Neuromodulation in Intractable Interstitial Cystitis and Related Pelvic Pain Syndromes

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1 Blackwell Publishing IncMalden, USAPMEPain Medicine American Academy of Pain Medicine20067S1S166S184 Original ArticleNeuromodulation in Interstitial CystitisBrookoff and Bennett PAIN MEDICINE Volume 7 Number S Neuromodulation in Intractable Interstitial Cystitis and Related Pelvic Pain Syndromes Daniel Brookoff, MD, PhD, and Daniel S. Bennett, MD, DABPM Integrative Treatment Centers, Denver, Colorado, USA ABSTRACT ABSTRACT Many people suffering with interstitial cystitis (IC) and related pelvic pain syndromes do not benefit from the standard medical or surgical treatments. The pathophysiology of IC bears striking similarities to a wide variety of disorders driven by neurogenic inflammation, many of which may someday be controlled through neuromodulation. Because the bladder is accessible to repeated inspection, functional monitoring, biopsy, and collection of effluents, the study of neuromodulation in IC promises to yield important insights into the successful application of neuromodulatory approaches to diseases of the pelvis and other areas. Clinical experience suggests that neuromodulation in pelvic pain syndromes can successfully normalize the motor function of the bladder and pelvic muscles, as well as their sensoria. Useful neuromodulatory approaches that have potential for the treatment of intractable IC and related syndromes, such as certain cases of chronic prostatitis and pelvic floor dysfunction, include stimulation of afferent pathways using high-frequency stimulation of sacral roots and low-frequency stimulation of motor fibers innervating pelvic floor muscles via sacral roots or the posterior tibial nerve. While the lifetime incidence of chronic pelvic pain in American women is estimated to be as high as 33%, fewer than 1% of these patients are ever seen by pain specialists. Developing neuromodulatory strategies for IC and pelvic pain may also hold promise for the effective treatment of certain syndromes involving intractable urinary retention, lower bowel disorders, or sexual dysfunction. Key Words. Interstitial Cystitis; CRPS; Sacral Nerve Stimulation; Pelvic Pain; Retrograde Sacral Stimulation; Prostatitis Introduction I nterstitial cystitis (IC) also known as painful bladder syndrome or IC/chronic pelvic pain syndrome [1] has long been characterized as a urologic disease, but it may be better understood as a complex visceral pain syndrome [2]. Indeed, IC has been likened to reflex sympathetic dystrophy of the bladder or CRPS I of the pelvis [3]. The epidemiology, pathology, and pattern of response to treatment in IC overlap so closely with those in certain types of chronic prostatitis, pelvic floor dysfunction, and frequency urgency syndrome that it now seems reasonable to conclude Reprint requests to: Daniel Brookoff, MD, PhD, Integrative Treatment Centers, North Dover Street, Suite 800, Westminster, CO 80021, USA. Tel: ; Fax: ; dbrookoff@ denverpain. com. that many instances of these syndromes represent different expressions of the same disease process. This may hold true for many other cases of chronic pelvic pain that had previously been attributed to adhesions, endometriosis, or uterine adenosis. Insights from the study of IC and related syndromes suggest that, in relcalcitrant cases, we should be directing our treatment toward the neurologic generators of nociception and dysfunction, and away from the visceral organs that were once presumed to be responsible for chronic pelvic pain [4]. The prevalence of IC and related syndromes has long been underestimated. Data from the Nurse s Health Study found that over 6% of American women have classical IC [5]. In addition to this, the prevalence of chronic pelvic pain syndrome in American women between the ages of 18 and 50 years has been estimated to be over American Academy of Pain Medicine /06/$15.00/S166 S166 S184

2 Neuromodulation in Interstitial Cystitis 10% [6]. As discussed below, many of these may represent undiagnosed cases of IC. In addition, the estimated prevalence of chronic abacterial prostatitis, which is the diagnosis most commonly given to adult men with a symptom-complex consistent with IC, is over 5% in the United States [7]. Certain cases of intractable overactive bladder syndrome (urgency, frequency, nocturia), may also represent a form of IC. Overactive bladder syndrome is estimated to occur in over 33 million Americans, amounting to over 15% of the adult population. The prevalence of this disorder does not vary by gender, and its burden is highest in the elderly, where it is associated with pressure ulcers, urinary tract infections, falls, and fractures [8]. The Clinical Features of Interstitial Cystitis Bladder Dysfunction and Pelvic Pain Urologists define IC as a syndrome characterized by chronic irritative voiding symptoms, sterile and cytologically negative urine, and characteristic cystoscopic findings along with failure to find a more objective cause for the clinical picture [9]. Even though IC has been recognized by physicians for over 150 years, it has defied strict definition by clinical signs or pathological findings. Many of its victims have been left to suffer in obscurity, often resorting to cystectomy or even suicide when the pain has become unbearable. Interstitial cystitis is essentially hypersensitivity of the urinary bladder. The hallmarks of this disorder are exaggerated and abnormal sensory and motor reactions to the presence of urine in the bladder which can progress to debilitating hyperalgesia and allodynia. IC often starts out as irritable bladder with the urgency to urinate accompanied by small urinary volumes. At the extreme, patients with IC may experience the compelling urge to urinate up to 80 times per day, suffering with constant disabling pelvic pain and intractable insomnia. IC and its associated syndromes such as chronic nonbacterial prostatitis and chronic pelvic pain syndrome, constitute the most disabling group of disorders seen by urologists and gynecologists [5,10,11]. Female predominance of up to 90% was noted early on in the study of IC [12]. Soon thereafter, IC came to be associated with psychiatric and emotional disturbance. An article from 1958 entitled Masochism and Interstitial Cystitis [13] talked about the etiology of IC being repressed hostility toward parental figures handled masochistically via bladder symptoms. Interestingly, S167 while many urologists have subscribed to the psychosomatic etiology of IC, they continued to advocate for surgical treatment [14]. One urology textbook, which strongly advocated for early cystectomy in the treatment of IC, described the syndrome as the end-stage of a bladder that has been made irritable by emotional disturbance a pathway for the discharge of unconscious hatreds [15]. It is important to point out that there is an association between chronic pelvic pain and a history of sexual victimization [16 20]. Unfortunately, this is often used to invalidate legitimate medical complaints. While the female predominance in IC may be real, it is no doubt exaggerated by the fact that men with a symptom-complex fitting IC are usually diagnosed with chronic nonbacterial prostatitis. Although originally thought to be a disease of the elderly, epidemiologic studies show that the onset of IC symptoms generally occurs between 30 and 50 years of age [21]. An increasing number of sufferers are found to have had urinary symptoms dating back to childhood [22]. Common Symptoms Interstitial cystitis most commonly presents with progressive urinary frequency and urgency. Half of patients initially report dysuria and nocturia [21]. Male patients will often describe perineal, scrotal, and groin discomfort [23]. Although patients often have a combination of voiding symptoms and pelvic pain, in most cases one of the two symptom complexes tends to predominate. In total, 50 75% of women with IC report dyspareunia [24], with spasmodic pelvic pain typically worse toward the end or after intercourse. By the time of diagnosis, many patients have chosen to abstain from sexual intercourse entirely [25]. Incontinence is rarely reported in IC but, when present, is generally of the urgency type. Certain disorders that are separately classified as urinary continence disorders, such as urgency frequency syndrome and urge incontinence, may also be forms of IC. In a large survey of IC patients, 92% reported urinary urgency, 91% urinary frequency, 70% pelvic pain, 60% dysuria, 37% pain for days after intercourse, and 22% hematuria. A total of 55% of these patients reported daily or constant pain, with 57% of them characterizing their pain as severe or excruciating [19] (see Table 1). Pelvic pain was often (but not always) increased by stress, ingestion of alcohol, tomatoes, acidic or carbon-

3 S168 Table 1 Symptoms in interstitial cystitis Daily (or constant) pain 55% Dysparunia 50 75% Dysuria 60% Hematuria 22% Nocturia 50% Pelvic pain 70% Perineal discomfort (scrotal/vaginal/groin) Prolonged pain after intercourse (i.e., days) 37% Urge Incontinence Rare Urinary frequency 91% Urinary urgency 92% ated beverages, high acidosis of the bladder, disturbances in sleep, and long car rides. The last one may be related to vibrations transmitted to the pelvis through the car frame. Interestingly, these patients often do not suffer the same exacerbations with airplane rides or in cars that have air suspension systems. Many of the foods which IC patients associate with bladder pain contain high concentrations of potassium, such as orange juice or apple juice. Many patients with IC report that the disease has caused significant disruptions in family relationships [26]. Patients with IC can often pinpoint the day that their symptoms started [27]. Many associate the onset of irritative voiding symptoms with a specific event such as a urinary tract infection or pelvic surgery [23]. Most of these patients are initially treated with antibiotics for acute bacterial cystitis despite negative urinalyses and cultures [27]. In general, patients will suffer with progressive symptoms for 3 7 years and undergo workup by more than four physicians before the diagnosis of IC is finally made [28]. Association with Trauma to Pelvic Nerves Interstitial cystitis has been associated with an antecedant history of pelvic surgery. The most common procedure is hysterectomy, which is known to be associated with chronic bladder dysfunction [29]. A large epidemiologic study in the United States found that 44% of women with IC had undergone hysterectomy within months before the onset of symptoms, while the rate for the control group was 17%. More recent studies suggest that many of these patients may have undergone their hysterectomies for the treatment of chronic pelvic pain with a missed diagnosis of IC [30]. Vaginal delivery also puts women at an increased risk of developing urge incontinence and nocturia. Women with urge incontinence 3 months after first delivery have a very high risk of developing long-lasting symptoms. This risk is Brookoff and Bennett further increased by episiotomy or vacuum extraction [31]. Another study found that the majority of men diagnosed with IC had undergone transuretheral prostatectomy within 6 months preceding diagnosis but, in many of these patients, the symptoms of IC may have preceded their surgeries [32]. Chronic Prostatitis and Interstitial Cystitis: Different Expressions of the Same Disease? Interstitial cystitis is rarely diagnosed in men, but that might not be because it is rare. Men presenting with irritative voiding symptoms and pelvic pain but with no evidence of infection are most commonly diagnosed as having chronic abacterial prostatitis (also called type III chronic prostatitis or prostadynia) [33]. The overall prevalence of chronic prostatitis among adult men in the United States has been estimated to be between 5% and 8%, with abacterial prostatitis accounting for more than 90% of these cases [7]. Although it is a common condition, the pathophysiology of chronic prostatitis, like that of IC, is enigmatic. One prominent urologist called the condition a wastebasket of clinical ignorance [34]. In fact, the pathologic evidence linking chronic abacterial prostatitis to any abnormality in the prostate gland per se is scant. Under recently revised National Institutes of Health (NIH) diagnostic classifications, chronic abacterial prostatitis has been renamed chronic pelvic pain syndrome [35]. The epidemiology of chronic abacterial prostatitis is similar to that of IC [36]. Up to 70% of men with chronic nonbacterial prostatitis and prostadynia have the cystoscopic appearance of IC when cystoscoped under anesthesia [37]. These and other significant overlaps in the epidemiology, pathophysiology, and response to therapy in these two syndromes have led many urologists to suggest that IC and chronic abacterial prostatitis represent different manifestations of the same disease [38 40]. Pelvic Floor Dysfunction Pelvic floor dysfunction associated with muscular hypertonus ( high tone pelvic floor dysfunction ) is a common source of chronic pelvic pain. The pelvic floor is composed of two muscular layers. The deeper layer is composed of the levator and its various components (a hammock-like structure attached to the pelvic brim supporting the internal pelvic organs). Contraction of the levator muscles lifts the pelvic organs upward and anteriorly toward the pubis bone and compresses the bladder

4 Neuromodulation in Interstitial Cystitis neck. This is dependent on stimulation of the S3 and S4 roots. The second layer is composed of the transversus peronei, the ischiocavernosis and bulbocavernosis muscles, the urethral sphincter, and the superficial anal sphincter. These muscles are innervated by the pudendal nerve, which is primarily derived from S2 and which is also responsible for perineal skin sensation. Stimulation of the pudendal nerve produces an anterior-posterior squeezing. Pelvic floor dysfunction occurs when contractions of these muscle layers are dyssynergic relative to each other or to the bladder [41]. In many cases, all or part of the pelvic pain in IC and related syndromes can be generated by dysfunction of pelvic floor muscles. Spasm or hypertonia of the pelvic floor can also give rise to urinary urgency, constipation, and dyspareunia [42]. Myofascial trigger points in the muscles of the pelvic floor can generate bladder pain and voiding symptoms. This muscle dysfunction can manifest as spasm or abnormal contractions when the bladder fills or when voiding is initiated. In addition, hypertonus of pelvic floor muscles can also trigger neurogenic inflammation of the bladder via antidromic reflexes contributing to bladder-related symptoms [43]. These symptoms are most commonly related to dysfunction of the Levator Ani complex, which includes the puborectalis, pubococcygeous, and ileococcygeous muscles. Visceral pain from pelvic organs and myofascial pain from muscular trigger points can share common characteristics. Referred pain from myofascial trigger points can commonly mimic visceral pain syndromes. Conversely, visceral pain syndromes can induce development of these trigger points. Many patients with IC have certain elements of their pain referable to an inflamed bladder lining (e.g., burning after eating certain foods) and other components related to pelvic floor dysfunction (e.g., positional pain, dyspareunia). A careful history of exacerbating factors can help identify the generators of pelvic pain, some of which may be associated with dysfunction of muscles outside the Levator Ani complex [44]. For example, hypertonus of the bulbospongiosis and ischiocavernosis muscles (vaginal constrictors, muscles which mediate penile and clitoral tumescence) can lead to tension myalgias of the pelvic floor. Premature contractions of detrusor muscles surrounding the bladder (termed detrusor instability ) can cause pelvic pain associated with voiding. Triggers in the obliques transversus muscles can cause pelvic, groin, and perineal pain. Triggers S169 in rectus abdominus muscles can cause pelvic pain associated with increased intra-abdomenal pressure. Spastic dysfunction of the pyramidalis muscles (spinal flexion and trunk rotation) can also cause detrusor spasm. Iliopsoas dysfunction (hip flexion, spinal extension on standing) can lead to groin pain. Dysfunctional hip adductor magnus muscles can trigger pelvic pain with thigh extension or gluteal contraction. Pelvic hypertonus can be assessed by a careful physical exam (including a rectal exam) and pelvic electromyography. All pelvic muscles are regulated via the S2 S4 nerves. The parasympathetic motor nuclei in S3 and S4 provide the principal motor input to the bladder, which is modulated by inputs from other dorsal roots and descending supraspinal pathways. Chronic pelvic floor dysfunction is often combined with lower urinary tract dysfunction, and both become maintained by up-regulated sacral reflex arcs. The Relationship of Other Pelvic Pain Syndromes and Interstitial Cystitis Many women presenting to gynecologists or family physicians with undifferentiated chronic pelvic pain have findings consistent with IC. In a large study of unselected patients presenting to gynecology practices for chronic pelvic pain, 84% had urinary symptoms and 81% had positive potassium tests (a clinical marker for hypersensitivity of the bladder epithelium). Positivity rates were comparable across all diagnoses, including endometriosis, vulvodynia, and chronic pelvic pain of unknown etiology. None of control patients tested positive for potassium sensitivity [45]. Repeat studies have borne this out, leading to the recommendation that screening for IC should be undertaken in all women presenting with chronic pelvic pain [46]. In one study, 75% of female patients presenting to gynecologists with undifferentiated chronic pelvic pain had findings consistent with IC, but less than 3% were correctly diagnosed [47]. Patients with pelvic pain attributed to endometriosis have a high incidence of findings consistent with IC [48]. There has also been a growing awareness of a relationship between IC and vulvar vestibulitis, which was previously thought to be solely a dermatologic condition [49]. The connection between IC and vulvar disease may be explained by the finding that chronic neurogenic inflammation of the bladder can lead to extravasation of plasma from cutaneous vessels in the vulva along with cutaneous sensitivity and trophic changes, such as thickening of subcutaneous tissue

5 S170 Brookoff and Bennett [50]. There is also a strong association between chronic pelvic pain and irritable bowel syndrome [51,52]. In large subgroups of patients with IC, vulvar vestibulitis, prostodynia/prostatitis, and loin pain-hematuria syndrome, inflammatory changes in the bowel and other visceral organs are observed for which no etiology can be identified. The clinical features of many of these syndromes are consistent with the type of chronic neurogenic inflammation that is associated with IC [53]. Overlap with Other Chronic Pain Syndromes Interstitial cystitis has also been associated with other poorly defined extra-pelvic pain syndromes that may involve neurogenic inflammation. In a large survey of patients with IC, there was a strong association with irritable bowel syndrome (64%) and high frequencies of atopia, fibromyalgia, and migraine headache [10]. When Clauw et al. compared age-matched patients with fibromyalgia, IC, and healthy controls, a commonality of reported symptoms was seen between the groups with fibromyalgia and IC, leading the investigators to conclude that similar disorders in pain processing were present [54]. Compared with normal controls, individuals with IC are 100 times more likely to have inflammatory bowel disease and 30 times more likely to have systemic lupus. In addition, allergies, irritable bowel syndrome, atopia, and fibromyalgia have an increased incidence among patients with IC [55]. Clinical Assessment of Interstitial Cystitis Voiding Diaries Voiding diaries are very useful in gauging frequency and nocturia and assessing the response to treatment. Frequent small-volume voids reflect bladder instability, hyperreflexia, hypersensitivity, or poor compliance with treatment. Two validated survey instruments, the interstitial cystitis symptom index and the interstitial cystitis problem index, are useful in the evaluation and management of patients with IC [56]. Figure 1 Hunner s patches. Inflammed granulation tissue that represent one form of interstitial cystitis, first described by Guy Hunner in Cystoscopy Cystoscopic examination of the bladder, though of questionable value, has been a standard maneuver in the diagnosis and assessment of IC ever since Guy Hunner described the characteristic ulcer in 1914 [57]. Based on cystoscopic findings, IC has traditionally been classified as either ulcerative (marked by the cystoscopic observation of Hunner s ulcers ) or nonulcerative [9]. These classifications may represent different stages of the same disease or different pathological processes [58]. Even though many practitioners still consider bladder ulcerations to be a sine qua non of IC, estimates of ulcerative IC range from only 5% to 20% [24,28]. At first, Hunner advocated for the resection of the ulcerated tissue, but the high recurrence rate led him to abandon this surgical approach, which he detailed in an article with the interesting title of Neurosis of the Bladder [59]. Actually, Hunner s ulcers are not even true ulcers but rather areas of inflamed granulation tissue that are probably better referred to as a Hunner s patches (see Figure 1). Another cystoscopic finding that is often regarded as characteristic of IC is the presence of strawberry-like hemorrhages called glomerulations (see Figure 2). Typically, glomerulations are not seen on first filling of the bladder but are found on re-distension. Although glomerulations are widely considered to be specific and sensitive for the diagnosis of IC, they are probably neither. A recent study of asymptomatic women undergoing tubal ligation showed that most of them had glomerulations on repeated cystoscopic distension of their bladders [60]. It has already been shown that the presence or absence of ulcers or glomerulations is not predictive of symptoms [58]. Potassium Testing Potassium sensitivity has been used by many urologists as a clinical marker for IC [45]. The potassium test assesses bladder discomfort after intravesicular instillation of 0.4 M KCl [61]. This

6 Neuromodulation in Interstitial Cystitis Figure 2 Glomerulations. Glomerulations or strawberrylike hemorrhages are often seen on refilling of the bladder. test can be extremely painful for patients with IC, although some patients with proven IC may not experience discomfort. The rationale behind this test is that the bladder wall in IC is abnormally permeable to solutes (see below). Some practitioners have tried to redesign the test using lower concentrations of potassium [62]. In our experience, potassium sensitivity is so often correlated with certain food sensitivities (e.g., bladder pain after ingesting alcohol or high-potassium foods such as orange juice) that the need to subject patients to this painful test may be obviated by taking a careful history. S171 Urodynamic Testing Urodynamic testing provides objective measures of the function of the lower urinary tract. We think that this is the most important test in assessing the generators of chronic pelvic pain. This is not universally accepted by urologists and gynecologists who rarely use urodynamic testing in the evaluation of chronic pelvic pain [63]. An innovative approach to the use of urodynamic testing (including pudendal nerve-evoked potentials and ano-rectal manometry) promises to advance the diagnosis and assessment of a wide variety of painful syndromes involving the genitourinary system, pelvis, the lower bowel, and even the spine. There are several components to urodynamic testing. Cystometry measures sense of fullness with different bladder volumes. The bladder is filled with warm water at a rate of 50 cc/min with the patient lying down. A normal adult should be able to hold 500 cc without much more than a sense of fullness. Uroflow testing measures pressures and flows during micturation and residual volumes to assess for voiding dysfunction. With detrusor overactivity, a rapid supernormal flow with abrupt cessation or intermittent flow due to detrusor spasm can be seen. The cystometrogram evaluates the compliance and stability of the detrusor muscles. Electromyography evaluates the electrical activity of the sphincter muscle. Urethral pressure readings assess pelvic floor hypertonus [64]. There is a strong correlation between daytime, nighttime, and 24-hour frequency and the urodynamic endpoints volume at first sensation to void (VFSV) and maximal cystometric capacity (VMCC). Urgency symptoms are correlated with uninhibited detrusor contractions. Urodynamics can also assess the response to neuromodulation and guide the programming of neurostimulators. Urgency frequency syndrome, which is often painful, is invariably accompanied by urodynamic evidence of detrusor instability. Guided by urodynamic testing, neuromodulation can increase total bladder capacity, increase volume at first sensation and mean volume at normal desire to void, and decrease total daily voids and total nighttime voids [65]. The Pathophysiology of Interstitial Cystitis Anatomical Pathways of Bladder Pain There are several potential anatomic pathways for the pain of IC. While classical neuroanatomy would implicate the pelvic nerves, fibers coming off the dome of the bladder joining the hypogastric nerve probably carry much of the burning pain and dysesthetic pain in chronic inflammatory syndromes of the bladder. The hypogastric nerve carries sympathetic preganglionic input to the pelvic ganglia and afferent input from the bladder to the thoraco-lumbar spinal cord. Activity in these pathways can explain how some patients with cord transections can still feel pain due to bladder infections. The afferents in this pathway are either lightly myelinated A-delta or unmyelinated C- fibers [66]. The A-delta fibers generally function

7 S172 as mechanoreceptors but can transmit nociceptive input to the spinal cord. Clinically, the different pathways correspond to different types of bladder pain. For example, the deep, gnawing pain of overdistension is probably transmitted via hypogastric nerves (with referral pattern in dermatomes of T ). The sharp pain of mucosal irritation, as is felt in acute bacterial cystitis, may be conducted via the pelvic nerves, with referred pain to the rectum, vagina, and perineum when there is bladder irritation. This certainly reflects the pattern of pain that is reported by patients with IC and often disbelieved by their physicians. Increased Bladder Permeability Pathologic clues to the causes of IC have been elusive. A popular concept holds that IC develops when the water-tight layer overlying the bladder epithelium has become dysfunctional and leaky [67]. Normal bladder mucosa is lined by a layer of negatively charged sulfonated glycosaminoglycans (GAG). This GAG layer maintains the permeability barrier between urine and the bladder wall, preventing the back-diffusion of water, potassium, and other solutes. Interestingly, in a study in which protamine sulfate (which will combine with and precipitate negatively charged GAG) was instilled into the bladders of normal volunteers, the subjects quickly developed the symptoms of IC [68]. In these cases, the permeability barrier could be restored and symptoms relieved by instilling a sulfated polysaccharide, such as heparin, into the bladder. Based on these findings, synthetic polysaccharides, such as sodium cromoglycate [69] and pentosan polysulfate (Elmiron), an orally bioavailable heparinoid compound, have become a mainstay in the treatment of IC [70]. These compounds may be more effective early on in the course of the disease but are probably not as effective once the process of continuous, self-reinforcing neurogenic inflammation has become established. There is some evidence that pentosan polysulfate may be acting by mechanisms unrelated to the bladder lining, e.g., as an anti-inflammatory agent or as an inhibitor of nerve growth or angiogenesis [71,72]. The reports of abnormalities in urinary GAG levels in IC patients are variable [73] but may point to congenital chemical differences among patients [74]. One study showed that there was no difference in the permeability of the bladders of IC patients and normal controls to 99m Tc-DTPA, a solute that is comparable to urea [75]. Brookoff and Bennett Abnormalities of Epithelial Proliferation Bladder epithelial cells in IC make a specific antiproliferative factor (APF) that may be a biomarker of the disease. Patients with IC also have decreased urinary levels of heparin-binding epidermal growth factor and increased levels of other epidermal growth factors. APF may cause epithelial thinning or denudation sometimes associated with IC and may be an abnormal form of a normally produced epithelial sialoglycopeptide [76]. Abnormalities of the Bladder Wall Biopsies of the bladder wall in people with IC typically show normal epithelial and muscularis layers with submucosal edema and vasodilatation [77]. Classical inflammatory changes are rare and are usually limited to the lamina propria. This pattern is reminiscent of the changes seen in biopsies of the colons of patients with ulcerative colitis. A total of 80% of bladder biopsies in IC will show perineural lymphocytic inflitrates. Despite severe symptoms in nonulcer patients, they may have very meager histopathologic findings. This may be because the actual disease process operates proximal to the bladder wall, e.g., in the nerve roots or the spinal cord. Evidence for Peripheral Neural Remodeling Biopsies from IC bladders often show increased nerve density in the bladder wall, specifically sympathetic nerves and fibers containing substance P. An increase in mast cells in the bladder walls of IC patients has been described, but this has not been a consistent finding [78]. While data on the density of mast cells vary, there is consistent evidence for increased mast cell degranulation in the bladder walls of patients with IC [78 81]. Peptidesecreting nerve fibers are often seen in close apposition to degranulating mast cells, which also release nerve growth factor (NGF). NGF is found in high concentrations in the urine of many patients with IC [82]. Similar findings are commonly seen in inflammatory diseases of gastrointestinal tract such as in ulcerative colitis and Crohn s disease, and other chronic inflammatory states such as psoriasis and certain types of inflammatory polyarthritis [83 87]. The Role of Neurogenic Inflammation in Interstitial Cystitis Neurogenic inflammation is the process by which central stimulation of peripheral sensory nerves elicits vasodilatation, plasma extravasation, and

8 Neuromodulation in Interstitial Cystitis other inflammatory changes in peripheral tissue [88]. This process can explain many of the pathologic features of IC. Although we have been taught that sensory nerve fibers function only as carriers of messages to the central nervous system, we now understand that in certain disease states, they can also act as efferents in the periphery, causing neurogenic inflammation through the release of neuropeptides from their dendritic terminals. For example, edema of the bladder wall can be elicited by direct stimulation of lumbar roots or pelvic nerves [88,89]. These findings provide an important rationale for the utility of neuromodulation in IC. Studies linking the release of neuropeptides to inflammation of the bladder wall and the development of urinary symptoms suggest that patients with IC possess altered afferent innervation and that their symptoms are, to some extent, generated by neurogenic inflammation. With persistent neurogenic inflammation, new nerve pathways are recruited potentiating the transmission of bladder pain. These pathways can include sacral dorsal root ganglion neurons, which carry afferent fibers from the bladder. These fibers are small, quiescent, and normally possess high threshholds for firing [90]. Because of this, they are called silent C fibers. With persistent bladder inflammation, these once-silent neurons become activated, expressing new sodium channels [91] and new receptors for neuropeptide pain mediators, such as the NK-1 receptor for substance P [92]. The role of inflammatory neuropeptides in IC may explain the relief that some patients experience after intravesicular instillation of capsaicin [93] or resiniferatoxin [94]. The decrease in IC pain soon after hydrodistension of the bladder may also be due to depletion of neuropeptides caused by transient damage to peripheral nerve fibers. For many patients, the pain returns and intensifies soon after this treatment. S173 An Animal Model of Interstitial Cystitis An animal model of pelvic pain supports the contention that neurogenic inflammation can be an important generator of IC. Dr. Stephen McMahon and colleagues described how nondestructive concentrations of a chemical irritant, turpentine oil, when instilled into the bladders of rats, caused persistent submucosal irritation [95]. In response to this, chemosensitive afferent fibers in the bladder wall were found to release vasoactive substances. The resulting neurogenic inflammation caused sensory and motor changes associated with hypermotility of the bladder, hypersensitivity to small volumes of urine, and behaviors associated with pain and allodynia. This was correlated with increases in NGF and substance P secretion by cells of the bladder wall into the urine [95]. With continued irritation, sensory fibers in the bladder wall that were normally silent became activated. Ultimately, the process of neurogenic inflammation progressed to the point that it no longer depended on the instillation of the irritating chemical. The rats developed persistent allodynia of the bladder. Persistent neurogenic inflammation of the bladder wall subsequently led to increased mucosal permeability [89]. High concentrations of potassium in the urine eventually caused structural changes in the bladder wall. These changes were ultimately translated to the central nervous system, where afferent neuronal cell bodies in the spinal cord hypertrophied in response to chronic bladder irritation [96,97]. Nerve growth factor manufactured by bladder smooth muscle triggered the growth of sensory and noradrenergic nerves [98,99]. In the animal models, blockade of NGF can prevent hypertrophy of dorsal root ganglion cells in the spinal cord in response to inflammation [100]. Thus, there is a firmly established relationship between secretion of NGF and alterations of nociceptive signaling both at peripheral and central sites. In human and animal trials, a single systemic injection of NGF can lower nociceptive threshholds for several days, and this effect can be blocked by treatments that deplete mast cells, block 5-HT receptors, or inhibit NGF [ ]. Mast cells respond to NGF by releasing serotonin that, in turn, causes long-lasting lowering of nociceptive threshholds promoting the inflammatory cascade [105]. With continued bladder inflammation, c-fos oncogene expression in sacral spinal cord cells is up-regulated, the degree of which is related to the severity and duration of the inflammation [106]. The spread of c-fos expression up the spinal cord may herald the spread of neurologic abnormalities (and new symptoms) into different dermatomes. In a different animal model, IC was induced in rats by manipulation of the thoracic and sacral spinal cord without direct insult to the bladder [107]. In this model, bladder inflammation was completely dependent on signals generated in the central nervous system and bore no relationship to events occurring within the bladder.

9 S174 Treatment of Interstitial Cystitis: Neurodestruction versus Neuromodulation While the bladder affected by IC provides a promising target for neuromodulation, the history of the treatment of this syndrome chronicles over 100 years of neurodestruction. Soon after the first medical reference to IC was published in 1836 [108], the use of intravesicular caustic silver nitrate was promoted as a treatment [109], one that unfortunately continues to be used to this day. Presacral neurectomy for the pain of IC was first described in 1926 and had been commonly conducted for over 40 years, although positive results were rare and transient [110]. Another neurosurgical approach recommended for the pain and sympathetic overactivity of IC was surgical excision of the superior hypogastric plexus [111], although this soon fell out of favor due to lack of benefit. In 1951, more selective neurectomies were described [112], but they too were unsuccessful. Several investigators have noted increased sympathetic activity in the lower extremities of IC patients compared with controls [113], and this led to the use of lumbar sympathetic blocks, but these rarely conferred pain relief [114]. In the 1930s, distension of the bladder under general anesthesia came into vogue for the treatment of chronic bladder pain [115]. This is still a standard urologic treatment for IC, although nowadays it is usually carried out without the anesthetic [116]. Hydrodistension and many of the early treatments for IC can be seen as primitive attempts at neuromodulation, which work by causing temporary damage to sensory fibers in the bladder wall. This would explain the temporary effectiveness of these and other treatments, such as the instillation of solvents like dimethyl sulfoxide [117] or caustic agents [118,119]. The process of neural remodeling would explain why, in most cases, the symptoms return with greater intensity in the weeks or months following these standard therapies and why even responsive patients often became refractory to treatment. As has been the case in other poorly understood chronic pain syndromes, many of the medical treatments for IC ultimately promote neurogenic inflammation and neural remodeling, thus advancing the disease process itself [71]. Until recently, when these treatments stopped working, many patients with IC were urged to undergo cystectomy, which also failed to relieve the pain in most cases [120]. Brookoff and Bennett Sacral Nerve Stimulation for Interstitial Cystitis and Other Chronic Pelvic Disorders Sacral nerve stimulation is an effective approach to modulating the activity of the bladder and pelvic floor muscles, and may be an effective treatment of IC and other pelvic pain syndromes. Sacral nerve stimulators were first implanted for intractable urge incontinence and urgency frequency syndrome over 25 years ago by Drs. E.A. Tanagho and R.A. Schmidt. In the years since, sacral nerve stimulation has become the standard of care for refractory overactive bladder, proving to be both effective and cost-efficient [121]. Targeted S3 neuromodulation can change sensory parameters in patients with urge incontinence, increasing the bladder volume at which the urge to void is triggered. Sacral neuromodulation can also re-establish pelvic floor muscle awareness and reduce pelvic floor hypertonus, relieving IC symptoms such as pelvic pain, daytime frequency, and nocturia. There is also evidence that sacral neuromodulation can promote the resolution of vestibulitis and vulvodynia, and normalize bowel function, which is often disrupted in patients with IC and related syndromes [122]. Low-Frequency Sacral Nerve Stimulation There have not been any well-controlled studies of neurostimulation in IC. Most of the studies of the mechanisms of neurostimulation in IC have been small case series involving low-frequency (5 50 Hz) stimulation of S3 via one or both sacral roots; the leads are placed 60 in relation to the S3 nerve rather than parallel to the nerve. S3 is generally targeted because approximately 70% of the closure pressure of the external urethral sphincter is due to somatic fibers that emanate from this root [123]. Sacral neurostimulation may directly affect both sensory and motor fibers. In some cases, S3 stimulation may also have a direct effect on striated sphincter function [124]. Low-frequency sacral neurostimulation has been successfully used to treat both urinary retention and urge incontinence. One explanation for this apparent contradiction is that stimulation of the posterior sacral roots supports the continence (storage) phase by reducing detrusor contraction and increasing bladder neck activity. Termination of stimulation can trigger bladder emptying through contraction of the detrusor vesicae muscles via the micturation reflex, increasing detrusor contraction and reducing bladder neck activity [125].

10 Neuromodulation in Interstitial Cystitis S175 the stimulators have been implanted in childhood and have been left operating for years [132]. Figure 3 Interstim. Transforaminal sacral stimulator, Food and Drug Administration approved for symptomatic urge incontinence. It is commonly placed at S3. Low-frequency sacral nerve stimulation may also work by inhibiting somatic afferents in pelvic floor. In addition to evoking a bellows type contraction of the perineum due to direct stimulation of dysfunctional levator muscles, stimulation of S3 can block abnormal C-fiber activity via suppression of interneuronal mechanisms, which do not have an inhibitory effect on voluntary voiding. This effect may only hold in hyperreflexic bladders through direct supraspinal excitatory input by the pelvic ganglion neurons [126]. There is a high degree of variability in the reported responses to sacral neuromodulation and this may be related to the high incidence of intradural bridging between adjacent sacral roots [127]. In addition to its action on peripheral nerves, sacral nerve stimulation may also operate in higher neural centers. Low-frequency stimulation of S3 generates impulses in the sensory cortex, which may not be consciously felt by the patient. This indicates that some of its effects may be mediated through a supraspinal site of modulation [128,129]. S3 stimulation also has pharmacologic effects on the bladder wall, increasing urinary concentrations of heparin-binding epidermal growth factor-like growth factor and reducing concentrations antiproliferative factor, the urinary marker correlated with symptoms of IC [130]. Long-term, lowfrequency stimulation at the intensity needed to alleviate voiding symptoms does not induce neural damage [131]. This has been the case even when Sacral Neurostimulation for Pelvic Pain While sacral nerve stimulation has been proven to be effective in the treatment of pelvic floor dysfunction, there is still some question about its utility in the treatment of pelvic pain per se. In 1997 the Food and Drug Administration approved an implantable pulse generator (Interstim, Medtronic, Minneapolis, MN) (see Figure 3) to stimulate sacral nerve roots transforaminally for the syndrome of urge incontinence (a symptom complex that probably includes cases of IC); the transforaminal approach places the electrode contacts at approximately 60 to the neural target (i.e., nerve) (see Figure 4). Interstim generates lowfrequency impulses (10 50 Hz, pulse width of 200 ms), which stimulate pelvic floor muscles. This device has been most effective in patients with associated detrusor instability; it cannot generate the frequencies that are usually necessary for the control of neuropathic pain [133]. Studies of the long-term use of Interstim have shown sustained clinical benefit in patients with urgency frequency syndrome including significant relief of pelvic pain [134,135]. A large multicenter trial of low-frequency sacral nerve stimulation showed decreases in symptoms including pain and increases in voided volumes in patients with IC who had been unresponsive to standard urologic therapies. Urodynamic testing showed that low-frequency S3 nerve stimulation did not adversely affect voiding function or cause nerve damage [136]. Complications of Interstim implantation have included pain at the site of the Nerve Root Sacral Plexus L5 Electrodes S3 Iliac Crest Electric Field Internal Program Generator Nerve Root Electrode Gluteus Maximus 60 Stimulated Portion of Nerve Root Figure 4 Interstim lead angle. Transforaminal lead angle is approximately 60 to the nerve.

11 S176 pulse generator, lead site pain, and lead migration. In one study, surgical revision was required in 32% of patients [137]. Patients with preexisting perineal pain have an increased incidence of device-related pain [138]. Low-frequency neurostimulation has been successful in older (>55 years) patients with urge incontinence, but the response rates were lower than those in younger patients [139,140]. Some of the effects of Interstim may be mediated by stimulation of pudendal afferents arising from S2 [141]. Uncontrolled case series suggest that sacral nerve stimulation can be effective in reducing pain related to long-standing IC and other pelvic disorders, as well as the irritative voiding symptoms [142]. In a prospective study of women with refractory IC having a mean duration of symptoms of more than 5 years, low-frequency S3 stimulation increased voiding volumes, decreased both daytime and nocturnal frequency, and significantly reduced pelvic pain scores [143]. Additional studies found that low-frequency S3 stimulation reduced pelvic pain and improved measured quality of life in patients with long-standing IC [ ]. A recent study of sacral neuromodulation with Interstim found that neuromodulation decreased opioid requirements in patients with severe chronic pain due to refractory IC [148]. Clinical improvement of IC symptoms in response to low-frequency stimulation has generally been greater in patients with a predominance of voiding symptoms (e.g., frequency and dysuria) over constant pelvic pain [149]. A large study showed that low-frequency sacral stimulation relieved chronic pelvic pain in men as well as in women, suggesting that it might be a useful modality for the treatment of chronic prostatitis [150]. In this study, success was related to urodynamic proof of dysfunctional voiding and inversely related to the degree of neuropathic pain. This led the investigators to conclude that the success of low-frequency stimulation was linked to the degree of demonstrated pelvic floor dysfunction [150]. There may be some utility in combining neuromodulation with medical treatments for IC, such as intravesicular instillation of heparin [151]. In patients with urinary symptoms due to detrusor instability, implantation of a low-frequency sacral nerve root stimulator can obviate the need for more invasive surgery. Peripheral Approach to Sacral Nerve Stimulation The sacral roots can be stimulated via the posterior tibial nerve with relief of IC symptoms and Brookoff and Bennett improvement of urodynamic parameters in patients with mild to moderate illness. Impulses with 10 Hz frequency 200 milliseconds wide can be delivered via a surface electrode [152]. An intermittent peripherally placed neuromodulation system (PerQ, SubQ) has been developed, which delivers low-frequency S3 stimulation via the tibial nerve. The temporary leads are placed subcutaneously near the ankle or lower tibia. This device has shown some success in the treatment of urge incontinence when used in 30-minute sessions once per week [153]. High-Frequency Sacral Nerve Stimulation Interstitial cystitis patients with a significant component of neuropathic pain may benefit from sacral nerve stimulation at higher frequencies than those that can be generated by the Interstim device. Using a spinal cord stimulator and bilateral S2 and S3 leads placed via a retrograde lumbar approach, Feler et al. reported significant reduction of pelvic pain in patients with IC who had failed aggressive treatment and were facing cystectomy for intractable bladder pain [154] (see Figure 5). Using this approach, the stimulating electrodes are parallel to the neural targets (see Figure 6). Some of these patients had previously Figure 5 Retrograde sacral stimulation. In this techniques, stimulation electrode arrays are placed in the sacral epidural space, overlying multiple sacral nerve rootlets allowing trans-sacral stimulation.

12 Neuromodulation in Interstitial Cystitis S177 failed low-frequency sacral stimulation and responded stimulation at frequencies in the range of 200 1,025 Hz. This approach not only gave the patient the opportunity to use a broader range of frequencies, but allowed for the use of a stimulator, which did not require an implanted battery and had better contacts with the nerve roots. Placement of leads using the lumbar retrograde approach either percutaneously or via S1/S2 laminectomy has yielded consistent coverage with limited lead migration [ ]. It is not clear whether S3 should be the sole neural target in the treatment of IC. Many pain specialists maintain that S2, S3, and S4 should be covered in these patients. Unlike the transforaminal systems, leads applied using the lumbar retrograde approach easily cover S2 S4. Our experience has been that with high-frequency stimulation or a combination of high and low frequencies, patients experience more complete relief of pain and other symptoms and soon progress to needing their stimulators only intermittently, e.g., several hours per week [158]. This has not been the experience with the transforamenal lowfrequency S3 stimulators, which require constant use and often give diminishing relief over time [159]. The ease with which the retrograde systems can be trialed and implanted and their apparent effectiveness suggest that it is reasonable to consider a trial of neuromodulation earlier on in the treatment of IC and related syndromes in order to avoid the injurious effects of hydrodistension, bladder instillations, and more complex surgeries such as bladder augmentation or cystectomy [3]. In addition to specifically treating the neuropathic component of pelvic pain, high-frequency stimulators are more effective in selectively stimulating the detrusor muscles [160]. Sacral Plexus S2 S3 S4 Nerve Root Stimulated Portion of Nerve Root Electrode Electric Field Figure 6 Retrograde sacral stimulation electrodes. Electrode arrays lie parallel to the neural targets with this technique, allowing maximum electrode to neural target contact. This provides for trans-sacral stimulation, allowing coverage of S2 S4. Urodynamic Guidance in Sacral Nerve Stimulation With the increasing success of neuromodulation in intractable IC, urodynamic testing will find a new role in the trialing and programming of sacral nerve stimulators. Even acute sacral neurostimulation can have a profound and immediate effect on key urodynamic parameters, increasing maximal bladder capacity, bladder volume at first uninhibited contraction, and maximal detrusor pressure during uninhibited contraction [161]. Adding electrodiagnostic monitoring to the assessment of clinical end points has been shown to increase the success rate of sacral nerve stimulation with refractory IC [162]. Eventually, sacral nerve stimulation systems should contain sensors so that the generator can be automatically activated or adjusted with increases in bladder pressure or pelvic floor contractions [163]. Sacral Nerve Stimulation in Other Pelvic Disorders Studies relating certain cases of chronic prostatitis to measurable pelvic floor dysfunction suggest that some of these patients may be treatable with sacral nerve stimulation. In addition to causing painful spasm, pelvic floor hypertonus can exacerbate prostatitis by increasing pressure in the prostatic urethra, causing reflux of urine into the prostatic ducts, and precipitating glandular irritation. In a case-series study of men with intractable pelvic pain that did not respond to muscle relaxants, alpha blockers, or anticholinergics, sacral nerve stimulation successfully corrected the voiding dysfunction and relieved the prostatitis pain [164]. There have also been reports of relief of prostatitis pain using a peripherally placed percutaneous stimulator [165]. The effects of sacral nerve stimulation on the pelvic floor predict that it should be a useful modality in the treatment of chronic urinary retention. Interstim has been studied in patients with neurogenic urinary retention and has been found to reduce residual bladder volume [166]. The syndrome of chronic urinary retention after hysterectomy is associated with deafferentation, and this too can be remedied with sacral nerve stimulation as can urinary retention due to spinal cord injuries [167]. Successful sacral nerve stimulation not only might increase quality of life in patients with spinal cord injuries, but may also reduce the incidence of life-threatening urinary tract infections. There is also evidence to suggest