Neurogenic bladder (NGB) - An overview

Contents

Introduction

Neurogenic bladder (NgB) or neurogenic lower urinary tract dysfunction (NLUTD), is a dysfunction of the urinary bladder and urethra due to disease of the central nervous system or peripheral nerves,

Aetiology

CNS abnormalities:

Multiple sclerosis:
- Neurogenic bladder (40-90% cases)
- Detrusor hyperreflexia (50-90% cases)
Parkinson disease (37-72% incidence)
Stroke (15% incidence)
Spinal cord injuries (70-84% incidence)
Spina bifida

Physiology

Micturition involves passive, low pressure filling of the bladder during the urine storage phase
Voiding requires coordination of detrusor contraction with urinary sphincter relaxation.

Peripheral innervation of the urinary tract:
Sympathetic innervation (T11-L2) arises in the thoracolumbar outflow of the spinal cord, whereas the parasympathetic (S2-S4) and somatic innervation originates in the sacral segments of the spinal cord.

Efferent pathways of the lower urinary tract: (a) Innervation of the female lower urinary tract. Sympathetic fibres (shown in blue) originate in the T11–L2 segments in the spinal cord and run through the inferior mesenteric ganglia (inferior mesenteric plexus, IMP) and the hypogastric nerve (HGN) or through the paravertebral chain to enter the pelvic nerves at the base of the bladder and the urethra. Parasympathetic preganglionic fibres (shown in green) arise from the S2–S4 spinal segments and travel in sacral roots and pelvic nerves (PEL) to ganglia in the pelvic plexus (PP) and in the bladder wall. This is where the postganglionic nerves that supply parasympathetic innervation to the bladder arise. Somatic motor nerves (shown in yellow) that supply the striated muscles of the external urethral sphincter arise from S2–S4 motor neurons and pass through the pudendal nerves. (b) Efferent pathways and neurotransmitter mechanisms that regulate the lower urinary tract. Parasympathetic postganglionic axons in the pelvic nerve release acetylcholine (ACh), which produces a bladder contraction by stimulating M3 muscarinic receptors in the bladder smooth muscle. Sympathetic postganglionic neurons release noradrenaline (NA), which activates β3 adrenergic receptors to relax bladder smooth muscle and activates α1 adrenergic receptors to contract urethral smooth muscle. Somatic axons in the pudendal nerve also release ACh, which produces a contraction of the external sphincter striated muscle by activating nicotinic cholinergic receptors. Parasympathetic postganglionic nerves also release ATP, which excites bladder smooth muscle, and nitric oxide, which relaxes urethral smooth muscle (not shown). L1, first lumbar root; S1, first sacral root; SHP, superior hypogastric plexus; SN, sciatic nerve; T9, ninth thoracic root. | Part (a): de Groat WC. In: Female Urology. 2nd. Raz S, editor. Saunders; Philadelphia: 1996. pp. 28–42. | Part (b): Fowler, C. J., Griffiths, D., & de Groat, W. C. (2008). The neural control of micturition. Nature reviews. Neuroscience, 9(6), 453–466. https://doi.org/10.1038/nrn2401

CNS pathways involved in micturition:
Neural pathways that control lower-urinary-tract function are organized as simple on–off switching circuits that maintain a reciprocal relationship between the urinary bladder and the urethral outlet. Storage reflexes are activated during bladder filling and are organized primarily in the spinal cord, whereas voiding is mediated by reflex mechanisms that are organized in the brain

Neural circuits that control continence and micturition: (a) Urine storage reflexes. During the storage of urine, distention of the bladder produces low-level vesical afferent firing. This in turn stimulates the sympathetic outflow in the hypogastric nerve to the bladder outlet (the bladder base and the urethra) and the pudendal outflow to the external urethral sphincter. These responses occur by spinal reflex pathways and represent guarding reflexes, which promote continence. Sympathetic firing also inhibits contraction of the detrusor muscle and modulates neurotransmission in bladder ganglia. A region in the rostral pons (the pontine storage centre) might increase striated urethral sphincter activity. (b) Voiding reflexes. During the elimination of urine, intense bladder-afferent firing in the pelvic nerve activates spinobulbospinal reflex pathways (shown in blue) that pass through the pontine micturition centre. This stimulates the parasympathetic outflow to the bladder and to the urethral smooth muscle (shown in green) and inhibits the sympathetic and pudendal outflow to the urethral outlet (shown in red). Ascending afferent input from the spinal cord might pass through relay neurons in the periaqueductal grey (PAG) before reaching the pontine micturition centre. | Note that these diagrams do not address the generation of conscious bladder sensations, nor the mechanisms that underlie the switch from storage to voiding, both of which presumably involve cerebral circuits above the PAG. R represents receptors on afferent nerve terminals.| Fowler, C. J., Griffiths, D., & de Groat, W. C. (2008). The neural control of micturition. Nature reviews. Neuroscience, 9(6), 453–466. https://doi.org/10.1038/nrn2401

Bladder filling and the guarding reflex:
Throughout bladder filling, the parasympathetic innervation of the detrusor is inhibited and the smooth and striated parts of the urethral sphincter are activated, preventing involuntary bladder emptying. This process is organized by urethral reflexes known collectively as the ‘guarding reflex’. They are activated by bladder afferent activity that is conveyed through the pelvic nerves, and are organized by interneuronal circuitry in the spinal cord

Brain areas involved in the regulation of urine storage: (a) Meta-analysis of positron-emission tomography and functional MRI studies that investigated which brain areas are involved in the regulation of micturition reveals that the thalamus, the insula, the prefrontal cortex, the anterior cingulate, the periaqueductal grey (PAG), the pons, the medulla and the supplementary motor area (SMA) are activated during the urinary storage. (b) Preliminary conceptual framework, based on functional brain-imaging studies, suggesting a scheme for the connections between various forebrain and brainstem structures that are involved in the control of the bladder and the sphincter in humans. Arrows show probable directions of connectivity but do not preclude connections in the opposite direction. | Part (a): DasGupta R, Kavia RB, Fowler CJ. Cerebral mechanisms and voiding function. BJU Int. 2007;99:731–734. | Part (b): Kavia R, DasGupta R, Fowler CJ. Functional imaging and central control of the bladder. J Comp Neurol. 2005;493:27–32.

Developmental changes:
In the fetus, before the nervous system has matured, urine is presumably eliminated from the bladder by non-neural mechanisms; however, at later stages of development voiding is regulated by primitive reflex pathways that are organized in the spinal cord. As the human CNS matures postnatally, reflex voiding is eventually brought under the modulating influence of higher brain centres. In adults, injury or disease of the nervous system can lead to the re-emergence of primitive reflexes.

Reflex voiding responses in an infant, a healthy adult and a paraplegic patient: Combined cystometrograms and sphincter electromyograms (EMGs, recorded with surface electrodes), allowing a schematic comparison of reflex voiding responses in an infant (a) and in a paraplegic patient (c) with a voluntary voiding response in a healthy adult (b). The abscissa in all recordings represents bladder volume in millilitres; the ordinates represent electrical activity of the EMG recording and detrusor pressure (the component of bladder pressure that is generated by the bladder itself) in cm H2O. On the left side of each trace (at 0 ml), a slow infusion of fluid into the bladder is started (bladder filling). In part b the start of sphincter relaxation, which precedes the bladder contraction by a few seconds, is indicated (‘start’). Note that a voluntary cessation of voiding (‘stop’) is associated with an initial increase in sphincter EMG and detrusor pressure (a myogenic response). A resumption of voiding is associated with sphincter relaxation and a decrease in detrusor pressure that continues as the bladder empties and relaxes. In the infant (a) sphincter relaxation is present but less complete. On the other hand, in the paraplegic patient (c) the reciprocal relationship between bladder and sphincter is abolished. During bladder filling, involuntary bladder contractions (detrusor overactivity) occur in association with sphincter activity. Each wave of bladder contraction is accompanied by simultaneous contraction of the sphincter (detrusor–sphincter dyssynergia), hindering urine flow. Loss of the reciprocal relationship between the bladder and the sphincter in paraplegic patients thus interferes with bladder emptying. | Fowler, C. J., Griffiths, D., & de Groat, W. C. (2008). The neural control of micturition. Nature reviews. Neuroscience, 9(6), 453–466. https://doi.org/10.1038/nrn2401

Pathophysiology

Disturbance to the normal micturition process as a result of neurological damage or disease is known as neurogenic bladder (NGB).

Anatomy and physiology of micturition with potential injury sites to urologic system (m: muscarinic receptor, α: alpha-adrenergic receptor, β: beta-adrenergic receptor). | Dorsher, P. T., & McIntosh, P. M. (2012). Neurogenic bladder. Advances in urology, 2012, 816274. https://doi.org/10.1155/2012/816274

Spinal cord injury (SCI):
SCI rostral to the lumbosacral level eliminates voluntary and supraspinal control of voiding, leading initially to an areflexic bladder and complete urinary retention, followed by a slow development of automatic micturition and neurogenic detrusor overactivity (NDO) that is mediated by spinal reflex pathways. However, voiding is commonly inefficient owing to simultaneous contractions of the bladder and the urethral sphincter (detrusor–sphincter dyssynergia)

Deafferentation (sensory fibres cut off): Reflex contractions abolished and bladder distended, thin-walled and hypertrophied
Complete denervation (afferent & efferent fibres cut off): Bladded initially distended, later shrinks and hypertrophies

Figure 8 Organization of the parasympathetic excitatory reflex pathway to the detrusor muscle: Micturition is initiated by a supraspinal reflex pathway that passes through a centre in the brainstem. The pathway is triggered by myelinated afferents (Aδ-fibres), which are connected to the tension receptors in the bladder wall. Injury to the spinal cord above the sacral segments interrupts the connections between the brain and spinal autonomic centres and initially blocks micturition. However, following cord injury a spinal reflex mechanism (shown in green) emerges that is triggered by unmyelinated vesical afferents (C-fibres); the A-fibre afferent inputs are ineffective. The C-fibre reflex pathway is usually weak or undetectable in animals with an intact nervous system. Stimulation of the C-fibre bladder afferents by installation of ice water into the bladder (cold stimulation) activates voiding responses in patients with spinal cord injury. Capsaicin (20–30 mg subcutaneously) blocks the C-fibre reflex in cats with spinal lesions but does not block micturition reflexes in intact cats. Intravesical capsaicin also suppresses detrusor hyperreflexia and cold-evoked reflexes in patients with neurogenic bladder dysfunction. | Fowler, C. J., Griffiths, D., & de Groat, W. C. (2008). The neural control of micturition. Nature reviews. Neuroscience, 9(6), 453–466. https://doi.org/10.1038/nrn2401

Madersbacher classification system:
Based on tone of bladder and urinary sphincter

Madersbacher classification system of neurogenic lower urinary tract dysfunction. | Powell C. R. (2016). Not all neurogenic bladders are the same: a proposal for a new neurogenic bladder classification system. Translational andrology and urology, 5(1), 12–21. https://doi.org/10.3978/j.issn.2223-4683.2016.01.02

Clinical features

The clinical findings typically correlate with the location of the lesion along the efferent (motor) or afferent (sensory) portions of the sacral arc pathway, alone or in combination.

Motor neurogenic bladder: Preserved sensation of bladder fullness and an inability to empty
- Efferent lesion that selectively spares afferent transmission to supraspinal centers
Sensory neurogenic bladder: Can void but have decreased sensation
- Pure afferent lesion

Complications

Short term complications:
- Urinary tract infections (UTI)
- Detrusor overdistension
Long term complications:
- Renal stones
- Refractory urinary incontinence
- Progressive upper urinary tract damage due to chronic, excessive detrusor pressures

Diagnosis

Urodynamic investigation:
Only method that can objectively assess the function and dysfunction of the LUT

Video-urodynamics findings of patients with NB. Typical detrusor overactivity (DO), detrusor external sphincter dyssynergia (DESD), and right vesicoureteral reflux (VUR) are shown. | Liao L. (2015). Evaluation and Management of Neurogenic Bladder: What Is New in China?. International journal of molecular sciences, 16(8), 18580–18600. https://doi.org/10.3390/ijms160818580

Magnetic resonance urography (MRU):

Grade 1 with UUTD-MRU grading system. | Liao L. (2015). Evaluation and Management of Neurogenic Bladder: What Is New in China?. International journal of molecular sciences, 16(8), 18580–18600. https://doi.org/10.3390/ijms160818580

Differential diagnosis:
Other causes of urinary dysfunction

Pelvic surgery
Pelvic & sacral fractures
Herniated disc
Infectious neurologic process

Management

The management of neurogenic bladder varies depending on the predominant symptoms but may involve behavioral modification, clean intermittent catheterization, pharmacotherapy, intradetrusor onabotulinumtoxin A injections, or major reconstructive surgery including bladder augmentation and urinary diversion.

Clean intermittent catheterization + anti-muscarinic agents
Intermittent self- or third-party catheterization is the gold standard for the management of NGB, The average frequency of catheterizations per day is 4-6 times and the catheter size should be 12–14 Fr. (French)

Medical management:

Anti-muscarinic drugs (first-line): Oxybutynin chloride, trospium chloride, tolterodine tartrate, and propiverine
Phosphodiesterase Inhibitors (PDE5Is)
β3-Adrenergic Receptor Agonist
α-Blockers
Botulinum Toxin A (BTX-A) Injection

Flowchart of pharmacologic treatment of neurogenic bladder based on symptoms and urodynamic findings. *, storage symptoms = urgency, frequency, urgency incontinence and nocturia; **, recommended starting dose 10 mg po BID-TID. | Cameron A. P. (2016). Medical management of neurogenic bladder with oral therapy. Translational andrology and urology, 5(1), 51–62. https://doi.org/10.3978/j.issn.2223-4683.2015.12.07

Minimally invasive surgical management:

Sacral neuromodulation (SNM)
Pudendal neuromodulation (PNM)
Percutaneous tibial nerve stimulation (PTNS)