English articles

The urethral bulking therapy in the treatment of stress urinary incontinence: Complications in females

     The ideal bulking agent should be biocompatible, nonantigenic, noncarcinogenic nondegradable ,nonmigratory and it should require a single injection for a satisfactory treatment .The perfect substance should be safe and provide anatomical integrity, it should also conserve its volume with time, and it should be ready available at low cost.(1)  The use of periurethral injections to restore the continence mechanism by increasing outflow resistence was first described in 1938 by Murless who reported on 20 patients injected with a sclerosing agent ( sodium morrhuate), which resulted in scarring and produced temporary continence.(2) In 1955 Quackels used paraffin wax (3)and in 1963 Sachse used sclerosing agents(4). Despite acceptable results these procedures were abandoned due to significant local problems at the injection site and cardiovascular complications.

     Periurethral bulking was popularised in the 1970s when polytetrafluoroethylene (PTFE) was reintroduced by Berg,(5) and subsequently by Politano(6). Despite good results PTFE did not gain widespread acceptance due to it increased viscosity, which made it difficult to inject. Subjective evaluation of PTFE injection outcomes reported up to 70% of women having an excellent or good response(7). Other series reported lower success rates (around 18%) (8).Polytetrafluoroethylene particles are seized between 4 and 40 μ. Particle seize is regarded as a critical factor for migration. Particles smaller than 80 μ are believed to tend to migrate (9 , 10). Since polytetrafluoroethylene particles are significantly smaller than this critical size, they are phagocytized into the reticuloendotelial system and  migrated locally as well as to distant sites(9)…

     Later reports described granuloma formation and migration from the injection site: in 1983 Mittlemann and Marraccini identified pulmonary polytetrafluoroethylene granulomas at autopsy 4 years after injection for stress urinary incontinence(11). Recently a previously healthy 6-year-old child had an ischemic stroke 1 year after polytetrafluoroethylene injection for correcting vesicoureteral reflux (12). The reason for distant migration may be an embolic phenomenon. Particle migration, in particular, led to the elimination of this substance from clinical use.

     Autologous materials, such as blood and fat, are readily available, inexpensive, and are not associated with tissue reaction. However, blood is readily absorbed, resulting in very short-lived bulking. Various series have evaluated autologous fat as a  bulking agent for ISD, with short-term objective success rates of up 78%(13). However, preparation of the aspirated fat for injection is time-consuming and is associated with fat lysis. In addition, injection can be difficult if the particle size achieved is too large to fit through the injection needle.

     Since cross-linked collagen has become clinically available, the use of autologous fat has been limited to patients who are allergic to bovine collagen. In addition, comparative series demonstrated greater success rates with collagen than fat injections(14). Most recently, a fat embolus resulting in postinjection death was reported, further increasing concerns regarding the use of autologous fat(15).

     In the early1990s GAX-collagen (Contigen ,Bard, Murray Hill.NJ USA) was approved by the Food and Drug Administration for injection in women with GSI(16). This bulking agent consists of a highly purified bovine dermal collagen that is cross-linked with gluteraldehyde and suspended in buffered physiologic saline. This sterile homogenous gel, which is  injected transurethrally or periurethrally, forms a cohesive fibrous network colonized by host connective tissue and vasculature. Perceived advantages of this substance include biologic compatibility, lack of foreign body reaction, no particle migration, and biodegradability. However, a 1-month skin test is required prior to treatment to asses the potential for allergic reactions(17). A following study reported cured or improved rates as high as 90%, with a mean of 6 treatments required to achieve a cure(18) .In a multicenter trial of periurethral GAX-collagen injection in 160 women with ISD, 150 (94%) reported significant improvement, and 125 (78%) were completely dry. Of  those  who reported cure,110 (88%) required 3 treatments or less, and 72  (58%) required only 1 treatment(19). Follow-up studies 1 to 2 years from treatment reported subjective cure or improvement  rates between  58% and 83% and objective  cure rates of up 48%(20 , 21). Another study evaluating long-term (mean, 21 months) outcome reported that 23% of  patients were dry and 52% were improved, while therapy failed in 25%(22). A recent study of GAX-collagen for GSI that used strict subjective and objective criteria reported only 13% cure rate at a mean follow-up of 1 year (23).

     The silicone macroparticles (Macroplastique, Uroplasty BV, Geleen, The Netherlands) has been available  for more than 10 years and is used routinely in clinical care , as it has not been approved by the FDA. Reported data  demonstrate its efficacy in the management of ISD (24) . Recently, however , the longevity of this bulkinf agent, especially in women with  ISD  and urethral hypermobility, has been called into question (25). Henly et al noted particle migration in silicone micro-implants (26) :they injected female dogs with small (median diameter 73 μ ) and large (median diameter 110 μ) silicone particles. In all dogs that received small particles the particles were identified in the lungs, lymph nodes, kidney and brain. In the dogs that received large particles distant migration was detected in 1.Henly et al examined silicone particle size distribution in the large and small particle mixtures, and noted that even in the suspension containing large particles there was a certain amount of small particles. Therefore, although polydimethylsiloxane has a diameter of 188 μ (27) , the presence of smaller particles that are prone to migration cannot be excluded.

      Pyrolitic carbon has long been used for medical applications, including cardiac implants. The use of pyrolitic , carbon –coated  zirconium oxide beads (Durasphere Injectable Bulking Agent, Carbon medical Technologies, Minneapolis, Minn. USA)  was recently  approved  by the FDA for the treatment of ISD, The carbon  beads are suspended in a gel carrier, The bead sizes  (212-500 μm) are too large for macrophage  ingestion, eliminating the possibility of distant particle migration. Due to larger size and irregular shape  of the Durasphere beads , the injection techinique differs from that used for GAX-collagen. Lightner et al reported a large multicenter trial of 355 women with ISD who were randomised to Durasphere versus Contigen injections and were followed for 12 months (28) . Improvement in continence was seen in 80% of Durasphere patients compared with 69% in the Contigen group. The Durasphere group also had a 59% reduction in urine loss compared with 63% in the Contigen group. Significantly less Durasphere than Contigen was injected to achieve these results. Pannek et al in a  pilot  study of 20 consecutive patients including 13 women and 7 men assessed  migration of the carbon beads in 2 patients (29). In a man the beads were present in the submucosal lining of the urethra and in the regional lymph nodes. In a woman beads were noted in the regional as well as in the distant lymph nodes. All radiological imaging was performed 3 months after injection in each case. The carbon coated beads used in the study had a diameter of 251 to 300 μ, thus the particles are considered too large to be phagocytized in any significant number then the exact reason for bead migration is unclear .

      Dextranomer/hyaluronic acid copolymer is a novel substance that has favourable properties for endoscopic treatment of vesicourethral reflux and ISD: it is stable in situ for up to 3 months, forming a framework for fibroblast ingrowth and new collagen formation. It has been reported that dextranomer/Hyaluronic acid copolymer is biodegradable, and has no immunogenic properties or potential for malignant transformation (30). Following injection dextranomer facilities ingrowth of fibroblast and collagen between the microspheres as hyaluronic acid is degraded. The lack of dextranomer migration is attributable to the relatilvely large size of microspheres (80 μm or greater). Because it is not possible for macrophages to transport the dextranomer particles, there should not be any migration. Nevertheless the problems  of this type of implant  seem to be related to a local  tissue reactivity: Bedir et al reported a case of  granuloma formation in the urethral meatus  causing urinary obstruction 5 years after implantation (31). We have observed 2 cases of  abscess formation  around the urethra with  tenderness, pain and obstruction: both the patient were treated by incision and drainage of the abscessed cavity.

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Fig. 1
A 62   years old women, 12  months after implant of transurethral Zuidex : evidence of  big, rubber ,tight bulking that  obstructs the urethra.
Fig. 2
The incision and drainage of the purulent mass .
Fig 3
A  59  years old women, 18  months after implant of transurethral Zuidex : evidence of  a bulking that  obstructs the urethra.
Fig 4
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