history, physical examination, and laboratory tests, as indicated.
Physical examination — A thorough physical examination of patients with PBS/IC is of critical importance in making a diagnosis, and also in treatment planning. On observation, many patients will be tearful and appear fatigued and/or depressed. Variable tenderness of the abdominal wall, hip girdle, soft tissues of the buttocks, pelvic floor, bladder base, and urethra is almost universally present, probably due to sensitization of afferent nerve fibers in the dermatomyotomes (thoracolumbar and sacral) to which the bladder refers. In males, scrotal and penile tenderness can be present.
In some women, adequate speculum and bimanual examination cannot be conducted due to exquisite tenderness of the pelvic tissues. Pelvic ultrasound can be helpful for assessing the pelvic organs in these patients. It is important to remember that allodynia (perception of non-noxious stimuli, such as light touch, as being noxious or painful) can be present in any patient who has been in chronic pain, and that adequate pelvic examination may be impossible in the awake patient. In this situation, clinicians may choose to begin empiric treatment for PBS/IC, and to defer full examination until either symptoms have improved to the point where examination is possible, or until symptoms have failed to respond to usual therapies and the diagnosis must be revisited.
Laboratory tests
Urinalysis with microscopy and urine culture should be performed in all patients to exclude significant hematuria and infection.
Urine cytology and cystoscopy are performed in high risk groups. (See "Epidemiology and etiology of urothelial bladder cancer").
A post-void residual urine volume should be measured, either using a catheter (usually avoided due to associated pain) or by ultrasound.
Examination of the urine for chlamydia is reserved for patients at high risk of sexually transmitted infections. Compliance with standard guidelines for screening for cervical, prostate, and colorectal cancers is important in all patients, including those with painful bladder disorders.
Cystoscopy — Cystoscopy is not mandatory and is typically performed at the discretion of the clinician. In the United States, it is usually reserved for patients with hematuria (gross or microscopic) or with symptoms that raise suspicion for other processes. As an example, synthetic mesh is frequently used for urologic and gynecologic surgery, and mesh erosion into the lower urinary tract has become an increasingly important cause of urinary symptoms. When a patient has a history of pelvic surgery that predates their symptoms, it is important to use cystoscopy to exclude the presence of foreign body in the lower urinary tract. (See "Reconstructive materials in urogynecology: Classification and host response").
Hydrodistension — Hydrodistension of the bladder is not required for diagnosis or treatment of PBS/IC, although strong opinions are voiced on both sides of this issue [38,39] . Patients are placed under anesthesia and the bladder is filled with water or saline until 70 cm of water pressure is reached, usually at a bladder volume that is far greater than the awake-capacity of the patient (eg, 1000 mL). This bladder dilation is maintained for several minutes, then the dilating fluid is released and the bladder is refilled. During this second bladder fill, the bladder epithelium is examined cystoscopically for characteristic findings of IC, which include glomerulations (petechial red areas) and reddened patches (Hunner's patches). Biopsies are taken from any suspicious areas.
Although many medical centers in the United States continue to perform hydrodistension, it has fallen from favor as glomerulations are now considered nonspecific findings (eg, one study found glomerulations in 45 percent of healthy patients [40] ), their presence does not correlate well with symptoms [41] , and the results of hydrodistension do not necessarily affect clinical management.
Bladder biopsy — Bladder biopsy is not required for a diagnosis of PBS/IC, except for exclusion of other disorders. The lack of utility of bladder biopsy was illustrated in a longitudinal study that investigated associations between bladder biopsy features and urinary symptoms in 204 patients with a clinical diagnosis of IC [41] . Only 50 percent of patients demonstrated an increase in mast cell count in the bladder lamina propria (>30 cells per mm(3)), 11 percent demonstrated complete loss of urothelium (ie, an ulcer), 14 percent demonstrated granulation tissue in the lamina propria, and submucosal hemorrhage of varying degree was seen in 67 percent. It is important to note that some of these biopsy findings may have been due to the hydrodistension procedure itself, and that chronic inflammation was present only in a minority of patients.
Findings such as these were behind the impetus to discourage routine use of the term "interstitial cystitis" to describe the clinical syndrome of urinary urgency, frequency and pain, since biopsies suggested that the process is neither "interstitial" nor "cystitis."
Potassium sensitivity test — The potassium sensitivity test (PST) has also been proposed by some researchers as useful for diagnosis of PBS/IC [42] , but is not recommended for routine use since its results are nonspecific for PBS/IC [43] . During this test, 40 mL sterile water is instilled into the bladder, and note is made of any associated pain. The bladder is drained and then filled with a 40 mL of 0.4 M potassium chloride; a finding of increased pain during this second fill is considered indicative of bladder hypersensitivity and suggestive of PBS/IC.
Symptom scales — Some centers use symptom scales to aid in diagnosis of PBS/IC, but in practice, use of these scales adds little to the ability to make a diagnosis and their use is not widespread. However, these scales can be useful in the monitoring of clinical progress after diagnosis [44,45] . Three such scales are the O'Leary-Sant IC symptom and problem index, the Pelvic Pain and Urgency/Frequency (PUF) patient symptom scale, and the University of Wisconsin Interstitial Cystitis Scale [44,46,47] .
Biomarkers — Several biomarkers are being considered as possibly useful for diagnosing PBS/IC. The most promising marker is APF (see "Etiology and pathogenesis" above). In a study in which urine from 219 patients with symptomatic IC was compared with that from 324 controls without IC, the sensitivity and specificity of APF for IC 94 and 95 percent, respectively [27] . Use of APF and other biomarkers requires further validation before they can be recommended clinically.
Urodynamic testing — Urodynamic testing is not currently considered to have a role in the diagnosis of PBS/IC.
INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Painful bladder syndrome and interstitial cystitis" and see "Patient information: Treatment of painful bladder syndrome and interstitial cystitis"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.
SUMMARY AND RECOMMENDATIONS
Painful bladder syndrome/interstitial cystitis (PBS/IC) refers to a chronic bladder pain syndrome. It is more common in women than men. (See "Definition" above and see "Epidemiology" above).
All patients with PBS/IC have pain, which is associated with bladder filling and/or emptying, and usually accompanied by urinary frequency, urgency, and nocturia. They may also describe chronic pelvic pain that is distinct from their bladder pain, as well as other ongoing, distinct pain symptoms, such as irritable bowel syndrome, dysmenorrhea, endometriosis, vulvodynia, or fibromyalgia. (See "Clinical manifestations" above).
The clinical diagnosis of PBS/IC is based upon the presence of characteristic symptoms, after other conditions with similar symptoms are excluded. (See "Diagnostic evaluation" above).
Physical examination is often remarkable for widespread tenderness of the abdominal wall, hip girdle, buttocks, thighs and pelvic floor, as well as tenderness of the bladder base and/or urethra. (See "Physical examination" above).
Urinalysis with microscopy and urine culture should be performed in all patients to exclude significant hematuria and infection. Cystoscopy, hydrodistension, bladder biopsy, and potassium sensitivity testing are not necessary for diagnosis of PBS/IC. (See "Diagnostic evaluation" above).
Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Sandy J Falk, MD
Last literature review version 16.2: May 2008 | This topic last updated: June 3, 2008 (More)
INTRODUCTION — Painful bladder syndrome/interstitial cystitis (PBS/IC) is a disorder characterized by bladder pain of variable severity, lasting over a protracted period of time. It can affect women or men, but is more common in women. The diagnosis and treatment of PBS/IC are controversial, similar to other enigmatic medical conditions of unknown origin that are difficult to treat.
The diagnosis and etiology of PBS/IC will be discussed here. Treatment of this disorder is reviewed separately. (See "Treatment of painful bladder syndrome/interstitial cystitis").
DEFINITION — Definitions of IC have widely varied over the past few decades. Before 2002, IC was defined in research settings according to the criteria of the National Institute for Diabetes and Diseases of the Kidney (NIDDK), the so-called "NIDDK criteria" (show table 1) [1] . The NIDDK criteria were soon recognized as being too restrictive for general use; therefore, in 2002 the International Continence Society (ICS) published new recommendations for definition of the painful bladder disorders (show table 1) [2] . Although this definition has been recognized as having some limitations, it is widely used. The ICS defines PBS as a clinical syndrome (ie, a complex of symptoms) consisting of "suprapubic pain related to bladder filling, accompanied by other symptoms, such as increased daytime and nighttime frequency in the absence of proven infection or other obvious pathology." By comparison, the term "interstitial cystitis (IC)" is reserved for patients who have PBS symptoms, but who also demonstrate "typical cystoscopic and histological features" during bladder hydrodistension.
In 2006, the European Society for the Study of IC/BPS (ESSIC) proposed yet another system that is likely to become popular (show table 1) [3] . The diagnosis of Bladder Pain Syndrome (BPS), distinct from PBS, is based upon the presence of pain related to the urinary bladder and accompanied by at least one other urinary symptom. Diseases that cause similar symptoms need to be excluded and cystoscopy with hydrodistension and biopsy (if indicated) should be performed. The ESSIC suggest avoiding the term IC, and instead using the term BPS, followed by a grade denoting severity of cystoscopic appearance and severity of biopsy findings (if performed).
It is likely that further refinement of terminology will occur during the coming years.
PREVALENCE — Because of variable diagnostic criteria, reported prevalence rates for PBS/IC vary widely.
Population-based studies report prevalence rates of 10 to 865 cases per 100,000 women [4,5] .
A survey of participants in the United States Nurses' Health Studies suggested a prevalence of 52 to 67 cases per 100,000 women [6] .
The prevalence of physician-diagnosed PBS/IC in a managed care population was 197 cases per 100,000 women and 41 per 100,000 men [7] , but the prevalence of PBS/IC symptoms in the same population was much higher, at 11 percent of women and 5 percent of men [8] .
A Canadian survey of the diagnostic patterns of 65 urologists found that 2.8 percent of patients seen during a two-week period were diagnosed with IC (7.9 percent of female and 0.4 percent of male patients seen in the office, female:male ratio 8:1) [9] .
The estimated clinical prevalence is highest in reports by researchers who believe that many, or even most, women with chronic pelvic pain may actually have IC; as well as those who feel that many men with lower urinary tract symptoms or prostatitis also may have IC and those who use somewhat nonspecific symptom questionnaires to make the diagnosis [10-12] . The "true prevalence" of PBS/IC will only be established when agreement is reached about diagnostic criteria, and a gold standard is available for its diagnosis.
EPIDEMIOLOGY — Studies have consistently found that PBS/IC is more common in women [12] , with a female:male ratio typically reported as 4.5 to 9 females to one male [5,9,13] . The mean age of diagnosis is probably about 42 to 45 years, although symptoms have been recognized in children [4,14,15] . A greater concordance of IC among monozygotic than dizygotic twin pairs suggests a genetic susceptibility to IC [16] .
ETIOLOGY AND PATHOGENESIS — Little is known about the etiology and pathogenesis of PBS/IC. Ongoing and future research will likely demonstrate that patients currently grouped together under the umbrella diagnosis of PBS/IC actually suffer from several distinct conditions with distinct etiologies. Several pathogenetic mechanisms have been proposed to explain the clinical phenomena, and it is accepted that any of several inciting factors may lead to the clinical manifestation of PBS/IC.
Many studies have documented that patients with IC have urothelial abnormalities present in bladder biopsies. Importantly, it is not known whether these urothelial abnormalities represent primary or secondary phenomena (ie, whether the bladder abnormalities are secondary to another process that is yet unrecognized). These abnormalities include: altered bladder epithelial expression of HLA Class I and II antigens, decreased expression of uroplakin and chondroitin sulfate, altered cytokeratin profile (towards a profile more typical of squamous cells), and altered integrity of the glycosaminoglycan (GAG) layer [17-23] . In addition, the expression of interleukin-6 and P2X3 ATP receptors is increased, and activation of the NFkB gene is enhanced.
The GAG layer normally coats the urothelial surface and renders it impermeable to solutes, thus defects in this layer may allow urinary irritants to penetrate the urothelium and activate the underlying nerve and muscle tissues [24] . This process may promote further tissue damage, pain, and hypersensitivity. Bladder mast cells may also play a role in the propagation of ongoing bladder damage after an initial insult [25,26] .
Antiproliferative factor (APF) may also have a pathogenetic role in the generation of PBS/IC symptoms. APF is a sialoglygopeptide that is produced by the urothelium of IC patients, but not by controls without IC [27] . APF may affect urothelial activity through altered production of growth factors and other proteins involved in urothelial growth and function [28] .
It is likely that neurologic upregulation with central sensitization and increased activation of bladder sensory neurons during normal bladder filling plays a role in the generation and maintenance of PBS/IC symptoms [29,30] . This increased sensitivity may be present in the bladder itself, or may be due to increased activity and new pathways within the central nervous system. Animal models suggest that hypersensitivity in bowel and other pelvic organs may be responsible for sensitization of the bladder [31] . Similar alterations in neural pathways may be responsible for the tenderness that is present in PBS/IC patients [32] . It is also possible that the increase in visceral (bladder) sensitivity is secondary to a primary somatic injury that has sensitized central pathways that overlap with afferents from the bladder.
CLINICAL MANIFESTATIONS — The presentation of PBS/IC is variable, but there are many common clinical features [33,34] . All patients with PBS/IC have pain, which is associated with bladder filling and/or emptying, and usually accompanied by urinary frequency, urgency, and nocturia. The pain that is thought to be of bladder origin is usually described as being suprapubic or urethral, although patterns such as unilateral lower abdominal pain or low back pain with bladder filling are not uncommon [35,36] . The severity of pain ranges from mild burning to severe and debilitating.
Increased urinary frequency arises because the pain of bladder filling is partially or completely relieved by voiding, so patients prefer to maintain low bladder volumes. Clinically, it is useful to ask patients why they void frequently to help distinguish PBS/IC from other causes of frequency. As an example, patients with overactive bladder syndrome void frequently to avoid urinary urge incontinence, whereas in PBS/IC they void frequently to avoid discomfort.
Affected patients may also describe chronic pelvic pain that is distinct from their bladder pain, as well as other ongoing, distinct pain symptoms. These patients often carry several diagnoses, such as irritable bowel syndrome (another visceral pain syndrome), dysmenorrhea, endometriosis, vulvodynia, or fibromyalgia [37] . They may also describe exacerbation of their PBS/IC symptoms during times when other pain symptoms are at their worst (eg, "flares" of PBS/IC when irritable bowel syndrome is symptomatic).
The character of symptoms may vary from one day to the next in a single patient. Exacerbation of PBS/IC symptoms may occur after intake of certain foods or drinks (eg, strawberries, oranges, beer, coffee), or during the luteal phase of the menstrual cycle, stressful times, or after activities such as exercise, sexual intercourse, or being seated for long periods of time (eg, a plane trip).
In severe disease, urinary frequency of as many as 60 voids daily may occur, with associated disruptions of daytime activities, and of sleep. Patients may describe sitting on the toilet for hours at a time in order to let urine dribble from their bladders more or less continuously so that bladders remain as empty as possible and pain is minimized. Associated disruption of home and work life, avoidance of sexual intimacy, chronic fatigue and pain, predictably result in some degree of worsening of quality of life in all affected patients. In surveys, 50 percent of patients reported being unable to work full-time, 75 percent described dyspareunia, 70 percent reported sleep disturbance, and 90 percent reported that PBS/IC affected their daily activities [36] .
The majority of patients describe symptoms that are of gradual onset, with worsening of discomfort, urgency and frequency over a period of months. A smaller subset of patients describes symptoms that are severe from their onset. Symptoms of PBS/IC begin suddenly, with some patients able to name the exact date on which symptoms began. In other patients, symptoms begin after an apparently uncomplicated urinary tract infection or surgical procedure, episode of vaginitis or prostatitis, or after a trauma, such as a fall onto the coccyx. In hindsight, these "sentinel events" have often been empirically diagnosed and treated, and usually are themselves somewhat enigmatic.
DIAGNOSTIC EVALUATION — The diagnosis of PBS/IC is based upon the presence of characteristic symptoms, provided that no symptoms or signs of other conditions are present. Confounding conditions, such as genitourinary cancers, urinary tract stones, urinary infection, urinary retention, or pelvic masses, should be excluded by careful history, physical examination, and laboratory tests, as indicated.
Physical examination — A thorough physical examination of patients with PBS/IC is of critical importance in making a diagnosis, and also in treatment planning. On observation, many patients will be tearful and appear fatigued and/or depressed. Variable tenderness of the abdominal wall, hip girdle, soft tissues of the buttocks, pelvic floor, bladder base, and urethra is almost universally present, probably due to sensitization of afferent nerve fibers in the dermatomyotomes (thoracolumbar and sacral) to which the bladder refers. In males, scrotal and penile tenderness can be present.
In some women, adequate speculum and bimanual examination cannot be conducted due to exquisite tenderness of the pelvic tissues. Pelvic ultrasound can be helpful for assessing the pelvic organs in these patients. It is important to remember that allodynia (perception of non-noxious stimuli, such as light touch, as being noxious or painful) can be present in any patient who has been in chronic pain, and that adequate pelvic examination may be impossible in the awake patient. In this situation, clinicians may choose to begin empiric treatment for PBS/IC, and to defer full examination until either symptoms have improved to the point where examination is possible, or until symptoms have failed to respond to usual therapies and the diagnosis must be revisited.
Laboratory tests
Urinalysis with microscopy and urine culture should be performed in all patients to exclude significant hematuria and infection.
Urine cytology and cystoscopy are performed in high risk groups. (See "Epidemiology and etiology of urothelial bladder cancer").
A post-void residual urine volume should be measured, either using a catheter (usually avoided due to associated pain) or by ultrasound.
Examination of the urine for chlamydia is reserved for patients at high risk of sexually transmitted infections. Compliance with standard guidelines for screening for cervical, prostate, and colorectal cancers is important in all patients, including those with painful bladder disorders.
Cystoscopy — Cystoscopy is not mandatory and is typically performed at the discretion of the clinician. In the United States, it is usually reserved for patients with hematuria (gross or microscopic) or with symptoms that raise suspicion for other processes. As an example, synthetic mesh is frequently used for urologic and gynecologic surgery, and mesh erosion into the lower urinary tract has become an increasingly important cause of urinary symptoms. When a patient has a history of pelvic surgery that predates their symptoms, it is important to use cystoscopy to exclude the presence of foreign body in the lower urinary tract. (See "Reconstructive materials in urogynecology: Classification and host response").
Hydrodistension — Hydrodistension of the bladder is not required for diagnosis or treatment of PBS/IC, although strong opinions are voiced on both sides of this issue [38,39] . Patients are placed under anesthesia and the bladder is filled with water or saline until 70 cm of water pressure is reached, usually at a bladder volume that is far greater than the awake-capacity of the patient (eg, 1000 mL). This bladder dilation is maintained for several minutes, then the dilating fluid is released and the bladder is refilled. During this second bladder fill, the bladder epithelium is examined cystoscopically for characteristic findings of IC, which include glomerulations (petechial red areas) and reddened patches (Hunner's patches). Biopsies are taken from any suspicious areas.
Although many medical centers in the United States continue to perform hydrodistension, it has fallen from favor as glomerulations are now considered nonspecific findings (eg, one study found glomerulations in 45 percent of healthy patients [40] ), their presence does not correlate well with symptoms [41] , and the results of hydrodistension do not necessarily affect clinical management.
Bladder biopsy — Bladder biopsy is not required for a diagnosis of PBS/IC, except for exclusion of other disorders. The lack of utility of bladder biopsy was illustrated in a longitudinal study that investigated associations between bladder biopsy features and urinary symptoms in 204 patients with a clinical diagnosis of IC [41] . Only 50 percent of patients demonstrated an increase in mast cell count in the bladder lamina propria (>30 cells per mm(3)), 11 percent demonstrated complete loss of urothelium (ie, an ulcer), 14 percent demonstrated granulation tissue in the lamina propria, and submucosal hemorrhage of varying degree was seen in 67 percent. It is important to note that some of these biopsy findings may have been due to the hydrodistension procedure itself, and that chronic inflammation was present only in a minority of patients.
Findings such as these were behind the impetus to discourage routine use of the term "interstitial cystitis" to describe the clinical syndrome of urinary urgency, frequency and pain, since biopsies suggested that the process is neither "interstitial" nor "cystitis."
Potassium sensitivity test — The potassium sensitivity test (PST) has also been proposed by some researchers as useful for diagnosis of PBS/IC [42] , but is not recommended for routine use since its results are nonspecific for PBS/IC [43] . During this test, 40 mL sterile water is instilled into the bladder, and note is made of any associated pain. The bladder is drained and then filled with a 40 mL of 0.4 M potassium chloride; a finding of increased pain during this second fill is considered indicative of bladder hypersensitivity and suggestive of PBS/IC.
Symptom scales — Some centers use symptom scales to aid in diagnosis of PBS/IC, but in practice, use of these scales adds little to the ability to make a diagnosis and their use is not widespread. However, these scales can be useful in the monitoring of clinical progress after diagnosis [44,45] . Three such scales are the O'Leary-Sant IC symptom and problem index, the Pelvic Pain and Urgency/Frequency (PUF) patient symptom scale, and the University of Wisconsin Interstitial Cystitis Scale [44,46,47] .
Biomarkers — Several biomarkers are being considered as possibly useful for diagnosing PBS/IC. The most promising marker is APF (see "Etiology and pathogenesis" above). In a study in which urine from 219 patients with symptomatic IC was compared with that from 324 controls without IC, the sensitivity and specificity of APF for IC 94 and 95 percent, respectively [27] . Use of APF and other biomarkers requires further validation before they can be recommended clinically.
Urodynamic testing — Urodynamic testing is not currently considered to have a role in the diagnosis of PBS/IC.
INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Painful bladder syndrome and interstitial cystitis" and see "Patient information: Treatment of painful bladder syndrome and interstitial cystitis"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.
SUMMARY AND RECOMMENDATIONS
Painful bladder syndrome/interstitial cystitis (PBS/IC) refers to a chronic bladder pain syndrome. It is more common in women than men. (See "Definition" above and see "Epidemiology" above).
All patients with PBS/IC have pain, which is associated with bladder filling and/or emptying, and usually accompanied by urinary frequency, urgency, and nocturia. They may also describe chronic pelvic pain that is distinct from their bladder pain, as well as other ongoing, distinct pain symptoms, such as irritable bowel syndrome, dysmenorrhea, endometriosis, vulvodynia, or fibromyalgia. (See "Clinical manifestations" above).
The clinical diagnosis of PBS/IC is based upon the presence of characteristic symptoms, after other conditions with similar symptoms are excluded. (See "Diagnostic evaluation" above).
Physical examination is often remarkable for widespread tenderness of the abdominal wall, hip girdle, buttocks, thighs and pelvic floor, as well as tenderness of the bladder base and/or urethra. (See "Physical examination" above).
Urinalysis with microscopy and urine culture should be performed in all patients to exclude significant hematuria and infection. Cystoscopy, hydrodistension, bladder biopsy, and potassium sensitivity testing are not necessary for diagnosis of PBS/IC. (See "Diagnostic evaluation" above).
Thursday, September 4, 2008
Noninvasive diagnosis of peripheral arterial disease
Noninvasive diagnosis of peripheral arterial disease
Author
Emile R Mohler, III, MD
Section Editor
Denis L Clement, MD, PhD
Deputy Editor
Gordon M Saperia, MD, FACC
Last literature review version 16.2: May 2008 | This topic last updated: April 15, 2008 (More)
INTRODUCTION — In patients with suspected lower extremity peripheral arterial disease (PAD) based upon the history and physical examination (eg, symptoms of intermittent claudication) or in patients with risk factors for vascular disease (eg, older age, smoking, diabetes mellitus), noninvasive tests are performed to confirm the clinical diagnosis and to further define the level and extent of obstruction [1] . (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease").
The noninvasive tests available to the clinician to diagnose lower extremity PAD will be reviewed here. The clinical manifestations and natural history of claudication and its management by medical therapy, angioplasty, or surgery are discussed separately. (See appropriate topic reviews).
GENERAL PRINCIPLES — The location of pain in patients with claudication varies with the vessels that are involved. The usual relationship between the site of pain and site of arterial disease can be summarized as follows:
• Buttock and hip — aortoiliac disease
• Thigh — common femoral artery or aortoiliac
• Upper two-thirds of the calf — superficial femoral artery
• Lower one-third of the calf — popliteal artery
• Foot claudication — tibial or peroneal artery
Despite these general relationships, the history and physical examination are not reliable for the detection of lower extremity PAD. It has been estimated that relying solely on the classic symptoms of claudication will miss up to 90 percent of cases [2,3] . This was best illustrated in a study of 6417 patients at risk for peripheral arterial disease (either age >70 or age 50 to 60 with a history of diabetes or more than 10 pack-years of cigarette smoking) in a primary care setting [2] . PAD, identified by an ankle-brachial index ≤0.9, was present in 1865 (29 percent), only 11 percent of whom presented with classic claudication symptoms. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease", section on Atypical symptoms and section on Asymptomatic disease).
The physical examination is also unreliable. As an example, an abnormal femoral pulse has a high specificity and positive predictive value but low sensitivity for large vessel disease [4] . The best single discriminator is an abnormal posterior tibial pulse.
Patients at risk — Given these limitations, the diagnosis of lower extremity PAD often begins with noninvasive testing. The 2005 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD and the 2007 TASC II consensus document on the management of patients with PAD identified the following groups at risk for lower extremity PAD [5,6] :
• Age ≥70 years
• Age 50 to 69 years with a history of smoking and.or diabetes
• Age 40 to 49 with diabetes and at least one other risk factor for
• atherosclerosis
• Leg symptoms suggestive of claudication with exertion or ischemic pain at rest
• Abnormal lower extremity pulse examination
• Known atherosclerosis at other sites (eg, coronary, carotid, or renal arterial disease)
• All patients with a Framingham risk score of 10 to 20 percent (see "Estimation of cardiovascular risk in an individual patient without known cardiovascular disease", section on Framingham risk score).
In such patients, the standard review of symptoms should include questions related to a history of walking impairment, symptoms of claudication, ischemic rest pain, or nonhealing wounds [5,6] . Measurement of the resting ankle-brachial index should be performed in patients with one or more of these findings.
NONINVASIVE TESTS — A variety of noninvasive examinations are available to assess the presence and degree of peripheral arterial disease (show algorithm 1 and show algorithm 2). They include the ankle-brachial index (ABI), exercise treadmill test, segmental limb pressures, segmental volume plethysmography, and ultrasonography. Data suggest that magnetic resonance imaging may become an important noninvasive method for assessment [7] ; however, the cost and the time necessary for the study limit its use as a routine screening modality at this time. (See "Clinical utility of cardiovascular magnetic resonance imaging").
Ankle-brachial index — A relatively simple and inexpensive method to confirm the clinical suspicion of arterial occlusive disease is to measure the resting and post-exercise systolic blood pressures in the ankle and arm. This measurement is referred to as the ankle-brachial (or ankle-arm) index or ratio, and provides a measure of the severity of peripheral arterial disease [8] .
Calculation of the ankle-brachial index (ABI) is performed by measuring the systolic blood pressure (by Doppler probe) in the brachial, posterior tibial, and dorsalis pedis arteries (show figure 1) [9,10] . The highest of the four measurements in the ankles and feet is divided by the higher of the two brachial measurements:
• The normal ABI is 1.0 to as high as 1.3, since the pressure is higher in the ankle than in the arm. Values above 1.30 suggest a noncompressible calcified vessel.
• An ABI below 0.9 has 95 percent sensitivity (and 100 percent specificity) for detecting angiogram-positive peripheral arterial disease and is associated with ≥50 percent stenosis in one or more major vessels.
• An ABI of 0.40 to 0.90 suggests a degree of arterial obstruction often associated with claudication.
• An ABI below 0.4 represents advanced ischemia.
The ABI should be measured in both legs in all new patients with suspected PAD both to confirm the diagnosis and to establish a baseline [5] .
If ABIs are normal at rest but symptoms strongly suggest claudication, ABIs and segmental pressures should be obtained before and after exercise on a treadmill (see "Exercise treadmill testing" below) or using active pedal plantarflexion, which involves repeatedly standing up on the toes [11] .
The ABI correlates with clinical measures of lower extremity function such as walking distance, velocity, balance, and overall physical activity [12] . In addition, a low ABI has been associated with a higher risk of coronary heart disease, stroke, transient ischemic attack, progressive renal insufficiency, and all-cause mortality [13-17] .
• In a prospective study among nearly 1500 women, 82 (5.5 percent) had an ABI of less than 0.9, 65 of whom had no symptoms of peripheral arterial disease. Compared to the cohort with an index greater than 0.9, this group had markedly increased relative risks of 3.1 and 3.7 for death and coronary heart disease at four years [14] .
• In a report from the Framingham study of 251 men and 423 women (mean age 80 years), 141 (21 percent) had an ABI less than 0.9 [16] . Those with a low ABI had at four years a significantly increased risk of transient ischemic attack or stroke (13 versus 5 percent; adjusted hazard ratio 2.0).
There is a general but not absolute correlation between symptoms and the site and severity of PAD. In a report described in detail elsewhere, patients with unilateral PAD as determined from the ABI often had bilateral leg pain and 14 percent of those with unilateral pain had pain in the other leg [18] . (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease", section on Correlation of ABI with symptoms and site of PAD).
High ABI — A potential source of error with the ABI is that calcified vessels may not compress normally, possibly resulting in falsely elevated Doppler signals. Thus, an ABI above 1.3 is suspicious for a calcified vessel. In some patients with arterial calcification, an accurate pressure may be obtained by measuring the toe pressure and calculating the toe-brachial index. In this setting, one must recognize that a pressure gradient of 20 to 30 mmHg normally exists between the ankle and the toe.
An abnormally high ABI (>1.4) is also associated with higher rates of leg pain [18] and of cardiovascular risk [15] . The increase in cardiovascular risk was suggested in a report of 4393 native American patients in the Strong Heart Study who had bilateral ABI measurements and were followed for a mean of eight years [15] . There were 1022 deaths (23 percent) of which 272 (27 percent of all deaths) were cardiovascular. Patients with an ABI ≤0.9 or >1.4 had an increased risk of all-cause mortality (adjusted hazard ratios 1.7 and 1.8) and cardiovascular mortality (adjusted hazard ratios 2.5 and 2.1).
Similarly, data from the National Health and Nutrition Survey (NHANES) estimated 1.4 percent of adults age >40 years in the United States have an ABI >1.4, accounting for approximately 20 percent of all adults with PAD [19] .
Exercise treadmill testing — The dynamics of blood flow across a stenotic lesion depend in part upon whether the individual is at rest or exercising and upon the severity of the obstruction. Exercise normally decreases vascular resistance and enhances blood flow to the exercising extremities. An arterial stenosis of less than 70 percent may not be of sufficient severity to significantly perturb blood flow at rest or to produce a systolic pressure gradient. Exercise in such patients can induce a systolic pressure gradient across the stenosis or, in patients with more severe disease, increase the systolic pressure gradient.
These changes may be detected clinically by a fall in the ABI followed by recovery. This pattern is detected by measurement of the ABI at one minute intervals for five minutes after exercise. As a result, exercise testing is a sensitive method for evaluating patients with typical symptoms of claudication in whom the resting ABI is normal.
Several protocols exist for treadmill testing and are generally divided into those using a fixed versus a graded routine [20] . The standard exercise test is a treadmill test for five minutes at 2 mph on a 12 percent incline. Severe claudication can be defined as an inability to complete the treadmill exercise due to leg symptoms and ankle systolic pressures below 50 mmHg.
Segmental limb pressures — Once the presence of arterial occlusive disease has been verified using ABI measurements at rest or during exercise, the level and extent of PAD is routinely assessed by segmental limb pressures. A 20 mmHg or greater reduction in pressure is considered significant if such a gradient is present either between segments along the same leg or when compared to the same level in the opposite leg.
As with ABI measurements, segmental pressure measurements may be artifactually increased or not interpretable in patients with noncompressible vessels [5] . (See "High ABI" above).
Several blood pressure cuff positions have been employed to detect the level of peripheral arterial disease [21] . As examples, a significant reduction in pressure [5] :
• Between the brachial artery and the upper thigh reflects aortoiliac disease
• Between the upper and lower thigh reflects superficial femoral artery disease
• Between the lower thigh and upper calf reflects distal superficial femoral artery or popliteal disease
• Between the upper and lower calf reflects infrapopliteal disease
In addition, a toe pressure of less than 60 percent of the ankle pressure indicates digital artery occlusive disease.
Use of two specially designed narrow blood pressure cuffs rather than one large cuff on the thigh permits the differentiation of aortoiliac and superficial femoral artery disease. This technique, which is performed in the vascular laboratory, involves placement of a narrow cuff on the upper and lower thigh. The upper (proximal) thigh cuff is inflated to a pressure above systolic and then gradually deflated to determine the systolic pressure as heard by Doppler at the foot. This process is then repeated for the lower (distal) thigh cuff.
If the upper thigh systolic pressure is reduced compared to the brachial pressure (thigh-brachial index [TBI] <1.1), then the patient has a lesion in the aortoiliac territory. If, on the other hand, the TBI is >1.1 in the upper thigh and less than 1.1 in the lower thigh, the lesion is in the superficial femoral artery. In one prospective study, the use of two narrow thigh cuffs correctly identified the location in 78 percent of extremities with peripheral arterial disease versus a rate of only 19 percent with the use of a large cuff [21] .
The localization of the lesion may also be suspected from the history in patients with intermittent claudication. Thus, one should ascertain whether the pain is in the buttock or hip (suggesting aortoiliac disease), thigh (common femoral disease), upper calf (superficial femoral disease), lower calf (popliteal disease), or foot (tibial or peroneal disease). (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease").
In the patient with possible upper extremity peripheral arterial disease, a difference of ≥10 mmHg between brachial pressures suggests innominate, subclavian, axillary, or proximal brachial arterial occlusion.
Potential disadvantages in using Doppler ultrasound for segmental limb pressures are that the technique is insensitive at extremely low blood flow rates (<3 cm per second) and a venous signal can be confused with an arterial signal (especially if pulsatile venous flow is present as can occur with congestive heart failure).
Segmental volume plethysmography — Plethysmography, or the measurement of volume change in an organ or limb, is usually used in conjunction with segmental limb pressures to assess the level of arterial disease. This technique is performed by injecting a standard volume of air into pneumatic cuffs placed at various levels along the extremity. Volume changes in the limb segment below the cuff are translated into pulsatile pressure, which is detected by a transducer and then displayed as a pressure pulse contour.
The normal pulse volume recording is composed of a systolic upstroke with a sharp systolic peak followed by a downstroke that contains a prominent dicrotic notch. A change in the pulse volume contour indicates proximal arterial obstruction and is due to the dissipated energy that occurs due to arterial narrowing [22,23] .
Variations in the contours of the pulse volume recording reflect disease severity (show figure 2). As an example, mild disease is characterized by the absence of a dicrotic notch. With progressive obstruction, the upstroke and downstroke become equal, and with severe disease, the amplitude of the waveform is blunted. Pulse volume recordings are most useful in detecting disease in calcified vessels which tend to yield falsely elevated pressures.
Since the absolute amplitude of plethysmographic recordings is influenced by cardiac output and vasomotor tone, interpretation of these measurements should be limited to the comparison of one side of an extremity to the other in the same patient and not between patients. The clinician should also recognize that a dicrotic notch may be absent from the recording of a normal artery in the presence of low resistance, as may occur after exercise.
Duplex ultrasonography — Although ultrasonography is accurate in detecting peripheral arterial disease, resting segmental pulse volumes and systolic pressures are the initial screening tests in many laboratories. Ultrasonography is currently used to depict anatomy, hemodynamics, and lesion morphology; ultrasonographic equipment used for these tasks include B-mode imaging, pulse wave Doppler, continuous wave Doppler, and color Doppler display [8] .
Lower extremity examinations using the duplex Doppler begins at the common femoral artery and proceeds distally to the popliteal artery. An area of stenosis is localized with color Doppler and assessed by measuring Doppler velocities at several arterial sites.
The normal peripheral arterial velocity waveform is triphasic and consists of [24,25] :
• A forward flow systolic peak
• Reversal of flow in early diastole
• Forward flow in late diastole
With progressive peripheral arterial disease, there is elimination of the reverse flow, a decrease in systolic peak and an increase in flow in diastole (show figure 3).
It has been suggested that the main purpose of duplex Doppler ultrasonography is to avoid diagnostic angiography before intervention in patients with arterial disease proximal to the calf [26] . A meta-analysis of 14 studies found that sensitivity and specificity of this technique for ≥50 percent stenosis or occlusion were 86 and 97 percent for aortoiliac disease and 80 and 98 percent for femoropopliteal disease [26] .
Multidetector computed tomography — The development of multidetector computed tomographic (MDCT) scanners now allows rapid acquisition of high resolution, intravenous contrast enhanced images from patients with suspected peripheral arterial disease. A number of reports of small series of patients have noted excellent correlation between MDCT and digital subtraction angiography (DSA) in the detection of aortic and lower extremity arterial disease [27-29] , but these findings have not been universal [30] . In addition the total burden of radiation is relatively high.
A meta-analysis of 12 studies in which MDCT was used to evaluate 9541 lower extremity arterial segments in 436 symptomatic patients compared test performance to DSA [31] . The sensitivity and specificity for detecting a stenosis of a least 50 percent were 92 and 93 percent, respectively, compared to DSA. In the three studies that evaluated subdivisions of the arterial system, diagnostic performance in the infrapopliteal tract was lower than, but not statistically different from, that in the aortoiliac and femoropopliteal tracts.
A separate issue is the ability of MDCT to guide therapy. In an initial series of 58 patients with claudication, the findings on MDCT were used to determine whether or not an intervention was necessary [32] . Among the 29 patients in whom conservative management was indicated by MDCT, none required revascularization at a mean follow-up of 501 days.
INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Claudication"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.
RECOMMENDATIONS — We agree with the recommendations of the 2005 ACC/AHA guideline and the 2007 TASC II consensus document on the management of PAD with regard to the identification of asymptomatic PAD and for the evaluation of patients with intermittent claudication [5,6] .
Asymptomatic patients — The main value of identifying patients with asymptomatic lower extremity PAD is related to the association of these lesions with an increased risk of myocardial infarction, stroke, and cardiovascular mortality [5,33-35] . PAD is considered to be a coronary equivalent and such patients should be treated with risk factor reduction. (See "Medical management of claudication" and see "Secondary prevention of cardiovascular disease: Risk factor reduction").
The ACC/AHA guidelines made the following general recommendations for patients with no leg symptoms or atypical leg symptoms [5] . (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease", section on Atypical symptoms and section on Asymptomatic patients).
• In patients ≥70 years of age or ≥50 years of age with a history of smoking and/or diabetes (ie, those at increased risk for PAD), the standard review of symptoms should include questions related to a history of walking impairment, symptoms of claudication, ischemic rest pain, or nonhealing wounds. Use of the Walking Impairment questionnaire can be considered. (See "Patients at risk" above).
• The resting ABI should be measured in patients with one or more of these findings. The ABI should be measured in both legs in all new patients with PAD to confirm the diagnosis and to establish a baseline.
These recommendations are consistent with those made in the 2007 TASC II consensus document on the management of PAD [6] .
Similar recommendations were made by the American Diabetes Association for monitoring asymptomatic patients with diabetes [36] . The guideline recommended that initial screening for PAD should include a history for claudication and an assessment of the pedal pulses and that consideration should be given to obtaining an ABI.
Further evaluation is dependent upon the ABI value [5] :
• An ABI ≤0.90 is diagnostic of PAD.
• An ABI of 0.91 to 1.30 is borderline or normal. Among patients with atypical symptoms, the ABI should be measured after exercise on a treadmill. An ABI that decreases by 20 percent following exercise is diagnostic of PAD, while a normal ABI following exercise eliminates the diagnosis and suggests the need to evaluate for other causes of the leg symptoms.
• An ABI >1.30 suggests the presence of calcified vessels and the need for additional vascular studies, such as pulse volume recording or measurement of the toe-brachial index. Abnormal results confirm the presence of PAD. (See "High ABI" above).
Symptomatic patients — The evaluation is similar in patients with classic claudication (cramping, pain, or muscle fatigue that is reproducibly induced by exercise and promptly resolves with rest). The history should document the degree of walking impairment and lifestyle limitation and the peripheral pulses should be examined.
Further evaluation is dependent upon the ABI value:
• An ABI ≤0.90 is diagnostic of PAD.
• An ABI of 0.91 to 1.30 should be followed by further testing, such as measurement of the ABI after exercise, segmental limb pressures, or duplex ultrasonography. An abnormal test is diagnostic of PAD, while a normal test excludes PAD although arterial entrapment syndromes may be considered.
Although considered the "gold standard" of diagnostic evaluation for peripheral atherosclerotic disease, the use of iodinated contrast agents involves exposure to the patient of risk from iodine allergy, contrast nephropathy and the risks inherent to percutaneous intervention. With the advent of rapid 3-D imaging sequences combined with existing extracellular gadolinium contrast agents, magnetic resonance angiography (MRA) has shown promise to become a time-efficient and cost-effective tool for the complete assessment of peripheral arterial disease [1-3] . Current available gadolinium compounds are typically used "off-label" and are not approved by FDA for MRA in the United States.
One potential complication with use of gadolinium in patients with chronic kidney disease is skin sclerosis and, therefore, should be used with caution in this population. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced renal failure", section on gadolinium).
MRA is usually performed if revascularization is being considered. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease" and see "Indications for surgery in the patient with claudication").
Author
Emile R Mohler, III, MD
Section Editor
Denis L Clement, MD, PhD
Deputy Editor
Gordon M Saperia, MD, FACC
Last literature review version 16.2: May 2008 | This topic last updated: April 15, 2008 (More)
INTRODUCTION — In patients with suspected lower extremity peripheral arterial disease (PAD) based upon the history and physical examination (eg, symptoms of intermittent claudication) or in patients with risk factors for vascular disease (eg, older age, smoking, diabetes mellitus), noninvasive tests are performed to confirm the clinical diagnosis and to further define the level and extent of obstruction [1] . (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease").
The noninvasive tests available to the clinician to diagnose lower extremity PAD will be reviewed here. The clinical manifestations and natural history of claudication and its management by medical therapy, angioplasty, or surgery are discussed separately. (See appropriate topic reviews).
GENERAL PRINCIPLES — The location of pain in patients with claudication varies with the vessels that are involved. The usual relationship between the site of pain and site of arterial disease can be summarized as follows:
• Buttock and hip — aortoiliac disease
• Thigh — common femoral artery or aortoiliac
• Upper two-thirds of the calf — superficial femoral artery
• Lower one-third of the calf — popliteal artery
• Foot claudication — tibial or peroneal artery
Despite these general relationships, the history and physical examination are not reliable for the detection of lower extremity PAD. It has been estimated that relying solely on the classic symptoms of claudication will miss up to 90 percent of cases [2,3] . This was best illustrated in a study of 6417 patients at risk for peripheral arterial disease (either age >70 or age 50 to 60 with a history of diabetes or more than 10 pack-years of cigarette smoking) in a primary care setting [2] . PAD, identified by an ankle-brachial index ≤0.9, was present in 1865 (29 percent), only 11 percent of whom presented with classic claudication symptoms. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease", section on Atypical symptoms and section on Asymptomatic disease).
The physical examination is also unreliable. As an example, an abnormal femoral pulse has a high specificity and positive predictive value but low sensitivity for large vessel disease [4] . The best single discriminator is an abnormal posterior tibial pulse.
Patients at risk — Given these limitations, the diagnosis of lower extremity PAD often begins with noninvasive testing. The 2005 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD and the 2007 TASC II consensus document on the management of patients with PAD identified the following groups at risk for lower extremity PAD [5,6] :
• Age ≥70 years
• Age 50 to 69 years with a history of smoking and.or diabetes
• Age 40 to 49 with diabetes and at least one other risk factor for
• atherosclerosis
• Leg symptoms suggestive of claudication with exertion or ischemic pain at rest
• Abnormal lower extremity pulse examination
• Known atherosclerosis at other sites (eg, coronary, carotid, or renal arterial disease)
• All patients with a Framingham risk score of 10 to 20 percent (see "Estimation of cardiovascular risk in an individual patient without known cardiovascular disease", section on Framingham risk score).
In such patients, the standard review of symptoms should include questions related to a history of walking impairment, symptoms of claudication, ischemic rest pain, or nonhealing wounds [5,6] . Measurement of the resting ankle-brachial index should be performed in patients with one or more of these findings.
NONINVASIVE TESTS — A variety of noninvasive examinations are available to assess the presence and degree of peripheral arterial disease (show algorithm 1 and show algorithm 2). They include the ankle-brachial index (ABI), exercise treadmill test, segmental limb pressures, segmental volume plethysmography, and ultrasonography. Data suggest that magnetic resonance imaging may become an important noninvasive method for assessment [7] ; however, the cost and the time necessary for the study limit its use as a routine screening modality at this time. (See "Clinical utility of cardiovascular magnetic resonance imaging").
Ankle-brachial index — A relatively simple and inexpensive method to confirm the clinical suspicion of arterial occlusive disease is to measure the resting and post-exercise systolic blood pressures in the ankle and arm. This measurement is referred to as the ankle-brachial (or ankle-arm) index or ratio, and provides a measure of the severity of peripheral arterial disease [8] .
Calculation of the ankle-brachial index (ABI) is performed by measuring the systolic blood pressure (by Doppler probe) in the brachial, posterior tibial, and dorsalis pedis arteries (show figure 1) [9,10] . The highest of the four measurements in the ankles and feet is divided by the higher of the two brachial measurements:
• The normal ABI is 1.0 to as high as 1.3, since the pressure is higher in the ankle than in the arm. Values above 1.30 suggest a noncompressible calcified vessel.
• An ABI below 0.9 has 95 percent sensitivity (and 100 percent specificity) for detecting angiogram-positive peripheral arterial disease and is associated with ≥50 percent stenosis in one or more major vessels.
• An ABI of 0.40 to 0.90 suggests a degree of arterial obstruction often associated with claudication.
• An ABI below 0.4 represents advanced ischemia.
The ABI should be measured in both legs in all new patients with suspected PAD both to confirm the diagnosis and to establish a baseline [5] .
If ABIs are normal at rest but symptoms strongly suggest claudication, ABIs and segmental pressures should be obtained before and after exercise on a treadmill (see "Exercise treadmill testing" below) or using active pedal plantarflexion, which involves repeatedly standing up on the toes [11] .
The ABI correlates with clinical measures of lower extremity function such as walking distance, velocity, balance, and overall physical activity [12] . In addition, a low ABI has been associated with a higher risk of coronary heart disease, stroke, transient ischemic attack, progressive renal insufficiency, and all-cause mortality [13-17] .
• In a prospective study among nearly 1500 women, 82 (5.5 percent) had an ABI of less than 0.9, 65 of whom had no symptoms of peripheral arterial disease. Compared to the cohort with an index greater than 0.9, this group had markedly increased relative risks of 3.1 and 3.7 for death and coronary heart disease at four years [14] .
• In a report from the Framingham study of 251 men and 423 women (mean age 80 years), 141 (21 percent) had an ABI less than 0.9 [16] . Those with a low ABI had at four years a significantly increased risk of transient ischemic attack or stroke (13 versus 5 percent; adjusted hazard ratio 2.0).
There is a general but not absolute correlation between symptoms and the site and severity of PAD. In a report described in detail elsewhere, patients with unilateral PAD as determined from the ABI often had bilateral leg pain and 14 percent of those with unilateral pain had pain in the other leg [18] . (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease", section on Correlation of ABI with symptoms and site of PAD).
High ABI — A potential source of error with the ABI is that calcified vessels may not compress normally, possibly resulting in falsely elevated Doppler signals. Thus, an ABI above 1.3 is suspicious for a calcified vessel. In some patients with arterial calcification, an accurate pressure may be obtained by measuring the toe pressure and calculating the toe-brachial index. In this setting, one must recognize that a pressure gradient of 20 to 30 mmHg normally exists between the ankle and the toe.
An abnormally high ABI (>1.4) is also associated with higher rates of leg pain [18] and of cardiovascular risk [15] . The increase in cardiovascular risk was suggested in a report of 4393 native American patients in the Strong Heart Study who had bilateral ABI measurements and were followed for a mean of eight years [15] . There were 1022 deaths (23 percent) of which 272 (27 percent of all deaths) were cardiovascular. Patients with an ABI ≤0.9 or >1.4 had an increased risk of all-cause mortality (adjusted hazard ratios 1.7 and 1.8) and cardiovascular mortality (adjusted hazard ratios 2.5 and 2.1).
Similarly, data from the National Health and Nutrition Survey (NHANES) estimated 1.4 percent of adults age >40 years in the United States have an ABI >1.4, accounting for approximately 20 percent of all adults with PAD [19] .
Exercise treadmill testing — The dynamics of blood flow across a stenotic lesion depend in part upon whether the individual is at rest or exercising and upon the severity of the obstruction. Exercise normally decreases vascular resistance and enhances blood flow to the exercising extremities. An arterial stenosis of less than 70 percent may not be of sufficient severity to significantly perturb blood flow at rest or to produce a systolic pressure gradient. Exercise in such patients can induce a systolic pressure gradient across the stenosis or, in patients with more severe disease, increase the systolic pressure gradient.
These changes may be detected clinically by a fall in the ABI followed by recovery. This pattern is detected by measurement of the ABI at one minute intervals for five minutes after exercise. As a result, exercise testing is a sensitive method for evaluating patients with typical symptoms of claudication in whom the resting ABI is normal.
Several protocols exist for treadmill testing and are generally divided into those using a fixed versus a graded routine [20] . The standard exercise test is a treadmill test for five minutes at 2 mph on a 12 percent incline. Severe claudication can be defined as an inability to complete the treadmill exercise due to leg symptoms and ankle systolic pressures below 50 mmHg.
Segmental limb pressures — Once the presence of arterial occlusive disease has been verified using ABI measurements at rest or during exercise, the level and extent of PAD is routinely assessed by segmental limb pressures. A 20 mmHg or greater reduction in pressure is considered significant if such a gradient is present either between segments along the same leg or when compared to the same level in the opposite leg.
As with ABI measurements, segmental pressure measurements may be artifactually increased or not interpretable in patients with noncompressible vessels [5] . (See "High ABI" above).
Several blood pressure cuff positions have been employed to detect the level of peripheral arterial disease [21] . As examples, a significant reduction in pressure [5] :
• Between the brachial artery and the upper thigh reflects aortoiliac disease
• Between the upper and lower thigh reflects superficial femoral artery disease
• Between the lower thigh and upper calf reflects distal superficial femoral artery or popliteal disease
• Between the upper and lower calf reflects infrapopliteal disease
In addition, a toe pressure of less than 60 percent of the ankle pressure indicates digital artery occlusive disease.
Use of two specially designed narrow blood pressure cuffs rather than one large cuff on the thigh permits the differentiation of aortoiliac and superficial femoral artery disease. This technique, which is performed in the vascular laboratory, involves placement of a narrow cuff on the upper and lower thigh. The upper (proximal) thigh cuff is inflated to a pressure above systolic and then gradually deflated to determine the systolic pressure as heard by Doppler at the foot. This process is then repeated for the lower (distal) thigh cuff.
If the upper thigh systolic pressure is reduced compared to the brachial pressure (thigh-brachial index [TBI] <1.1), then the patient has a lesion in the aortoiliac territory. If, on the other hand, the TBI is >1.1 in the upper thigh and less than 1.1 in the lower thigh, the lesion is in the superficial femoral artery. In one prospective study, the use of two narrow thigh cuffs correctly identified the location in 78 percent of extremities with peripheral arterial disease versus a rate of only 19 percent with the use of a large cuff [21] .
The localization of the lesion may also be suspected from the history in patients with intermittent claudication. Thus, one should ascertain whether the pain is in the buttock or hip (suggesting aortoiliac disease), thigh (common femoral disease), upper calf (superficial femoral disease), lower calf (popliteal disease), or foot (tibial or peroneal disease). (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease").
In the patient with possible upper extremity peripheral arterial disease, a difference of ≥10 mmHg between brachial pressures suggests innominate, subclavian, axillary, or proximal brachial arterial occlusion.
Potential disadvantages in using Doppler ultrasound for segmental limb pressures are that the technique is insensitive at extremely low blood flow rates (<3 cm per second) and a venous signal can be confused with an arterial signal (especially if pulsatile venous flow is present as can occur with congestive heart failure).
Segmental volume plethysmography — Plethysmography, or the measurement of volume change in an organ or limb, is usually used in conjunction with segmental limb pressures to assess the level of arterial disease. This technique is performed by injecting a standard volume of air into pneumatic cuffs placed at various levels along the extremity. Volume changes in the limb segment below the cuff are translated into pulsatile pressure, which is detected by a transducer and then displayed as a pressure pulse contour.
The normal pulse volume recording is composed of a systolic upstroke with a sharp systolic peak followed by a downstroke that contains a prominent dicrotic notch. A change in the pulse volume contour indicates proximal arterial obstruction and is due to the dissipated energy that occurs due to arterial narrowing [22,23] .
Variations in the contours of the pulse volume recording reflect disease severity (show figure 2). As an example, mild disease is characterized by the absence of a dicrotic notch. With progressive obstruction, the upstroke and downstroke become equal, and with severe disease, the amplitude of the waveform is blunted. Pulse volume recordings are most useful in detecting disease in calcified vessels which tend to yield falsely elevated pressures.
Since the absolute amplitude of plethysmographic recordings is influenced by cardiac output and vasomotor tone, interpretation of these measurements should be limited to the comparison of one side of an extremity to the other in the same patient and not between patients. The clinician should also recognize that a dicrotic notch may be absent from the recording of a normal artery in the presence of low resistance, as may occur after exercise.
Duplex ultrasonography — Although ultrasonography is accurate in detecting peripheral arterial disease, resting segmental pulse volumes and systolic pressures are the initial screening tests in many laboratories. Ultrasonography is currently used to depict anatomy, hemodynamics, and lesion morphology; ultrasonographic equipment used for these tasks include B-mode imaging, pulse wave Doppler, continuous wave Doppler, and color Doppler display [8] .
Lower extremity examinations using the duplex Doppler begins at the common femoral artery and proceeds distally to the popliteal artery. An area of stenosis is localized with color Doppler and assessed by measuring Doppler velocities at several arterial sites.
The normal peripheral arterial velocity waveform is triphasic and consists of [24,25] :
• A forward flow systolic peak
• Reversal of flow in early diastole
• Forward flow in late diastole
With progressive peripheral arterial disease, there is elimination of the reverse flow, a decrease in systolic peak and an increase in flow in diastole (show figure 3).
It has been suggested that the main purpose of duplex Doppler ultrasonography is to avoid diagnostic angiography before intervention in patients with arterial disease proximal to the calf [26] . A meta-analysis of 14 studies found that sensitivity and specificity of this technique for ≥50 percent stenosis or occlusion were 86 and 97 percent for aortoiliac disease and 80 and 98 percent for femoropopliteal disease [26] .
Multidetector computed tomography — The development of multidetector computed tomographic (MDCT) scanners now allows rapid acquisition of high resolution, intravenous contrast enhanced images from patients with suspected peripheral arterial disease. A number of reports of small series of patients have noted excellent correlation between MDCT and digital subtraction angiography (DSA) in the detection of aortic and lower extremity arterial disease [27-29] , but these findings have not been universal [30] . In addition the total burden of radiation is relatively high.
A meta-analysis of 12 studies in which MDCT was used to evaluate 9541 lower extremity arterial segments in 436 symptomatic patients compared test performance to DSA [31] . The sensitivity and specificity for detecting a stenosis of a least 50 percent were 92 and 93 percent, respectively, compared to DSA. In the three studies that evaluated subdivisions of the arterial system, diagnostic performance in the infrapopliteal tract was lower than, but not statistically different from, that in the aortoiliac and femoropopliteal tracts.
A separate issue is the ability of MDCT to guide therapy. In an initial series of 58 patients with claudication, the findings on MDCT were used to determine whether or not an intervention was necessary [32] . Among the 29 patients in whom conservative management was indicated by MDCT, none required revascularization at a mean follow-up of 501 days.
INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Claudication"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.
RECOMMENDATIONS — We agree with the recommendations of the 2005 ACC/AHA guideline and the 2007 TASC II consensus document on the management of PAD with regard to the identification of asymptomatic PAD and for the evaluation of patients with intermittent claudication [5,6] .
Asymptomatic patients — The main value of identifying patients with asymptomatic lower extremity PAD is related to the association of these lesions with an increased risk of myocardial infarction, stroke, and cardiovascular mortality [5,33-35] . PAD is considered to be a coronary equivalent and such patients should be treated with risk factor reduction. (See "Medical management of claudication" and see "Secondary prevention of cardiovascular disease: Risk factor reduction").
The ACC/AHA guidelines made the following general recommendations for patients with no leg symptoms or atypical leg symptoms [5] . (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease", section on Atypical symptoms and section on Asymptomatic patients).
• In patients ≥70 years of age or ≥50 years of age with a history of smoking and/or diabetes (ie, those at increased risk for PAD), the standard review of symptoms should include questions related to a history of walking impairment, symptoms of claudication, ischemic rest pain, or nonhealing wounds. Use of the Walking Impairment questionnaire can be considered. (See "Patients at risk" above).
• The resting ABI should be measured in patients with one or more of these findings. The ABI should be measured in both legs in all new patients with PAD to confirm the diagnosis and to establish a baseline.
These recommendations are consistent with those made in the 2007 TASC II consensus document on the management of PAD [6] .
Similar recommendations were made by the American Diabetes Association for monitoring asymptomatic patients with diabetes [36] . The guideline recommended that initial screening for PAD should include a history for claudication and an assessment of the pedal pulses and that consideration should be given to obtaining an ABI.
Further evaluation is dependent upon the ABI value [5] :
• An ABI ≤0.90 is diagnostic of PAD.
• An ABI of 0.91 to 1.30 is borderline or normal. Among patients with atypical symptoms, the ABI should be measured after exercise on a treadmill. An ABI that decreases by 20 percent following exercise is diagnostic of PAD, while a normal ABI following exercise eliminates the diagnosis and suggests the need to evaluate for other causes of the leg symptoms.
• An ABI >1.30 suggests the presence of calcified vessels and the need for additional vascular studies, such as pulse volume recording or measurement of the toe-brachial index. Abnormal results confirm the presence of PAD. (See "High ABI" above).
Symptomatic patients — The evaluation is similar in patients with classic claudication (cramping, pain, or muscle fatigue that is reproducibly induced by exercise and promptly resolves with rest). The history should document the degree of walking impairment and lifestyle limitation and the peripheral pulses should be examined.
Further evaluation is dependent upon the ABI value:
• An ABI ≤0.90 is diagnostic of PAD.
• An ABI of 0.91 to 1.30 should be followed by further testing, such as measurement of the ABI after exercise, segmental limb pressures, or duplex ultrasonography. An abnormal test is diagnostic of PAD, while a normal test excludes PAD although arterial entrapment syndromes may be considered.
Although considered the "gold standard" of diagnostic evaluation for peripheral atherosclerotic disease, the use of iodinated contrast agents involves exposure to the patient of risk from iodine allergy, contrast nephropathy and the risks inherent to percutaneous intervention. With the advent of rapid 3-D imaging sequences combined with existing extracellular gadolinium contrast agents, magnetic resonance angiography (MRA) has shown promise to become a time-efficient and cost-effective tool for the complete assessment of peripheral arterial disease [1-3] . Current available gadolinium compounds are typically used "off-label" and are not approved by FDA for MRA in the United States.
One potential complication with use of gadolinium in patients with chronic kidney disease is skin sclerosis and, therefore, should be used with caution in this population. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced renal failure", section on gadolinium).
MRA is usually performed if revascularization is being considered. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease" and see "Indications for surgery in the patient with claudication").
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