ronmental component has also been estab- lished. People descended from Scandina- vian countries and colder climates in gen- eral have been reported to have a higher The in incidence of multiple sclerosis. This debil- itating neurologic disease affects 1 of 1000 multiple sclerosis Americans.1,2 Most patients present in the most productive years of life, therefore JARAD S. FINGERMAN, DO making multiple sclerosis even more dev- LEONARD H. FINKELSTEIN, DO, FACOS astating. Multiple sclerosis has been related to an autoimmune attack on the myelin-pro- ducing oligodendrocytes of the central nervous system, causing demyelination of Multiple sclerosis is a common neurologic disorder that often affects the genitouri- the affected nerve. Although there is nary system. One of the most common symptoms of multiple sclerosis is the hyper- preservation of the axon, this demyelina- active bladder. These patients will have symptoms that may affect their lifestyle, such tion results in decreased conduction as , urgency, and frequency. They may also suffer from debil- through the nerve. The demyelination itating urinary tract symptoms, such as frequent or recurrent urinary tract most often affects the posterior and lateral and also on occasion, damage to the upper urinary tract. Fortunately, the neurogenic columns of the cervical spinal cord, but the bladder dysfunction associated with multiple sclerosis can be treated with a reasonable lumbar and sacral cords as well as the chance of success. With proper treatment, related symptoms may be brought under optic nerve, cerebrum, cerebellum, and control, allowing the physician to concentrate on the more debilitating aspects of this brainstem are also commonly involved. disease. The clinical course of multiple sclerosis (Key words: multiple sclerosis, overactive bladdeer, urinary incontinence, is one of relapses and remissions with dis- urgency, frequency, parasympathetic agents, anticholinergic agents, oxybutynin tinct neurologic deficits related to the var- chloride, tolterodine tartrate, propantheline bromide) ious regions affected.

Bladder overactivity or illustrative purposes, we describe determined by bladder scan revealed 20 Bladder overactivity is a common disorder. Fthe case of a 36-year-old woman who mL of fluid. Serum chemistry studies It is characterized by involuntary detrusor was seen in the urologist’s office com- revealed normal renal function. Findings contractions that may occur spontaneously plaining of urinary urge incontinence. on renal examination were or may be provoked (such as by rapid Three years earlier, multiple sclerosis was also normal, without evidence of renal filling, changes in posture, coughing, walk- diagnosed after she had had visual changes scarring or hydronephrosis. ing, and jumping) while the person is and ataxia. Flexible and urodynamic attempting to suppress them. The over- History revealed that she soaked three evaluation (Figure 1) revealed a first sen- active bladder is referred to as unstable to four pads a day, with significant social sation to void at 30 mL and an uninitiat- when the etiology is nonneurogenic, and impact. Occasional ed detrusor contraction at 80 mL. There as hyperreflexic when the etiology is neu- occurred in which a cough or Valsalva was no involuntary sphincter contraction rogenic. The term overactive bladder refers maneuver would promote a complete mic- at the time of detrusor contraction. These to the storage phase of the bladder only, turition episode. She was able to ambulate findings were consistent with bladder not to micturition (the voiding phase), without significant difficulty, so there was hyperactivity without detrusor-sphincter and is diagnosed by the filling cystometry minimal functional component attributing dyssynergia. phase of urodynamics.3 to her incontinence. The patient was started on oxybutynin Unlike other human visceral systems During a recent hospitalization for chloride (Ditropan) therapy (2.5 mg oral- that require an intact autonomic nervous rehabilitation, an indwelling was ly three times a day), and she was followed system (such as the gastrointestinal and placed and later left in place to control up closely for evidence of urinary reten- cardiovascular systems), the lower uri- her socially debilitating incontinence. tion. She was placed on a timed voiding reg- nary tract depends partly on the voluntary The initial urologic workup revealed imen five times a day. Although her incon- central nervous system to function in the normal findings on urinalysis and negative tinence resolved, close follow-up revealed storage and evacuation of . Micturi- culture. Postvoid residual urine volume an increased postvoid residual urine volume tion is under voluntary control and of 100 mL, which eventually normalized. depends on learned behavior that develops She is presently continent with oxybutynin during maturation of the nervous system. From the Department of , Philadelphia College of Osteopathic Medicine (PCOM), and is catheter free. Damage to the brain and spinal cord can where Dr Fingerman is a resident. Dr Finkel- induce bladder overactivity by reducing stein is president and chief executive officer of Multiple sclerosis the parasympathetic inhibition that nor- PCOM. Multiple sclerosis is the most common mally allows the bladder to fill. It has also Correspondence to Jarad S. Fingerman, DO, Department of Urology, 4190 City Ave, neurologic disorder in the 20- to 45-year- been noted that damage to the inhibitory Philadelphia, PA 19131-1695. old age group. There is a 2:1 female-to- axonal pathways in the spinal cord can E-mail: [email protected] male predilection, and a genetic and envi- lead to the emergence and unmasking of

Fingerman and Finkelstein • The overactive bladder in multiple sclerosis JAOA • Vol 100 • No 3 • Supplement to March 2000 • S9 by the fact that the urodynamic findings change as the disease waxes and wanes. As the majority of patients have over- active bladder contractions, the inconti- Flow rate nence associated with hyperactivity may (filling) represent the most socially disabling symp- 5 mL/s tom of the disease. Aside from the social aspects of bladder overactivity, it is imper- ative to effectively treat the neurogenic Vesical bladder and the resulting urinary tract (bladder) pressure infections. Many patients with multiple 10 cm H O sclerosis are treated with immunosup- 2 pressive medications, and these infections can lead to devastating complications and sepsis.8 It is therefore quite important that Abdominal pressure physicians diagnose and treat these dis- abling and potentially dangerous condi- 10 cm H2O tions.

Treatment Detrusor As already mentioned, the wide array of pressure 10 cm H O urologic symptoms and abnormalities 2 associated with multiple sclerosis poses a therapeutic dilemma. Each patient must have a specific treatment plan aimed toward his or her own objective urody- namic abnormalities. It has been noted Figure 1. Cystometrogram indicating detrusor hyperreflexia. First sensation to void recently that as many as 73% of patients at 15 mL; urgency to void at 34 mL; bladder capacity, 65 mL. with multiple sclerosis without undergo- ing urodynamic evaluation were treated inappropriately.7 As stated earlier, the primitive spinal bladder voiding reflex- patients with multiple sclerosis had detru- majority of patients with multiple sclero- es.4 Upper motor neuron lesions affect- sor hyperreflexia as the primary urody- sis will demonstrate detrusor hyperreflexia ing the genitourinary system can result in namic diagnosis.7 This hyperreflexia com- on cystometric evaluation, but some may bladder hyperactivity and hyperreflexia. monly manifests symptomatically as demonstrate the opposite. The hyperreflexic bladder is one of the urgency, frequency, and generalized “irri- The goals of therapy of the neurogenic most common symptoms of multiple scle- tative” symptoms.7 Very often, there is bladder in multiple sclerosis are conti- rosis. Lower urinary tract symptoms occur associated sphincter dyssynergia, defined nence and, when sphincter dyssynergia is in up to 90% of patients with multiple as simultaneous contractions of the blad- present, reduction of residual urine. A sclerosis at some time in the course of their der and urethral sphincter. This dyssyn- high residual urine volume may cause cys- disease.5 They occur primarily because the ergia can lead to more serious complica- titis, and the upper urinary tract is at risk. neural control system for the urinary blad- tions, as the unstable bladder will contract The use of indwelling urethral or supra- der is distributed throughout the central against a closed urethral sphincter. It can pubic should only be the treat- nervous system. Therefore, clinically, mul- be stated with moderate assurance that ment of last resort, as indwelling catheters tiple sclerosis can manifest itself urologically any patient whose symptom complex con- produce chronic irritation and predispose in many ways. sists of hyperreflexia with an increased the patient to , erosion or stricture postvoid residual urine volume has evi- of the , formation, Clinical relevance dence of dyssynergia. and possibly malignancy. Between 50% and 90% of all patients The urinary tract symptoms associated Because of acetylcholine-induced stim- with multiple sclerosis complain of voiding with multiple sclerosis vary widely. They ulation of detrusor receptor cells, it would symptoms at some time in their life. Often, can present along the spectrum from detru- seem logical that anticholinergic agents voiding dysfunction is part of the present- sor hypoactivity and to be considered the medications of choice ing symptom complex (between 2% and detrusor hyperactivity, incontinence, and for treatment of bladder overactivity. This 15%),6 but the number of those patients generalized irritative symptoms. There- hypothesis has, in fact, proved to be true. with urinary tract symptoms increases as fore, the treatment must be tailored appro- Oxybutynin or tolterodine tartrate (Detrol) the duration of disease increases. priately to each individual patient. This should be the first line of treatment (Fig- Bladder overactivity is the most com- necessity is exemplified by the fact that ure 2).9 Oxybutynin has shown moderate mon urodynamic abnormality detected. the volume of postvoid residual urine var- potency as an anticholinergic agent, and it It is present in 50% to 99% of patients. A ied widely in one recent study from 50 has also been shown to possess local anes- recent meta-analysis of 1882 patients mL to 900 mL in patients with multiple thetic activity.10 The recommended dosage revealed that 62% of symptomatic sclerosis.7 Therapy is further complicated is 2.5 mg to 5.0 mg two to four times

S10 • JAOA • Vol 100 • No 3 • Supplement to March 2000 Fingerman and Finkelstein • The overactive bladder in multiple sclerosis daily. It has recently been released in Patient with multiple extended-release form that has signifi- 11 sclerosis cantly fewer side effects. Tolterodine is a newly approved and similar medication that has proven effective; it also appears to 12-20 Urodynamic abnormality have fewer side effects. The optimal Detrusor hypoactivity and urinary dosage is 1 mg to 2 mg twice retention daily.14,15,17,18 Tolterodine is a competi- Detrusor hyperactivity tive muscarinic receptor antagonist. It has Incontinence been shown that con- Generalized irritative symptoms traction is mediated via cholinergic mus- carinic receptors. Another well-tolerated anticholinergic agent is propantheline bromide (Pro-Ban- Goals thene). It is considered the second-line Continence anticholinergic medication for bladder Treatment 9 Reduction of residual urine when hyperactivity. The dosage is 7.5 mg to 30 sphincter dyssynergia present mg three to five times a day. Hyoscyamine sulfate (Levsin) is another commonly used second-line anticholinergic and antispas- modic medication (0.125 mg to 0.375 mg orally or sublingually every 4 hours as Timed voiding or catheterization PLUS needed). This medication has the added Anticholinergic agents regimen if residual urine is benefit of rapid sublingual onset of action. excessive A notable study reported in 1991 showed increased bladder volume at the first involuntary contraction of 51 mL with oxybutynin, compared with 11.2 Oxybutynin chloride, 2.5 mg to mL with propantheline. Mean cystomet- 5.0 mg two to four times a day ric bladder capacity increased by 80.1 mL First-line therapy Tolterodine tartrate, 1 mg or with oxybutynin and 48.9 mL with 2 mg twice daily propantheline.21 All anticholinergic agents have the potential side effects related to their anti- cholinergic mechanism of action. These side effects include dry mouth, blurred Propantheline bromide, 7.5 mg to 30 mg three to five times a day vision, tachycardia, drowsiness, and con- Second-line therapy Hyoscyamine sulfate, 0.125 mg stipation. Usually, these side effects are to 0.375 mg orally or sublingually well tolerated. every 4 hours as needed It should be mentioned that anti- cholinergic agents do not increase the time between sensation to void and actually voiding. There are also often an increase in the patient’s residual urine and a Tricyclic antidepressants decrease in detrusor pressure. Therefore, Third-line therapy (imipramine hydrochloride in particular) when not contraindi these agents can be used with a timed cated voiding or timed catheterization regimen if excess residual urine warrants. The next line of treatment, in patients who have no contraindications to them, are tricyclic antidepressants, imipramine Central and peripheral hydrocloride (Tofranil) in particular. These anticholinergic effects Clean intermittent catherization drugs have shown central and peripheral Facilitate bladder storage if residual urine is a anticholinergic effects, and they have Decrease bladder contractility, problem proven useful in facilitating bladder stor- simultaneously increase bladder outlet resistance age. They decrease bladder contractility and simultaneously increase bladder out- let resistance. This class of pharmaceutical agents blocks the active reuptake of sero- Figure 2. Flow chart for treatment of overactive bladder in patients with multiple tonin and norepinephrine. The exact sclerosis. mechanism of action on the lower uri-

Fingerman and Finkelstein • The overactive bladder in multiple sclerosis JAOA • Vol 100 • No 3 • Supplement to March 2000 • S11 nary tract remains a topic of debate.9 Bladder overactivity often responds 13. Appell RA. Clinical efficacy and safety of tolterodine In addition to the pharmacologic ther- well to pharmacologic therapy. If there in the treatment of overactive bladder: a pooled anal- ysis. Urology 1997;50(6A Suppl):90-96; discussion apy for bladder overactivity, clean inter- is a component of sphincteric dyssynergia 97-99. mittent catheterization (CIC) is essential if and there is a high postvoid residual urine residual urine is a problem. Clean inter- volume, it may be necessary to include 14. Rentzhog L, Stanton SL, Cardozo L, Nelson E, Fall M, Abrams P. Efficacy and safety of tolterodine in mittent catheterization has been proven to CIC in the treatment regimen. These patients with detrusor instability: a dose-ranging study. reduce the residual urine volume, thereby modalities have proven to be effective in Br J Urol 1998;81:42-48. reducing the risk of infection. It has also relieving the most distressing urologic 15. Larsson G, Hallen B, Nilvebrant L. Tolterodine in the been shown to improve continence. As symptoms of multiple sclerosis. treatment of overactive bladder: analysis of the pooled already stated, these are the two main phase II efficacy and safety data. Urology 1999;53:990- goals of treatment. References 998. Depending on the patient’s general 1. Koop CE. Multiple sclerosis. Dr C. Everett Koop 16. Millard R, Tuttle J, Moore K, Susset J, Clarke B, medical status, CIC is performed by the Web site. Available at: http://www.krkoop.com/...s/Mul- Dwyer P, et al. Clinical efficacy and safety of tolterodine tiple_Sclerosis. Accessed March 7, 2000. compared to placebo in detrusor overactivity. J Urol patient or the patient’s caretaker. It is usu- 1999;161:1551-1555. ally performed four to five times a day. 2. US Census Bureau Home Page. United States Department of Commerce Web site. Available at: 17. Atan A, Konety BR, Erickson Jr, Yokoyama T, Clean intermittent catheterization allows http://www.census.gov. Accessed March 7, 2000. Kim DY, Chancellor MB. Tolterodine for overactive regular emptying of the bladder, leading to bladder: time to onset of action, preferred dosage, and 3. Hampel C, Wienhold D, Benken N, Eggersmann C, 9-month follow-up. Tech Urol 1999;5(2):67-70. a lower incidence of cystitis, and no resid- Thuroff JW. Definition of overactive bladder and epi- 8 ual urine. The lack of an indwelling demiology of urinary incontinence. Urology 1997;50(6A 18. Abrams P, Freeman R, Anderstrom C, Mattias- catheter also decreases the risk of bladder Suppl):4-14; discussion 15-17. son A. Tolterodine, a new antimuscarinic agent: as effective as but better tolerated than oxybutynin in carcinoma and stone formation associat- 4. de Groat WC. A neurologic basis for the overactive patients with an overactive bladder. Br J Urol bladder. Urology 1997;50(6A suppl):36-52; discussion ed with the resultant chronic irritation 1998;81:801-810. from such a catheter. 53-56. 19. Drutz HP, Appell RA, Gleason D, Klimberg I, 5. Mayo ME, Chetner MP. Lower urinary tract dys- It has been shown that the treatment of Radomski S. Clinical efficacy and safety of tolterodine function in multiple sclerosis. Urology 1992;39:67-70. neurogenic bladder in patients with mul- compared to oxybutynin and placebo in patients with tiple sclerosis is effective, beneficial, and 6. Hinson JL, Boone TB. Urodynamics and multiple overactive bladder. Int Urogynecol J Pelvic Floor Dys- cost-effective. It is recommended that all sclerosis. Urol Clin North Am 1996;23:475-481. funct 1999;19:283-289. patients with multiple sclerosis with lower 7. Litwiller SE, Frohman EM, Zimmern PE. Multiple 20. Ruscin JM, Morgenstern NE. Tolterodine use for urinary tract symptoms be appropriately sclerosis and the urologist. J Urol 1999;161:743-757. symptoms of overactive bladder. Ann Pharmacother 1999;33:1073-1082. evaluated and treated. 8. Kornhuber HH, Schutz A. Efficient treatment of neu- rogenic bladder disorders in multiple sclerosis with ini- 21. Thuroff JW, Bunke B, Ebner A, Faber P, de Geeter, Comment tial intermittent catheterization and ultrasound-controlled Hannappel J, et al. Randomized, double-blind, multi- training. Eur Neurol 1990;30:260-267. center trial on treatment of frequency, urgency and Detrusor hyperreflexia is common in incontinence related to detrusor hyperactivity: oxybu- patients with multiple sclerosis. The patho- 9. Wein AJ. Pharmacologic options for the overactive tynin versus propantheline versus placebo. J Urol physiologic process that causes multiple blad der. Urology 1998;51(2A Suppl):43-47. 1991;145:813-817; discussion 816-817. sclerosis often causes detrusor hyper- 10. Carter JP, Noronha-Blob L, Audia VH, Dupont AC, reflexia. The resultant symptoms can be McPherson DW, Natalie KJ Jr, et al. Analogues of oxy- butynin. syntehsis and antimuscarinic and bladder activ- very distressing and socially unacceptable ity of some substituted 7-amino-1-hydroxy-5-heptyn- for the patient with multiple sclerosis. 2-ones and related compounds. J Med Chem After a thorough urologic evaluation and 1991;34:3065-3074. the exclusion of other causes, appropriate 11. Gleason DM, Susset J, White C, Munoz DR, Sand treatment can be planned. PK. Evaluation of a new once-daily formulation of oxy- butynin for the treatment of urinary urge incontinence. Ditropan XL Study Group. Urology 1999;54:420-423.

12. Jonas U, Hofner K, Madershacher H, Holmdahl TH. Efficacy and safety of two doses of tolterodine ver- sus placebo in patients with detrusor overactivity and symptoms of frequency, urge incontinence, and urgen- cy: urodynamic evaluation. The International Study Group. World J Urol 1997;15:144-151.

S12 • JAOA • Vol 100 • No 3 • Supplement to March 2000 Fingerman and Finkelstein • The overactive bladder in multiple sclerosis