Urinary Aspects of Multiple Sclerosis chronic condition with innovative treatment strategies. Dr. Boris Friedman May 2, 2012 OBJECTIVES

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1 Urinary Aspects of Multiple Sclerosis chronic condition with innovative treatment strategies Dr. Boris Friedman May 2, 2012 OBJECTIVES 1) Definition and classification of MS 2) Interventional radiology related to MS 3) Current urologic therapy 1

2 Multiple Sclerosis : Definition A slowly progressive CNS disease characterized by patches of demyelination in the brain and spinal cord, resulting in multiple neurological symptoms MS: Epidemiology Most common neurodegenerative disease of young adults (20-40 years). Average age at onset 28 years. High prevalence (120/100,000) in : Europe, Canada, Northern USA, Israel, New Zealand Low prevalence (5/100,000) : Asia, Africa Migrants from high risk to low risk area retain the MS risk of their birth place only if they are at least 15 years of age at time of migration. Female : male ratio = 2:1 2

3 What causes MS? Combination of genes and environment Environment: Viruses (measles, rubella, mumps, and the herpes viruses) Bacterial infections Nutritional factors Exposure to animals, minerals, chemical agents, metals, organic solvents, and various occupational hazards 3

4 What causes MS? Genetic MS most probably polygenic Chromosomes 1, 6, 10, 17, and 19. Possible etiology of MS: Molecular mimicry An antigen initiates an immune response The resulting antibody bind to a self protein that mimics the antigen (auto-antigen) Auto-antigen is destroyed. In MS the BBB is broken down in a section of the brain or spinal cord, allowing T lymphocytes to cross over and destroy the myelin. 4

5 Results of Demyelination conduction block at the site of lesion slower conduction time along the affected nerve 5

6 Disease progression-axon loss Demyelination-induced axon loss is irreversible The progressive disability is believed to result from cumulative axon damage and degeneration, along with neuron lossà brain atrophy. Types of MS Classified by progression of symptoms Benign Relapsing-Remitting Secondary progressive Primary progressive 6

7 Types of MS Benign 10-20% of cases Minimal symptoms progress Return to normal between attacks Relapsing-remitting 75% to 80% of individuals with MS Unpredictable relapses lasting 24 hours or more followed by periods of months to years of remission Types of MS Secondary progressive ~80% of those with initial relapsing-remitting MS Occurs after years, median age of 39.1 neurological decline without any definite periods of remission. Insidious progression of clinical symptoms 7

8 Types of MS Primary progressive About 10% of individuals never have remission after their initial MS symptoms Decline occurs continuously Affects people who are older at disease onset Diagnosis MS is diagnosed on the basis of clinical findings and supporting evidence from ancillary tests: Magnetic resonance imaging (MRI) CSF- protein electrophoresis shows oligoclonal IgG bands (OGBs) Visual evoked potentials (VEPs) and somatosensory evoked potentials (SEPs) Future tests: measurement of specific Ab against myelin Typical MRI characteristics: white matter abnormalities 95% of patients white lesions indicate areas of fresh inflammation 8

9 EDDS: Expanded Disability Status Scale aims to describe the patient s clinical condition is based on the presence of certain symptoms in a typical neurological examination. The EDSS provides a total score on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability For example : If the patient s condition is rated as 5, they are able to walk about 200 metres without assistance or rest. However, a patient who scores 8 on the EDSS scale, is essentially restricted to a wheelchair Main symptoms of MS 50% to 80% of patients 9

10 Urinary dysfunction in MS Lower urinary tract dysfunction is mainly the result of spinal cord disease à the several types of resulting bladder dysfunction are those known to result from disconnection between centres in the brainstem and the sacral part of the spinal cord Upper tract complications are much less common in patients with MS than in spinal cord injury. The reason for this is unknown Urinary dysfunction in MS 10

11 Summary of Urodynamic Abnormalities Found in Patients With MS Urodynamic abnormality Neurogenic detrusor overactivity without bladder outlet obstruction Neurogenic detrusor overactivity with DSD Incidence in patients with MS (%) Detrusor underactivity 20 None 8 DSD, detrusor-sphincter dyssynergia 11

12 Objective :to determine the prevalence of urinary symptoms in MS Each underwent a urodynamic investigation and evaluated using Expanded Disability Status Scale (EDSS) Results 12

13 Results Bladder dysfunction was the initial symptom in 13.3% No correlation between disease characteristics and urinary symptoms, or urodynamic findings Mean age and mean illness duration were higher in patients with urinary symptoms Management of urinary complications in MS Management algorithm for patients with MS presenting with urinary tract symptoms. CISC, clean intermittent self catheterisation; PVR, post void residual volume; UTI, urinary tract infection. 13

14 Urodynamics in MS Elevated PVR In patients with refractory urinary urgency and incontinence When surgical or intravesical treatments are being planned Interventional radiology related to MS 14

15 Treatment options MANAGEMENT OF IMPAIRED VOIDING Clean intermittent self-catheterisation à Recommended in any patient with a persistent residual volume in excess of 150 ml Long term indwelling catheter (suprapubic) Treatment options MANAGEMENT OF OVERACTIVE BLADDER Antimuscarinic medications Detrusor injection of botulinum toxin A Neuromodulation Surgical treatments Agents used by MS patients that may have urinary affect Cannabinoids 15

16 Anticholinergics Anticholinergic agents may use as a first treatment choice for patients with MS presenting with neurological bladder dysfunction In the presence of raised post micturition residual volume, detrusor contractions will continue despite the use of antimuscarinicsà The post micturition residual volume should be rechecked in patients who have not responded to anticholinergics Anticholinergics CNS side effects :possible deterioration in memory or the onset of confusion (require vigilance in the cognitively impaired) To avoid CNS complication : use antimuscarinics which reduces crossing of the blood brain barrier or which selectively block the M3 receptor which is not known to be involved in cognition Intravesical oxybutynin has been shown to be effective in patients with spinal cord damage, including MS 16

17 Botulinum toxin A Block the presynaptic release of acetylcholine from the parasympathetic efferent nerve. à Reduce cholinergic nerve induced bladder activityà inhibitory effect on detrusor Botulinum toxin A Dykstra et al. [1988] were the first to introduce BTX injection therapy into urology. They injected it into the spastic external sphincter muscle in a quadrant pattern in 11 tetraplegic patients with DSD and high residual volumes. Maximal urethral pressure decreased by 27 cmh2o, and residual volume by 146 ml The effects lasted an average of 50 days 17

18 Botulinum toxin A Schurch et al reported the first preliminary data on detrusor injections At 6-week follow-up: overall mean reflex volume and maximal cystometric capacity increased significantly Maximal detrusor voiding pressure decreased from 65.6 to 35 cmh2o. The duration of action was at least 36 weeks 43 patients with MS suffering from severe urgency incontinence were treated with detrusor injections of botulinum toxin A. flexible cystoscope in a day-case setting was used to inject the detrusor muscle at 30 points Patients were followed up at 4 and 16 weeks after treatment by urinalysis, recording of AE, cystometry, voiding diaries, and QoL questionnaire 18

19 Results Kalsi et al

20 Results The duration of effect was shown to be 9.7 months with a range of 3 to 16 months Side effects Although before the treatment only 65% of the patients needed CISC, it subsequently became necessary in almost all patients UTI (9%) à Nevertheless, results show a positive impact of the treatment on patients QoL Kalsi et al

21 Conclusions the use of intradetrusor injection of BTA, through its extraordinary efficacy and minimal side effects, has transformed the management of patients with MS troubled by severe symptoms of an overactive bladder Kalsi et al.2007 EUROPEAN UROLOGY. July First large multicentre, randomised, double-blind, placebo controlled patients with neurogenic detrusor overactivity (14 UI episodes per week). MS(n=154) or spinal cord injury (n =121) 21

22 Patients received 30 intradetrusor injections of - Onabotulinumtoxin A 200 U (n = 92) - Onabotulinumtoxin A 300 U (n = 91) - Placebo (n = 92) The study drug was administered via cystoscopy as intradetrusor injections (1 ml each) approximately 1cm apart and to a depth of 2 mm, sparing the trigone. Primary end point : change from baseline in UI episodes per week (week 6). Cruz et al 2011 Change from baseline weekly urinary incontinence (UI) episodes during first 12 wk of treatment proportion of responders at week 6 22

23 Change from baseline in Incontinence Quality of Life (I-QOL) total score at weeks 6 and 12 Cruz et al 2011 Conclusions : Botox 200 U and 300 U significantly reduced incontinence and improved urodynamic parameters and QOL in patients with UI secondary to NDO. There dose-ceiling effect - no clinically significant additional benefit was observed with a dose of 300U Cruz et al

24 Botulinum Toxin A : Summary There is level I evidence that Botulinum toxin A should be recommended in patients with MS with detrusor overactivity who have failed to respond to oral antimuscarinics, and who are willing to perform clean intermittent self-catheterisation. Sacral neuromodulation Mechanism of action is thought to be through the inhibition of sacral afferent signals and hence interruption of inappropriate detrusor contractions Bosch and Groen* reported a reduction in incontinence episodes from 4 to 0.3 per day after sacral nerve stimulation in 6 patients with MS who suffered from refractory urge incontinence * Bosch and Groen.Lancet

25 Am J Obstet Gynecol 2007 Results were evaluated by pre- and postoperative voiding diaries. Ninety-three percent reported overall satisfaction PTNS :Percutaneous posterior tibial nerve stimulation PTNS inhibits bladder activity by depolarizing somatic sacral and lumbar afferents fibers PTNS: unilateral insertion of a 34-gauge needle electrode at a 60 degree angle approximately 5 cm cephalad to the medial malleolus and slightly posterior to the tibia, PTNS surface electrode on the ipsilateral calcaneus connected to Urgent PC stimulator. 25

26 21 patients with MS and LUTS unresponsive to anticholinergics were treated with 12 sessions of PTNS Transcutaneous PTNS (TPTNS) 26

27 Transcutaneous PTNS (TPTNS) Marianne de S`eze et al. Neurourology and Urodynamics 2011 A multicentric study enrolled 70 MS patients Intervention: Daily sessions of 20 min of TPTNS Results : - Clinical improvement of OAB was shown in 82.6% and 83.3% of the patients on D30 and D90, respectively - Urgency resolved in 51.3% of the patients - Frequency improved in 66.7% of the patients, with a reduction of 2.7 voiding episode per day - Cystometric response to TPTNS was positive in 51.2% of the patients (increase of >30% of cystometric capacity and/ or reflex volume) Surgical treatment Intractable urge incontinence: Bladder augmentation surgery and urinary diversion Catheter intolerant with frequent catheter blockages, recurrent UTIs, systemic sepsis or frequent peri-catheter leakage can also benefit from urinary diversion There is no evidence that patients with MS will suffer neurological deterioration following bladder surgery Women with MS may suffer from stress urinary incontinence should be offered surgical treatment for this problem 27

28 Agents used by MS patients that may have urinary affect: Cannaboids A questionnaire study of MS patients regularly using cannabis for symptom relief found that of those subjects with urinary problems, over half claimed improvement in urgency (Conscore 1997) Agents used by MS patients that may have urinary affect: Cannaboids Several studies demonstrated existence of cannabinoid receptors in rodent bladder, the activation of which reduces bladder motility. cannabinoid receptors were also found in regions of the central nervous system associated with bladder control 28

29 part of the multicentre trial of the Cannabinoids in Multiple Sclerosis (CAMS) study randomised 630 MS patients to receive oral administration of cannabis extract or matched placebo. The results showed a significant reduction in UIEs from baseline in both cannabis groups of between 33 and 38% from baseline compared with an 18% reduction for placebo. PATIENT INFORMATION Patients should be encouraged to access information on bladder dysfunction and its management

30 Conclusions Antimuscarinic agents may be the first line choice for treatment CISC can make a crucial difference to management of patients in whom incomplete voiding is contributing to bladder dysfunction. Botox is approved to use in MS and SCI Neuromodulation is an option in refractory patients Surgery should be reserved as last option 30