Sheridan W. Shirley, MD, Bruce H. Stewart, MD, and Simon Mirelman, MD
Departments of Urology Cleveland Clinic Foundation Cleveland, Ohio and University of Alabama Birmingham, Alabama
Intravesical dimethyl sulfoxide (DMSO) has been used in the treatment of 213 patients with various inflammatory conditions involving the lower genitourinary tract, including intractable interstitial cystitis, radiation cystitis, chronic prostatitis, and chronic female trigonitis. Significant symptomatic relief has been achieved in the majority of patients so treated, and no systemic or local toxicity has been noted. Some patients failed to respond entirely, and others relapsed after DMSO treatment periods of several months, ultimately coming to augmentation cystoplasty or urinary diversion. However, because of its simplicity and ease of administration, intravesical DMSO therapy is recommended in all noninfectious or non-neoplastic inflammatory conditions presenting initially with severe symptoms, or that have failed to respond to conventional therapy.
Dimethyl sulfoxide (DMSO) was first synthesized in 1867, has been available as a byproduct of the paper pulp industry for many years, and is now used chiefly as an industrial solvent. In 1964 Jacob, Bischel, and Herschler1 first described the remarkable medicinal properties of DMSO. When applied to intact human skin, the drug penetrates rapidly and produces a wide range of pharmacologic actions, including antiinflammation, local analgesia, bacteriostasis, diuresis, cholinesterase inhibition, enhancement of the action of concomitantly adininistered drugs, influence on collagen, nonspeciflc enhancement of immunity, vasodilation, and lessening of adhesiveness of blood platelets.2 As a result the drug has been used widely as treatment for various conditions, including arthritis, bursitis, acute musculoskeletal trauma, scleroderma, troublesome urogenital disorders, and various postoperative pain syndromes. To date little, if any, local or systemic toxicity has been noted in the human after the administration of DMSO.3
Experience with the intravesical installation of dimethyl sulfoxide in patients with classic interstitial cystitis has recently been reported, with effective symptomatic relief achieved in about two thirds of the patients so treated.4-6 This therapeutic regimen was believed to be attractive because of its low cost, simplicity, safety, and availability as an office procedure. Because of the encouraging experience with DMSO in patients with interstitial cystitis, other patients with a variety of intractable bladder irritative conditions were treated in a similar fashion. This report will summarize the preliminary findings in 213 patients with various conditions, including intractable interstitial cystitis, radiation cystitis, chronic prostatitis, and atypical cystitis in the females
Patients with various intractable irritable bladder conditions were considered candidates for DMSO therapy. All patients were first investigated by careful history, complete physical examination, routine urine analysis with culture and cytology studies, intravenous urography and renal function studies, routine hemogram, and SMA-12 profiles. Cystoscopic examination, usually under anesthesia, was performed in all cases; and when indicated, a cystometrogram was also performed. A bIadder biopsy was done in most cases.
After the diagnosis had been established, treatment was begun as an office procedure, instilling 50 cc. of a 50 percent solution of DMSO into the bladder under local urethral lubricant analgesia. A small catheter was used to administer the drug in most cases, although particularly sensitive patients were treated by direct instillation with an Asepto syringe. An occasional patient was distended to capacity with 20 percent DMSO, followed by the routine instillation of 50 cc. of a 50 percent solution. Rare cases not responding to the 50 percent solution were given the medication in a concentration of 70 percent. The medication was instilled slowly to avoid spasm, and belladonna and opiate suppositories were inserted just prior to treatment in particularly sensitive patients. Treatments were repeated as often as necessary to control symptoms, ranging from weekly intervals in patients with severe symptoms up to periods of three to six months in patients with symptomatic relief. The treatment protocol varied somewhat in male patients with chronic prostatitis. Here, a Robinson catheter of 14-16 F was passed gently to the level of the membranous urethra, and the medication was slowly instilled directly into the prostatic urethra and then into the bladder. In some cases the panendoscope was passed under direct vision to the level of the membranous urethra, and the medication instilled through the panendoscope directly into the prostatic fossa. In occasional patients with severe symptoms, this appeared to afford the greatest relief, although admittedly part of the good results could have been psychologic in nature. In rare patients with extremely sensitive bladders, the first treatments were given under general anesthesia.
Chronic interstitial cystitis
In females: One hundred women with classic chronic interstitial cystitis, refractory to conventional methods of therapy, were treated by intravesical DMSO. Ages ranged from twenty-three to eighty-one years. All had had progressively severe symptoms or suprapubic pain, frequency, and nocturia despite intermittent hydrodistention under anesthesia, intravesical electrodesiccation or chemofulguration, instillation with various medications, or various types of antispasmotic and analgesic medication. All patients underwent baseline cystoscopy, with biopsy to rule out carcinoma, and also had pretreatment bladder capacity determinations, urine culture, and cytology studies, as well as routine hematologic and ophthalmologic testing.
(Similar baseline studies were performed in the majority of patients with other inflammatory conditions described below.)
Length of treatment varied from one to eleven years in 79 patients, with the majority receiving ten to twenty treatments over times averaging one to three years. The remaining 21 patients have been under treatment for less than one year and are therefore not included in the statistical review of this series.
Gradation of treatment response included:
In males. Fourteen men, ranging in ages from twenty-eight to seventy-one, were given intermittent intravesical DMSO for the treatment of chronic interstitial cystitis. All had severely progressive bladder pain, frequency and nocturia, and had failed to respond to analgesic, antibacterial, and antispasmodic medication. Many of these patients had not been diagnosed as interstitial cystitis in the past, but instead had been treated for "prostatitis," and 13 of the 14 had undergone previous transurethral prostatectomy without relief of symptoms. All patients underwent baseline cystoscopy with multiple bladder biopsies, measurement of bladder capacity, and urine culture and cytology determinations to rule out underlying carcinoma. Treatment with intravesical DMSO was carried out from twelve to forty-five times over a fifteen to thirty-one month period of time in this group.
Several additional patients had been referred to treatment of interstitial cystitis, but were actually found to have carcinoma of the bladder and therefore underwent appropriate operative therapy and are not included in this report.
Twelve patients with radiation cystitis were treated with intravesical DMSO. Most or these patients had previously undergone pelvic irradiaition for treatment of carcinoma of the uterus or cervix, with a few patients receiving therapy for carcinoma of the bladder. None had any evidence of residual bladder carcinoma at the time of DMSO therapy. In all patients severe irritative bladder symptoms had developed several months to several years after radiation therapy, and all had failed to respond to conservative management. Six to 20 treatments have been administered over an eight to thirty-six-month period.
Thirty-five patients with atypical chronic prostatitis have been treated with intermittent intravesical DMSO. Ages of these patients ranged from thirty-eight to seventy years, with most in their fifties and early sixties. All had suffered chronic perineal discomfort, usually increased following coitus, and in many variable bladder irritative symptoms had also developed. All had undergone transurethral prostatectomy without relief of symptoms. Two patients had undergone open prostatectomy in lieu of a transurethral procedure. Evidence of chronic prostatitis was found in the resected specimen in all cases. Findings on repeat urine culture and cytology studies were negative in all cases. Six to nineteen transurethral instillations of DMSO were given over a five to thirty-five month period in this group. Only 3 patients have been under DMSO tliertpy for less than one year.
Atypical chronic cystitis--female
Thirty-one women with intractable bladder irritative symptoms, most of whom have been previously diagnosed as chronic trigonitis or urethral syndrome, were treated with intermittent intravesical DMSO. Mild nonspecific inflammatory changes had been noted endoscopically in the region of the trigone and upper urethra in most of these patients, and neurogenic disease had been ruled out in all. Five to sixteen instillations have been administered to patients in this group over a twelve to thirty-two month period. Fifteen patients have been under DMSO therapy for less than one year and will not be included in the statistical analysis of this series.
Chronic intertitial cystitis--female: symptomatic response to intravesical DMSOa
Chronic interstitial cystitis
In females. On the basis of the previously described criteria, 54 percent of the total group received good to excellent clinical results and remain on long-term therapy. Another 9 patients (11 percent) had an initially good to excellent response for periods ranging from one to three years but then relapsed to their pretreatment levels. Seven of these ultimately underwent surgical correction (ileocystoplasty in 3 cases, colocystoplasty in 2 cases, biodegradable augmentation cystoplasty in 1 case, and ileal conduit diversion in one; good to excellent results have been obtained in all of these operated cases. Two additional cases are back on intermmittent hydrodistention and chemofulguration, with fair to good results). The remaining 35 per cent of patients had fair to poor results, and many were sufficiently symptomatic to warrant operative treatment.7 Objective endoscopic improvement in the disease was noted in about 85 percent of patients treated. Improvement in bladder capacity of 100 to over 300 cc. was noted in about 60 percent of cases (Tables 1 and 2).
In males. Nine of the fourteen, or about 64 percent of the patients, had good (6 cases) to excellent (3 cases) symptomatic relief and continue on therapy. Another 30 percent experienced transient relief of symptoms but subsequently relapsed and ultimately underwent augmentation cystoplasty (3 cases) or total prostatectomy (1 case) twenty-eight to thirty-nine months after onset of therapy. The one remaining patient is under fair symptomatic control but is not yet considered to be a candidate for surgical intervention.
Improvement in bladder capacity in 60 patients undergoing intermittent intravesical DMSO
Twelve patients with radiation cystitis after treatment for various neoplastic conditions were treated with intermittent intravesical DMSO. Symptomatic response has been excellent in 3 patients, good in 2, and fair in 1, for an over-all satisfactory, clinical response rate of 50 percent. Six patients continue to have severe symptoms despite DMSO therapy, with three undergoing ileal conduit diversion and three augmentation cystoplasty five to twenty-seven months after the onset of DMSO therapy. Objective endoscopic improvement in the disease was noted in 6 of the 12 patients, with an increase in bladder capacity of more than 200 cc. in all 6 of these cases.
Twenty-six of the 35 cases (75 percent) experienced good (14 cases) to excellent (12 cases) symptomatic relief from the treatment. The remaining 25 percent continue to have significant svmptoms, although not of such severity to warrant supravesical diversion or other forms of operative therapy. Objective endoscopic improvement in the inflamed prostatic urethra was noted in nearly 90 per cent of cases so treated, but bladder capacity, which was normal in most cases before therapy, increased over 100 cc. in only 3 cases. It should be noted that the cystoscopic findings in this group of patients indicated a relatively normal bladder, with the inflammatory response localized to the mucosa of the prostatic and membranous urethra. It should also be noted that optimal results in this group of patients recurred when the catheter was passed down only to the level of the membranous urethra, and the DMSO was instilled directly into the prostatic fossa and then on into the bladder. In cases in which the membranous urethra was difflcult to localize, a Foley catheter was inserted into the bladder, brought down to the bladder neck with the balloon inflated, and then after deflating the balloon advanced another 2 cm. into the prostatic urethra where the medication was instilled.
Atypical chronic cystitis -- female
Twenty-three of the 31 patients (74 percent) have had good (10 cases) to excellent (13 cases) symptomatic relief and remain on therapy. In the remaining patients results were fair in 4 and poor in 4. Cystoscopic improvement was noted in over 90 per cent of patients under treatment, although the bladder capacity prior to therapy was normal in most cases and improved more than 100 cc. in only about 20 percent of the cases. Two patients had large-capacity bladders prior to therapy and were also maintained on intermittent self-catheterization programs. Many of these patients have been thought to have coexistent psychoneuroses, and about one third of the patients remained symptomatic despite all attempts at conservative management. To date, none of the patients has been considered to be a candidate for operative therapy. Most of the failures had increased residual urines and/or chronic bacteria] infection.
In addition, 3 male patients with atypical inflammatory conditions of the bladder have been treated, with one excellent, one good, and one fair result. Two of these patients had undergone transurethral prostatectomy prior to DMSO therapy. Finally, 3 children, all female, with chronic inflammatory changes in the trigone and proximal urethra have been treated with intermittent intravesical DMSO, given under general anesthesia in many cases, all with good results to date. Neoplasm, obstruction, and neurogenic disease had been ruled out in all 3 of these children.
Certain irritative genitourinary conditions may fail to respond to conventional methods of treatment, and thereby result in chronic frustration both to the patient and to the attending urologist. In fact, many forms of "conventional therapy" such as hydrodistention and fulguration may actually result in more fibrosis and aggravate rather than improve these conditions, especially when given over long periods of time. The use of intravesical DMSO in these situations represents a new therapeutic approach that can improve the symptoms and obviate the need for radical surgery in many cases.
Patients with a clear-cut diagnosis of chronic interstitial cystitis or radiation cystitis appear to respond favorably and predictably to intravesical DMSO. Long-term satisfactory symptomatic relief has occurred in over half of these patients, with endoscopic improvement in the appearance of the disease and concomitant increase in bladder capacity. In general. patients with extremely small fibrotic and ulcerated bladders respond less well to DMSO, and some of these patients will require augmentation cystoplasty or supravesical diversion.7 An additional 20 percent of patients undergoing DMSO therapy for chronic interstitial cystitis have subsequently relapsed after an initial period of improvement lasting from one to three years, and have ultimately come to augmentation cystoplasty or diversion.
A small group of male patients, thought initially to be suffering from chronic prostatitis, have been subsequently found by endoscopic examination to have what is probably an atypical form of chronic interstitial cystitis. Results of urine culture and cytology studies have been negative in all of these patients, and biopsies have rated out the possibility of carcinoma in situ. Long-term symptomatic relief has been achieved by intravesical DMSO therapy in about two thirds of these patients. A few have had an initially favorable response, only to relapse and ultimately come to augmentation cystoplasty.
Again as emphasized by Utz and Zincke,8 we know that many male patients with similar intractable irritative bladder symptoms, actually suffer from diffuse carcinoma in situ. Careful endoscopic examination with random biopsy of the bladder and multiple urinary cytology studies should be done in all such cases before advising a course of intravesical DMSO. In addition, appropriate cultures to rule out genitourinary tuberculosis should be done.
Another interesting group of male patients with chronic refractory "prostatitis" has been treated with transurethral instillation of DMSO. All of these patients had suffered chronic perineal discomfort, variable decrease in stream, and bladder irritative symptoms, and all had undergone transurethral prostatectomy with evidence of chronic prostatitis found in the resected operative specimens. The age group is considerably younger than patients with the usual signs and symptoms of obstructing prostatism, with many of the patients in their forties and early fifties, and some in their early sixties. Urine culture and cytology studies were negative in all of these patients, and symptoms persisted despite prostatectomy and the usual long-term antibacterial and antispasmotic medications. Good to excellent symptomatic relief has been achieved for one to two years in 75 percent of these patients treated with DMSO, with objective improvement in the inflammatory changes in the prostatic and membranous urithra noted on endoscopic examination. One might speculate on the advisability of beginning intraurethral instillations of DMSO in patients of this type before considering transurethral prostatectomy, particularly if endoscopic findings fail to show significant bladder outlet obstruction, and if needle biopsy studies indicate chronic prostatitis. Perhaps the early use of intravesical DMSO will obviate the need for transurethral surgery in these individuals.
The female patient with a diagnosis of intractable trigonitis or urethral syndrome can represent a particularly difficult management problem. Many of these patients are thought to have coexisting psychiatric disability. Treatment with intermittent intravesical DMSO in a group of these patients has resulted in significant symptomatic relief in about three fourths of the cases, with treatment periods ranging from eight to twenty-two months. A trial of DMSO certainly appears to be indicated in refractory patients of this type, who have not responded to conventional therapy and in whom specific infections, urethral diverticula, or bladder neoplasia have been ruled out.
To date, no systemic or local toxicity has been noted during or following intravesical DMSO therapy, and patients with favorable therapeutic responses have remained on treatment for periods of several years without difficulty. Continued use of this therapeutic regimen in patients with intractable inflammatory conditions of the lower urinary tract, either as primary treatment or in patients who have not responded to "conventional therapy," would appear justified. Hopefully, this drug will soon be made available for general clinical usage.
Intravesical DMSO therapy has been used in 213 patients with troublesome genitourinary disorders, including classic interstitial cystitis in the female (100 cases), interstitial cystitis in the male (14 cases), radiation cystitis (12 cases), chronic prostatitis (35 cases), refractory chronic female trigonitis (46 cases), and other (6 cases). Significant symptomatic relief has been achieved in the majority of patients so treated. Some patients failed to respond entirely, and others relapsed after DMSO treatment periods of several months, ultimately coming to augmentation cystoplasty or supravesical diversion.
No systemic or local toxicity has been noted. Because of its simplicity and ease of administration, intravesical DMSO therapy is recommended in all such patients who have failed to respond to conventional forms of therapy, or who present initially with severe symptoms secondary to these chronic inflammatory conditions.
Source: Urology, March 1978, Volume XI, Number 3, pp. 215-220
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