Clare J.Fowler

National Hospital for Neurology and Neurosurgery

& Institute of Neurology, UCL

Annual Scientific Update in

Urogynaecology-

Joint RCOG/BSUG Meeting

Neurogenic bladder dysfunction

Aims • Background

•Brain processing of bladder afferents

•Urinary retention in young women

•Response to sacral neuromodulation

•Joint Best Abstract at ICS 2009

San Francisco “An fMRI study of the effect of

sacral neuromodulation on brain responses in

women with urinary retention”

• ICS Discussed Poster 32 “The possible role of opiates in women with urinary retention-

observations from a prospective clinical study”

S2-4 in cauda equina

pelvic & pudendal ns

PAG PMC

S2-4 in cauda equina

pelvic & pudendal ns

How full is my

bladder?

Is this the right

time and place

to void?

Fowler, de Groat and Griffith, 2008

Derek Griffiths’ Triple Circuit theory of bladder control

Circuit 1

Circuit 1 and 2

Derek Griffiths’ Triple Circuit theory of bladder control

Circuit 1, 2 and 3

Derek Griffiths’ Triple Circuit theory of bladder control

PAG

PMC

TH

ACC

H

RI/LPFC MPFC

PAG

PMC

MPFC RI/LPFC

TH

ACC

H

PMC

S2-4 in cauda equina

pelvic & pudendal ns

Urinary retention in young women

Manchester

Belfast

Edinburgh

Guernsey

Map of Referrals

Of women in retention

Key and Number of

referrals

2001 – 55 Referrals

2002 – 55 Referrals

2003 – 66 Referrals

2004 – 71 Referrals

2005 – 62 Referrals

2006/7 – 83 Referrals

London (within M25)

2001 – 17 Referrals

2002 – 18 Referrals

2003 – 26 Referrals

2004 – 27 Referrals

2005 – 21 Referrals

2006/7 – 35 Referrals

Birmingham

Cardiff London

55%

25%

6%

6%

9%

Cause undetermined(n=29)

Fowler's Syndrome(n=13)

Chronic intestinal pseudoobstruction (n=3)

Postoperative* (n=3)

Under investigation (n=5)

*Surgeries: Anterior resection of colon, rectopexy, caudal block

Causes for retention (n=53)

Primary disorder of sphincter relaxation

involuntary involuntary

Clinical History of FS

• Female

• Aged between onset of menarche and menopause

• No evidence of urological disease, gynaecological or

neurological disease

• Retention with a volume in excess of >1000 mL

• No sense of urinary urgency despite high bladder

volumes

• Straining does not help emptying

• Sense of “something gripping” or difficulty on removing

the catheter

• No history of urological abnormalities in childhood or

associated abnormalities of the urinary tract.

• Association with polycystic ovarian syndrome and

endometriosis

Laboratory Findings

• Raised urethral pressure (> 50% expected

value for age)

• Characteristic urethral sphincter EMG

• (Increased sphincter volume on USS

assessment)

urethral

afferents

PAG

Sacral cord

higher brain centres

bladder

afferents urethral

afferents

PAG

Sacral cord

higher brain centres

bladder

afferents

A B

“Pro-continence reflex”

Response to sacral neuromodulation (SNM)

20

5y

Time to recurrent retention0

10

20

30

40

50

70

80

90

100

110

120

130

140

1505y

0

10

20

30

40

50

60

70

80

90

100

110

FOWLER

NON-FOWLER

Time

Perc

en

t su

rviv

al

Success over time

P=0.005

De Ridder et al. Eur Urol. 2007 Jan;51(1):229-33.

PNE

An fMRI study of the effect of sacral

neuromodulation on brain responses in

women with Fowler’s Syndrome

Rajesh Kavia, Ranan DasGupta,

Hugo Critchley, Clare Fowler and

Derek Griffiths

Fowler’s Syndrome: our hypothesis

We expected:

• weak or no bladder signals in

response to bladder filling

– weak or no response at gateway

to brain (PAG)

• weak or no response to

bladder filling where

sensation is registered

– (insula)

• normalization by SNM

PAG

insula

Methods

• 6 women with FS aged 18 – 39 years

– had responded to temporary SNM therapy

– fMRI with 1.5 Tesla scanner

– 1 scan per 3.24s, covering brain in 36 slices

• 280 scans in 15 min

– measured brain responses to repeated rapid

bladder filling and withdrawal

Methods

• In each session:

– repeated infusion and withdrawal of 50 ml saline (over 7 s)

• with reporting of change in desire to void

• Response to filling taken as infusion minus withdrawal

empty full

infuse withdraw

Methods: 4 sessions

Near-empty

bladder

Full bladder

(> 600 ml)

No SNM

(baseline)

With (just after)

SNM

Baseline findings Fowler’s syndrome normal

blue = deactivated red = activated

insula

Findings

• We expected weak or no activation but

instead we find

– widespread brain deactivation in Fowler’s

syndrome

– the opposite of normal behavior

• Is this an artifact?

– If this is real we expect larger deactivation in

more pronounced disease (higher MUCP)

Test: deactivation more pronounced in

patients with higher MUCP: not an artifact

Higher MUCP

Mo

re d

eacti

vati

on

Which regions are deactivated?

• Right insula

– visceral sensory cortex

deactivated

• PAG (or nearby)

– gateway to brain

deactivated

insula

PAG

Effect of filling bladder and SNM

• With full bladder

• or after SNM

– more activation

– less deactivation

• More nearly normal

• The deactivations we saw before

– empty bladder

– no SNM

fill bladder

SNM

Where is activation restored by full

bladder and SNM?

• Restored activation of

PAG

– gateway to brain

– restored bladder signals

• and right insula

– seat of bladder sensation

• Patients report restored

sensation

– (and ability to void) insula

PAG

Older PET study showed similar PAG

behavior with SNM

fMRI PET

Method reminder

• In each session:

– repeated infusion and withdrawal of 50 ml saline (over 7 s)

• with reporting of change in desire to void

• Response to filling taken as infusion minus withdrawal

empty full

infuse withdraw

Suggested mechanism

SNM

Conclusions • Existing conundrum – how does SNM work in DO,

OAB AND retention?

In Fowler’s Syndrome SNM partly rectifies situation by

supplying afferent input to midbrain

• What does “blue brain” before SNM in FS mean?

Brain responses to bladder filling abnormal causing

deactivation instead of activation

Reduced bladder afferents, reduced sensation

Stronger with higher MUCP

Opiate use in 61 patients with urinary retention

Panicker, 2009 , ICS San Francisco

PAG

Sacral cord

higher brain centres

bladder

afferents urethral

afferents

PAG

Sacral cord

higher brain centres

bladder

afferents urethral

afferents

opiates

A B

Conclusions

• FS is a common cause of urinary retention in young women

• These patients respond particularly well to sacral neuromodulation

• It works by “re-informing” the brain about bladder sensation

• However, we are now alert to the possibility that opiates may have an additive effect on the pathophysiology of FS.