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Intravesical Dimethyl Sulfoxide Instillations in the Treatment of Secondary Amyloidosis of the Bladder
--0022-534 7 /90/1434-0808$02.00/0 THE JOURNAL OF UROLOGY Copyright© 1990 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 143, April
Printed in U.S.A.
INTRAVESICAL DIMETHYL SULFOXIDE INSTILLATIONS IN THE TREATMENT OF SECONDARY AMYLOIDOSIS OF THE BLADDER M. J. NURMI, T. 0. EKFORS, P. 0. RAJALA AND P. V. PUNTALA From the Departments of Surgery and Pathology, University of Turku, Turku, Finland
ABSTRACT
A-22-year-old woman with long-standing rheumatoid arthritis and secondary amyloidosis of the bladder had recurrent profuse macroscopic hematuria. She was treated with intravesical dimethyl sulfoxide instillation every 2 weeks for 1 year. She remained asymptomatic during the treatment and at 6 months. Progressive disappearance of amyloid from the superficial mucosa of the bladder was demonstrated in sequential histological examinations. (J. Ural., 143: 808-810, 1990) Secondary amyloidosis of the bladder has been reported rarely as a cause of hematuria, with only 15 cases in the literature. 1-1o Of these cases 5 were from our department. 10 We report on a patient with recurrent bleeding from secondary amyloidosis of the bladder treated successfully with intravesical dimethyl sulfoxide. CASE REPORT
A 22-year-old woman had recurrent profuse macroscopic hematuria and continuous milder bleeding. The patient had long-standing rheumatoid arthritis and secondary amyloidosis was diagnosed previously in subcutaneous tissue. Emergency treatment included cystoscopy, clot evacuation, fulguration and continuous bladder irrigation with 1 % alum solution. Ultrasound examination of the upper urinary tract was normal. After 3 bleeding episodes dimethyl sulfoxide treatment was Accepted for publication November 10, 1989.
begun at 1 instillation every 2 weeks for 1 year. Initially, 50 ml. 1% lidocaine were instilled. After 30 minutes the bladder was emptied and 50 ml. 50% dimethyl sulfoxide solution were instilled and allowed to remain in the bladder for 30 minutes. After the initiation of dimethyl sulfoxide instillations the hematuria ceased and blood hemoglobin concentration remained stable. Histological examinations of biopsies from the bladder stained with congo red .showed abundant amyloid in the mucosa and muscle before initiation of therapy. The amyloid diminished gradually in biopsies repeated every 3 months. After 12 months amyloid disappeared from the superficial mucosa but it was present in the muscular layer (figs. 1 and 2). Six months after the end of treatment the patient was asymptomatic and the histological findings had remained similar. Halitosis was the only adverse effect directly related to the dimethyl sulfoxide treatment. In addition, urine culture twice demonstrated significant bacteriuria (Citrobacter freundi at more than 105 ), while at the start of treatment the urine was
FIG. 1. Pre-treatment specimen of bladder mucosa in 22-year-old woman with massive hematuria due to secondary amyloidosis caused by rheumatoid arthritis. A, abundant collections of hyaline material diffusely and in vascular walls with marked mononuclear inflammatory reaction. H & E, reduced from X270. B, in polarized light clear-cut birefringence is noted. Congo red stain, reduced from X270. 808
809
SECONDARY AMYLOIDOSIS OF BLADDER
FIG. 2. Bladder mucosa after 1 year of dimethyl sulfoxide treatment. No amyloid can be discerned in superficial mucosa. A, H & Estain. B, congo red stain in polarized light. Reduced from X270.
sterile. The serum creatinine concentration remained at the same level before and after treatment. DISCUSSION
Secondary amyloidosis probably is a more common cause of bleeding from the bladder in patients with rheumatoid arthritis than generally is realized. There are no reliable diagnostic findings at cystoscopy. The diagnosis is missed easily even in the histological examination if the pathologist has not been informed of the underlying disease. On routine microscopy without special staining amyloid may be overlooked and the condition misinterpreted as hemorrhagic cystitis because of inflammatory changes resulting from the distension of the bladder and procedures performed before the biopsy. Without vigorous treatment the outcome may be fatal. The actual mortality rate is unknown but 5 of the 15 patients reported in the literature have died. 1 - 10 Another patient recently died of massive bleeding and bladder rupture at our clinic. Isobe and Osserman reported in 1976 that amyloid fibrils are degraded in vitro by dimethyl sulfoxide, which has been used as an industrial solvent since the 19th century. 11 Subsequently, systemic dimethyl sulfoxide therapy of generalized amyloidosis with beneficial effect and without significant side effects has been described. 12- 15 Tokunaka and associates treated primary localized amyloidosis of the bladder successfully with dimethyl sulfoxide instillations 16 according to the procedure of Stewart and Shirley originally suggested for interstitial cystitis. 17 The disappearance of amyloid fibrils could be demonstrated at the ultrastructural level after 12 instillations in 5 months. In our patient hematuria ceased abruptly after dimethyl sulfoxide treatment was begun. The gradual decrease of amyloid could be documented after 6 instillations in 3 months. After 1 year no material positive for congo red could be seen in the superficial bladder mucosa, although the deeper layers still contained such material abundantly. The most probable explanation as to the mechanism of dimethyl sulfoxide action on mucosal amyloid is local dissolution of the fibrils. An alternative interpretation could be that the solvent, being an irritant or excoriating agent, might simply remove the mucosa from the
bladder and during the course of healing and repair, new tissue is formed that does not contain deposits of amyloid. We regard this theory as unlikely because no ulcerative lesions appeared after the instillations. Based on the experience of our patient we conclude that intravesical dimethyl sulfoxide treatment seems to be useful in cases of symptomatic secondary amyloidosis of the bladder. No episodes of hematuria occurred since the initiation of treatment and the disappearance of amyloid could be documented objectively. REFERENCES 1. Ahmad, E., Johansson, S. L. and Fall, M.: Blue spotted bladder-
2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
a manifestation of bladder amyloidosis. Scand. J. Urol. Nephrol., 20: 145, 1986. Bender, L. I. and Kelly, C. E.: Secondary amyloidosis of the bladder: a case report. J. Urol., 102: 60, 1969. Missen, G. A. K. and Tribe, C.R.: Catastrophic haemorrhage from the bladder due to unrecognised secondary amyloidosis. Brit. J. Urol., 42: 43, 1970. Malek, R. S., Greene, L. F. and Farrow, G. M.: Amyloidosis of the urinary bladder. Brit. J. Urol., 43: 189, 1971. Montie, J. E. and Stewart, B. H.: Massive bladder hemorrhage after cystoscopy in a patient with secondary systemic amyloidosis. J. Urol., 109: 49, 1973. Abramovici, I., Chwatt, S. and Nussenson, M.: Massive hematuria and perforation in a case of amyloidosis of the bladder: case report and review of the literature. J. Urol., 118: 964, 1977. Dixon, P. J. V., Matthews, P. N. and Williams, G. B.: Massive haemorrhage following biopsy of amyloidosis of the bladder. Brit. J. Surg., 71: 650, 1984. Tofte, T., Albers, C. and Nielsen, P. W.: Haematuria resulting from secondary amyloidosis in the bladder. Ugeskr. Laeger., 146: 3377, 1984. Vakili, B. F., Lin, H. H. and Danielski, E. F., Jr.: Hemorrhagic shock in amyloidosis of the urinary bladder. N. Y. State Med. J., 86: 272, 1986. Nurmi, M. J., Ekfors, T. 0. and Puntala, P. V.: Secondary amyloidosis of the bladder: a cause of massive hematuria. J. Urol., 138: 44, 1987. Isobe, T. and Osserman, E. F.: Effects of dimethyl sulfoxide (DMSO) on Bence Jones proteins, amyloid fibrils and casein-
810
NURMI AND ASSOCIATES
induced amyloidosis. In: Amyloidosis. Edited by 0. Wegelius and A. Pasternack. New York: Academic Press, pp. 247-257, 1976. 12. Osserman, E. F., Isobe, T. and Farhangi, M.: Effect of dimethyl sulfoxide (DMSO) in the treatment of amyloidosis. In: Amyloidosis. Edited by 0. Wegelius and A. Pasternack. New York: Academic Press, pp. 553-564, 1976. 13. van Rijswijk, M. H., Ruinen, L., Donker, A. J. M., Marrink, J., Ockhuizen, Th., de Blecourt, J. J. and Mandema, E.: Successful treatment with dimethylsulfoxide of human amyloidosis secondary to rheumatoid arthritis. In: Amyloid and Amyloidosis. Edited by G. G. Glenner and P. P. Costa. Amsterdam: Excerpta Medica, pp. 570-577, 1980.
14. Kito, S., Itoga, E., lnokawa, M., Hironaka, M., Kishida, T. and Shinoda, T.: Studies on biological actions of dimethyl sulfoxide in familial amyloidosis. Ann. N. Y. Acad. Sci., 411: 52, 1983. 15. Scheinberg, M. A., Carlos Pernambuco, J. and Benson, M. D.: DMSO and colchicine therapy in amyloid disease. Ann. Rheum. Dis., 43: 421, 1984. 16. Tokunaka, S., Osanai, H., Morikawa, M. and Yachika, S.: Experience with dimethyl sulfoxide treatment for primary localized amyloidosis of the bladder. J. Urol., 135: 580, 1986. 17. Stewart, B. H. and Shirley, S. W.: Further experience with intravesical dimethyl sulfoxide in the treatment of interstitial cystitis. J. Urol., 1 Hi: 36, 1976.
Vol. 143, April
Printed in U.S.A.
INTRAVESICAL DIMETHYL SULFOXIDE INSTILLATIONS IN THE TREATMENT OF SECONDARY AMYLOIDOSIS OF THE BLADDER M. J. NURMI, T. 0. EKFORS, P. 0. RAJALA AND P. V. PUNTALA From the Departments of Surgery and Pathology, University of Turku, Turku, Finland
ABSTRACT
A-22-year-old woman with long-standing rheumatoid arthritis and secondary amyloidosis of the bladder had recurrent profuse macroscopic hematuria. She was treated with intravesical dimethyl sulfoxide instillation every 2 weeks for 1 year. She remained asymptomatic during the treatment and at 6 months. Progressive disappearance of amyloid from the superficial mucosa of the bladder was demonstrated in sequential histological examinations. (J. Ural., 143: 808-810, 1990) Secondary amyloidosis of the bladder has been reported rarely as a cause of hematuria, with only 15 cases in the literature. 1-1o Of these cases 5 were from our department. 10 We report on a patient with recurrent bleeding from secondary amyloidosis of the bladder treated successfully with intravesical dimethyl sulfoxide. CASE REPORT
A 22-year-old woman had recurrent profuse macroscopic hematuria and continuous milder bleeding. The patient had long-standing rheumatoid arthritis and secondary amyloidosis was diagnosed previously in subcutaneous tissue. Emergency treatment included cystoscopy, clot evacuation, fulguration and continuous bladder irrigation with 1 % alum solution. Ultrasound examination of the upper urinary tract was normal. After 3 bleeding episodes dimethyl sulfoxide treatment was Accepted for publication November 10, 1989.
begun at 1 instillation every 2 weeks for 1 year. Initially, 50 ml. 1% lidocaine were instilled. After 30 minutes the bladder was emptied and 50 ml. 50% dimethyl sulfoxide solution were instilled and allowed to remain in the bladder for 30 minutes. After the initiation of dimethyl sulfoxide instillations the hematuria ceased and blood hemoglobin concentration remained stable. Histological examinations of biopsies from the bladder stained with congo red .showed abundant amyloid in the mucosa and muscle before initiation of therapy. The amyloid diminished gradually in biopsies repeated every 3 months. After 12 months amyloid disappeared from the superficial mucosa but it was present in the muscular layer (figs. 1 and 2). Six months after the end of treatment the patient was asymptomatic and the histological findings had remained similar. Halitosis was the only adverse effect directly related to the dimethyl sulfoxide treatment. In addition, urine culture twice demonstrated significant bacteriuria (Citrobacter freundi at more than 105 ), while at the start of treatment the urine was
FIG. 1. Pre-treatment specimen of bladder mucosa in 22-year-old woman with massive hematuria due to secondary amyloidosis caused by rheumatoid arthritis. A, abundant collections of hyaline material diffusely and in vascular walls with marked mononuclear inflammatory reaction. H & E, reduced from X270. B, in polarized light clear-cut birefringence is noted. Congo red stain, reduced from X270. 808
809
SECONDARY AMYLOIDOSIS OF BLADDER
FIG. 2. Bladder mucosa after 1 year of dimethyl sulfoxide treatment. No amyloid can be discerned in superficial mucosa. A, H & Estain. B, congo red stain in polarized light. Reduced from X270.
sterile. The serum creatinine concentration remained at the same level before and after treatment. DISCUSSION
Secondary amyloidosis probably is a more common cause of bleeding from the bladder in patients with rheumatoid arthritis than generally is realized. There are no reliable diagnostic findings at cystoscopy. The diagnosis is missed easily even in the histological examination if the pathologist has not been informed of the underlying disease. On routine microscopy without special staining amyloid may be overlooked and the condition misinterpreted as hemorrhagic cystitis because of inflammatory changes resulting from the distension of the bladder and procedures performed before the biopsy. Without vigorous treatment the outcome may be fatal. The actual mortality rate is unknown but 5 of the 15 patients reported in the literature have died. 1 - 10 Another patient recently died of massive bleeding and bladder rupture at our clinic. Isobe and Osserman reported in 1976 that amyloid fibrils are degraded in vitro by dimethyl sulfoxide, which has been used as an industrial solvent since the 19th century. 11 Subsequently, systemic dimethyl sulfoxide therapy of generalized amyloidosis with beneficial effect and without significant side effects has been described. 12- 15 Tokunaka and associates treated primary localized amyloidosis of the bladder successfully with dimethyl sulfoxide instillations 16 according to the procedure of Stewart and Shirley originally suggested for interstitial cystitis. 17 The disappearance of amyloid fibrils could be demonstrated at the ultrastructural level after 12 instillations in 5 months. In our patient hematuria ceased abruptly after dimethyl sulfoxide treatment was begun. The gradual decrease of amyloid could be documented after 6 instillations in 3 months. After 1 year no material positive for congo red could be seen in the superficial bladder mucosa, although the deeper layers still contained such material abundantly. The most probable explanation as to the mechanism of dimethyl sulfoxide action on mucosal amyloid is local dissolution of the fibrils. An alternative interpretation could be that the solvent, being an irritant or excoriating agent, might simply remove the mucosa from the
bladder and during the course of healing and repair, new tissue is formed that does not contain deposits of amyloid. We regard this theory as unlikely because no ulcerative lesions appeared after the instillations. Based on the experience of our patient we conclude that intravesical dimethyl sulfoxide treatment seems to be useful in cases of symptomatic secondary amyloidosis of the bladder. No episodes of hematuria occurred since the initiation of treatment and the disappearance of amyloid could be documented objectively. REFERENCES 1. Ahmad, E., Johansson, S. L. and Fall, M.: Blue spotted bladder-
2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
a manifestation of bladder amyloidosis. Scand. J. Urol. Nephrol., 20: 145, 1986. Bender, L. I. and Kelly, C. E.: Secondary amyloidosis of the bladder: a case report. J. Urol., 102: 60, 1969. Missen, G. A. K. and Tribe, C.R.: Catastrophic haemorrhage from the bladder due to unrecognised secondary amyloidosis. Brit. J. Urol., 42: 43, 1970. Malek, R. S., Greene, L. F. and Farrow, G. M.: Amyloidosis of the urinary bladder. Brit. J. Urol., 43: 189, 1971. Montie, J. E. and Stewart, B. H.: Massive bladder hemorrhage after cystoscopy in a patient with secondary systemic amyloidosis. J. Urol., 109: 49, 1973. Abramovici, I., Chwatt, S. and Nussenson, M.: Massive hematuria and perforation in a case of amyloidosis of the bladder: case report and review of the literature. J. Urol., 118: 964, 1977. Dixon, P. J. V., Matthews, P. N. and Williams, G. B.: Massive haemorrhage following biopsy of amyloidosis of the bladder. Brit. J. Surg., 71: 650, 1984. Tofte, T., Albers, C. and Nielsen, P. W.: Haematuria resulting from secondary amyloidosis in the bladder. Ugeskr. Laeger., 146: 3377, 1984. Vakili, B. F., Lin, H. H. and Danielski, E. F., Jr.: Hemorrhagic shock in amyloidosis of the urinary bladder. N. Y. State Med. J., 86: 272, 1986. Nurmi, M. J., Ekfors, T. 0. and Puntala, P. V.: Secondary amyloidosis of the bladder: a cause of massive hematuria. J. Urol., 138: 44, 1987. Isobe, T. and Osserman, E. F.: Effects of dimethyl sulfoxide (DMSO) on Bence Jones proteins, amyloid fibrils and casein-
810
NURMI AND ASSOCIATES
induced amyloidosis. In: Amyloidosis. Edited by 0. Wegelius and A. Pasternack. New York: Academic Press, pp. 247-257, 1976. 12. Osserman, E. F., Isobe, T. and Farhangi, M.: Effect of dimethyl sulfoxide (DMSO) in the treatment of amyloidosis. In: Amyloidosis. Edited by 0. Wegelius and A. Pasternack. New York: Academic Press, pp. 553-564, 1976. 13. van Rijswijk, M. H., Ruinen, L., Donker, A. J. M., Marrink, J., Ockhuizen, Th., de Blecourt, J. J. and Mandema, E.: Successful treatment with dimethylsulfoxide of human amyloidosis secondary to rheumatoid arthritis. In: Amyloid and Amyloidosis. Edited by G. G. Glenner and P. P. Costa. Amsterdam: Excerpta Medica, pp. 570-577, 1980.
14. Kito, S., Itoga, E., lnokawa, M., Hironaka, M., Kishida, T. and Shinoda, T.: Studies on biological actions of dimethyl sulfoxide in familial amyloidosis. Ann. N. Y. Acad. Sci., 411: 52, 1983. 15. Scheinberg, M. A., Carlos Pernambuco, J. and Benson, M. D.: DMSO and colchicine therapy in amyloid disease. Ann. Rheum. Dis., 43: 421, 1984. 16. Tokunaka, S., Osanai, H., Morikawa, M. and Yachika, S.: Experience with dimethyl sulfoxide treatment for primary localized amyloidosis of the bladder. J. Urol., 135: 580, 1986. 17. Stewart, B. H. and Shirley, S. W.: Further experience with intravesical dimethyl sulfoxide in the treatment of interstitial cystitis. J. Urol., 1 Hi: 36, 1976.