Diagnosis and treatment of perianal fistulas in Crohn disease.

Perianal fistulas are a frequent manifestation of Crohn disease and can result in substantial morbidity, including scarring, continual seepage, and fecal incontinence. We review the epidemiology, pathogenesis, diagnosis, classification, and medical and surgical treatment options for fistulizing Crohn disease. We searched the MEDLINE database for articles on the medical and surgical treatment of Crohn disease and perianal Crohn disease. The bibliographies of relevant studies were also reviewed. Epidemiology The frequency of perianal fistulas in patients with Crohn disease in referral populations varies from 17% to 43% (110). Two population-based studies have estimated the cumulative incidence of perianal fistulas in patients with Crohn disease. Hellers and colleagues (11) reported that the cumulative incidence of perianal fistulas in Stockholm County, Sweden, between 1955 and 1974 was 23%. Similarly, Schwartz and associates (12) showed recently that the cumulative incidence of fistulizing Crohn disease in Olmsted County, Minnesota, between 1970 and 1993 was 38%. The location of Crohn disease in the bowel affects the frequency of perianal fistulas. Patients with disease confined to the colon have a higher incidence of perianal fistulas (3, 11), and the rate of perianal fistulas approaches 100% in patients with Crohn disease involving the rectum (11). Up to 5% of patients with Crohn disease will present initially with perianal fistulas in the absence of other evidence suggestive of Crohn disease (13). Perianal Anatomy An understanding of perianal anatomy is required to correctly classify fistulas before choosing an appropriate surgical therapy. The anal canal comprises two muscular cylinders (Figure 1). The inner cylinder, called the internal anal sphincter, is a 3-cm long thickened continuation of the circular smooth muscle of the rectum (14). The outer cylinder, called the external anal sphincter, is a 4-cm long downward extension of the skeletal muscle of the puborectalis. The skeletal muscle above the puborectalis fans out to form the levator ani muscles that divide the perineum from the abdominal cavity. The intersphincteric plane lies between these two cylinders. Figure 1. Anatomic relationships in the perianal region. Modified with permission from: Fry RD, Kodner IJ. Anorectal disorders. Clin Symp. 1985; 37:2-32. Modified figure copyright 2000, Mayo Clinic. The dentate or pectinate line separates the transitional and columnar epithelium of the rectum from the squamous epithelium of the anus. The dentate line is located in the middle portion of the internal anal sphincter. Anal crypts are present at the dentate line. Anal glands exist at the base of many of these crypts and occasionally penetrate into the intersphincteric space. Fistula-in-ano occurs when these glands become infected (15). Theories of Pathogenesis The specific pathogenesis of perianal fistulas is unknown. There are two candidate theories. The first suggests that fistulas begin as deep penetrating ulcers in the anus or rectum (16). Over time, feces collect in these ulcers, and the pressure of defecation forces the fecal matter into the subcutaneous tissue, extending the ulcer and creating a fistula. The second suggests that fistulas result from an anal gland abscess that serves as the point of origin for a fistula tract (15). From the intersphincteric space, a fistula can penetrate through the external anal sphincter and track downward to the skin or upward in the intersphincteric space, leading to the different types of perianal fistulas commonly seen. Fistula Classification Classification schemes describing perianal fistulizing disease are useful in determining what surgical procedure (if any) should be performed. Several classification systems have been proposed (1618). The most anatomically precise (and therefore most clinically useful) fistula classification system is that devised by Parks and colleagues, which uses the external anal sphincter as a central point of reference (Figure 2) (19). Figure 2. The classification system of Parks and colleagues. A. A superficial fistula tracks below both the internal anal sphincter and external anal sphincter complexes. B. An intersphincteric fistula tracks between the internal anal sphincter and the external anal sphincter in the intersphincteric space. C. A transsphincteric fistula tracks from the intersphincteric space through the external anal sphincter. D. A suprasphincteric fistula leaves the intersphincteric space over the top of the puborectalis and penetrates the levator muscle before tracking down to the skin. E. An extrasphincteric fistula tracks outside of the external anal sphincter and penetrates the levator muscle into the rectum. Modified with permission from reference 19. Modified figure copyright 2000, Mayo Clinic. Measurement of Fistula Disease Activity Measurement instruments that quantify the disease activity of fistulas are useful in clinical trials to assess whether a patient has responded to treatment. The standard index for measuring the overall activity of Crohn disease, the Crohn disease activity index, was not designed to be sensitive to the type of morbidity experienced by patients with perianal fistulas (20). Instead, investigators have used other techniques to measure perianal disease activity in patients with Crohn disease (21, 22). The Perianal Disease Activity Index provides the most comprehensive measure of the morbidity caused by perianal Crohn disease. It evaluates five categories affected by fistulas: discharge, pain, restriction of sexual activity, type of perianal disease, and degree of induration (Table 1) (23). This index has yet to be fully validated. Table 1. Perianal Crohn Disease Activity Index Diagnostic Methods Digital rectal examination and insertion of probes into fistula tracts in the operating room under general anesthesia (a combination called examination under anesthesia) is currently the gold standard for assessment of perianal fistulas. However, if used as the diagnostic test, examination under anesthesia has limitations. Spencer and associates (24) reported on the course of 37 patients with Crohn disease and perianal fistulas for a minimum of 14 months after baseline evaluation with both magnetic resonance imaging (MRI) and examination under anesthesia. In that study, MRI predicted patient outcomes better than examination under anesthesia. Nonsurgical methods of assessing perianal fistulas include fistulography, computed tomography, MRI, and endoscopic ultrasonography. The accuracy of fistulography in determining the tract of the fistula ranges from 16% to 50% (2529). Likewise, computed tomography has proved to be relatively unreliable in assessing perianal disease; its accuracy ranges from 24% to 60% (3036). The diagnostic accuracy of MRI appears to be somewhat better, ranging from 76% to 100% (3739). Similar results have been obtained with endoanal ultrasonography (30, 4042). In clinical practice, it may be useful to perform more than one diagnostic test, and the methods chosen should take into account expertise at the local institution. Patients in whom complicated perianal disease is suspected should undergo examination under anesthesia and some type of imaging study to help guide therapy. Medical Treatment Options for medical treatment that have proven or probable efficacy for fistulizing Crohn are shown in Table 2. Table 2. Medical Therapies for Perianal Fistulas in Crohn Disease Antibiotics In 1975, Ursing and Kamme (43) reported that metronidazole closed perianal fistulas in three patients. Subsequently, Bernstein and colleagues (44) conducted an open study of metronidazole (20 mg/kg of body weight daily) in 21 consecutive patients with perianal fistulas and Crohn disease. The fistulas closed in 83% of patients. Four additional open studies support the observation that metronidazole treatment may result in complete closure of fistulas in 34% to 50% of patients (4548). Clinical improvement is usually seen after 6 to 8 weeks of therapy; however, fistulas frequently reoccur after metronidazole treatment is discontinued (46, 48). No controlled trials of metronidazole in patients with fistulizing Crohn disease have been performed. Adverse events associated with metronidazole include metallic taste, glossitis, nausea, and distal peripheral sensory neuropathy. Because of the high incidence of adverse events associated with metronidazole, clinicians began to use ciprofloxacin to empirically treat Crohn disease in the early 1990s (49). Although ciprofloxacin is now widely used, its efficacy has been studied only anecdotally. Turunen and colleagues (50) treated eight patients with active perianal disease and one patient with an enterocutaneous fistula with ciprofloxacin, 1000 to 1500 mg/d, for 3 to 12 months (50). Although the investigators reported improvement in all patients after treatment, four patients had persistent perianal discharge and surgical excision was required in several cases. As with metronidazole, fistulas frequently recur once ciprofloxacin therapy is discontinued. No controlled trials of ciprofloxacin in fistulizing Crohn disease have been performed. Adverse events associated with ciprofloxacin are uncommon but can include headache, nausea, diarrhea, and rash. Azathioprine and 6-Mercaptopurine 6-Mercaptopurine and its prodrug azathioprine are used frequently to treat perianal fistulas in patients with Crohn disease. A meta-analysis of five controlled trials of azathioprine and 6-mercaptopurine for Crohn disease in which fistula closure was described in detail (21, 5154) reported that 22 of 41 (54%) patients treated with azathioprine or 6-mercaptopurine responded versus 6 of 29 (21%) patients treated with placebo; the pooled odds ratio favoring fistula healing was 4.44 (55). These results should be interpreted with caution because the primary goal of the studies was to treat symptoms of active inflammatory Crohn disease rat