Neurogenic bladder (NB) or neurogenic lower urinary tract dysfunction of the urinary bladder and urethra, due to central and/or peripheral nervous system diseases, is one of the most challenging problems in urology. Various disorders or injuries affecting the nervous system may cause chronic bladder dysfunction , which type depends on central or peripheral nervous system damage level and intensity. The bladder can become overactive (emptying too frequently/quickly) or underactive (not emptying completely), with urethral complex overactivity (leading to dyssynergia with partial/complete urinary retention) or underperformance (evoking incontinence). Therefore, NB pathophysiology should be described as neurogenic detrusor overactivity, neurogenic detrusor underactivity, detrusor-sphincter dyssynergia, and neurogenic sphincter deficiency. It should be noted that studies investigating pathophysiological mechanisms of NB utilize both human and animal models. As human tissues are more difficult to obtain, our current knowledge on NB pathophysiology is mainly based on animal studies and clinical observations.

Neurogenic detrusor overactivity (NDO ) is a clinical diagnosis of detrusor contractions occurring during the filling phase of urodynamics (detrusor overactivity ) in the presence of relevant neurological condition [1]. However, presented definition has some limitations. Neurologically diagnosed patients may suffer from other diseases/conditions which can lead to similar symptom presentation and/or urodynamic findings. Elderly male patients with a neurological disorder may have a concomitant diagnosis of benign prostatic hyperplasia with an overactive detrusor due to bladder outlet obstruction. Both female and male patients may suffer from idiopathic overactive bladder (OAB) despite confirmed diagnosis of neurological impairment. Furthermore, uninhibited detrusor contractions can be observed in up to 30% of elderly men and women [2].

Underlying mechanism of NDO may include a lack of inhibition of motor pathway or enhancement of sensory input and/or motor output. As a consequence, pathophysiological abnormalities occur in different anatomic sites :

There is increasing evidence that bladder epithelial cells play an important role in modulation of bladder activity [3]. Bladder urothelium contains mechanosensitive and chemosensitive receptors and ion channels . They are mainly represented by receptors for bradykinin, purines (P2X, P2Y), neurotrophins, protease activated receptors, epithelial sodium channels (ENaC), and transient receptor potential channels (TRPC) [4]. Urothelial cells also release a wide variety of specific and non-specific transmitters like adenosine triphosphate (ATP) and prostaglandins. Suburothelial layer includes myofibroblasts with gap junction proteins (connexin 43 and cadherin-11) and are able to generate spontaneous electrical activity [5]. Afferent signals in normal bladders are carried by Aδ fibers and in lesser degree by C fibers. This chemical and structural network does allow transmission and communication between different cell types, bladder compartments, and afferent nerves . In considering the pathophysiology of NDO, special attention should be paid for urothelial ATP as it can stimulate suburothelial myofibroblasts and/or afferent nerves via purinergic receptors triggering bladder overactivity [3, 6, 7]. Of note, both myofibroblasts and afferent nerves may release ATP as well. Structural and functional changes in bladder urothelium /suburothelium have been demonstrated in patients after spinal cord injury (SCI) even in early post-trauma period [8]. Similar findings with a predominant role of ATP in NDO pathophysiology have been investigated in urothelial tissues from patients suffering from multiple sclerosis [9]. Nevertheless, studies performed by Roosen et al. stressed that increased gap junction formations (upregulations of connexin 43 and cadherin-11) in the bladder suburothelium of neurologically impaired patients has a more significant role in the pathogenesis of the neurogenic detrusor abnormality [10, 11]. In turn, de Groat et al. emphasized the role of disturbances in afferent innervation after spinal cord transection in cats and described the switching of bladder transmission from Aδ to C fibers [12]. The C-fiber afferents transmit signals of micturition reflex with a shorter latency (a condition of being temporarily inactive) than Aδ fibers, thus leading to bladder overactivity. Similar findings have been found in human bladders of patients after SCI [13]. Further studies of Yoshimura et al. on C-fiber neurons have demonstrated changes in their electrophysiologic functional properties after SCI indicating the increase in expression of TTx-sensitive sodium channels as a potential reason of short latency in micturition reflex [14]. Moreover, Apostolidis et al. have shown upregulation in the expression of P2X3 and TRPV1 receptors in suburothelial nerve fibers in NDO bladders [15]. To conclude, urothelium-afferent junction can be altered structurally and functionally in NDO and play an important role in NDO pathophysiology.

Detrusor smooth muscle with the autonomic innervation of postganglionic efferent nerves represents the main functional component in the clinical presentation of NB. One of the mechanisms leading to NDO describes postjunctional detrusor smooth muscle supersensitivity as a result of partial bladder denervation [16–18]. Due to this postjunctional pathology with reduced autonomic motor innervation, detrusor smooth muscle responses in exaggerated (supersensitive) mode to specific and non-specific neurotransmitters. Another mechanism of NDO development includes abnormalities in neurotransmitters’ release and their receptors’ distribution. It has been shown that after SCI the excitatory neurotransmitter mechanism changes from a purinergic to a cholinergic system [19]. In the normal bladder, the detrusor muscle mainly contains M2 and M3 cholinergic (muscarinic) receptors , with the M3 subtype playing a major role in detrusor contraction [20]. Interestingly, the proportion and role of these detrusor cholinergic receptors have recently been demonstrated to evolve after acute suprasacral SCI and chronic antimuscarinic treatment. Braverman et al. reported that total muscarinic receptor density is significantly higher in spinal cord transected rats than in normal controls [21]. M2 receptors accounted for the entire increase, with no change in M3 receptor density. Moreover, they showed a switch from M3-mediated detrusor contractions in normal rats to M2-mediated detrusor contractions in rats after spinal cord transection . Interestingly, Biardeau et al. have recently demonstrated, in a spinal cord transected rat model, that early administration of selective muscarinic receptor antagonist could prevent NDO [22]. Another studies have shown that downregulation of calcium-activated potassium channels (BK) may lead to increased spontaneous contractile activity [23] and K_ATP and SK_Ca potassium channels are the main regulating channels of spontaneous contractile activity in neurologically impaired detrusor smooth muscle [24, 25]. Figure 2.1 presents an overview of abnormalities in bladder compartments described in pathophysiology of NDO [26].

Spinal cord represents platform between urothelium-afferent and detrusor-efferent junctions . Communication is provided by a wide network of various neurotransmitters. Among them special attention should be paid for vasoactive intestinal peptide (VIP) , pituitary adenylate cyclase-activating polypeptide (PACAP) , and γ-aminobutyric acid (GABA) , the most important spinal cord neurotransmitters in NDO pathophysiology [27]. Whereas VIP and PACAP are pro-micturition agents with upregulation after spinal transection, GABA is an anti-micturition agent characterized by downregulation in spinally transected animals [28, 29]. Other transmitters have also been investigated. Animal studies have shown significant higher release of ATP, substance P, and neurokinin A in rats’ spinal cord after transection [7, 30]. Since they are considered as excitatory neurotransmitters, their elevated concentrations can significantly contribute to NDO development . Intact communication between afferent and efferent neurons within spinal cord is supported by interneurons which modulate the micturition reflex. Their function may be altered after SCI due to the mechanism of synaptic plasticity and descending axonal degeneration after SCI may reveal axonal sprouting in interneurons [31]. This synaptic plasticity promotes more communication between afferent and efferent neurons leading to and promoting NDO. Of note, whereas presented pathophysiological abnormalities appear in various levels of the spinal cord, bladder dysfunction characterized as NDO is usually found in spinal cord damage or injury above the sacral region (further described in Chap. 3, “Pathologies Responsible for the Development of the Neurogenic Bladder”).

The contribution of brain changes in NDO pathophysiology has not been well investigated. Brain plasticity after SCI has been recently descried by employing functional magnetic resonance imaging (fMRI) and neurophysiological analyses [32]. It has been shown that significant changes appear in topographical representation of different somatosensory projections within cerebral cortex after SCI. Authors hypothesized that this reorganization may have clinical consequences and proposed similar neural plasticity for bladder function. In contrast, studies utilizing middle cerebral artery occlusion animal model indicated that the forebrain augmentation contributes to the maintenance of NDO [33].

Neurogenic detrusor underactivity (NDU ) is defined as a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span during urodynamic study (detrusor underactivity) with underlying neurological pathology [34]. This definition excludes idiopathic, myogenic, and drug-induced causes of underactive detrusor [35, 36]. Within the spectrum of underactive detrusor, the condition when contractions cannot be demonstrated during urodynamics is defined as acontractile detrusor (AD) . As efferent output of urine flow can be activated reflexively by both spinal and brain afferent input supported by impulsation from the pelvic visceral organs and somatic pathways from the perineal muscle and skin, underlying mechanism of NDU may include dysfunctions of sensory input (with defects in axonal conduction or synaptic transmission), decreased motor output, reduced central excitatory transmission, or enhanced central inhibition [37–39]. Therefore, NDU may be presented in damages of bladder peripheral afferent nerves , bladder peripheral efferent nerves , spinal cord, and brain. Whereas the disruption of the afferent tract leads to early termination of voiding reflex, the disturbances of the efferent pathway contribute to impaired activation of detrusor [40]. Brain and spinal cord play a role of integrative control centers. It should be noted that different mechanisms may occur simultaneously when NDU is diagnosed. Nonetheless, the final effect of reduced acetylcholine release from parasympathetic nerve endings to the synaptic cleft resulting in a lack of a contractile stimulus is the same for all these pathologies [38].

Underlying cause of bladder neural tract damage may be traumatic or non-traumatic. Traumatic injuries of central or peripheral bladder innervation are critical for signals circulating. In damages of bladder afferent pathways, both Aδ and C fibers may be in disrepair, leading to various intensifications of sensory disturbances. Pathophysiology of neural tract damage contains primary and secondary mechanism [41, 42]. Whereas the first is a combination of the initial impact and the subsequent persisting compression finally resulting in interruption of neural continuity, the latter includes progressive necrotization and inflammatory cell infiltration, alternations in endothelial cell function with free radical formation, ionic derangements with the largest variations in extra- and intracellular K⁺ and Ca²⁺ levels, apoptosis and excitotoxin release [43–47]. These factors significantly influence on neuroplasticity. Note that bladder dysfunction characterized as NDU is usually found in damage or injury located in the sacral spinal cord or in the peripheral nervous system (discussed in Chap. 3).

In non-traumatic entities of NDU , particularly in systemic disorders causing polyneuropathy (e.g., diabetes), impaired bladder behavior described as bladder underactivity has also been documented. Studies on patients suffering from diabetic cystopathy have shown that altered metabolism of glucose, ischemia, impaired axonal transport, superoxide-induced free radical formation, and metabolic derangement of the Schwann cells have significant contribution to damage of bladder neural pathways [48, 49]. Recently published data suggest that various systemic disorders leading to NDU may also influence on other bladder compartments such as detrusor smooth muscle or urothelium [48]. Animal studies of diabetes mellitus (DM) rats have shown increased depolarization of myocytes to externally applied acetylcholine and decreased spontaneous activity, presumably related to altered purinergic transmission [50]. Changolkar et al. demonstrated that bladder underactivity related to diabetes is associated with disturbances in detrusor smooth muscle characterized as an oxidative stress, increase in lipid peroxides and sorbitol, overexpression of aldose reductase and activation of polyol pathway [51]. Other studies stressed the role of variations in neurotransmitters levels . Decreased levels of nerve growth factor (NGF) and neurotrophin-3 (NT-3) in bladder compartments and afferent nerves have been considered as the most important changes leading to detrusor underactivity [52–54]. On the other hand, Pinna et al. demonstrated that urothelial levels of endogenous prostaglandins E2 and F2α were higher in DM rats than in controls [55]. As these factors are considered as bladder relaxants, they can contribute to bladder underactivity. Similar findings were reported with regard to changes in nitric oxide synthase (NOS) and reactive nitrogen species formation [56]. NOS has been discovered as upregulated in the urothelium , lamina propria, and smooth muscle of DM rat bladders. Non-traumatic damage of bladder neural tracts may also be seen in neurological infections. The infection mechanism involves autoimmune reaction to peripheral nerves and/or roots or spreading of the infection from cutaneous nerve endings to the corresponding dorsal root ganglia. The neuropathy affecting the bladder often takes the form of an autonomic neuropathy, which may involve both the sympathetic and the parasympathetic, as well as afferent and efferent, innervation of the bladder and urethra [57].

NDU may also be observed in damages of the pons and the pontine micturition center (located in the dorsal pontine tegmentum) [58]. Decreased output from these structures results in a lack of a contractile stimulus. Burney et al. indicated cerebellum as a possible brain representation of NDU. They reported that patients with cerebellar infarctions are highly predisposed to detrusor underactivity with preserved function of sphincter [59] but other studies presented opposite results [60]. Studies on monkeys with medically induced Parkinson disease showed that selective destruction of striatal dopaminergic neurons which pass from the substantia nigra pars compacta to the putamen significantly contributes to detrusor underactivity [61, 62].

Detrusor-sphincter dyssynergia (DSD ) is defined as a detrusor contraction synchronous with an involuntary contraction of the urethral and/or peri-urethral striated muscle [63]. DSD is also known as detrusor-striated sphincter dyssynergia and detrusor-external sphincter dyssynergia [64]. This condition is caused by the interruption of the spinal pathways between the brainstem (pontine micturition center) and the sacral spinal cord (sacral micturition center) [65, 66]. In the absence of neurological disorder, impaired coordination between detrusor and sphincter during voiding is more appropriately referred to as dysfunctional voiding or pelvic floor hyperactivity [67, 68].

Presented incoordination was hypothesized to be an abnormal flexor response of the perineal musculature to bladder contraction and considered as a continence reflex exaggerated by the loss of supraspinal influence [69, 70]. Thus, current understanding of DSD includes failed inhibition of spinal guarding reflexes and incorrect excitation of Onuf’s nucleus [64, 67, 71] but underlying cellular and subcellular mechanisms of this phenomenon have not been investigated. Furthermore, studies on the initial description of DSD and chronology of events present rather conflicting results. Researchers have shown that urethral sphincter may contract before, after, or at the same time as detrusor [72–74].

Neurogenic sphincter deficiency (NSD ) is a clinical diagnosis of urethral weakness or low resistance to bladder leakage due to intrinsic sphincter deficiency (ISD) caused by a neurological condition. Readers should be aware that universal agreement on this definition nor on definition of ISD has not been achieved [75]. Nevertheless, implementation of neurological contribution to the NSD term allows to exclude other non-neurogenic causes of ISD, e.g. previous pelvic surgery, aging, or hypoestrogenic state.

The pathophysiology of intrinsic sphincter insufficiency due to neurological diseases has not been well investigated. It is known that the internal urethral sphincter is under control of the autonomic nervous system, in contrast to external sphincter with somatic innervation [76]. It has been hypothesized that disorders of anterior grey column and/or anterior nerve roots with nerve fibers travelling to the sphincter may lead to the de-innervation of intrinsic sphincter and result in ISD [77]. Another hypothesis stresses that the damage of sympathetic thoracolumbar intermediolateral nuclei is responsible for clinical presentation of NSD [78]. Currently, there is no data on underlying cellular and subcellular mechanisms of NSD .