Anatomic Neurourology
Annah Vollstedt
Larry T. Sirls
Kenneth M. Peters
Introduction: Neuro-anatomy of the Female Lower Urinary Tract
The lower urinary tract (LUT) has two discrete modes: bladder storage and bladder emptying. These two processes are dependent on the coordination of peripheral, spinal and central neuropathways. Continence, or bladder storage, is maintained by inhibition of detrusor muscle contraction and activation of the external urethral sphincter (EUS). After sensation of a full bladder, voiding, or bladder emptying, is initiated by a neural reflex that causes the EUS to relax and the detrusor muscle to contract. In general, storage of urine is a sympathetic nervous system response and voiding is a parasympathetic response. This can be considered in the context of the flight-or-fight response, with the large sympathetic burst when running from a predator one would not want to leave a trail of urine.
The brain and the spinal cord make up the central nervous system (CNS). The peripheral nervous system (PNS) consists of afferent (sensory) and efferent (motor) neurons that communicate with the CNS. The parasympathetic, sympathetic, and the pudendal nerves are the nerves with afferent and efferent fibers that are involved in the coordination of storage and emptying. Figure 4.1 shows an overview of these neural pathways. Lesions along any of these neural pathways may result in LUT dysfunction. The clinical symptoms that are observed are dependent on the area affected. Application of the knowledge of these complex systems can be used to treat neurologic causes of LUT dysfunction, such as with neuromodulation or nerve rerouting. In this chapter, we discuss these neural pathways as well as some of the pertinent clinical applications.
EFFERENT INNERVATION TO THE LOWER URINARY TRACT
Efferent nerve fibers send impulses from the CNS to the limbs and organs. The efferent innervation of the female LUT includes the parasympathetic, sympathetic, and pudendal nerves.
The parasympathetic nerves originate in the intermediolateral gray matter of the sacral spinal cord at the level of S2-S4. The axons then travel a long distance within the pelvic nerve to the ganglia (pelvic plexus), which is located immediately adjacent to the end organ (bladder).1,2 The preganglionic and postganglionic parasympathetic fibers release acetylcholine (ACh), which is an excitatory neurotransmitter. ACh acts on the muscarinic receptors on the detrusor muscle, which then results in bladder contractions. There are five subtypes of the muscarinic cholinergic receptor (M1 to M5). The bladder contains M2 and M3 receptors. M2 is the more abundant subtype, but M3 is the primary receptor that mediates detrusor contraction. Activation of M3 receptors triggers intracellular calcium release, whereas activation of M2 receptors inhibits adenylate cyclase. The latter may contribute to bladder contractions by suppressing adrenergic inhibitory mechanisms which are mediated by β-adrenergic receptors and stimulation of adenylate cyclase.3
CLINICAL CORRELATION
Anticholinergic medications, such as oxybutynin, tolterodine, and solifenacin, are used to treat overactive bladder (OAB) because they decrease bladder contractions. Inhibition of muscarinic receptors outside the bladder can cause side effects.
Inhibition of M3 in the eye can cause pupil dilation and blurry vision.
Inhibition of M3 in the salivary glands can cause decreased saliva secretion and dry mouth.
Inhibition of M3 in the intestine causes decreased motility and constipation.
Inhibition of M2 in the sinus node of the heart can cause tachycardia.
Inhibition of M1 in the brain impairs cognition and memory.
Because the parasympathetic postganglionic neurons are located in the both the detrusor wall and the pelvic plexus, patients with cauda equina syndrome or pelvic plexus injury may not be completely denervated.4
 FIGURE 4.1 Nerve supply to the bladder and urethra. The bladder is innervated by the sympathetic, parasympathetic, and somatic nervous systems. The pudendal nerve maintains external sphincter and pelvic muscle tone. The pelvic nerve (parasympathetic) stimulates bladder contraction. The hypogastric nerve (sympathetic) stimulates internal sphincter closure and detrusor relaxation. (Reprinted from Norris TL. Porth’s pathology: Concepts of altered health states, 10th ed. Philadelphia: Wolters Kluwer, 2018.) |
The preganglionic sympathetic nerves arise from the thoracolumbar spinal cord at the level of T10-L2. The sympathetic efferent nerves to the LUT are located in the bilateral hypogastric nerves.2 These noradrenergic nerves originate in the sympathetic chain ganglia and travel to the inferior mesenteric ganglia and then through the hypogastric nerves to the pelvic ganglia. They provide inhibitory input during bladder filling via β-3 receptors and excitatory input to the urethra and the bladder neck via a-1 receptors during filling/storage, which results in detrusor relaxation and EUS contraction. The primary neurotransmitter for postganglionic sympathetic fibers is norepinephrine, but the primary neurotransmitter for preganglionic sympathetic fibers is ACh.
Figure 4.2 shows the distribution of the sympathetic and parasympathetic contributions to the autonomic pelvic plexus.
CLINICAL CORRELATION
The sympathetic nerves promote urine storage by both relaxing the bladder and closing the bladder neck. Injury to sympathetic nerves during pelvic surgery can lead to a decrease in bladder capacity and relaxation of the bladder neck, causing a decrease in outflow resistance. Clinically, patients may present with increased voiding frequency, “bladder spasms,” and urge incontinence.
The pudendal nerve is a somatic nerve whose efferents innervate the striated muscle of the EUS and the pelvic floor muscles. The nerve bodies originate in Onuf nucleus, along the lateral border of the ventral gray matter at the S2-S4 region of the spinal cord (Fig. 4.3).5
The efferent nerve fibers travel within the pudendal nerve to the EUS.2 Its nerve terminals release ACh, which acts on nicotinic cholinergic receptors within the EUS, causing contraction of the EUS during storage/filling.
During voiding/emptying, activation of the parasympathetic pathway leads to the release of nitric oxide (NO), which causes removal of the adrenergic and somatic cholinergic excitation and relaxation of the urethral smooth muscle.6
CLINICAL CORRELATION
During a sacrospinous ligament fixation, the pudendal nerve is susceptible to entrapment injuries because it runs behind the lateral aspect of the sacrospinous ligament. Patients may report postoperative gluteal, perineal, and/or vulvar pain, which worsens in the seated position.3
AFFERENT INNERVATION TO THE LOWER URINARY TRACT
Afferent nerves receive information from the sensory organs and transmit the input to the CNS. Afferent nerves have been identified both in the detrusor muscle and the suburothelium.2 The suburothelial afferent nerve fibers form a plexus, with some nerve terminals extending into the urothelium itself. This plexus is more prominent in the trigone and bladder neck compared to the bladder dome.2 The pelvic, hypogastric, and pudendal nerves carry afferent input from the LUT to the lumbosacral spinal cord.7 These peripheral nerves carry both afferent and efferent information between the end organs and the spinal cord.2 The majority of afferent input from the bladder and urethra is transmitted via the pelvic nerve, with a smaller amount carried by the hypogastric nerve. The pudendal nerve carries input from the striated muscle of the EUS and the pelvic floor. The afferent nerves release several different neurotransmitters, including vasoactive intestinal polypeptide, substance P, neurokinins, and calcitonin gene-related polypeptide.2
The primary afferent neurons of the pelvic and pudendal nerves are contained in the sacral dorsal root
ganglia (DRG) (Fig. 4.4).7 The afferent neurons of the hypogastric nerve arise in the lumbar DRG.7 Afferent fibers enter the spinal cord through the dorsal horn and then diverge and project either locally to interneurons or to second-order neurons and then ascend to supraspinal centers in the micturition centers in the brain.8
ganglia (DRG) (Fig. 4.4).7 The afferent neurons of the hypogastric nerve arise in the lumbar DRG.7 Afferent fibers enter the spinal cord through the dorsal horn and then diverge and project either locally to interneurons or to second-order neurons and then ascend to supraspinal centers in the micturition centers in the brain.8
 FIGURE 4.2 Sympathetic and parasympathetic contributions to the pelvic autonomic nervous plexus. The superior hypogastric plexus is formed by sympathetic fibers from the celiac plexus and the first four lumbar splanchnic nerves. Anterior to the bifurcation of the aorta, it divides into two hypogastric nerves that enter the pelvis medial to the internal iliac vessels, anterior to the sacrum, and deep to the endopelvic fascia. The pelvic continuations of the sympathetic trunks pass deep to the common iliac vessels and medial to the sacral foramina and fuse in front of the coccyx at the ganglion impar. Each chain comprises four to five ganglia that send branches anterolaterally to participate in the formation of the inferior hypogastric plexus. Presynaptic parasympathetic innervation arises from the intermediolateral cell column of the sacral cord. Fibers emerge from the second, third, and fourth sacral spinal nerves as the parasympathetic pelvic splanchnic nerves (nervi erigentes) to join the hypogastric nerves and branches from the sacral sympathetic ganglia to form the inferior hypogastric plexus. Note that in older texts, the superior hypogastric plexus is called the hypogastric plexus or presacral plexus and the that inferior hypogastric plexus is called the pelvic plexus. (Reprinted from Dalley AF, Agur AM. Moore’s clinically oriented anatomy, 9th ed. Philadelphia: Wolters Kluwer, 2022.) |
 FIGURE 4.3 Onuf nucleus. In the sacral spinal cord, Onuf nucleus is the origin of the pudendal nerve. Serotonin and norepinephrine (NE) stimulate the receptors 5-hydroxytryptamine-2 receptor (5HT2) and a1-adrenergic receptors (a1) to increase activity of the pudendal nerve and cause contraction of the skeletal component of the EUS. DC, dorsal column; DH, dorsal horn; LF, lateral funiculus; VH, ventral horn. (Reprinted by permission from Springer: Jost W, Marsalek P. Duloxetine: Mechanism of action at the lower urinary tract and Onuf’s nucleus. Clin Auton Res 2004;14[4]:220-227.) |
 FIGURE 4.4 Location of afferent sensory information and efferent motor information within the spinal cord. |
The pelvic nerve afferent fibers monitor bladder volume and amplitude of bladder contractions. These afferent fibers are made up of myelinated (A-delta) and unmyelinated (C) fibers (Table 4.1). The A-delta fibers are located with the detrusor smooth muscle and communicate a sense of fullness, responding to detrusor stretching during bladder filling and are quiescent when the bladder is empty.9 Compared to the unmyelinated C fibers, the A-delta fibers are more sensitive to increases in volumes and gradually increase in discharge frequency at intravesical pressures less than 25 mm Hg.10,11 The unmyelinated C fibers are located within both the detrusor muscle and the lamina propria, adjacent to urothelial cells.12 Those located in the muscle function as nociceptors, responding to overdistention by discharging at a higher range of physiologic bladder volumes.10 In animal studies, C fibers have been described as mechanoinsensitive and have been termed “silent C fibers” because of the lack of response to normal bladder stretching.7 Instead, they respond to other stimuli, such as cold, chemical, or noxious stimulation like high potassium, low pH, high osmolality, or irritants like capsaicin.13,14,15 In spinal cord injury (SCI) patients, the C fibers can become sensitized leading to a new type of spinal cord reflex that results in aberrant bladder contractions.16 In patients with pelvic pain, there is evidence that neuropathy/inflammation/injury of the bladder/pelvic floor can lead to recruitment of C fibers to form a new functional afferent pathway, which may lead to bladder pain and urgency incontinence.7,17 Thus, C fibers may be important targets for clinical interventions.
TABLE 4.1 Bladder Afferent Properties | ||||||||||||||||||||
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