Professor Vik Khullar, BSc, FRCOG, MD, AKC.

Disorders of bladder function

JOINT HYPERMOBILITY SYNDROME (JHS)

üIncreased passive or active movement of a joint beyond its normal range.

üJHS is a common, heritable disorder of connective tissue

üFrequently overlookedü It is almost certainly identical to the Ehlers-Danlos

Syndrome, hypermobility type.

BJHS – A MULTISYSTEM DISORDER

Fikree et al 2013

LUTS in children with EDS

De Kort et al 2003

• 89 JHM children and 116 controls• Diagnosed on Beighton and Bulbena scales• Girls day and night incontinence 38% vs 14%

and 13% vs 2%• Urinary tract infections 24% vs 11%

• 175 women with lower urinary tract dysfunction• Five point self reported questionnaire• EDS diagnosed in 26% (46)• Women with EDS had an odds ratio of 1.53 (95% 0.78

– 3.03) to demonstrate Detrusor overactivity • USI and UMI were less likely diagnoses for women in

the EDS group

Derpapas et al 2015

JHS and lower urinary tract dysfunction

LUTS in women with JHM

Masteroudes et al 2013

• 30 women with EDS (Beighton score +4)• 30 controls• Kings Health Questionnaire• Urinary incontinence 60% vs 30%• Anal incontinence 23% vs 0%

• Significant quality of life impairment

Urinary incontinence in members of the HMSA

• 373 female members (confirmed hospital diagnoses)• 148 responses (39%)• Urinary incontinence reported 68.9%

(controls 30%)• Faecal incontinence reported 14.9%

(controls 2.2%)• Increasing BMI associated with FI

Arunkalaivanan et al 2009

POTS and urinary incontinence

• 22 women with confirmed POTS and EDS

• 20 women found to have detrusor overactivity on urodynamics

• Painful bladder co-existing in 14 women

Ford et al 2016

EDS-hypermobility type and LUTS

• More common in women (4:1 ratio)

• Divide into 3 groups• Infrequent voiders some who then develop retention• Frequency/urgency• Painful bladder pain

Cystoscopy

MAST cell count 58/mm2

BACTERIA IN THE BLADDER WALL

üElectron microscopic studies in mice bladders have shown that E coli has the ability to invade superficial bladder epithelium and mature into biofilms, creating pod like bulges (bipods) on the bladder surface.

üThese biopods are capable of evading host defences and serve as a source for recurrent cystitis

Andersson GG et al

Image of a biopod on the surface of mouse bladder

Intracellular colonies of bacteria inside the biopod

Hanan et al 2011

BACTERIA IN THE BLADDER WALL

Potential roles of the urinary microbiota in homeostasis of the urinary tract

Whiteside, S. A. et al. 2015

Urinary microbiome and incontinence

ØExtended Error Bar showing that AerococcusChristensenii is associated with patients suffering fromUrinary Incontinence.

Host bacterial and inflammatory interaction

Hanan et al 2011

INNATE IMMUNITY

• MAST CELLS AND HISTAMINE

INNATE IMMUNITY –The Lectin Pathway

Immune System and the bladder

• Higher rates of Painful Bladder Syndrome in women with EDS

• 40% have reduced diamine oxidase activity (less than 10, normal above 20) such that they have histamine intolerance

• 35% have reduced mannose binding lectin levels associated with recurrent urinary tract infections

INNATE IMMUNITY

ü Increased Inflammation due to MAST cells

üOverproduction of mast cells

üReduced breakdown of histamine by Diamine oxidase and other enzymes (histamine intolerance)

EDS hypermobility type and Inflammationü 25 families with EDS-h investigated for their

symptoms ofü Fatiqueü Fibromyalgiaü Irritable bowel syndromeü Skin rashes

ü Increased symptoms associated with increased serum tryptase levels and more copies of the alpha-tryptase gene

Lyons et al 2016

Investigation of urine infections in hEDS

• 200 women with confirmed urinary tract infections and hEDS

• Urinalysis was only positive in 10%

• 40% had multiple organisms grown

• 60% had growths below the standard cut off of 100,000 cfu/ml

Khullar et al 2019

Treatment of Bladder problems in hEDS

• Treatment towards dominant symptom

• Overactive bladder then physiotherapy and mirabegron work well

• Stress incontinence involves physiotherapy and potential surgery but care about diagnosis

• Bladder pain responds to oral or intravesical medications but infection must be treated

Conclusion

• Higher rates of overactive bladder in women with EDS –hypermobility type

• Urine and bladder biopsies show multiple organisms often less than 105 cfu/ml

• Reduced diamine oxidase activity or mannose binding lectin leading to more urinary tract infections or inflamed bladders secondary to abnormal innate immune system