Multiple Sclerosis. Véronique Phé, MD, PhD Pitié-Salpêtrière Academic Hospital Department of Urology Paris 6 University Paris, FRANCE

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1 Queen Square Uro-neurology course, London, UK 20 th -21 st October 2016 Multiple Sclerosis Véronique Phé, MD, PhD Pitié-Salpêtrière Academic Hospital Department of Urology Paris 6 University Paris, FRANCE

2 Affiliations to disclose: Astellas: Enter Organisation/Relationship consultant, speaker, investigator Boston scientific: consultant Allergan: consultant, speaker Medtronic: speaker aaa Pierre Fabre: consultant Ipsen: investigator Funding for speaker to attend: Enter X in appropriate box Self-Funded x Institution (non-industry) funded Sponsored by: Enter Company Name

3 Prevalence of LUT symptoms in MS Reported by % of patients (Panicker 2009) Symptoms might occur during the early stages of the neurological disease and sometimes at the initial presentation (10%) (Nortvedt 2007) But generally after 6 years of evolution of MS (Mayo 1992) Only 43% of patients with the disease with moderate to severe OAB symptoms had their symptoms evaluated by a urologist (Mahajan 2010)

5 Clinical presentation Wide range of LUT symptoms (Norvedt 2007, Giannantoni 1998, Amarenco 1995, Betts 1993, Koldejwin 1995, De Seze 2007) - Storage phase: 17-82% - Voiding phase: 34-73% - Storage + voiding phase>50% - Stress urinary incontinence: 56% Correlation of prevalence of LUT symptoms with - Severity of pyramidal syndrome - Presence of cerebellar syndrome - EDSS score - But precise correlation between neurological lesions and LUT dysfunction difficult - And symptoms can vary with time ((Cianco 2007) No correlation between type of symptoms and (Mahajan 2010) - Age - Duration and type of MS

6 Urodynamic presentation References N= Duration of MS Detrusor overactivity Detrusor hypoactivity Detrusor normal activity Low bladder compliance Detrusor sphincteric dyssynergia Amarenco ,8 70% 9% 21% 2% 82% Araki ,8 44% 37% 3% 3% 41% Betts % 0% 9% Gallien % 25% 34% 59% Giannantoni ,5 81% 24% 10% 10% 42% Kasabian % 31% 13% 5% Koldewijn ,5 34% 8% 34% 13% Frequent coexistence - DO+ DSD (43-80%) - DO + acontractility (5-9%) Poor clinical/urodynamic correlations

Urological complications of LUT dysfunction Lower UTIs :

bladder: 4-30% Ureteral reflux: 0-15% Stones : 2-11% Upper

7 Urological complications of LUT dysfunction Lower UTIs : 13-80% Upper UTIs: 0-23% Morphological modifications of bladder: 4-30% Ureteral reflux: 0-15% Stones : 2-11% Upper urinary tract dilation: 0-25% Kidney failure: 0-10% Bladder cancer: 0.29% 3 risk factors (De Sèze 2007, Castel- Lacanal 2015) - Duration of MS (>15 y) - High intravesical pressures - Indwelling catheter

8 Clinical investigations- Bladder diary The ICS recommends the use of a bladder diary

9 Clinical investigations- Quality of life assessment Only Qualiveen (MAPI research trust, Lyon, France) is validated for evaluation of the QOL of patients with neurological disease (Bonniaud 2005) Recommended by the EAU 30-item questionnaire - Bother (9 items) - Constraints (8 items) - Fears (8 items) - Feelings (5items) Currently translated into six different languages.

10 Clinical investigations- Urinalysis See yesterday course

11 Ultrasonography Renal ultrasonography - Entirely normal - Hydronephrosis - Stones Uroflowmetry and Post-void residual volume

12 Urodynamic investigations DO NOT offer urodynamic investigations routinely to patients who are known to have a low risk of renal complications DO offer urodynamics in the initial diagnosis of patients DO offer urodynamics Risk factors predisposing to upper urinary tract damage Concomitant SUI Failure of first-line treatment Surgical treatment

13 Other investigations Creatinine clearance Cystoscopy, retrograde uretrocystography on a case-by-case basis

14 Management Goals: To protect the upper urinary tract To achieve continence To improve quality of life

15 Guidelines for managing bladder dysfunction: consensual approach Urologists Primary care Neurologists Stakeholders Nurses- eg. continence nurses Patient groups

16 Management Storage symptoms

17 General measures and physical treatments A fluid intake of L/day Reduction in caffeine intake <100 mg/day to reduce symptoms of the storage phase (Bryant 2002) Pelvic floor rehabilitation (De Ridder 1999, De Sèze 2014) MS Patients with mild disability Intact neural control of their pelvic floor muscles No cognitive impairments

18 Antimuscarinics In patients with MS, the evidence base supporting the clinical use of antimuscarinics is limited Not all currently available antimuscarinics have been systematically investigated in patients with MS and their use is often based upon data from other patient groups Cochrane Review (Nicholas, 2010) - 3 RCT in MS Hebjorn 1977, n=64, oxybutinin Gajewski 1986, n=34, oxybutinin Fader 2007, n=34, flavoxate - incontinence episodes and intravesical pressure - Improvement of QOL But sides effects: >2/3 of patients stop the treatment after 6 months

5 Outcomes in MS Same efficacy as SCI: urinary incontinence, urodynamics, QOL

19 Intradetrusor botulinum toxin A injections DIGNITY (Cruz 2011, Ginsberg 2012) N=241 placebo, N=227 botox, 57.3% MS EDSS <6.5 Outcomes in MS Same efficacy as SCI: urinary incontinence, urodynamics, QOL Complications vs placebo - Acute urinary retention 29.5% (vs 4.6%) - De novo ISC 31.4% (vs 4.5%) - UTIs 53.5% (vs 29.2%)

20 Intradetrusor botulinum toxin A injections Khan, 2011 Prospective, n=137 MS, repeated injections of Botox 300 U FU= 29 mo (9-80) Almost all ISC 83% incontinent before Botox vs 76% dry 4 wks after Botox

21 UI Episodes/Day (Mean Change From Baseline) *P<.001 vs. placebo based on least-squared means; P<.001 vs. placebo based on mean change from baseline. OnabotA = onabotulinumtoxina; UI = urinary incontinence. Proportion of Patients Achieving 100% UI Reduction (%) Efficacy and Safety of OnabotulinumtoxinA 100U for Treatment of Urinary Incontinence Due to Neurogenic Detrusor Overactivity in Non-catheterising Multiple Sclerosis Patients Chartier-Kastler et al., EAU OnabotulinumtoxinA 100U significantly reduced daily UI episodes versus placebo Over 50% of onabotulinumtoxina-treated patients achieved 100% UI reduction * OnabotA 100U (n=66) Placebo (n=78) 10.3

22 I-QOL Scores (Mean Change From Baseline) * Improvements in I-QOL total summary score were significantly greater with onabotulinumtoxina 100U versus placebo and were approximately 3 times the MID Compared with placebo, onabotulinumtoxina 100U treatment resulted in significant improvements in MCC and significant reductions in MDP during first IDC OnabotA (n=66) 9.92 Placebo (n=78) MID OnabotulinumtoxinA was well tolerated with no unexpected safety signals CIC rate was 15.2% with 100U onabotulinumtoxina in this study compared to 31% with 200U in non-catheterising MS patients in the phase 3 studies 1 Conclusions In non-catheterising MS patients who were inadequately managed by 1 anticholinergic, treatment with onabotulinumtoxina 100U resulted in significant and clinically-meaningful improvements from baseline in incontinence, urodynamic parameters, and QOL *P<.001 vs. placebo based on least-squared means. 1 Ginsberg D, et al. Adv Ther (9):819. I-QOL = Incontinence Quality of Life; MID = minimally important difference (+11 points); OnabotA = onabotulinumtoxina.

23 Tibial nerve stimulation De Sèze, 2011 Prospective and multicentric N=70 MS, EDSS <7 Stimulation 20 min/d Improvement of symptoms at D30 and 90 in 82.6% et 83.3% of patients Well-tolerated

24 Sacral neuromodulation Minardi, 2012 Retrospective n=25 MS FU 49.4 mo, age 45.2 y

25 Augmentation cystoplasty Karsenty 2006

Incontinent urinary diversion If catheterisation is impossible, incontinent

Ultimately, it could be considered in patients Who are wheelchair bound or

In devastated LUTS When the upper urinary tract is severely compromised In

26 Incontinent urinary diversion If catheterisation is impossible, incontinent diversion with urine collecting devices are indicated. Ultimately, it could be considered in patients Who are wheelchair bound or bed-ridden (skin ulcers included) With intractable and untreatable incontinence In devastated LUTS When the upper urinary tract is severely compromised In patients who refuse other therapies Always discuss cystectomy Complications: skin, stoma, infection permanent follow-up

4%) - Chronic urinary retention or indwelling catheter (54.2%) - Urinary incontinence (37.

27 Incontinent urinary diversion: Ileal conduit Guillotreau 2011 Prospective N=48 neurological patients, among them n=38 MS with EDSS 7.5 Cystectomy + ileal conduit (laparoscopy) Indications - Recurrent UTIs (60.4%) - Chronic urinary retention or indwelling catheter (54.2%) - Urinary incontinence (37.5%) - Chronic renal disease (22.9%) - False passage due to catheterization (6.3%) - Improvement of bladder related QOL - No improvement of overall QOL

28 Management Voiding symptoms

Catheterization Intermittent self-catheterization=

catheter - Preservation of the urethra - But risk

urethral lesions Barnes DG et al, Br J Urol

29 Catheterization Intermittent self-catheterization= method of choice to empty the bladder Suprapubic catheter - Preservation of the urethra - But risk of infection in 60% patients Indwelling catheter: to avoid? - Complications: Kidney, infections, stones, urethral lesions Barnes DG et al, Br J Urol 1993;72(2): Perrouin-Verbe B et al, Paraplegia 1995;33(11): Perkash I et al, J Urol 1993;149(5): Mitsui T, et al, Eur Urol 2000;38(4): Jacobs Scet al, J Urol 1978;119(6):740-1

30 Self-intermittent cateterization Castel-Lacanal et al Prospective, N=23 MS, 15F/8M, 49.3 y+/-10.3, EDSS 4.5 (1-7.5) FU 9.3 mo +/- 3 mo

Continent urinary diversion For cosmetic reasons, the umbilicus

request for it Well controlled bladder (Urodynamics +++) Hand

patients) The continence rates are over 80% and good protection

31 Continent urinary diversion For cosmetic reasons, the umbilicus is often used for the stoma site Pre-requisites: Patient request for it Well controlled bladder (Urodynamics +++) Hand dexterity must be good (tetraplegic patients are challenging patients) The continence rates are over 80% and good protection of the upper urinary tract is achieved. But complications: stenosis, leakage

32 Continent urinary diversion Karsenty 2006

33 Follow-up monitoring Presence of specific risk factors - Duration of multiple sclerosis >15 years - Presence of an indwelling catheter - Ample uninhibited detrusor contractions - High detrusor pressure - DSD For patients who are risk-free: systematic annual evaluation - 3-day bladder diary - Uroflowmetry with measurement of the post-void residual volume - Urodynamic investigation every 3 years (GENULF) or in the event of second-line or intravesical treatment being required, or when a patient is considered to be at risk of damage to the upper urinary tract (UK consensus) For patients who are deemed to have a higher risk of rapid worsening of LUT symptoms - Ultrasonography of the urinary tract - Measurement of renal creatinine clearance - Quality-of-life assessment - Urodynamic Expert multidisciplinary team

34 Conclusions LUT symptoms are common in patients with MS Symptoms vary in type and severity, and can evolve with progression of the disease Consensual approach and consideration of possible progression of the disease ISC is essential for the management of voiding symptoms, but might also have a role in management of those with storage symptoms Intradetrusor botulinum toxin A injections are a highly effective treatment Surgical options should be performed only after careful selection of patients Regular long-term follow-up monitoring

Guidelines on Neurogenic Lower Urinary Tract Dysfunction

Guidelines on Neurogenic Lower Urinary Tract Dysfunction (Text update March 2009) M. Stöhrer (chairman), B. Blok, D. Castro-Diaz, E. Chartier- Kastler, P. Denys, G. Kramer, J. Pannek, G. del Popolo, P.