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Introduction
The classical treatment of urge incontinence
is to use anticholinergic drugs against the so-called bladder instability.
But sometimes this approach is insufficient and there is a need to other
solutions.
Our
partner's information
Some different
approaches
1.
Interest of retro-anal levator plate myorrhaphy in selected cases of
descending perineum syndrome with positive anti-sagging test
NEW
2. Pudendal nerve
decompression in the treatment of overactive bladder syndrome
NEW
3. The use of botox in bladder instability and high pressure urethral
sphincter
4.
"Prepubien" section: a new surgical treatment of frequency, nocturia and urge incontinence?
5. Electrical treatment of urinary dysfunction
6. Urge incontinence is maybe
the first step of an interstitial cystitis
The Perineology webring
1. www.perineology.com
: is the main website giving the definition of this new approach of the female
perineum called Perineology.
2.
www.ultrasonography.org : practical
approach of ultrasound in Perineology. 3.
www.vaginaltape.com : treatment
of stress urinary incontinence with a small mesh. 4.
www.pudendal.com : a
website dedicated to the management of pudendal neuropathy. 5.
www.monaccouchement.com :
everything about childbirth for the future mothers (in French).
6. www.perineology.TV
: the videos of our webring are available on streaming (RealPlayer) on behealth.TV
the Belgium Medical web TV.
INTERSTITIAL
CYSTITIS: AN IRREVERSIBLE PROBLEM?
Gero Hohlbrugger and Claus R. Riedl
Introduction
The clinical picture of interstitial cystitis (IC) combines sterile urine with chronic cystitis symptoms and inflammatory changes preferably in the mucosa and submucosa of the bladder. The term "interstitial cystitis" is an unhappy choice and can be traced to a morphological-descriptive naming based on the presence of increased numbers of inflammatory cells (mast cells) in the bladder wall.
The initial stages of this disease are often characterized by recurrent urinary tract infection, moderate urethral and pelvic pain, dyspareunia, irritable bladder complaints or urge incontinence. As a rule, patients are treated with anticholinergics, tricyclic anti-depressants, estrogens, possibly with pelvic floor training, electrotherapy or psychotherapy, and in view of the symptoms of urinary tract infection, unfortunately also with antibiotics, even when no pathogens are identified. IC remains mostly uninfluenced by these therapies, and takes its chronically progressive course over years which might even culminate in cystectomy. Because of rigid diagnostic criteria employed which preferably identify the irreversible end-stage IC (Hunner´s ulcers, contracted bladder) (1), characterized by constant and intractable pain, IC is then diagnosed when it is often too late to initiate any meaningful therapy.
It is not only women who are affected by IC. Recent investigations have shown that symptoms typical for IC and endoscopic IC criteria (mucosal hemorrhage after hydrodistension) can be found in up to 80% of male patients in whom a diagnosis of "chronic, abacterial prostatitis" was made on the basis of a painful palpation of the prostate (2). The increasing incidence of this disease has lead the NIH to classify IC as a health problem with highest priority.
We are convinced that the full-blown clinical picture of IC can be avoided by employing at the proper time therapy oriented to the etiology of the disease. We are furthermore convinced that focusing on this disease will represent to all, in particular to office urologists, an important, interesting and satisfying area of activity in the future. The preconditions for this, however, is a proper understanding of the pathogenesis, diagnosis and therapy of IC.
Pathogenesis
Several factors such as exposure to cold (3), psychological stress (4), excessive coffee intake, radiation (5), medication (above all cytostatic drugs) (6,7), inflammatory or autoimmune neurological diseases such as multiple sclerosis (9,10) can lead to urothelial secretion of substances which have not been clearly identified so far. These substances in turn activate stress proteins present in urine (11), which are directed against the urothelium and which impair the most important active urothelial function namely, the production of a protective mucous layer. This mucous comprises predominately of heparin, chondroitin- as well as dermatan sulfate (glycosaminoglycan = GAG-layer) and hyaluronic acid. So-called "core proteins" are responsible for the attachment of the GAG layer to the urothelium (12). It is a lack of this mucous layer that facilitates occurrence of urinary tract infections (13). Thus, recurrent urinary tract infections often mark the beginning of IC.
Afferent C-fiber nerve endings of the bladder located between and below the urothelial cells react not only to filling (mechanoception), but also to low pH, high potassium (K+) levels and hyperosmolarity (chemoception) (14). Only pain (from trauma or inflammation) is transmitted by the C fibers to the cortex (15). Otherwise, firing of the C-fibers will be switched in the sacral "continence" center to parasympathetic (cholinergic) activation of the detrusor (Fig. 1) (16,17). Urinary urge is transmitted to the cortex only above a particular threshold value of detrusor activation and exclusively by the intramurally distributed A-delta fibers (18). In the course of sympathetic (adrenergic) urge control, it is not only the activity of the detrusor which is inhibited and that of the blader neck strengthened. There is additional release of NO from the urothelial cells (19) as well as tachykinins (substance P) from the plasma cells in the tissue and from the C-fiber endings (20,21). This results in enhanced permeability of the urothelium and the suburothelial blood vessels (15,22). Concomitantly, vesical blood flow is increased relative to filling and concentrated urine (23,24) and consequently, urinary K+ held at the urothelial niveau is washed out towards the lumen, following the pressure gradient between circulation and bladder (Fig. 1). In this way, the chemoceptive (concentrated urine) components of the C-fiber endings and thereby the urinary urge is under control for a
while.
Fig. 1: The C-fiber reflex, urge transmission via a-delta fibers, and (somato-) sympathetic urge control directed from the cortex via the pontine micturition
center.
The sympathetic innervation ensures not only urge control, but equally triggers urothelial GAG production and/or secretion (25). Therefore, urothelial dysfunction, that results in a GAG-layer deficiency, initiates compensatory sympathetic overactivity (Fig. 2) (26,27). In the course of this, release of NO from urothelial cells and tachykinins (substance P) from local plasma cells and from suburothelial C-fiber endings is triggered at smallest filling volumes. This increases permeability of urothelium and the suburothelial blood vessels. The now increased transurothelial K+ transfer leads to a K+ induced vasoconstriction (28). Consequently, these changes are accompanied, in contrast to the normal situation, not by an increase, but rather by a decrease (relative to filling) of bladder wall circulation (28,29,30). According to the resulting hemodynamic thrust reversal urinary K+ is not washed out towards the lumen, but can reach the detrusor unhindered in order to depolarize it (Fig. 2). Thus, urinary urge becomes, despite sympathetic overactivity, uncontrollable even at smallest filling volumes. Ongoing permanent depolarisation leads to fatigue of the detrusor. This can explain the often described absence of instable detrusor contractions during conventional cystometry. The restriction of bladder capacity in IC caused by the above-mentioned processes is only functional and as long as there is no bladder wall fibrosis, a nearly normal bladder capacity can be evaluated (with isotonic NaCl as filling medium) under general or local anesthesia.
If IC reaches the bladder neck, K+ -induced permanent depolarization and/or detrusor overactivity lead to fatigue of the bladder neck. The consequence of an open bladder neck is expressed in the female patient as urethral burning (urethral syndrome). Entrance of urine in the posterior urethra in IC causes not only an additional irritation, but also activates the detrusor in a vicious circle (31). Lasting intensive urinary urge in IC leads, via the involuntary C-fiber reflex activation of the sphincter (Fig. 1) and via the voluntary pelvic floor contraction for avoidance of incontinence, to an overactivation of the rhabdosphincter and to spasms of the pelvic floor (28,32). If the spasms continue even during voiding, it becomes dysfunctional. The consequences are a weak urinary stream, bladder wall trabeculae and frequently also residual urine. Therefor, subvesical obstruction demonstrated in the context with IC is not structural to be eliminated by urethral overdistension in females or TUR of the prostate, but rather functional.
Relative ischemia results in additional damage to the urothelium (33). With increasing duration of the disease, there is an increase in the sensitivity of the detrusor cells towards K+ (34) and the sensitivity of the C-fiber endings to sympathetic impulses (15,21,35). The latter, in particular, is responsible for the progress of the (abacterial) inflammation and thus for the bladder pain (transmitted by the C-fibers directly to the cerebral cortex). Timely and successful therapeutic substitution of the defective GAG-layer eliminates the agent triggering the sympathetic overactivity. With this, the permeability of the urothelium and suburothelial blood vessels is normalized and thereby also the vesical circulation (28). The urothelial cells are now once again able to produce GAG´s by themselves. In principle then, IC is a reversible disease. If the IC remains untreated for years, the sympathetic overactivity can get into a state of fatigue (25). In this irreversible end stage, the mucosal inflammatory cascade disassociates itself from sympathetic impulses. Therefore, induction of pain is maintained. On the other hand, the enhanced urothelial permeability can no longer be demonstrated. IC cannot develop from any of the conditions such as structural obstruction, arteriosclerosis, complete upper and lower QS syndrome, SHT or dementia of the elderly. Sympathetic hypoactivity can certainly induce a GAG layer deficit and an associated enhanced susceptibility to infection in the corresponding bladder problems, but in no case an enhanced urothelial permeability (Fig. 2) (25).
Fig. 2: Pathogenesis of IC in comparison with mucosal changes in the absence of sympathetic impulses. As a consequence of fatigue of the sympathetic hyperactivity, in the irreversible end stage, IC tends to the latter.
Diagnosis
General aspects
For a long time, diagnosis of IC was established primarily by excluding other diseases. Thus, one could still find in the criteria for IC as defined by the NIH in 1987 more exclusion than inclusion conditions (1). The criteria are comprehensive and rather frighten off the majority of urologists from making a diagnosis, since the clarifications required appear to be costly and time-consuming. In the meantime, several investigations have shown that strict adherence to the criteria is certainly meaningful when a comparative cohort study of IC is to be carried out. However, early stages and milder forms of IC will not be identified and these patients, if the criteria are strictly adhered to, will be excluded from therapy. There is another failure to make a diagnosis because often at the beginning, IC appears to be harmless and also because of spontaneous remissions (either temporary or permanent) after elimination of the triggering noxa.
Suspicion of IC can be based on clinical symptoms alone. Typical symptoms encountered here are irritative complaints without demonstrable pathogens, urinary urgency, frequency, nocturia, retro-/suprasymphysial pain that worsens with bladder filling, continues even after complete bladder emptying, urethral burning, genital pain, but also chronic pelvic pain including dyspareunia. In addition to the classical clinical picture of IC, cystoscopic finding of glomerular hemorrhage after hydrodistension is generally accepted as the most indicative morphological substrate. This typical endoscopic impression is seldom observed in the early stages of the disease, but almost always one can see angiogenesis, bulging veins, spiral arterioles, but seldom edema or cystic granules (Fig. 3a). The extent of angiogenesis never corresponds with the severity of complaints (36). Nonetheless they are pathognomonic. Dysfunctional voiding or pelvic floor spasms can be read off the presence of bladder wall trabecula (Fig. 3a).
Fig. 3a (left): Angiogenesis; 3b (right): Trabeculation as a sequela of dysfunctional voiding.
If a cystoscope shaft (15 or 17 Ch) passes the urethra effortlessly, it is highly unlikely that there is a structural defect in the form of a urethral stricture. If it does not, it is enough to push the bougie 1-2 Ch beyond the shaft caliber for overcoming resistance to the insertion of the endoscope. If a spastic rhabdosphincter is dilated with violence to Ch 30, muscle fibers can tear, which on healing leave scars behind. Repeated use of the bougie converts a functional into a structural stenosis, and sets the patient upon his trail of suffering by initiating the need for a periodic urethral overdistension lifelong (37). That is why this procedure must be absolutely avoided if there is the slightest suspicion of sphincter spasm.
Urge provocation as the most important diagnostic criterion
Urge provocation by potassium chloride (KCl) is regarded as the most important diagnostic criterion. Whereas in a normal bladder instilling 0.4 molar KCl solution does not show a sensory difference with normal saline, in nearly 70% of IC patients ("leakers" = increased urothelial permeability) KCl comparably causes moderate to severe urgency (5) and sometimes long-lasting bladder cramps, so that use of this diagnostic method cannot be recommended as a routine measure. There is a better method which is gentler on the patient but has equal diagnostic reliability (and for this reason recommended by us) and that is, a comparative cystometry after filling the bladder with a normal NaCl solution and thereafter with 0.2 molar KCl (comparative urodynamics) (28). A more than 15% reduction of maximal bladder capacity has been established to indicate "leakage".
If the cystomanometry is complemented with a pressure-flow study, dysfunctional voiding (spastic pelvic floor/urethra) takes place because of uninterrupted EMG activity or a significantly decreased urine flow, under KCl approximately three times more frequently (28). In a urologist´s office, suspected "leakage" can be verified - equally satisfactorily and in a much shorter period of time - with infusion stander, NaCl and KCl solutions, infusion set, catheter and measuring cup. The crucial importance of KCl-testing is that of identifying "leakers". This is important, for in the current state of the art, only these patients can be treated with the aim of reinstating of the urothelial integrity (38). For the remaining patients, only palliative measures are available. In the future, KCl-testing will be indispensable in the male for making a differential diagnosis by excluding irritative complaints resulting from structural obstructions. In cases of general sclerosis, senile dementia, brain trauma, complete spinal cord lesions as well as in children, the KCl-test also remains negative. Table 1 shows the step-by-step diagnostic procedure for IC.
Therapy
A. Positive KCl provocation (= restitution of integrity is possible)
1. Exclusion of noxa
Patients are advised to avoid caffein-containing drinks and other acidic dietary constituents such as white wine, sparkling wine, citrus fruits etc. in order to prevent excitation of the pH-sensitive components of the C--fiber endings. Prelief® should help reduce resorption of acidic dietary components. Exposure to cold should be absolutely avoided. After every antibiotic treatment, the vaginal lactobacilli must be reestablished. Soaps, deodorants etc. must not be used in the vagina. Antibiotics and excessive hygiene can destroy vaginal lactobacilli. In their place, stool pathogens and fungi spread. Under these circumstances, often the pathogens find their way into the bladder even without any sexual activity.
2. Substitution of the GAG (mucous) layer
As a first line of therapy, intravesical instillation has proved to be of value, since substances that might possibly used for this purpose such as hyaluronic acid or heparin are degraded in the gut if administered orally. As far as oral drugs are concerned, only elmiron® (a minimum of 300mg / per day) (38,39) or cranberry syrup provide therapeutic benefit, in particular for achieving metaphylaxis. Elmiron® also inhibits mast cell histamin secretion (40). Mild to moderately severe complaints can be handled adequately with weekly instillations of 50 ml of 50% DMSO + 100 mg hydrocortisone + 100mg elmiron® (or 2,500 IU Heparin) + 0.1 molar Na-bicarb for 20 minutes (41). After emptying of this cocktail, 5 mg verapramil (not in the presence of residual urine!) + 200 mg elmiron® (or 5,000 IU heparin) should be retained in the bladder as long as possible. It should be noted here that in the course of the DMSO therapy, there is a temporary aggravation of the disease symptoms. The excretion of the DMSO via the lungs causes the breath to have a garlic smell, and this can continue for up to 48 hours. Patients should be informed of these side effects.
Standard therapy for all IC patients, especially those in advanced stages of the disease, consists in instillation of 40 mg hyaluronic acid once weekly (42) as also 300 mg elmiron® (or 10,000 IU heparin) (43,44) + 5 mg verapramil (not in the presence of residual urine!) 3 times weekly. The medications are to be retained in the bladder as long as possible. If it is not possible to hold back for longer than an hour, a prior 30-minute application of 20 ml 2% of a local anesthetic can help prolong the effectiveness of the medication. Regardless of the severity of IC, therapy should be continued for a minimum of six and a maximum of 10 weeks. During the course of the therapy, antibiotic protection on instillation days is recommended (e.g. nitrofurantoin prior to instillation). Placement of a temporary suprapubic minifistula would save repeated therapeutic catheterizations. In addition to the instillation therapy, use of measures for promoting vesical blood flow would improve therapy results.
3. Electrostimulation
Maximal pudendal short-time (20 min) electrostimulation - vaginal, rectal, clitoral or penile - helps achieve not only effective detrusor inhibition, but also improves vesical blood flow (45,46,47). For this reason, parallel to instillation therapy, electrostimulation should be carried out in all IC patients. If residual urine is retained in spite of normalization of the outlet resistance, the most efficient method currently available for toning up the detrusor is that of intravesical electrotherapy (48).
In refractory cases, after temporary successful long-time stimulation an implantation of a permanent sacral neuromodulator can be considered (49). This (cost-intensive) method exerts its effect in individual cases by possibly normalizing the C fiber reflex and the sympathetic efference. The urothelium, the C- fiber endings (pain), vesical blood flow, detrusor activity (urge, open bladder neck) and rhabdosphincter (dysfunctional voiding) all profit from this measure.
4. Pelvic floor relaxation training
Should dysfunctional voiding be maintained as a learned reflex, there is often an early relaps (a few months later). Since dysfunctional voiding is the sequela of overactivity of the C-fiber reflex, pelvic floor relaxation training is meaningful only after (!) successful instillation therapy and thus after stabilization of the C-fiber endings. As a supportive measure for training of the voluntary muscles, overstimulation of the pelvic floor (emptying the cholinergic depots) represents a valuable complementation.
5. Neuromuscular medication
A positive K+ provocation should be seen as a contra-indication for anticholinergics: direct detrusor depolarization by urinary K+ and afferent pain transmission by C- fibers have nothing to do with interference with neuromuscular (parasympathetic) transmission. In the light of sympathetic overactivity present in IC, the use of alpha- blockers appears to be favourable in female patients, too.
Verapramil as a calcium antagonist is added to the instillation cocktail. Calcium antagonists (50), calcium channel openers (51), or phosphodiesterase blockers (52) are able to stabilize the resting membrane potential of the detrusor and mucosal vessels even in the presence of higher extra-cellular K+ concentrations. However, oral administration of such drugs is not recommended in view of the adverse side effects on circulation.
It may be mentioned here that there are reports of success in treating IC patients with tricyclic (38) or with some of the newer anti-depressants as complementing the standard therapy.
6. Strengthening/weakening the urothelial immune response
There are hints to the effect that IC appears also in patients with a predisposition to enhanced allergic reactions or in those with autoimmune diseases. A few studies have reported that in such cases, hydroxin (53), an antihistamine (H1 receptor antagonist), and cyclosporin (54) as well as IPD-1151T (55) have resulted in an improvement of the symptoms of IC. Remission has been reported also after BCG instillation (as in cases of recurring bladder tumour) (56), although this mode of therapy obviously promotes inflammation .
7. Interventional therapies
An understanding of the pathogenesis of IC will reduce in the future the incidence of training for pelvic floor strengthening, anti-incontinence surgery (both of them because of dysfunctional voiding), overdilation of urethra or bladder (both of them because of induction of muscle fiber tears with subsequent shrinking due to scars) (37,57), as also TUR of the "small" prostate (maintenance of IC on the bladder neck, retrograde ejaculation). In spite of all this, in isolated refractory cases of IC associated with severely reduced bladder capacity, hydrodistension of the bladder (under general or local anesthesia) can lead to short- or long-term remissions.
B. Negative KCl -provocation (only palliation is possible)
1. Vanilloides (toxic damage to C fiber endings)
Hopes had been pinned on capsaicin, which has been found to be effective in neurogenic hyper-reflexia, but the substance has proved to be disappointing in the treatment of IC (58). The effectiveness of resiniferatoxin, a successor of capsaicin, has not yet been adequately investigated (59,60).
2. Surgery
In patients with therapy-resistant contracted bladder, cystectomy and creation of an artificial bladder represent the last resort for re-establishing an acceptable quality of life (61). If the suffering caused by IC has lasted long enough, the "worst case scenario" of a life as a bladder cripple with "pelvic pain without pelvic organs", - phantom pain - cannot be excluded (62).
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Summary: step-by-step procedure for diagnosis
History:
surgery (particularly lower abdominal), radiation / chemotherapy, recurrent UTI (STD), spondylogenic complaints, gynecological problems, neurological, psychiatric and rheumatic diseases, medications, allergies, treatments so far
Symptoms:
onset of complaints, urgency / frequency, nocturia
pain: a) supra/retro-symphysial, urethral, vaginal, vulvar, dyspareunia, with
worsening during ovulation or menses
b) with full bladder
c) post micturition
urinary incontinence
symptom score
Investigations:
1. Clinical investigation:
females: STD/vaginal swab, vaginal palpation (DD pain from pelvic floor or
parametrium)
males: culture of the ejaculate, DRE + PSA
2. Laboratory investigation: urine culture, urine cytology (in particular in the presence of microhematuria)
3. Sonography: residual urine, endovesical prostate growth
4. Cystoscopy: possibly under anesthesia and without preceding urethral calibration: angiogenesis, edema, granules, trabeculation, Hunner´s ulcer, + hydrodistension (petechial hemorrhage), exclusion of a urethral diverticula
5. 0.2 molar KCl test or comparative urodynamics
6. Imaging procedures (ivP, pelvic CT) not obligatory
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