W15: Neurodegenerative disease's impact on bladder function: A multidisciplinary ... · 2019-10-01 · Society (ICS) joint report on the terminology for the conservative and nonpharmacological

W15: Neurodegenerative disease's impact on bladder

function: A multidisciplinary approach in diagnosis,

treatment and improving quality of life Workshop Chair: Christian Cobreros, Argentina

03 September 2019 14:00 - 15:30

Start End Topic Speakers

14:00 14:10 Understanding clinical differences in neurodegenerative

diseases

Christian Cobreros

14:10 14:15 Discussion Christian Cobreros

David Castro-Diaz

Carlos D'Ancona

Gustavo Garrido

14:15 14:25 Urodynamic Assessment in This Population. When? Why? Are

There Any Other Diagnostic Methods That You Should Use?

Gustavo Garrido


David Castro-Diaz

Carlos D'Ancona

Gustavo Garrido

14:30 14:40 Is it always easy to differentiate urgency from another clinical

presentation of these patients? How can we avoid over

medication?

David Castro-Diaz


David Castro-Diaz

Carlos D'Ancona

Gustavo Garrido

14:45 14:55 Oral medication. What do we have today? Is combination

better? How to decide when to move to another step?

Christian Cobreros


David Castro-Diaz

Carlos D'Ancona

Gustavo Garrido

15:00 15:10 Surgical Approach: Botulinum toxin, NTS, Neuromodulation

Carlos D'Ancona


David Castro-Diaz

Carlos D'Ancona

Gustavo Garrido

15:15 15:25 Bladder Outlet Obstruction in Neurodegenerative Patients Gustavo Garrido


David Castro-Diaz

Carlos D'Ancona

Gustavo Garrido

Aims of Workshop

In the past decades, the aim of the urologist was to treat the neurogenic bladder dysfunction through antimuscarinics and

surgical procedures (e.g. bladder augmentation). More recently, new drugs have been approved and new surgical procedures

have been developed, but more importantly a new role for the multidisciplinary approach has been established. We will

encourge this new concept of treatment to the audience, taking into account differences in incomes of different societes.

This a new workshop based on the state of the art knowledge and latest tecniques that are available and with an international

pannel of experts we will extent our experience in working under different economic circunstances

Learning Objectives

Identify the different patterns of neurological bladdder impacts of neurologic diseases.

Target Audience

Urology, Conservative Management

Advanced/Basic

Intermediate

Suggested Learning before Workshop Attendance

-ICS teaching module: Cystometry (basic module).

-ICS teaching module: Analysis of voiding, pressure flow analysis (basic module).

-ICS Workshop 2015: SUPPORTING SELF-MANAGEMENT OF THE NEUROGENIC BLADDER

-Neurourol Urodyn. 2017 Nov 17. An International Continence Society (ICS) report on the terminology for adult neurogenic

lower urinary tract dysfunction (ANLUTD).

-Eur Urol. 2014 Feb;65(2):389-98. Detrusor underactivity and the underactive bladder: a new clinical entity? A review of current

terminology, definitions, epidemiology, aetiology, and diagnosis.

-Curr Urol Rep. 2014 Sep;15(9):433. UTIs in patients with neurogenic bladder.

-Eur Urol. 2014 May;65(5):981-90. doi: 10.1016/j.eururo.2013.10.033. Epub 2013 Nov 1. An updated systematic review and

statistical comparison of standardised mean outcomes for the use of botulinum toxin in the management of lower urinary tract

disorders.

-Int Urogynecol J. 2017 Feb;28(2):191-213. An International Urogynecological Association (IUGA)/International Continence

Society (ICS) joint report on the terminology for the conservative and nonpharmacological management of female pelvic floor

dysfunction.

-Neurourol Urodyn. 2017 Jun;36(5):1243-1260. Epub 2016 Dec 5. Review. International Continence Society Good Urodynamic

Practices and Terms 2016: Urodynamics, uroflowmetry, cystometry, and pressure-flow study.

-Cochrane Database Syst Rev. 2014 Sep 23;(9):Types of indwelling urethral catheters for short-term catheterisation in

hospitalised adults.

-Cochrane Database Syst Rev. 2015 Dec 10;(12):Urethral (indwelling or intermittent) or suprapubic routes for short-term

catheterisation in hospitalised adults.

-Cochrane Database Syst Rev. 2017 Aug 8;8:WITHDRAWN: Intermittent catheterisation for long-term bladder management.

-Cochrane Database Syst Rev. 2013 Nov 18;(11): Review. Catheter policies for management of long term voiding problems in

adults with neurogenic bladder disorders.

Understanding clinical differences in neurodegenerative disesases

Christian Cobreros

Understanding clinical presentations in lower urinary tract dysfunction due to neurological disorders is very challenging.

Nevertheless, we do know that a wide variety of neurological conditions, acute or chronic, may affect the functionality of the

bladder, or sphincter, or the pelvic floor musculature innervation resulting in different conditions as well as similar ones. Their

clinical p resentations is determined by the site and the nature of the lesion.

In a simple classification, but a very useful one, is to base the clinical urodynamic findings in terms of the lesion level, we also

expected classical symptoms for each level:

• Suprapontine lesion: detrusor over activity due the lack of cortical inhibition, so storage symptoms are to be expected.

• Pontine micturition: if its preserved the control of the coordination of detrusor –sphincter mechanism will be preserved,

as this center is the responsible for the coordination of the relaxation of the sphincter and pelvic floor musculature

during bladder contraction

• Infrapontine-suprasacral lesions: this patient may present with a variety of clinical presentations due to a complete or

partial lesion, in case of cortex and coordinated signal from the pontine center are injured the patient could present

with neurogenic and detrusor over activity and sphincter dyssynergia

• Sacral micturition center: when this center is compromise we should expect involuntary contractions of the bladder as

if it is a reflex center for bladder contractions

• Infrasacral lesions: In these lesions, even the reflex bladder contractions are lot due to and interruption of the signals

between the bladder and all micturition centers, which will result in a clinical manifestation of a neurogenic detrusor

underactivity or arreflexic detrusor or even a sphincter deficiency.

Although this systematic and practice review of lesion level of neurogenic urological disease the clinical presentations in

neurogenerative diseases may vary form presented above, and this classification although its more useful in traumatic lesions but

in the clinical practice in neurogenerative diseases we should expected some evolution of the clinical presentations and in some

cases a completed different pattern within the clinical evaluation due to a progressive neurological disease.

Suprapontine Lesion (Brain)

Cerebrovascular Accident (Stroke)

- acute phase of CVAs patients

- post-acute (chronic) phase of stroke

- LUT dysfunction following stroke

Degeneration disease and syndromes

– Parkinsonian Syndrome

– Multiple System Atrophy

– Alzeihemer disease

– Intracranial tumors

Spinal cord : Infrapontine-Suprasacral lesions

– Demyelination (multiple sclerosis, transverse myelitis)

Spinal Cord and Peripheral Nervous System: Sacral-Infrasacral Lesion

– Intervertebral Disk Prolapse

– Peripheral Neuropathies (Diabetes Diabetes mellitus , radiation therapy)

Urodynamic assessment in this population. When? Why? Are there any other diagnostic methods that you should use?

Gustavo Garrido

Neurodegenerative disorders (ND) such as Parkinson´s Disease (PD), Alzheimer Disease (AD), Multiple Sclerosis (MS),

Multisystemic Atrophy (MSA) and other forms, are systemic diseases which leads to loss of control of various motor and non-

motor systems including the lower urinary tract. They are chronic and progressive challenging clinical entities which severely

affects quality of life. Frequently associated with lower urinary tract dysfunction like urinary incontinence, nocturia or urinary

retention, they often lead to complications like dermatitis, urinary tract infections, social retraction and could be the reason for

early institutionalization.

ND and Benign Prostate Hyperplasia (BPH) is highly prevalent in late middle-aged men, as Urinary Incontinence (UI) is in middle-

aged women, making the chance of concomitance of both pathology highly probable. This situation is a complex picture for

decision making.

Urodynamic studies are a useful diagnostic approach for understanding bladder and urethral dysfunction associated with

neurodegenerative disorders.

Overactive detrusor is the most common finding in urodynamic tests, however weak or absent voluntary detrusor function is also

a common finding. Findings like Detrusor-sphincter dyssynergia (DSD) is not uncommon. And half of the patients with PD have

mild urethral obstruction, due to impaired relaxation or delayed striated sphincter relaxation (also known as Sphincter

bradykinesia). In addition, the DSD is present in almost half of patients with MSA and Detrusor Hyperactivity during bladder filling

phase with Impaired Contraction during voiding (DHIC) is not uncommon.

Differentiating among different urodynamic conditions is particularly important for the evolution and prognosis of lower urinary

tract symptoms (LUTS), especially during the early course of the disease.

Urodynamic investigations in patients with ND is crucial for a correct diagnosis that leads to a better comprehension about the

physiopathology of such complex diseases.

Is it always easy to differentiate urgency from another clinical presentation of these patients (e.g. pain, hypersensitivity,

bladder irritation, infection)? How can we avoid over medication?

David Castro-Diaz

Many different conditions affecting the lower urinary tract function origin in the nervous system and it is important to recognise

that lower urinary tract symptoms (LUTS) may be one of the first signs of neurodegenerative disorders such Alzheimer’s disease

(AD), Parkinson’s disease (PD), dementia and PD-related disorders, Huntington’s disease (HD), Spinocerebellar ataxia (SCA or

Spinal muscular atrophy (SMA).

The symptom “Urgency”, defined as “the complaint of a sudden compelling desire to pass urine, which is difficult to defer”, is

sometimes one of the first symptoms indicating a neurodegenerative disorder which may later lead the patient to a fatal outcome.

PD patients and others with neurodegenerative disorders suffer loss of dopaminergic neurons inducing deficit or abnormality of

the neurologic control of micturition. More than 60% of patients with PD have LUTS and 30 % refer urinary incontinence. Patients

suffering neurodegenerative disorders often express LUTS and its onset may even serve as a diagnostic marker. Patients with

bladder pain syndrome/Interstitial cystitis (BPS/IC) and those with hypersensitive bladder, usually refer the symptom of urgency

as linked to fair to pain while patients with neurodegenerative disease or overactive bladder may express urgency as linked to fair

to incontinence. However, differentiating urgency from another clinical presentation is not easy particularly in patients with

cognitive disorders.

The onset of disease and timescale of symptoms may give clues to the cause of urinary problems. In some cases, LUTS occur early,

in the course of disease, whereas in others they may develop later, and could be confused with dysfunctions of a non-neurogenic

origin, such as benign prostatic enlargement or bladder outlet obstruction. The extent to which symptoms ‘bother’ the patient is

important and should be determined both subjectively and objectively, through a proper clinical history and the use of a voiding

diary, questionnaires and quality of life evaluation. This approach enables us to match therapy with patient´s motivation and to

monitor the success of treatment. The physical status of the patient will have an important influence on the capabilities for

maintaining a therapeutic strategy.

Attention should be paid to any medications taken by the patient, as several drugs can have detrimental effects on the urinary

tract. For example, diuretics prescribed for hypertension are associated with bladder overstretching. Furthermore, the use of any

antihypertensive agent in younger patients should alert the urologist to the likelihood kidney dysfunction due to obstructive

urophathy. Drugs that can alter the functioning of the urinary tract include opiate-containing painkillers, which reduce bowel

motility and antiparkinsonian agents which act as parasympatholytics and so impair detrusor contractility. Muscle relaxants used

to treat spasticity may also cause bladder hypocontractility and urinary retention; alternatively, they can induce pelvic floor laxity

leading to stress incontinence.

Sufferers of neurodegenerative disorders and elderly people require taking multiple medications which may have side effects and

unwanted drug reactions. Muscarinic receptors antagonists have been shown to cause cognitive disorders in elderly patients and

should be used with caution in patients with neurodegenerative disorders preferably choosing those drugs which do not cross the

blood-brain barrier. As some commonly used drugs have antimuscarinic properties it is important to avoid overmedication that

may increase the exposure to side effects. Potential signs of overmedication include drowsiness, physical complications like dry

mouth and ulcers, confusion, withdrawal from family or friends, hallucinations, dizziness or falls, fractures and seizures.

Oral medication. What do we have today? Is combination better? How to decide when to move to another step?

Christian Cobreros

We will review the most current literature on oral medication for neurogenic bladder to treat not only detrusor overactivity, but

also to improve bladder capacity, compliance and to treat urinary incontinence.

Medical therapies will be discussed in this section as we do have another section in which advances therapies as

onatoxinabotulinum will be discussed.

At the same time we will go into the improvment of quality of life of single drug vs combination and when it’s the optimal time

to move to the next step.

Drugs that have action in the storage phase

-Antimuscarinic drugs

-Choice of Antimuscarinic agents

-Side-effects

-Why do they have such a great drop out?

-Agonist β 3

-Its combination better ?

Drugs that have action in the pressure flow phase

-Alpha blockers

-Phosphodiesterase inhibitors (PDE5Is)

Drugs with different mechanisms of action

-Detrusor underactivity

-Decreasing bladder outlet resistance

-Increasing bladder outlet resistance

Is combination better?

When to move to the next step?

Surgical approach: neurostimualtion, botulinun toxin, neuromodulation, bladder augmentation

Carlos D'Ancona

The surgical approach in neurogenic detrusor overactivity is indicated when failures occur in pelvic floor muscles training and

drugs administration. The classification of failure is not well defined but we can consider it to be, when the patient is unsatisfied.

Between neurostimuation, neurotoxin, neuromodulation and bladder augmentation, the question is how to choose one of this?

Transcutaneous or percutaneous nerve stimulation is a minimal invasive treatment with good response in patients with multiple

sclerosis and Parkinson’s disease. The botulinum toxin has the advantage that is reversible after 8 to 12 months. Can be use as

test before a definite treatment. The results of BT are excellent improving in symptoms, in urodynamics and Quality of Life. There

is still the question for how long it is possible to use this treatment. Many papers show that it is effective for more than 10 years.

For neuromodulation treatment, there should be some neuronal connections between the bladder and brain. So, patients with

complete spinal cord injury are not a candidate for implantation of neuromodulation. However, patients with multiple sclerosis

and Parkinson disease present good results with a long follow up.

Performing bladder augmentation decreased much due to the other techniques used. This technique presents some adverse

effects such as bladder stone, urinary tract infection, perforation of the reservoir and others. The advantages of this technique

are the long-term good results. Myelomeningocele and spinal cord injury patients have a great life expectancy and this

technique should be considered.

Bladder outlet obstruction in neurodegenerative patients

Gustavo Garrido

Neurodegenerative Disorders (ND) and Lower Urinary Tract Symptoms (LUTS) due to Bladder Outlet Obstruction (BOO) caused

by Benign Prostate Hyperplasia (BPH) are very frequent findings in middle-aged men. Different ND can present contrasting

urodynamic conditions which makes treatment decision a challenging circumstance.

ND are systemic diseases which involves neuronal degeneration, leading to a loss of control of various motor and non-motor

systems, including the lower urinary tract. Motor symptoms such as gait difficulties, postural instability, rigidity and resting

tremor are frequent and have a direct impact in LUTS management. LUTS could precede non-motor symptoms like orthostatic

hypotension and other motor disorders in early stages of the disease leading to increased urological pharmacological related

treatment adverse effects.

Dementia, cognitive impairment and hallucinations are not uncommon in patients with PD and must be taken in account at the

time of BOO treatment.

Published data indicate a high incidence of postprostatectomy urinary incontinence in patients with ND and particularly PD,

compared to those without ND who undergo surgery. However poor outcomes of patients following prostate surgery might be a

result of the inadvertent inclusion of patients with MSA, which are misdiagnose as PD. And more than half of all MSA patients

have urinary symptoms before development of motor symptoms, resulting in a risk of inappropriate indication of BPH surgery.

Surgical treatment of patients with ND and comorbid BPH can be performed in selected patients. The correct neurologic

diagnosis together with the exact urodynamic condition are crucial in the decision for best treatment strategy.

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Brittain KR, Perry SI, Peet SM, Shaw C, Dallosso H, Assassa RP, et al. Prevalence and impact of urinary symptoms among

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Burney TL, Senapati M, Desai S, Choudhary ST, Badlani GH. Acute cerebrovascular accident and lower urinary tract

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Han KS, Heo SH, Lee SJ, Jeon SH, Yoo KH. Comparison of urodynamics between ischemic and hemorrhagic stroke patients;

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Thomas LH, Barrett J, Cross S, French B, Leathley M, Sutton C, et al. Prevention and treatment of urinary incontinence after

stroke in adults. Cochrane Database Syst Rev. 2005;3:CD004462.

Pizzi A, Falsini C, Martini M, Rossetti MA, Verdesca S, Tosto A. Urinary incontinence after ischemic stroke: clinical and

urodynamic studies. Neurourol Urodyn. 2014;33(4):420–5.

Patel M, Coshall C, Rudd AG, Wolfe CD. Natural history and effects on 2-year outcomes of urinary incontinence after stroke.

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Tsuchida S, Noto H, Yamaguchi O, Itoh M. Urodynamic studies on hemiplegic patients after cerebrovascular accident. Urology.

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Rotar M, Blagus R, Jeromel M, Skrbec M, Trsinar B, Vodusek DB. Stroke patients who regain urinary continence in the first

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Neurodegenerative disease’s impact on bladder function:

A multidisciplinary approach in diagnosis, treatment and improving quality of life

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Step 2, locate workshop

Step 3, scroll to find evaluation button

Step 4, complete survey –

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- CHRISTIAN COBREROS, MD

UROLOGIST, BUENOS AIRES, ARGENTINA

- DAVID CASTRO DIAZ, MD, Phd

UROLOGIST, TENERIFE, SPAIN

- CARLOS LEVI D’ANCONA, MD, Phd

UROLOGIST, CAMPINAS UNIV., BRAZIL

- GUSTAVO GARRIDO, MD, Phd

UROLOGIST, BUENOS AIRES, ARGENTINA

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Neurodegenerative disease’s impact on bladder function:A multidisciplinary approach in diagnosis, treatment and improving quality of life

UNDERSTANDING CLINICAL DIFFERENCES IN NEURODEGENERATIVE DISEASE

CHRISTIAN COBREROS, MDHOSPITAL DURAND , BUENOS AIRES

IUBA, INSTITUTO DE UROLOGIA DE BUENOS AIRESBUENOS AIRES, ARGENTINA

IPSEN (as PI in clinical studies, phase III)

ASTELLAS (as PI in clinical study , phase III)

X PROMEDON

CHRISTIAN COBREROS, MDHOSPITAL DURAND , BUENOS AIRES

IUBA, INSTITUTO DE UROLOGIA DE BUENOS AIRESBUENOS AIRES, ARGENTINA


Suzman R, Beard J. Global health and aging: preface. National Institute on Aging website. www.nia.nih.gov/research/publication/global-health-and-aging/preface. Published October 2011. Updated January 22, 2015. Accessed August 1,

2015.

NLUTS are one of the mostchallenging problems in urology

Ferri CP, Prince M, Brayne C et al. (2005). Global prevalence of dementia: a Delphi consensus study. Lancet 366 (9503): 2112–2117.

WORWILDE DEMOGRAPHIC AGING IS PROVING THAT HEALTHCARE IS IMPROVING

TIME-LENGHT OF SPECIFIC DISORDER(Multiple Sclerosis, Parkinson disease, Dementia, etc)

NEUROGENIC LOWER URINARY TRACT DYSFUNCTION (NLUTD)OF THE URINARY BLADDER AND URETHRA

CENTRAL OR PERIPHERAL NERVOUS SYSTEM DISEASES

THE TYPE OF DYSFUNCTION DEPENDS ON DAMAGE LEVEL, INTENSITY, AND EXTENT

NEUROLOGICAL CLINICAL PRESENTATIONS ARE AN STATIC CONDITIONS


NEUROGENIC LOWER URINARY TRACT DYSFUNCTION (NLUTD)OF THE URINARY BLADDER AND URETHRA

SYNDROME(BOO…)

TREATMENT

ALTERED BEHAVIOR

IMPAIREDATTENTION

MOTORDISSABILITY

NLUTD

THIS CLINICAL SCENARIOS MAY ALL BE COMBINED TOGETHER, SO ITS IMPORTANT TO DIFFERENTIATE THE SYMPTOMS IN EARLY STAGES

Alzheimer’s disease (AD)

Alcorn, G., Law, E., Connelly, P. J., & Starr, J. M. (2013). Urinary incontinence in people with Alzheimer’s disease. International Journal of Geriatric Psychiatry, 29(1), 107–109. doi:10.1002/gps.3991

• In Western countries is the most common cause of moving into a nursinghome

• Alzheimer’s disease is the most common cause of dementia

OAB

ReducedEnviromental

Selfawarness

Impaired attention and orientation

Increase the impact of OAB

Advance ageDeficits in attentionReduced verbal fluencyGait disorders

ALZHEIMER’S DISEASE / WML / DEMENTIA WITH LEWY BODIES

Prince M, Jackson J (2009). World Alzheimer Report. Alzheimer’s Disease International, London.

Desinhibition

Significantrelationship

with

Urinary Incontinence

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The management of NLUTD in Alzheimer’s disease (AD) it is difficult for several reasons:

1. Impaired attention and orientation interfere with the self-managmentof an OAB due to preventing voiding, double voiding, or an adequateresponse to urgency

2. Antimuscarinic drugs may worsen cognition and interact withacetylcolinesterase inhibitors given to improve cognition and activity of daily living


Dementia with Lewy bodies

6.5 years after dementia onset

3.2 years after dementia onset

White matter disease

5 years after dementia onset

Alzeheimer’s diseaseTime of onset

of Urinary

Incontinence is important


MARKER OF INSTITUTIONALIZATION

PREDICTOR OF POOR OUTCOME

Impossiblity to have a normal micturirion

Alzheimer’s disease Dementia with Lewy bodies WMD

Cognitive decline Gait disturbance(parkinsonism)

Neurogenic Detrusor Overactivity (NDO)

Dementia

Medial frontal cortex Basal ganglia

Cortex atrophyHippocampus atrophy

Loss of iniative

Urge Urinary Incontinence

Cerebral cortex


Takahashi O, Sakakibara R, Panicker J et al. (2012). White matter lesions or Alzheimer’s disease: which con- tributes more to overactive bladder and incontinence in elderly adults with dementia? J Am Geriatr Soc 60 (12): 2370–2371.


UDs NDO ??

0

10

20

30

40

50

60

70

80

AD alone AD + WMLs WMLs alone

%

%

Takahashi O, Sakakibara R, Panicker J et al. (2012). White matter lesions or Alzheimer’s disease: which con- tributes more to overactive bladder and incontinence in elderly adults with dementia? J Am Geriatr Soc 60 (12): 2370–2371.


WMLs

There is an alteretion of the bladder circuitof micturition

determining a PREMATURE “first decide to void”

HIGH URGENCY PATTERN URINARY INCONTINENCE

Hanyu H, Shimuzu S, Tanaka Y et al. Cerebral blood flow patterns in Binswanger’s disease: A SPECT study using three-dimensional stereotactic surface projections. J Neurol Sci 2004;220:79–84.


PET STUDIES SHOWN THAT FRONTAL HIPOPERFUSION IS COMMON IN WML

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Pavlakis AJ, Siroky MB, Goldstein I, Krane RJ. Neurourologic findings in Parkinson’s disease. J Urol. 1983;129(1):80–3

Yeo, L., Singh, R., Gundeti, M. et al. Int Urol Nephrol (2012) 44: 415. https://doi.org/10.1007/s11255-011-9969-y

Herzog J, Weiss PH, Assmus A, et al. Improved sensory gating of urinary bladder afferents in Parkinson’s disease following subthalamic stimulation. Brain 2008;131:132–45.

Winge K, Skau AM, Stimpel H, Nielsen KK, Werdelin L. Prevalence of bladder dysfunction in Parkinsons disease. Neurourol Urodyn. 2006;25(2):116–22

Bonnet AM, Pichon J, Vidailhet M, Gouider-Khouja N, Robain G, Perrigot M, et al. Urinary disturbances in striatonigral degeneration and Parkinson’s disease: clinical and urodynamic aspects. Mov Disord. 1997;12(4):509–13.

The net effect of the basal ganglia on the micturition reflex is inhibitory

MOTOR SYMTOMPS ----- related from degeneration of nigrostrital dopaminergic neurons

Urgency, Nocturia, Frequency

(onset of 5-6 years after motor symptoms)

PARKINSON’S DISEASE:

2º most common degenerative neurological disease

NON MOTOR ----- Dysfhagia (30-82%)Constipation (50%)Orthostatic hypotension (20-58%)Depression (>16%)Cognitive decline (6 times higher than healthy individuals)Sexual dysfunction (43-81%)LUTS

PARKINSON’S DISEASE

it was 8 points higher for fatigue (mean UPDRS score

27.5 6 13.6 vs. 19.6 6 11.0), 6.5 points higher for ap-

athy (28.7 6 14.9 vs. 22.2 6 11.8), and 6.4 points

higher for attention/memory problems (27.7 6 13.9 vs.

21.3 6 11.8) and gastrointestinal symptoms (26.6 6

13.8 vs. 20.3 6 10.9).

NMS and Cognitive Impairment

Twenty-one patients (2%) did not complete the

MMSE questionnaire and were excluded from analy-

ses. Eleven percent (N 5 119) of patients with PD had

MMSE score lower than 23.8.

Patients with PD and cognitive impairment com-

plained about more NMS than those without (Fig. 2).

Cognitive impairment (MMSE 23.8) was associated

with greater frequency of apathy, attention/memory, fa-

tigue, psychiatric, and respiratory features (Fisher exact

Test; P < 0.0001). A similar difference was found for

gastrointestinal symptoms (Fisher exact Test; P 5

0.0026) but not for other NMSd.

Twenty-nine percent of patients (N 5 311) had

missing items at the FAB and were thus excluded from

TABLE 3. Prevalence of NMS domains and disease stage

NMS domains

All

Disease Stage (Hoehn and Yahr scale)

1 1.5–2 2.5–3 4–5

N 5 1,072 (%) N 5 167 (%) N 5 515 (%) N 5 325 (%) N 5 49 (%)

Gastrointestinal 654 (61.0) 76 (45.5) 280 (54.4) 250 (76.9) 36 (73.5)Pain 653 (60.9) 85 (50.9) 302 (58.6) 218 (67.1) 39 (79.6)Urinary 614 (57.3) 72 (43.1) 266 (51.7) 222 (68.3) 44 (89.8)Cardiovascular 158 (14.7) 22 (13.2) 70 (13.6) 53 (16.3) 11 (22.5)Sleep 687 (64.1) 80 (47.9) 312 (60.6) 245 (75.4) 40 (81.6)Fatigue 623 (58.1) 63 (37.7) 291 (56.5) 224 (68.9) 40 (81.6)Apathy 328 (30.6) 41 (24.6) 138 (26.8) 119 (36.6) 24 (49.0)Attention/memory 479 (44.7) 63 (37.7) 208 (40.4) 168 (51.7) 32 (65.3)Skin 260 (24.3) 24 (14.4) 102 (19.8) 112 (34.5) 16 (32.7)Psychiatric 716 (66.8) 102 (61.1) 326 (63.3) 238 (73.2) 41 (83.7)Respiratory 191 (17.8) 16 (9.6) 80 (15.5) 74 (22.8) 15 (30.6)Miscellaneous 515 (48.0) 62 (37.1) 247 (48.0) 168 (51.7) 29 (59.2)

Cochran-Armitage trend test < 0.0045 (with Bonferroni’s correction) for all NMS except cardiovascular symptoms (P 5 0.0774).

FIG. 1. Prevalence of NMS domains according to patients’ clinical status. Fisher exact test < 0.0042 (with Bonferroni’s correction) for the fol-lowing NMSd: gastrointestinal, urinary symptoms, pain, sleep disorders, skin. Patients’ clinical status is indicated in the ‘‘Data Collection andMethods’’ section.

1645NONMOTOR SYMPTOMS IN PD

Movement Disorders, Vol. 24, No. 11, 2009




Tremor Bradykinesia

Postural instability

FOR THE PATIENT IT IS DIFFICULT TO UNDERSTAND

THE RELATION BETWEEN THE MOVEMENT DISORDERS AND

AUTONOMIC SYMPTOMS

NOCTURIA OAB

NOCTURNAL POLYUIRIA

ALTERED BLADDER CAPACITYY

VS

VS

VSINCREASED NOCTURAL URINE PRODUCTION

IN ORTHOSTATIC HYPOTHENSIONVS

INCREASED PVR DUE TO ORAL TREATMENTWITH ANTIMUSCARINIC

LUTS IN PD MAY REQUIRE A BETTER UNDERSTANDING OF THE NATURE OF BLADDER SYMPTOMPS AND REQUIRES

CONTINUOS REEVALUATION Stocchi F, Carbone A, Inghilleri M et al. Urodynamic and neurophysiological evaluation in Parkinson’s disease and multiple system atrophy. J Neurol Neurosurg Psychiatry 1997; 62: 507–11.

Berger Y, Salinas JM, Blaivas JG. Urodynamic differentiation of Parkinson disease and the Shy–Drager syndrome. Neurourol Urodynam 1990; 9: 117–21. Sakakibara R, Hattori T, Uchiyama T et al. Videourodynamic and sphincter motor unit potential analyses in Parkinson’s disease and multiple system atrophy. J Neurol Neurosurg Psychiatry 2001; 71: 600–6.

OPEN BLADDER NECK AT THE START OF BLADDER FILLING 53%

MSA PATIENTS

BASAL GANGLIA:

DETUSOR SPHINCTER DYSINERGIA IN 33% MSA

PATIENTS

INCOMPLETE BALDDER EMPTYING IS A SIGNIFICANT

FEATURE IN MSA (47%) (>100ml)

Ito T, Sakakibara R, Nakazawa K et al. Effects of electrical stimulation of the raphe area on the micturition reflex in cats. Neuroscience 2006; 142(4): 1273–80.

Ito T, Sakakibara R, Yasuda K et al. Incomplete emptying and urinary retention in multiple system atrophy: When does it occur and how do we manage it? Mov Disord 2006; 21(6): 816–23.

MULTIPLE SYSTEMIC ATROPHY

NDO IS THOUGHT TO BE MORE IMPORTANT URIDYNAMIC FINDING IN MSA PATIENTS

As in other Basal Ganglia disease Urinary Symptoms preceeds motors manifestations in MSA

Abrams P, Cardozo L, Fall M et al. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. NeurourolUrodyn 2002; 21: 167–78.

Sakakibara R, Hattori T, Uchiyama T et al. Urinary dysfunction and orthostatic hypotension in multiple system atrophy: Which is the more common and earlier manifestation? J Neurol Neurosurg Psychiatry 2000; 68

Yamamoto T, Sakakibara R, Uchiyama T et al. Questionnaire-based assessment of pelvic organ dysfunction in multiple system atrophy. Mov Disord 2009; 24: 972–8.

This indicates that many of these

patients seek urological advice

early in the course of their

disease.

MULTIPLE SYSTEMIC ATROPHYBASAL GANGLIA: MULTIPLE SYSTEMIC ATROPHYBASAL GANGLIA:

Ito T, Sakakibara R, Yasuda K et al. (2006). Incomplete emptying and urinary retention in multiple-system atrophy: when does it occur and how do we manage it? Mov Disord 21 (6): 816–823.

COMPLEX COMBINATION

IN MSA AS THE CLINICAL PRESENTATION GET WORSE

LESS BLADDER CAPACITY

INCOMPLETE BLADDER EMPTYING

URGE INCONTINENCE

CONTINENCE IS FURTHER

COMPROMISE

OPEN BLADDER NECK

WEAKNESS OF STRIATED URETHRAL SPHINCTER

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Multiple sclerosis

Modified from Fernandez O. J Neurol 2002; 249:

All the pathways can be affected simultaniously or not.

So ther are a lot a variable symptoms and combinations of them that can be present in

clinical presentation.

MRI findings, cuould be present, without a clinicall significance first af all, at the first stages of the desease (during the

first years) but they can turn into clinically significant.

MULTIPLE SCLEROSIS

Modified from Litwiller SE, Frohman EM, Zimmern PE. J Urol 1999; 161: 743–57.

Meta-analysis

urodynamic findings in MS patients

N: 1900

Bemelmans BL, Hommes OR, Van Kerrebroek PEV et al. Evidence for early lower urinary tract dysfunction in clinically silent multiple sclerosis. J Urol 1991; 145: 1219–24. Litwiller SE, Frohman EM, Zimmern PE. Multiple sclerosis and the urologist. J Urol 1999; 161: 743–57.

symptomatic patients

asymptomatic patients

Abnormal Urodynamics findings

100%

10%

MULTIPLE SCLEROSIS

TAKE HOME MESSAGES

• URODYNAMICS ASSESMENT IS NECESARY FOR DETECTING NDO WITH BLADDER OUTLET OBSTRUCTION AS IT IS A THREATENING CONDITION

IN NEURODEGENERATIVE DISEASES:

• CLINCAL UROLOGICAL MANIFESTATIONS SHOULD NOT BE TAKEN AS A UNIQUE MANIFESTATION; AGE, COGNITIVE IMPAIRMENT, MOTOR DISABALITY, COMORBID CONDITIONS SHOULD BE CONSIDER FOR A PROPER DIAGNOSIS

• UROLOGICAL MANIFESTATIONS CON PRECEED OTHER MANIFESTATIONS FOR YEARS

• CLINICAL AND URODYNAMICS UROLOGICAL FINDINGS CAN CHANGE OVER TIME DUE TO CHANGES IN THE NEUROLOGICAL DISORDER

THANK YOU

GRACIAS

OBRIGADO


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Urodynamic Assessment in This Population. When? Why? Are There Any Other Diagnostic

Methods That You Should Use? Prof. Dr. Gustavo L. Garrido

Hospital de Clínicas “José de San Martín”

Universidad de Buenos Aires

Argentina

Affiliations to disclose†:

Funding for speaker to attend:

Self-funded

Institution (non-industry) funded

Sponsored by:

Gustavo Luis Garrido

Nothing to Declare

X

† All financial ties (over the last year) that you may have with any business organisation with respect to the subjects mentioned during your presentation

Symptoms

38% to 71 % patients with PD reported symptoms• Storage Symptoms: urgency, frequency, nocturia, incontinence

• Voiding Symptoms: hesitancy, poor stream, interrupted stream, double voiding

Men >60 years may have BOO due to BPH.

Women may have SUI.

Sakakibara, R., Tateno, F., Kishi, et al (2012). Pathophysiology of bladder dysfunction in Parkinson’s disease. Neurobiologyof Disease, 46(3), 565–571.

Symptoms

Severity of LUTS increases with Progression of PD

Other Autonomic Dysfunctions are present

Impacts QoL

Autonomic Dysfunction

Magerkurth, C., Schnitzer, R., & Braune, S. (2005). Symptoms of autonomic failure in Parkinson's disease: prevalence and impact on daily life. Clinical Autonomic Research, 15(2), 76–82.

Falls

Falls are one of the most serious complications of gait disturbances in Parkinson’s disease (PD).

More than 50 % of PD patients fall at least twice in a given year and 1/5 of these patients experience trauma including bone fractures and intracranial hematomas as a result of a fall.

Urinary Incontinence was the factor that most significantly predicted falls status.

Balash, Y., Peretz, C., Leibovich, G., Herman, T., Hausdorff, J. M., & Giladi, N. (2005). Falls in outpatients with Parkinson’sdisease. Journal of Neurology, 252(11), 1310–1315.

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Urodynamic Findings

In a study of PD and multiple system atrophy (MSA) patients, foundurinary symptoms in 72% of PD patients that were mainly attributed to DO (81%) and external sphincter relaxation problems (33%)

Sakakibara, R. (2001). Videourodynamic and sphincter motor unit potential analyses in Parkinson’s disease and multiplesystem atrophy. Journal of Neurology, Neurosurgery & Psychiatry, 71(5), 600–606.

Bradykinesia and Pseudo Dysinergia

Pavlakis AJ, Siroky MB, Goldstein I, et al. Neurourological findings in Parkinson’s disease. J Urol 1983;129:80–3.

Detrusor hypocontractility

Bladder Outlet Obstruction

Sakakibara, R.

Bladder Outlet Obstruction Post Void Residuals

Sakakibara, R.

Urodynamic Findings

Sakakibara, R.

Videourodynamics

Sakakibara, R.

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Zhang, L., Haga, N., Ogawa, S., Matsuoka, K., Koguchi, T., Akaihata, H., … Kojima, Y. (2017). Case of possible multiple systematrophy with a characteristic imaging finding of open bladder neck during storage phase as an initial sign. International Journalof Urology, 24(11), 816–819.

Post Void Residuals

PVR > 150 ml during free-flow study might be more useful than other UDS parameters in clinically differentiating MSA from PD

Yamamoto, T., Asahina, M., Yamanaka, Y., Uchiyama, T., Hirano, S., Fuse, M.,Kuwabara, S. (2017). Postvoid residual predicts thediagnosis of multiple system atrophy in Parkinsonian syndrome. Journal of the Neurological Sciences, 381, 230–234.doi:10.1016/j.jns.2017.08.3262

Multiple Sclerosis

Over 80% of patients with multiple sclerosis report the incidence of LUT symptoms.

LUT symptoms generally appear after a mean of 6 years of evolution of the neurological disease

• Urgency: 38–99%• Frequency: 26–82%• Urge Incontinence: 27–66%

• SUI: 56%

• Voiding Symptoms: 6–49%

• Both storage and voiding symptoms coexist in 50% of patients

Phé, V., Chartier–Kastler, E., & Panicker, J. N. (2016). Management of neurogenic bladder in patients with multiple sclerosis. Nature Reviews Urology, 13(5), 275–288.doi:10.1038/nrurol.2016.53

Urodynamic in MS

Detrusor overactivity: 34–91%

Detrusor underactivity: 37%

Low bladder compliance: 2–10%

Detrusor–sphincter dyssynergia (DSD): 5–60%

DSD + detrusor overactivity: 43–80%

DSD + detrusor underactivity: 5–9%


Evolution MS

The prevalence of DSD increases with the duration of multiple sclerosis.

DSD:• 13% after 48 months of evolution

• 15% between 48 months and 109 months,

• 48% 109 months after diagnosis


Urodinamics in MS?

The UK National Institute for Health and Care Excellence (NICE) and a Turkish consensus statement recommend not to offer urodynamic investigations (such as filling cystometry and/or pressure–flow studies) routinely to patients with neurological disease who are known to have a low risk of renal complications (for example, most patients with multiple sclerosis)


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Urodynamics in MS?

The International Francophone Neuro-Urological Expert Study Group (GENULF) recommends using urodynamics in the initial diagnosis of patients

Urodynamic investigations:• patients with risk factors predisposing to upper urinary tract damage

• concomitant SUI

• failure to first-line treatment

• if surgical treatment is being considered


Nocturia

Considerable impact on QOL

Associated with sleep disturbances, falls, hip fractures and greater mortality.

Possible Causes: • sleep disorders

• reduced bladder capacity and DO,

• Nocturnal polyuria

Sakakibara, R. , Panicker, J. , Finazzi‐Agro, E. , Iacovelli, V. , Bruschini, H. and , (2016), A guideline for the management of bladderdysfunction in Parkinson's disease and other gait disorders. Neurourol. Urodynam., 35: 551-563. doi:10.1002/nau.22764

Nocturia

Non-Motor Symptoms:• nocturia (77.3%)

• Urinary urgency (61.9%)

• Constipation (59.8%)

• Dementia (58.8%)

• Insomnia (52.6%)

• Orthostatic hypotension (52.6%).

Tanveer K, Attique I, Sadiq W, et al. (October 04, 2018) Non-motor Symptoms in Patients with Parkinson’sDisease: A Cross-sectional Survey. Cureus 10(10): e3412.

Bladder Diary

Dementia and Related Diseases

LUTS in dementia patients can be caused• by the dementia itself

• by the neurological and urological pharmacotherapy

• by the ageing bladder or comorbidities.

Urgency and UI: Lewis Body Dementia > ALD

Detrusor Overactivity: LBD > ALD

Averbeck, M. A., Altaweel, W. , Manu‐Marin, A. and Madersbacher, H. (2017), Management of LUTS in patients with dementia and associated disorders . Neurourol. Urodynam. , 36: 245-252. doi:10.1002/nau.22928

Cerebral Spinal Fluid Tap Test in NPH

Normal Pressure Hydrocephalia

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CSF Tap Test in NPH

Urodynamic testing after lumbar puncture may predict the outcome of a shunt operation in these cases.

Ahlberg J, Norlen L, Blomstrand C, et al. Outcome of shunt operation on urinary incontinence in normal pressure hydrocephalus predicted by lumbar puncture. J Neurol Neurosurg Psychiatry 1988;51:105–8.

Before CSF Tap Test

After CSF Tap Test

Afterr Shunt Operation

Normal-Pressure Hydrocephalia

The recovery rate of bladder function after shunt surgery ranges 30–70% of patients.

The recovery rate of OAB and urinary incontinence in iNPH rangesaround 20-80%.

Sakakibara R, Panicker J, Fowler CJ, et al. ‘‘Vascular incontinence’’ and normalpressure hydrocephalus: Two common sources of elderly ncontinence with brain etiologies. Curr Drug Ther 2012;7:67–76.

Conclusions

Multiple and Diverse Variety of Symptoms

Multiple and Diverse Urodynamic Conditions

Check NMS (Autonomic Dysfunction) / Nocturia / Falls / QoL

Bladder Diary

PVR (MSA)

CFS Tap Test (NPH)

Identify Risk Factors (WMD)

Urodynamic / Videourodynamic…Always

White Matter Disease

For vascular incontinence, early identification of risk factors and initiation of secondary prevention are necessary.

Control of vascular risk factors: hypertension, dyslipidemiaand diabetes.

Prevention might arrest the disease progress.

Sakakibara R, Panicker J, Fowler CJ, et al. ‘‘Vascular incontinence’’ and normalpressure hydrocephalus: Two common sources of elderly incontinence with brain etiologies. Curr Drug Ther 2012;7:67–76.

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Correct Diagnosis

As many as 50% of MSA patients are commonly misdiagnosed as having PD. It is important to distinguish these 2 similar clinical entities because their urologic management is different.

Quinn N. Parkinsonism, recognition and differential diagnosis. Br Med J 1995;310:447–52.

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Self-funded


Sponsored by:

David Castro-Diaz

Astellas

Boston Scientific

Contura

Neomedic

Medtronic

x


It is always easy to differentiate urgency from another clinical presentation of these

patients (e.g. pain, hypersensitivity, bladder irritation, infection)? How can we avoid overmedication?

David Castro-Díaz

Spain

Workshop 15

Neurodegenerative disease's impact on bladder function:

A multidisciplinary approach in diagnosis, treatment and improving quality of life

Neurodegenerative disorders

Parkinsonian syndromes include PD and atypical parkinsonism.

Atypical parkinsonism includes multiple system atrophy (MSA), progressive

supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with

Lewy bodies (DLB).

• Alzheimer's disease (AD) and other dementias.

• Parkinson's disease (PD) and PD-related disorders.

• Prion disease.

• Motor neurone diseases (MND)

• Huntington's disease (HD)

• Spinocerebellar ataxia (SCA)

• Spinal muscular atrophy (SMA)

• Increase number of people with Neurodegenerative disorders due to worldwide aging

• 24.2 million people living with dementia in 2001 & 4.6 million new cases anually1

• Predicted to double every year to 80 million cases by 20402

• Total cost of brain disorders in 2010=798 billions€ in Europe (105b for dementia&14b for PD)3

• Need for medical care and hospital visits & reduce QoL among elderly

• High rate of dementia & dependence (PD and ND 70% in within 8 years4

1.-Ferri 2005, 2.-Matthews 2013, 3.-Olesen 2012, 4.-Aarsland 2005


Symptoms of advanced disease & comorbidity expected to rise accordingly


Bladder dysfunctionIntegrated part of the syndrome

Due to other conditions

A consequence of the treatment given

Comorbidity – ↑Complications

Cognitive dysfunction & dementia– ↑LUTS impact

LUT dysfunction rarely link to the neurologic disorder

• Multiple phenotypes sharing burden of disease progression without hope for cure

• It is important to identify symptoms & complications leading to further loss of

mobility and poorer QoL

• Mixed pathology is common

• Psychological factors & cognitive deficit interfere with copying

• LUTS have major impact on patients to stay independent

Degeneration of dopaminergic neurons of substantia nigra & depletion of striatal dopamine

Dopaminergic striatal activity induces selective disinhibition

Dopaminergic loss leads to hyperactivity of globus palidus & excessive input to thalamus & cortex-decrease activity of PAG, thalamic-insula pathway→Neurogenic detrusor overactivity


Crossman AR 2015

(Winge K 2015)

Brucker B 2017

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Pontine and suprapontine injuries EAU Guidelines 2019

Adapted from Winge K, 2015

LUT Symptoms in Parkinson Disease

Nocturia is the most common complaint = 60%

Urgency = 33% to 54%

Frequency= 16% to 36%

Urinary incontinence= 26% ♂ and 28% ♀1

Storage Symptoms

Voiding Symptoms

Reported less commonly than storage symptoms

Hesitancy & poor stream 44% to 70% ♂

Straining to void ♀2

1.-Bonnet AM 1997,2.-Campos-Sousa RN 2003, 3.-Sakakibara R 2001

LUTD In PD follow the onset of motor disturbances by 4 to 6 years1First symptoms in multiple system atrophy

Mckay JH 2018

Number of MSA subjects from the cohort of 30 subjects reporting specific symptoms: as the very first symptom (black), during the firstsymptomatic year (medium grey), and at the time of evaluation (light grey)

Chapple CR et al. BJU Int 2005;95: 335–40.

•Central mechanisms

•LUT mechanisms– Myogenic

• Overt detrusor contractions

• Micromotions

• Abnormalities of myofibroblasts

– Neural

– Urothelium

•Viscerocutaneous or pelvic floor causes

Khasar J Nsci 28:5721-30 2008

What Causes Urgency? OAB vs BPS

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Urodynamic findings between LUTS in PD and BPH/BOO

Urodynamic parameter Parkinson Disease BPH/BPO

Detrusor overactivity Phasic at low volume Mostly terminal

DOA incontinence More common Less common

Pressure flow Non-obstructed voiding Obstructed voiding

Sphincteric activity Bradykinesia Normal guarding reflex

Postvoid residual Insignificant Can be elevated

Urodynamics

Adapted from Defreitas GA 2003

Urodynamic Parameter PD MSA

Detrusor overactivity At small fill more profound At larger fill less profound

Sensation More sensate Delayed

DESD Rare Common

Straining/weak stream Rare Common

Voiding efficiency Preserved Impaired

PVR Insignificant High

Bladder neck on VUD Closed Open

Urodynamic abnormalities may differentiate between MSA and PD

Adapted from Brucker B 2017

Pharmacotherapy for LUTD

• Alpha adrenergic agonists: (Retention & related symptoms)

• Alpha adrenergic antagonist: (SUI)

• Antimuscarinics agents (UR & constipation)

• Angiotensin converting enzyme (ACE) inhibitors (cough)

• Calcium channel blockers (UR & constipation)

• Cholinesterase inhibitors (increase bladder contractility)

• Diuretics

• Psychotropic drugs

• Opioid analgesics

• Other drugs (pyridines, gabapentin, glitazones, non-steroidal

anti-inflammatory agents)

Older people and patients with neurodegenerative diseases take multiple drugs

Many of them are over-the counter (OTC) medications, vitamins or supplements

Adverse drug reactions result in > 700.000 visits to emergency/year

• AC+ participants showed lower mean scores on Weschler Memory Scale-Revised Logical Memory

Immediate Recall

• AC+ participants had a longer Trail Making Test

• AC+ participants had a lower executive function

composite score test

• AC+ participants had reduced total cortical

volume and temporal lobe cortical thickness and greater lateral ventricle and inferior lateral ventricle

volumes

Subjects with higher serum anticholinergic activity have lower cognitive performance scores

Anticholinergics and Cognitive Function

Amyloid plaque densities are more than 2.5-fold higher in cases treated with antimuscarinic medication in the long-term compared with untreated or short-term treated cases.

Comparison of senile plaque in Parkinson´s disease cases grouped according to antimuscarinic drub treatment none, short-term (<2 a), long-

term (>2 a)

Klausner, A.P. 2007

Antimuscarinic treatment in PD´s patients

Anticholinergic load in older people

Of 25 drugs commonly prescribed to older patients, 14 produced detectable anticholinergic effects

Tune LE, et al. Am J Psychiatry 1992;149:1393–4

• Ranitidine

• Codeine

• Dipyramidole

• Warfarin

• Isosorbide

• Theophylline

• Nifedipine

• Digoxin

• Lanoxin

• Prednisolone

• Cimetidine

• Furosemide

• Captopril

• Dyazide

The drugs in this study that showed no detectable anticholinergic effects were: Hydrochlorothiazide, Propanolol, Salicylic acid, Nitroglycerin, Insulin, Ibuprofen, Diltiazem,Atenolol,Metoprolol,Timolol

Commonly used drugs with anticholinergic properties

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How to avoid over medication

Recommendations of the American Geriatrics Society

Ask before taking an OTC

Make a list and keep it updated

Review your medications

Ask questions (why, how, when, etc.?)

Organize your medications

Follow directions

Report problems

Medication dont´s

Health in Aging Foundation 2015

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Dr. Christian CobrerosUrology Division - Hospital Carlos G. Durand

IUBA – Instituto Urologico de Buenos Aires

Buenos Aires - Argentina

Oral medication

What do we have today ?

Its combination better ?

How to decide when to move to another step ?


Dr. Christian CobrerosHOSPITAL CARLOS G DURAND – BUENOS AIRES

IUBA – INSTITUTO DE UROLOGIA DE BUENOS AIRESBuenos Aires - Argentina

IPSEN (as PI in clinical studies, phase III)

ASTELLAS (as PI in clinical study , phase III)

X PROMEDON


This presentation leads primary to specific issues in pharmacothaerapy in

neurogenic patients

IN THIS NEUROGENICS SUBPOPULATIONTHE MOST IMPORTANCE CAUSE OF UI

NDOAnd/or

INCOMPETENCE IN URETHRAL CLOSING FUNCTION

DECREASE STORAGE

PHASE DETRUSOR PRESSURE

INCREASE BLADDER CAPACITY

RESTORE A REGULAR BLADDER

EMPTYINGTOLERABLE

OR WITHOUT

PVR

ORAL MEDICATION WILL BE HELPFULL IN MILD DEGREES OF NDO WHEN SYMPTOMPS ARE MORE PROFOUND FURTHER TREATMENTS WILL BE NEEDED

Stohrer M, Blok B, Castro-Diaz D, Chartier-Kastler E, Del Popolo G, Kramer G et al. EAU guidelines on neurogenic lower urinary tract dysfunction. Eur Urol 2009; 56, 81–88.

AIMS OF ORAL TREATMENT IN PATIENTS WITH NDO Oral bladder relaxants: Antimuscarinics

Propiverine Trospium Tolterodine Solifenacine Darifenacine Fesoteradine Imidafenacine

Stöhrer et al.

NDOPropiverine vsOxybutynin

were equallyeffective inincreasingbladdercapacity andloweringbladderpressure

Better tolerability achieved significance for dryness of the mouth (LOE1).

quaternary ammonium

derivative withantimuscarinic

actions

Significantly * reduce the number of urinations *increase cystometriccapacity* increase mean effective volume of the bladder* reduce the incidence of urgent voids

not pass the healthy blood-brain-barrier

competitive muscarinic

receptor antagonist

a high selectivity in

vitro and exhibits

selectivity for the urinary

bladder over the salivary

glands

Ethans

in enhancing bladder volume and improving continence, but with less dry mouth

Solifenacinhas been the antimuscarini

c that has been more studied in

OAB

Krebs and Pannek(2013)

SONIC

Zesiewiczet.al.(2015)

High relative selectivity for the M3 receptor compared with other anticholinergics.

Dariferacinhas been extensively studied in OAB, but not in neurogenicbladder dysfunction

Prodrug

Active metabolite

5-HMT

Phase 3 trials have evaluated fesoterodine in

OAB

Sakakibara et. alN: 62Mean age: 70 yoNDOUDS + cognitive tests

Q: ameliorated

urinary urgencynight-timeurinaryfrequency andimprove qualityof life

three cognitivemeasures didnot changesignificantly

UDS : increasedbladder capacitybut NDO did notchangesignificantly

Oxibutinine

Bennett et al.

Franco et al.

Gajewski et al

Lee et.al

agent with a pronounced muscle relaxant activity and local anesthetic activity

• Oxibutinine

• Propiverine

• Trospium

30 – 40 % decrease in MAXIMUM DETRUSOR PRESSURE

30 – 40 % in CISTOMETRIC BALDEER CAPACITY Less pressure

More capacity

Antimuscarinics

LARGE PLACEBO CONTROL STUDIES

• Oxibutinine

• Propiverine

• Trospium

30 – 40 % decrease in MAXIMUM DETRUSOR PRESSURE

30 – 40 % in CISTOMETRIC BALDEER CAPACITY Less pressure

More capacity

Other parameters were not adequately investigated:

•UI inbetween cathteterization

•long term data, patients are in AM therapy for decades

All based on Urodynamcis measurements

Antimuscarinics

LARGE PLACEBO CONTROL STUDIES

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REFRACTORY PATIENTS FOR AN ORAL ANTIMUSCARINICCAN I USE DOUBLE THERAPY WITH ANTIMUSCARINCS ?

Nadeau G et al Double anticholinergie therapy for refractory neurogenic and nonneurogenic detrusor overactivity in children: long-term results of a prospective open-label study. Can Urol Assoc J 2014; 8(5-6):175-80.

Amend B, et al. Effective treatment of neurogenic detrusor dysfunction by combined high-dosed antimuscarinics without increased side-effects. Eur Urol. 2008 May: 53:1021-8

Amend et al , 2008With combined high-dosage antimuscarinic medications, 85% of the patients who previously demonstrated

unsatisfactory were treated successfully with combination of AM. The appearance of side-effects was comparable to that of normal-dosed antimuscarinics.

Nadeau et al , 2014Dual therapy in children with mielomeningocele(between combinations of oxybutynin, tolterodine and trospium) to be effective and well tolerated in a few patients with NDO• Urodynamic capacity improved • Maximal pressure of contractions decreased (p < 0.0001) 20 % of drop out for adverse events 36 months of F-UP

NDO and OAB in spinal cord injury patients on IC . Neither the monotherapy nor a combination of Oxybutynin with Trospium allowed full continence

What about patients with cognitive impairment in this population?

ANTIMUSCARINIC AGENTS

BLOOD-BRAINBARRIER COGNITIVE IMPAIRMENT

HOW MUCH ?

BIAS IN RESEARCH TRIALS

IN DEMENTIA CONCOMITANT TREATMENT WITH

DOPENEZIL SHOULD BE AVOID

THIS POPULATION IS PROBABLY ELDERLYSO IMPLICATIONS OF DRUG-DRUG

INTERACTIONS MAY APPLY

IT´S BLOOD-BARRIER INTACT IN STROKE, DEMENTIA, OR OTHER

NEUROLOGICAL DESESASE?

CLINICAL TRIALS ARE PERFOM IN PATIENTS WITH

INTACT HEMATO ENCEPHALIC BARRIER

What about antimuscarinics drug interactions?

SLOW GASTROINTESTINAL MOTILITY

POTENTIALLY CAN ALTER THE ABSORTION OF OTHER

DRUGS

CYP3A4 -MACROLIDE ANTIBIOTICSAZOLE ANTIFUNGALSCYCLOSPORINVINBLASTINE

CHOLINESTERASE INHIBITORS

were more likely to then be prescribed a bladder antimuscarinicthan those residents with dementia not given a cholinesterase inhibitor

PRESCRIBING CASCADE

Antimuscarinics

Propiverine Trospium Tolterodine Solifenacine Darifenacine Fesoteradine Imidafenacine

Stöhrer et al.

NDOPropiverine vsOxybutynin

were equallyeffective inincreasing bladdercapacity andlowering bladderpressure

Better tolerability achieved significance for dryness of the mouth (LOE1).

quaternary ammonium

derivative withantimuscarinic

actions

Significantly * reduce the number of urinations *increase cystometric capacity * increase mean effective volume of the bladder* reduce the incidence of urgent voids in neurogenicpatients

not pass the healthy blood-brain-barrier

a competitive muscarinicreceptor

antagonist

a high selectivity in

vitro and exhibits

selectivity for the urinary

bladder over the salivary

glands

Ethansin enhancing bladder volume and improving continence, but with less dry mouth

Solifenacin has been the antimuscarinicthat has been more

studied in OAB

Krebs and Pannek(2013)

SONIC

Zesiewiczet.al.(2015)

High relative selectivity for the M3 receptor compared with other anticholinergics.

Dariferacin has been extensively studied in OAB, but not in neurogenicbladder dysfunction

ProdrugActive metabolite

5-HMT

Phase 3 trials have evaluated

fesoterodine in OAB

Sakakibara et. al

N: 62Mean age: 70 yoNDOUDS + cognitive tests

Q: ameliorated

urinary urgencynight-time urinaryfrequency andimprove quality oflife

three cognitivemeasures did notchange significantly

UDS : increasedbladder capacitybut NDO did notchange significantly

ANTIMUSCARINC DRUGS IMPROVES BLADDER STORAGE FUNCTION

HIGH INCIDENCE OF SIDE EFFECTS ALTHOUGH CONTROLLED-RELEASED HAVE LESS SIDE EFFECTS THAT INMEDIATE REALESE PRESENTATIONS

IN PATIENTS WITH COGNITIVE IMPAIRED, ANTIMUSCARINICS SHOULD BE PRESCRIBRED WITH A WARNING, CAUSE THERE ARE PROVES THAT OXINBUTININE CAUSED SIGNIFICANT MEMORY DETERIORIATION

Beta 3 adrenoreceptor agonist

Wöllner J, Pannek J. Initial experience with the treatment of neurogenic detrusor overactivity with a new beta-3 agonost (Mirabegron) in patients with spinal cord injury. Spinal Cord 2015

N: 15 NDO SCIRetrospective studyMirabegron for a period of at least 6 weeks

Bladder evacuation per 24 h 8.1 vs 6.4, P=0.003

Incontinence episodes per 24 h 2.9 vs 1.3, P=0.027

Improvements in bladder capacity from 365 to 419 ml

Compliance

DP storage phase

28 to 45ml cm/H20

45.8 vs 30 cm H20

M of A: activation of adenylyl cyclase with the subsequent formation of cAMPdown-regulation of ACh release, resulting in an inhibitory control of parasympathetic activity

Mirabegron is an alternative in NDO if antimuscarinics are contraindicated

Cognitive impairment should not occur

WHAT IS SAID IN THE GUIDELINES ?

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What is “refractory to pharmacotherapy” or “drug” ?

Nitti VW, Kopp Z, Lin AT, et al. Can we predict which patient will fail drug treatment for overactive bladder? A think tank discussion. Neurourol Urodyn. 2010;29:652–657.

FURTHERMORE, THE MANAGEMENT IN THIS SITUATION IS INCONSISTENTLY NAMED

second-line treatment ? third line management ? step-up treatment ?

ICI guidelines

after attempting to treat OAB for 3 months with an

AM, taking the step toward “second-line” therapy isworthwhile and justified

Gormley EA, Lightner DJ, Faraday M, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: aUA/ SUFU guideline amendment. J Urol. 2015;193:1572–1580.

AUA guidelines

BTX-A , PTNS and SNMMay be offered carefully in

counselled patients who are “refractory” to 1° and 2° line

treatments

FDA

injections for adults with OAB who “cannot use or do not

adequately respond to a class of medications known as

anticholinergics.”

http://wwwfdagov/newsevents/newsroompress announcements/ucm336101htm.

So independently of the definitions HOW DO WE TREAT THIS PATIENTS WHEN ORAL TREATMENT

FALIED OR ADVERSE EVENTS CAN NOT BE TOLERATED ?

THANK YOU

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01/10/2019

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Carlos D’Ancona

Professor Urology

Unicamp



Self-funded


Sponsored by:

No conflict of interest

X


Quality of Life

Combination of clinical and urodynamics• Urinary incontinence

• Pdet.max > 40 cmH2O

Peyronnet B. et all. Progres en Urologie. 2015, 25: 1219-24.

1. Protection of upper urinary tract

2. Improvement of urinary incontinence

3. Restoration (or partial restoration) of LUT function

4. Improvement of patient’s QoL

Blok B. et all. EAU Guideline, 2018.

Botulinum toxin

Sacral neuro modulation

Bladder augmentation

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T1 image

with contrastT2 image

Multiple Sclerosis

Effective doses were 200-300 U for Ona/A and 500-750 U for

Abo/A injected under cystoscopic guidance in 20-30 sites

preserving or not the trigone.

Controlled studies with placebo

NATURE REVIEWS | UROLOGY. 2016, 13: 275 -88.

Significant results with 200 – 300U BoNT-A

88% need CIC

100 U BoNTA

Significative improvement of urgency, frequency, noctúria and

urinary incontinence

Improvement of urodinamics results

Espontaneus voiding

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• MS should be carefully evaluated however, there is a lack of randomized controlled trials

• SNM is usually offered if the neurological disorder can be considered stable or slowly progressive

• It has been reported that the loss of efficacy over time is a result of a new

relapse.

• One study found that patients with relapsing disease required the

adjustment of the stimulation parameters.

• 84% obtain > 50% improvement

• Eight patients with implanted SNM undergoing

MRI at 1.5 Tesla without safety concerns

Saral neuro modulation

9 patients

Increase maximal cystometric capacity

Decrease detrusor pressure

17 patients

15 were followed up for 15 months

14/15 (93%) had successful outcomes based on Patient Global

Impression of improvement

93% continent

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Conclusion - MS

Botulinum toxin → good results

SNM → select cases

Surgery → failure of others methods

Parkinson Disease

Corpo striatum

Produção de dopamina e acetilcolina

Controle do movimento/ postura

Blackett et al 2009

• 200U BoNT A

• 20 sites include trigone

• No urinary retention

Baldder diary & QoL

Urodynamic

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• 4 of 6 patients SNM are implanted

• Parkinson disease is progressive and may have variable

responses over time

Conclusion - PD


SNM → select cases

Surgery → exceptional

Spinal cord injury

Group I• 33 patients

• Oxibutinin 5mg. three times a day

Group II• 28 patients

• Intradetrusor Onobotulintoxin A

Ferreira RS, D'Ancona CAL, Oelke M, Carneiro MR. Einstein (Sao Paulo). 2018, 6;16(3)

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GROUP I

Oxibutininn=33

GROUP II

Onabotulinumtoxinan=28

p

Sex (M/F) 26/7 23/5 0.743*

Age (years) ± SD

(median)

31.94 ± 8.73

(31.00)

33.54 ± 11.86

(32.00)

0.839**

Time of lesion (months) ± SD

(median)

25.24 ± 10.29

(23.00)

23.75 ± 8.73

(22.00)

0.533**

Lesion level 0.956***

T1-T6 23 21

T7- T12 9 7

L1 1 0

ASIA score**** 1.000***

A 20 16

B 11 10

C 2 2

D 0 0

72.1

26.2

1.70

10

20

30

40

50

60

70

80

Car accidents Gun fire Falls

0

100

200

300

400

500

OxibutininaTBA

Grupo

Ca

pa

cid

ad

e c

isto

mé

tric

a m

áxim

a (

ml)

Dife

ren

ça

en

tre

an

tes e

ap

ós 2

4 s

em

an

as

. *Mann-Whitney test, p<0.001


-80

-60

-40

-20

0

20

OxibutininaTBA

Grupo

Pre

ssã

o d

etr

uso

ra m

áxim

a (

Pd

et m

ax)

Dife

ren

ça

en

tre

an

tes e

ap

ós 2

4 s

em

an

as



-16

-12

-8

-4

0

4

OxibutininaTBA

Grupo

Ep

isó

dio

s d

e p

erd

as u

rin

ári

as /

24

h

Dife

ren

ça

en

tre

an

tes e

ap

ós 2

4 s

em

an

as



-16

-12

-8

-4

0

4

OxibutininaTBA

Grupo

Esco

re d

o IC

IQ-S

F

Dife

ren

ça

en

tre

an

tes e

ap

ós 2

4 s

em

an

as



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Comparing the objective response (urodynamic study) and subjective (quality-of-

life questionnaires) of the two drugs, BoNT A proved to be more effective than

oxybutynin in all evaluated parameters, as well as having a better tolerability

profile.


40% discontinued of these:

52% no response

42% patinet’s request

• 50 incomplete SCI patients

• 32 implanted SNM

• No improvement in NDO during storage phase

• Regular urodynamic follow up is mandatory

• 8 articles met all inclusion criteria

• During the test phase, the merged success rate was 45%

• 99 patients underwent SNM implantation

• Success rate of permanent SNM was 75%

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Elevated filling pressure

Diminished bladder capacity

Not responsive to other treatments

Kurpad R, Kennelly MJ. Current Urology Report. 2014, 15: 444

It is very effective

88% satisfaction score in spinal cord injury

Failure of conservative treatment

More permanent solution

Change in bladder capacity + 130%

Change in bladder compliance + 87%

Change in presence of detrusor overactivity

-54

CIC to empty the bladder (72.5%)

UTI episodes (65%)

Urinary incontinence (10%)

Stones in the reservoir (32.5%)

Upper urinary tract stones (22.5%)

2015, 7: 85-99

>90% achieved nocturnal continence

91-100% achieved diurnal continence

QoL improved rates 90%

92% satisfaction in long term follow up

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Great benefit in female wheelchair patients

Conclusion - SCI


SNM → partial lesion

Surgery → excellent

• Preserve upper urinary tract

• Promote continence

• Listen to the patient

• The treatment should be adjusted to each

patient’s needs

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Bladder Outlet Obstruction in Neurodegenerative Patients

Prof. Dr. Gustavo L. Garrido

Hospital de Clínicas “José de San Martín”

Universidad de Buenos Aires

Argentina



Self-funded


Sponsored by:

Gustavo Luis Garrido

Nothing to Declare

X


PD and BPH are frequent concomitant diseases.


Alpha Blockers and PD

The use of alpha blockers in mild/moderate obstructions

offers limited but positive voiding improvement.

Gomes CM, Sammour ZM, Bessa Jr. J, et al. Predicting response to doxazosin in patients with voiding dysfunction and Parkinson disease: Impact of the neurological impairment. Neurourol Urodyn 2010;29:313.


The severity of neurological impairment was assessed

with the Unified Parkinson’s Disease Rating Scale (UPDRS).

https://www.neurotoolkit.com/updrs/


The severity of neurological impairment was a good predictor of the clinical response

UPDRS < 70 have 3:1 higher chance of clinical improvement than scores > 70


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In contrast, urodynamic parameters did not predict treatment outcomes


Patients may be treated with a combination of alphablocker

and anticholinergic/anti-muscarinic therapy.

Beware with orthostatic hypotension, which is already common in the PD population.

Madan A, Ray S, Burdick D, Agarwal P. (2017) Management of lower urinary tract symptoms in Parkinson's disease in the neurology clinic, International Journal of Neuroscience, 127:12, 1136-1149, DOI:10.1080/00207454.2017.1327857

Alpha Blockers and MSA

Especially in patients with MSA.

Brucker BM, Kalra S. Parkinson's Disease and Its Effect on the Lower Urinary Tract: Evaluation of Complications and Treatment Strategies. Urol Clin North Am. 2017 Aug;44(3):415-428. doi: 10.1016/j.ucl.2017.04.008.

PD and BPH Surgery

Retrospective study

N: 23 PD (MSA excluded). Completed TURP

Median Age: 73 yrs

Hoehn and Yahr Scale: 2

14 preoperative indwelling urinary catheter

TURP restored voiding in 9 patients (64%), and only 5 patients (36%) required catheterisation postoperatively.

Roth B, Studer UE, Fowler CJ, et al. Benign prostatic obstruction and Parkinson’s disease should transurethral resection of the prostate be avoided. J Urol 2009;181:2209–13.

PD and BPH Surgery

PD is no longer be considered a contraindication for transurethral resection of the prostate (TURP)


PD and BPH Surgery

Patients who are able to contract the sphincter are unlikely to develop urgency urinary incontinence after a prostatectomy, whereas the risk of post-prostatectomy incontinence is high in those who are unable to voluntarily contract the sphincter ani

Staskin DS, Vardi Y, Siroky MB. Post-prostatectomy continence in the parkinsonian patient: The significance of poor voluntary sphincter control. J Urol 1988;140:117–8.

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PD and BPH Surgery

Staskin DS, Vardi Y, Siroky MB. Post-prostatectomy continence in the parkinsonian patient: The significance of poor voluntary sphincter control. J Urol 1988;140:117–8.

The indication for prostatic surgery must be carefully considered and preceded by precise clinical, urodynamic and sometimes electromyography evaluation

Soler JM, Le Portz B. Bladder sphincter disorders in Parkinson’s disease. Annales. d’urologie 2004;38:S57–61.

MSA and BOO

There is a consensus between experts that the incontinence of MSA rarely improves after prostate surgery.

If there is a clinical suspicion that a patient has MSA, only non-surgical management of bladder symptoms should be considered

Sakakibara R, Panicker J, Finazzi-Agro E, et al. A guideline for the management of bladder dysfunction in Parkinson’s disease and other gait disorders. Neurourol Urodyn 2016;35:551–63.

MSA and BOO

A useful discriminator for the differential diagnosis of MSA from PD

Post-void residuals >100 ml.

Ito T, Sakakibara R, Yasuda K, et al. Incomplete emptying and urinary retention in multiple-system atrophy: When does it occur and how do we manage it. Mov Disord 2006;21:816–23.

MSA and BOO

Another predictor of MSA was an open bladder neck at the start of bladder filling without accompanying DO, which was found in 53% of patients with MSA but no PD patients

Sakakibara, R. (2001). Videourodynamic and sphincter motor unit potential analyses in Parkinson’s disease and multiplesystem atrophy. Journal of Neurology, Neurosurgery & Psychiatry, 71(5), 600–606.

The most important predictor of MSA was the neurogenic change of sphincter EMG, which is rarely seen in patients with PD. This simple test can differentiate MSA from PD

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Dementia and BPH Surgery

Limited evidence on outcomes of surgical

N:13

Age: 74 to 98.

4/13 urinary retention.

Postoperative complications:• 1 acute myocardial infarction

• 1 multiple gastric ulcers

• 1 decubitus ulcers

3 died beyond 3 months

Mean followup 26 months.

6 patients reported good urination

3 reported improvement although requiring IC

1 developed mild incontinence.

Yonou H, Kagawa H, Oda A, et al. Transurethral resection of the prostate for patients with dementia. Hinyokika Kiyo 1999;45:241–4.

Dementia and BPH Surgery

Green-LightPV

N:4 with severe dementia (Performance status of >3).

Mean age: 81 years old (range 67–94)

Mean prostate volume: 63.8 ml (range 19–120).

Mean peak flow rate increased to 18 ml/s

Mean post-void residual urine decreased to 46.9 ml at 3 months.

No postoperative complications were observed.

Kuwahara Y, Otsuki H, Nagakubo I, et al. Photoselective vaporization of the prostate in severe heart disease or dementiapatients who are not candidates for TUR-P. Nihon Hinyokika Gakkai Zasshi 2008;99:688–93.

Conclusions

Alpha Blockers

Unified Parkinson’s Disease Rating Scale (UPDRS).

Combined Therapy (Beware Orthostatic Hypotension)

Surgery and PD: OK

Check External Sphincter: VSC / EMG

Caution in MSA (PVR / VideoUrodynamics)

Surgery and Dementia: OK

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Documents

W15: Neurodegenerative disease's impact on bladder function: A multidisciplinary ... · 2019-10-01 · Society (ICS) joint report on the terminology for the conservative and nonpharmacological