Therapy Insight: Bladder Dysfunction Associated With Multiple Sclerosis

Management of Lower Urinary Tract Symptoms in Multiple Sclerosis

First-line Treatments

Anticholinergic Medication. Anticholinergic agents are a logical first treatment choice for patients with MS presenting with neurological bladder dysfunction, as the most common symptoms are caused by detrusor overactivity.^[2] The majority of muscarinic receptors expressed in the detrusor muscle are M2;^[27,28] however, the functionally important receptors in the detrusor muscle are the M3 receptors, as these maintain normal bladder function.^[27,29] The benefit of selective blockade of M2 or M3 muscarinic receptors, including the possible advantage of not affecting brain M1 receptors, has yet to be translated into clinical effect.

A number of antimuscarinic agents, some of them only recently licensed in the UK, are available to treat symptoms of detrusor overactivity ( Table 2 ). The long-acting (extended-life ['XL']) formulation of these medications gives a significant advantage to patients, who need only take the tablet once a day to provide 24-hour cover for symptoms. The chemical structure of the antimuscarinic agents tolterodine and trospium renders them less lipophilic and, therefore, theoretically less likely to cross the blood-brain barrier than other antimuscarinic agents, resulting in fewer central adverse effects.^[30,31] These drugs might therefore have particular benefit for patients with cognitive impairment.

Prior to prescribing an anticholinergic for patients complaining predominantly of symptoms of detrusor overactivity, it is important to measure their postvoid residual (PVR) urine volume.^[32,33] This is particularly important if the patient's symptoms indicate that there is a component of incomplete voiding. The PVR urine volume can now be conveniently measured using a small hand-held ultrasound device (Figure 2), to which many specialist nurse continence advisors and MS clinic nurses now have access, allowing them to conduct these examinations. The importance of recognizing incomplete emptying is that any residual volume in the bladder can trigger volume-determined reflex detrusor contractions, exacerbating the clinical situation through worsening of the symptoms of frequency, urgency and urgency incontinence.^[34]

Often patients cannot gauge the extent to which they have incomplete bladder emptying, but it has been shown that those who suspect that they have this problem are often correct.^[2] It is therefore important to ask patients whether they have a sensation of incomplete bladder emptying or if they are able to pass the same amount of urine at a second void only minutes after the first, as these points are strong indicators that a high PVR volume could be contributing to their bladder problems.

Complex management and investigation protocols, such as the Clinical Practice Guidelines for the Multiple Sclerosis Council,^[35] have been proposed for bladder dysfunction and MS. Figure 3 shows a simple algorithm based on two main interventions (medication with anticholinergics and intermittent catheterization) for the initial management of the most common symptoms of bladder dysfunction in MS. Although there has yet to be a controlled study into the efficacy of this algorithm, it has provided a convenient, low-cost management scheme, and has been used daily in the authors' department for 15 years. The role of cystometry and video cystometry in the investigation of patients with MS has been promoted by some authors, because it is only through these investigations that DSD can be diagnosed.^[15,36,37] Since there is no definitive treatment for DSD, however, other than managing the resulting incomplete bladder emptying and raised detrusor pressure, a pragmatic approach would recommend the use of cystometry and video cystometry.

Conservative Measures to Improve Bladder Emptying. Reduction of a raised PVR volume is necessary to improve symptoms. This can be achieved by the patient, or sometimes by their caregiver, through clean intermittent self-catheterization (CISC). If a symptomatic patient has a PVR volume of over 100 ml, CISC is advocated. Important considerations when deciding whether patients are appropriate for this intervention include their motivation, whether they have good cognitive skills and adequate manual dexterity, and their overall physical status.

Unfortunately, there are few other proven methods for improving bladder emptying. There have been claims that α-blockers can reduce PVR volumes,^[38,39] although this has not been confirmed by other studies. The clinical impression that α-blockers are effective in individual patients is not strong, possibly because incomplete bladder emptying in patients with MS is thought to be the result of a combination of poorly sustained and ill-coordinated detrusor contractions, or of an inappropriate contraction of the striated urethral sphincter, a muscle on which α-blockers are thought to be ineffective.^[40]

The application of a suprapubic vibrating stimulus is the only other proven means of improving bladder emptying, and is a method that has benefited some patients.^[41,42] In patients with reflex detrusor overactivity, the vibrating stimulus might help to initiate micturition and possibly improve bladder emptying by triggering a detrusor contraction; these results might not be seen when intact innervation is present, however. Several devices are commercially available for suprapubic vibration, including small hand-held, battery-operated vibrators.^[42,43]

Desmopressin. The synthetic antidiuretic hormone desmopressin (DDAVP^®, Rhone-Poulenc Rorer Pharmaceuticals Inc., Collegeville, PA), was originally licensed to treat the polyuria of diabetes insipidus. Having become an established treatment for nocturnal enuresis,^[44] its efficacy for the treatment of women with MS experiencing night-time frequency has been shown.^[45] Its effectiveness, if taken during the day, in providing patients with up to 6 hours during which they were untroubled by urinary frequency, without any rebound night-time frequency, has been demonstrated by a number of small studies.^[46,47]

Desmopressin (10-20 µg) should only be taken once in every 24-hour period, and should not be given to patients over 65 years of age, or used in patients with dependant leg edema resulting from immobility who have night-time frequency when recumbent. In spite of these precautions, a number of patients find that this drug can provide additional benefit to that conferred by the other first-line measures if they are looking to be reliably free of symptoms for a long journey or a particular social event.^[47]

Indications for Additional Investigations

The first-line treatments for lower urinary tract symptoms consist of oral anticholinergics with or without CISC, and many neurologists and neurorehabilitation physicians, with the help of continence advisors, can advise patients accordingly. Patients experiencing recurrent urinary tract infections, hematuria, or pain that is thought to originate from the upper or lower urinary tract, and those with evidence of impaired renal function, should be referred to a urologist.

In aging men with MS, an element of lower urinary tract symptoms might be attributable to benign prostatic hyperplasia (BPH).^[48] The challenge in these patients, therefore, is to establish to what extent the symptoms are due to BPH, and how they much they bother the patient. The degree to which the symptoms of BPH are bothersome will help to determine further management, which could include watchful waiting, medical, minimally invasive or surgical therapies. Initial evaluation of these patients should include a detailed medical history to identify the causes of voiding dysfunction, a physical examination, and both a digital rectal examination and a focused neurological examination. Following the evaluation, a urinary-flow-rate recording and measurement of the PVR might be helpful. Surgery is only recommended in patients who have renal insufficiency that is clearly due to BPH, and in those patients with recurrent urinary tract infections, recurrent gross hematuria, or bladder stones that are clearly due to BPH and refractory to other therapies.^[49] These patients should be referred to a urologist.

Second-line Treatments for Overactive Bladder Syndrome

Undoubtedly there is a point in the progression of MS where first-line treatment might be insufficient to control urinary symptoms, and yet the patient does not want to have a long-term indwelling catheter (Figure 4). This point is often reached as patients' neurological disability, especially their mobility, is deteriorating such that they are not in a sufficiently robust state to undergo major surgery (such as an augmentation cystoplasty). Various new nonsurgical and, at the time of writing, unlicensed treatment options are emerging for these patients.

Cannabinoids. The illegal use of cannabis by patients with MS has become common in the UK, to such an extent that a diagnosis of MS was sometimes debated as an extenuating argument by people found growing Cannabis sativa. In 1998, further exploration into the medicinal properties of cannabis was proposed by a high-level UK government report,^[50] resulting in a number of small-scale, open-label studies that examined the effect of medicinal cannabinoid extracts on patients with chronic pain or MS. Included in these trials was a small open-label study in patients with advanced MS, refractory to conventional treatments, and in whom having a long-term indwelling catheter was a looming prospect. The results of this pilot study demonstrated a significant decrease in urinary urgency and a reduction in the number and volume of incontinence episodes, as well as a reduction in frequency and nocturia. Daily total voided and catheterized volume, and urinary incontinence pad weights, were also significantly decreased, whilst patients reported significant improvements in spasticity, quality of sleep and level of pain (measured by patient self-assessment).^[51] Large, multicenter, randomized placebo-controlled trials are underway, although no results are available.

The Cannabis in Multiple Sclerosis (CAMS) study, a large, multicenter, placebo-controlled trial funded by the UK Medical Research Council, was established to look at the effect of oral nabilone and tetrahydrocannabinol (THC) on patients with MS. Although the study is ongoing, results so far have shown no change in the ashworth scale scores ( Table 3 ); however, the patients did report subjective improvements in spasticity.^[52] A subsidiary study looked at the effect of oral nabilone and THC on bladder symptoms and, although the data are only reported in an abstract, the results suggest that there is a lessening of urinary urgency and a reduced number of episodes of urge incontinence on active treatment.^[53] Whether or not this medication becomes a licensed therapy in the UK, or other countries, for the treatment of specific symptoms in MS such as spasticity and urinary urgency and frequency, is yet to be decided.

Intravesical Vanilloids. The use of intravesical vanilloids to reduce the number of afferent nerve endings of the bladder was rationalized by the knowledge of the importance of the emergence of C-fiber reflex causing detrusor overactivity following a spinal cord lesion.^[16] Intravesical capsaicin was the first vanilloid to be used in patients with neurogenic detrusor overactivity.^[54] Although there is good evidence that intravesical capsaicin has a therapeutic effect,^[55] its use has been largely abandoned because it is not licensed and could cause considerable discomfort to patients when instilled. The prospect, therefore, of using intravesical resiniferatoxin (RTX®, Afferon Corporation, Scottsdale, AZ), an ultra-potent capsaicinoid^[56] that is thought to have the same neurotoxic effect on bladder afferents^[57] but is less pungent,^[58] was greeted with enthusiasm. Clinical trials have been hampered by the compound's tendency to adhere to plastic, however. In the studies published, the number of patients in whom this treatment was effective was small.^[59] It now seems unlikely that a pharmaceutical company will market this medication in the future.

Further work with capsaicin has shown that its irritant effects can be reduced if glucidic acid, rather than 30% alcohol, is used as the diluting solution. A randomized controlled trial compared the efficacy and tolerability of capsaicin in glucidic acid and resiniferatoxin in 10% alcohol in patients with neurogenic bladder overactivity. The results revealed that the formulations were highly comparable in relieving symptoms of detrusor overactivity.^[60] Intravesical capsaicin is still offered as a treatment option in a neurorehabilitation and research center in Bordeaux, France.

Detrusor Injections of Botulinum Neurotoxin Type A. First described by Schürch et al. in 2000 for patients with spinal cord injuries, botulinum neurotoxin type A (BoNT/A) injected directly into the smooth muscle of the detrusor is having a major impact on the treatment of neurogenic detrusor overactivity.^[61,62] Originally proposed on the basis that BoNT/A would merely paralyze the detrusor by blocking the presynaptic release of parasympathetic acetylcholine-mediating detrusor contraction, the benefits of this treatment appear to exceed those expected. It seems likely that BoNT/A also affects the vesicular release of neurotransmitters involved in the afferent arm of reflex bladder contractions; work on this is ongoing.^[63]

In our own studies, a series of 31 patients with MS have received injections of 300 units of BoNT/A (Botox^®, Allergan, Irvine, CA)^[64] using a minimally invasive local anesthetic outpatient technique, pioneered in our department.^[65] Sparing the trigone, for reasons of tolerability and potential ureteric reflux, this technique involves injecting 30 equally spaced points in the bladder, using a flexible cystoscope and a superfine 27-gauge disposable needle that locks into a reusable sheath (Figure 5). Each injection is comprised of 10 units of Botox^® (1 ml).

Voiding-diary data are showing exceptional clinical efficacy for BoNT/A, with significant improvements compared to baseline of urinary urgency, frequency and incontinence episodes at 4 and 16 weeks postinjection. Urodynamic parameters, namely maximum cystometric capacity and detrusor pressures during filling, have also shown significant and sustained improvement.^[64] Because there is an increased incidence in incomplete bladder emptying following treatment in patients with neurogenic bladder dysfunction, patients must be willing and able to perform CISC, if they are not already doing so.

Initial results of trials investigating repeated injections show similar beneficial effects and duration of treatment action for these and primary injections. Projected cost consequences are modest (UK£780 per annum per patient) compared with surgery or long-term anticholiergics or neuromodulation, with a median time of 13 months between injections.^[66] Cost-effectiveness studies comparing intradetrusor BoNT/A with anticholinergics, neuromodulation and surgery, are currently being set up. Although not yet licensed for this use, BoNT/A is emerging as an effective and popular second-line treatment for symptoms of neurogenic detrusor overactivity, which is increasingly being adopted by many urology, neurology and rehabilitation centers worldwide.

Surgical Management. The advent of effective noninvasive treatments for patients with bladder dysfunction secondary to MS has caused surgical management techniques to take a lesser role. Denervation procedures, including selective posterior rhizotomy, subtrigonal injection of phenol or alcohol, bladder myotomy and transection, might have shown good short-term results, but long-term results have been much less satisfactory.^[67] Augmentation procedures of the bladder, such as augmentation cystoplasty (with or without a catheterizable limb), might allow large volumes of urine to be contained within the bladder at low pressures, but most patients need to perform CISC.^[68,69] The ability to do so is often lost as the neurological condition of the patient deteriorates.

Sacral-nerve neuromodulation is being investigated in patients with MS, and a small study of nine patients with neurogenic detrusor overactivity, five of whom had MS, reported clinical and urodynamic improvement at 46 months follow-up.^[70] Longer follow-up and larger cohorts of patients with MS are needed to assess carefully the cost-effectiveness of this intervention.

Long-term Indwelling Catheter. There is a stage in the patient's progression at which a long-term indwelling catheter becomes necessary. This is usually when the patient has become severely disabled, being unable to stand, or being chair-bound or even bed-bound. Cognitive impairment, lower-limb spasticity, and loss of manual dexterity, together with increasing detrusor overactivity, mean that CISC, even with the aid of a caregiver, is no longer feasible. In these cases an indwelling catheter is appropriate, and initially a urethral catheter connected to a leg bag will familiarize the patient and their carer with what is involved in indwelling catheterization. The urethral catheter should then ideally be promptly replaced by a suprapubic catheter.^[71] Long-term urethral catheters are not advisable because of the urethral trauma they commonly inflict.

Suprapubic catheters should ideally be sited by a urological surgeon, who might want to give the patient a general anesthetic so that the bladder can be distended to facilitate the suprapubic puncture into the otherwise shrunken bladder. Once the suprapubic tract has been epithelialized, usually 6-8 weeks post-puncture, the catheter can be changed for the first time. The first catheter change should ideally be performed under the care of a urology team; subsequent changes at intervals of 3 months can be carried out by district or practice nurses.

Nat Clin Pract Urol. 2005;2(10):492-501. © 2005  Nature Publishing Group

Cite this: Therapy Insight: Bladder Dysfunction Associated With Multiple Sclerosis - Medscape - Oct 01, 2005.