Pathophysiology of OAB

1. Pathophysiology of OAB Jun Jang Deajeon St. Mary’s Hospital

2. 3 3 Definition of OAB 1 3 Symptoms of OAB 2 Pathophysiology of OAB Conclusions 4 www.themegallery.com Contents

3. www.themegallery.com Definition of Overactive Bladder • a symptom syndrome • Urinary urgency, with or without urge incontinence, usually accompanied by frequency and nocturia • No signs of other pathology or infection Abrams P et al. Neurourol Urodyn.2002;21:167-178.

4. www.themegallery.com Symptoms of Overactive Bladder • Urgency; the complaint of a sudden compelling desire to pass urine, which is difficult to defer • Urge urinary incontinence; the complaint of involuntary loss of urine accompanied by or immediately preceding by urgency • Frequency, Nocturia Abrams P et al. Neurourol Urodyn.2002;21:167-178.

5. www.themegallery.com Pathophysiology of OAB Neurogenic Detrusor Overactivity Myogenic

6. www.themegallery.com Pathophysiology of OAB • a sudden increase in intravesical pressure at low volumes during the filling phase • increased spontaneous myogenic activity • fused tetanic contractions • altered responsiveness to stimuli • characteristic changes in smooth muscle ultrastructure

7. www.themegallery.com Morphologic changes of the detrusor • patchy denervation • increased coupling • enlarged sensory neurons • increased spinal micturition reflex

8. www.themegallery.com Morphologic changes of the detrusor • Patchy denervation of the detrusor muscle bundles in bladder biopsies of OAB patients → a notable increase in connective tissue between normal muscle bundles ; Increased infiltration of connective tissue → complete denervation hypertrophy of the smooth muscle incomplete emptying of the bladder during micturition

9. www.themegallery.com Morphologic changes of the detrusor • Lack of electrical coupling in normal bladder - Detrusor; made up of smooth muscle bundles - allows the bladder to ignore irrelevant electrical impulses that would otherwise cause an unwarranted response. • Unstable bladder; increased coupling of smooth muscle → increased excitability in the event of inadvertent low-grade efferent stimuli triggering the sense of urgency and culminating in an involuntary contraction • age related or a result of nerve damage from disease, injury, or obstruction.

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11. www.themegallery.com Neurological changes • Neuroplasticity • the ability of the nervous system to change transmitters, reflexes, or synaptic transmission in the event of disease or injury • afferent neurons in the dorsal root ganglia enlarge → a shortened delay in the central transmission of the micturition reflex • The micturition pathway is reorganized from a spinobulbospinal loop to a predominantly spinal network. • Activation of secondary excitatory parasympathetic afferents (myelinated Aδ- and unmyelinated C-fibers), which are usually silent, can then trigger micturition.

12. 3. Enhanced synaptic transmission: increased expression of GAP-43 and axonal sprouting 2. Recruitment of lower-threshold, spontaneously firing afferents www.themegallery.com Afferent Plasticity in the Inflamed or Obstructed Bladder Dorsal horn interneuron Afferent neuron 4. Storage Symptoms (?) Preganglionicneuron Sacral spinal cord 1. Irritated or obstructedbladder Parasympathetic postganglionicneuron GAP-43 = growth-associated protein 43 Adapted from Steers WD. Rev Urol. 2002;4:S7-S18.

13. www.themegallery.com Neurological changes • Ischemia → nerve injury → smooth muscle damage & impaired contractility • Peripheral vascular disease, benign prostatic hyperplasia, urethral stricture, detrusor–sphincter dyssynergia, or diabetic neuropathy → may cause severe obstruction, reduced blood flow, and neuronal death • The coexistence of neurologic factors and ischemia gives rise to detrusor hyperactivity with impaired contractility or unstable contractions in the absence of sensation of urgency.

14. www.themegallery.com Neurological changes • A possible molecular trigger for changes in bladder afferents or synaptic transmission in the CNS • Nerve growth factor - a naturally occurring molecule - stimulates growth and differentiation of the sympathetic and certain sensory nerves - responsible for neuronal regrowth after injury • Patients with OAB, benign prostatic hyperplasia, or interstitial cystitis may have elevated levels of nerve growth factor in their bladders.

15. www.themegallery.com OAB, Neurogenic • DO may result from • Decreased central inhibitory control • Increased afferent activity • Increased detrusor sensitivity to motor input • DO may reflect • Cerebrovascular disease • Neurologic disease

16. www.themegallery.com OAB, Myogenic • DO may result from • Alterations in structural and functional properties of the detrusor muscle • Partial denervation of the detrusor muscle • DO is reflected by • Abnormal spontaneous mechanical activity • Supersensitivity to acetylcholine (ACh) • Increased sensitivity to direct electrical stimulation • Depressed responses to intrinsic nerve stimulation

17. www.themegallery.com Pathophysiology of mixed UI • Unclear and multifactorial • Entrance of urine into the proximal urethra during descent and opening of the bladder neck  evoke urethro-detrusor facilitative reflex  stimulate afferent n. of the bladder  detrusor contraction Bump RC. Obstet Gynceol Report 1990(2);295-302

18. www.themegallery.com Potential Etiology of OAB in Men With BPO Supersensitivity to Ach Reduced response to intramural nerve stimulation Partial denervation Ischemia Increased electrical coupling between cells Hypertrophy/hyperplasia Instability of membrane potential Altered intracellular Ca2+-regulation Detrusor muscle Outflow Obstruction Overactive bladder Reorganization of spinal micturition reflex(C-fiber-mediated) Altered Na+ channelexpression/function Expression of nerve growth factor Hypertrophy of afferent and efferent neurons Steers WD. Rev Urol. 2002;4:S7-S18

19. www.themegallery.com Detrusor hyperactivity and impaired contractility in elderly patients • symptoms and cystometric evidence of bladder overactivity are found together with incomplete emptying that is not caused by obstruction. • Histologic changes in the bladders of aging humans have provided evidence of changes in cell-to-cell connections manifested by increased protrusion junctions. • In patients with impaired contractility, there was also degeneration of muscle cells and nerve axons Elbadawi A, et al. J Urol 1997;157:1814–1822

20. www.themegallery.com OAB in the elderly • caused by age-related diseases that indirectly alter normal urinary tract function • Metabolic, degenerative, or neurogenic diseases • Stroke, Alzheimer disease, multi-infarct or other dementias, Parkinson disease, or multiple sclerosis → may impair higher cortical inhibition of the bladder → neurogenic detrusor overactivity • DM → poor blood glucose control → osmotic diuresis and polyuria • Sleep disorders → nocturia • Disorders of the PFM(POP, fecal incontinence) → lessen their capacity to resist sudden increases in intravesical bladder pressure during the filling phase → bladder control problems, especially SUI

21. www.themegallery.com Hypersensitivity-induced overactivity • Unmyelinated, capsaicin-sensitive C-afferents - mediate pain - contribute to other sensations of bladder fullness and urgency • normally inactive; “silent C-fibers” • During neuropathic conditions and possibly inflammatory conditions, there is recruitment of C fibers that form a new functional afferent pathway that can cause urge incontinence and possibly bladder pain.

22. www.themegallery.com Idiopathic bladder overactivity • Denervation in biopsy specimens from humans with clinical evidence of OAB → muscle abnormalities may be a frequent cause • some sort of change in smooth muscle properties may be a necessary prerequisite for bladder overactivity. Mills IW et al. J Urol 2000;163: 646–651 Brading AF. Urology 1997;50(S6A): 57–67; discussion 68–73 Brading AF et al. Br J Urol 1994;73: 3–8

23. www.themegallery.com Other causes • Depression or anxiety • OAB more often than the general population. • associated with disturbances in brain circuits using specific neurotransmitters, in particular serotonin (5-hydroxytryptamine, or 5-HT). • Actions of 5-HT; very complex - facilitating effect on voiding via modulation of bladder afferents, volume thresholds, and bladder contractions

24. www.themegallery.com Conclusions • The ICS definition of overactive bladder emphasizes the symptomatic nature of the disease • The symptoms of OAB is originated from the change in both afferent neuron and detrusor. • Modulation of these components appears to be a promising area for clinical intervention in the management of OAB.

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