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Int Neurourol J > Volume 22(1); 2018 > Article
Jang, Kwon, and Cho: Central Regulation of Micturition and Its Association With Epilepsy

ABSTRACT

Micturition is a complex process involving the bladder, spinal cord, and the brain. Highly sophisticated central neural program controls bladder function by utilizing multiple brain regions, including pons and suprapontine structures. Periaqueductal grey, insula, anterior cingulate cortex, and medial prefrontal cortex are components of suprapontine micturition centers. Under pathologic conditions such as epilepsy, urinary dysfunction is a frequent symptom and it seems to be associated with increased suprapontine cortical activity. Interestingly, micturition can also trigger seizures known as reflex epilepsy. During voiding behavior, frontotemporal cortical activation has been reported and it may induce reflex seizures. As current researches are only limited to present clinical cases, more rigorous investigations are needed to elucidate biological mechanisms of micturition to advance our knowledge on the process of micturition in physiology and pathology.

INTRODUCTION

Micturition is a complex process finely controlled by the brain and the spinal cord [1]. The bladder functions by either storing or emptying urine. Considering that a normal voiding process takes only less than 5 minutes, the bladder is in the storage mode for most of the time. Switching from one state to the other of the bladder can be modulated by the central neural program. It is known that higher micturition centers including pons and suprapontine brain regions decide whether to void after comprehensive integration of information such as bladder fullness and social appropriateness [2]. This information is then transmitted to the spinal cord and subsequent peripheral nerves so that bladder function is under normal control. Since the voiding behavior transits from involuntary to voluntary processes during the postnatal periods [3], complicated regulation of micturition at cellular and network level needs to be established for proper urination. Thus, it is critical to understand how neurophysiological control of the bladder function takes place.
Many neurological diseases affecting the brain, spinal cord and the peripheral nervous system can manifest urinary dysfunction [4]. For example, cerebral palsy, stroke, head injury, multiple sclerosis, Parkinson disease, dementia, spinal cord injury, and peripheral neuropathy show various urinary symptoms, including urinary incontinence, urgency, hesitancy, and urinary retention [4,5]. This can further help us identify important central nervous system regions for micturition and understand how the voiding process is dysregulated under pathologic circumstances. However, there have been no comprehensive reviews of urinary dysfunction in relation to epilepsy, one of the most common neurological disorders affecting more than 50 million people worldwide [6]. As seizures are abnormal and excessive neuronal excitation that can occur in any brain regions, physiologic micturition pathways can be disrupted in epilepsy. Therefore, we will review physiologic mechanisms of micturition first. The current status of the researches reporting urinary dysfunctions in epilepsy and micturition-induced reflex epilepsy is also then discussed.

PHYSIOLOGIC CONTROL OF MICTURITION

In human, voiding happens involuntarily until 3 to 5 years after birth. It then becomes a voluntary process [3]. Bladder switches between filling and voiding modes depending on signals from the spinal cord and the brain. At early stages of bladder filling, signals from the spinal cord are main determinants of bladder filling (Fig. 1B, C lower parts). Spinal cord receives sensory signals from the bladder via pelvic and hypogastric nerves informing the tension of bladder wall. It then sends sympathetic, parasympathetic, and somatic outputs back to bladder [7]. Sympathetic output leaves the spinal cord at the level of thoracolumbar segments as the hypogastric nerve, inhibiting the contraction of detrusor muscles and promoting the contraction of urethral outlet. With regard to somatic outputs, the pudendal nerve leaving the spinal cord from the sacral segment promotes the contraction of the external urethral sphincter. Finally, the pelvic nerve corresponds to parasympathetic output of the spinal cord and it comes from the sacral segment. In general, increase in both sympathetic and somatic signaling results in inhibition of voiding so that bladder can be filled. These signaling pathways comprise the basic spinal reflex mechanism to inhibit involuntary voiding [1]. On the contrary, increase in parasympathetic tone can cause voiding by promoting contraction of detrusor muscles and inducing relaxation of urethral outlet simultaneously.
At the early stage of bladder filling, sympathetic and somatic signals from the spinal cord are the main stimuli to fill the bladder that is rarely affected by brain activity [8]. However, as the bladder gets further distended, sensory signals can ascend the spinal tract and reach higher micturition centers where multiple brain regions interact with each other to sophisticatedly control bladder filling and voiding (Fig. 1A) [9,10]. In detail, spinal afferent fibers convey signals of bladder filling states to the periaqueductal grey (PAG) (Fig. 1B, C upper parts) [11,12]. PAG acts as a relay center for bladder sensory input [13]. PAG then distributes the information about the bladder filing status to higher brain centers via thalamus. Insula is one of first targets of bladder sensory signals reaching higher brain centers. It is a core part of the interoception [14] and the degree of bladder filling is encoded here. The signal from the insula can be transmitted to anterior cingulate cortex (ACC) that interprets the subjective sensation on how much the bladder is filled [15,16]. Although both insula and ACC can cooperate for generating the desire to void and emotional responses to bladder filling [17], the feeling of urgency is believed to be mediated by ACC. However, the urgent feeling does not instantly lead to urination because the prefrontal cortex (PFC) usually suppresses the voiding behavior until the socio-emotional situation is acceptable for voiding. To hold voiding, multiple brain regions can be recruited to enhance sympathetic and somatic outflow to the bladder. For instance, ACC and supplementary motor area are activated to increase thoracolumbar sympathetic outflow [17]. Pontine storage center (PSC) located at the ventrolateral part of the pons can also send signals to stimulate striated urethral sphincter activity [1]. Together, these signals eventually enhance the spinal reflex to inhibit voiding as described earlier.
Final decision to void can be mediated by PFC, especially medial PFC (mPFC) that can act through the default mode network (Fig. 1A) [18]. When the bladder is not full without strong need to suppress voiding, mPFC sends the signals to PAG as a default mode of action. This signal is summated in PAG together with sensory inputs from the bladder [17]. When the bladder is further filled with desire to void, mPFC will determine whether to void or not. If the situation is inadequate to void, mPFC is deactivated with decreased signal to PAG (shown as thin dark grey rectangle). Thus, total neural inputs to PAG fail to reach the set-point (Fig. 1B). On the other hand, when it is good to void, mPFC is activated to stimulate PAG (shown as thick dark grey rectangle) (Fig. 1C). Finally, summated signals from mPFC (shown as dark grey rectangle) and the bladder (shown as grey rectangle) can exceed the set-point in PAG, thus activating pontine micturition center (PMC) located in the medial part of the pons (Fig. 1C) [17,19]. PMC then activates parasympathetic nucleus in the spinal cord and inhibits sympathetic outflow to the bladder. Parasympathetic input to the bladder can initiate voiding by inducing both detrusor muscle contraction and urethral outlet relaxation [1]. Once the urine starts to flow through the urethra, a secondary reflex in the spinal cord continuously enhances further bladder emptying.
Although we described key brain and spinal circuits responsible for the voiding process in this review, it remains unclear how continence and micturition are delicately controlled by the central nervous system. As new brain regions such as parahippocampal complex and hypothalamus that play roles in complicated voiding processes are being discovered [17], it will be interesting to identify critical components of higher micturition centers and their contributions to bladder control for better understanding of voiding mechanisms.

DYSREGULATION OF MICTURITION UNDER PATHOLOGIC CONDITIONS

Urinary Dysfunction in Epilepsy

Patients with epilepsy often show urinary dysfunction [20-22]. Despite urinary complaints can be regarded as autonomic signs accompanied with epileptic seizures, one cross-sectional study has examined the prevalence of urinary symptoms in epilepsy [20]. They found that approximately 39% of patients with epilepsy had at least one urinary symptom. Specifically, incontinence was the most common problem, followed by urinary urgency, frequency, retention, and hesitancy. However, except for this study, limited work has explored genitourinary complications in epilepsy.
It has been reported that urinary incontinence occurs at the end of the clonic phases of tonic-clonic generalized seizures when sphincter muscles are relaxed [20,22]. In an effort to elucidate neurophysiological mechanisms, Rosenzweig et al. [23] have described that a patient with more than 30 years of epilepsy history suffers from urinary incontinence following seizures (Table 1). Ictal electroencephalogram (EEG) indicated a seizure onset from posterior parts of the right middle and inferior frontal gyrus. Since the supracallosal part of the medial frontal cortex has been reported to be one of the suprapontine micturition centers, incontinence of this patient may be attributed to cortical seizures, supporting that the frontal lobe plays a significant role in the regulation of micturition.
Urinary urgency, a relatively rare symptom in patients with epilepsy compared to urinary incontinence, refers to having intense desire to urinate. It has been reported that several patients with temporal lobe epilepsy experience urinary urge during aura or at the beginning of seizures (Table 1) [24]. In addition, one recent case of ictal urinary urge originated from the nondominant right temporal lobe has been described [25], further supporting previous case studies (Table 1). To localize seizure focus, closer analysis by single photon emission computed tomography has revealed hyperperfusion of the insula and the superior temporal gyrus [24,25]. Considering that insula in micturition plays a role as a relay region sensing the amount of bladder filling and sending a signal of voiding desire to PFC, ictal urinary urge in patients might be attributed to abnormal hyperactivity of the insula.
Urinary retention refers to lack of desire to urinate. Motamedi et al. [20] have reported that urinary retention is one of main postictal deficits, different from the urinary incontinence and urgency that are associated with peri-ictal periods. A study presenting 3 cases of patients with epilepsy [26] further supports that urinary retention is a postictal symptom (Table 1). Moreover, EEG monitoring discloses epileptiform activity in the frontotemporal or bitemporal regions, implying that alteration of cortical activity on suprapontine micturition-associated structures might result in postictal urinary retention.

Micturition-Induced Seizures

Micturition can trigger the genesis of seizures (called reflex epilepsy). Reflex seizures are provoked seizures caused by a specific sensory stimulus, including visual precipitants, reading, writing, eating, bathing, and thinking. Micturition is one of these stimulants. Although micturition-induced seizures are rare and seldom reported, several clinical cases affecting children and young adults have been reported (Table 2) [27-35]. The presence of normal consciousness was variable as three patients lost their awareness while 2 patients preserved consciousness [27,28,30,31,35]. All cases included variable motor components such as tonic posturing and clonic movements [27-35]. Semiology of seizures indicated that the seizure focus was midline or frontotemporal regions. These data suggest the following possible mechanism of micturition-induced seizures: while voiding, midline or frontotemporal lobe that plays a role in micturition might be excessively activated that seizures are generated shortly after the voiding process. Urodynamic studies can also be helpful to understand how micturition induces seizures as one study reported phasic detrusor overactivity with normal urinary flow despite seizures were not detected during the test [33]. Interestingly, of previously reported cases, many patients had developmental delay, raising the possibility that micturition-induced seizures might be associated with neurodevelopmental abnormalities [27-29,31,34]. To advance our understanding about how micturition is regulated by the central nervous system, more studies are needed to not only demonstrate the basic epidemiologic information, but also determine molecular and cellular mechanisms of micturition-induced reflex epilepsy.

CONCLUSIONS

In this article, we reviewed neurophysiological regulation of the micturition and its disruption in pathologic conditions showing seizures. Voluntary control of the micturition can be executed by complex neuronal interactions among several brain regions and the spinal cord. For example, PAG, insula, ACC, and mPFC are known to influence PMC and PSC so that the bladder can switch between voiding and storage modes. Patients with epilepsy displayed various urinary dysfunctions, including incontinence, urgency, and retention, although the micturition itself can also trigger seizures. These patients showed increased activities in the frontal cortex, the insula, and the temporal cortex, supporting that suprapontine micturition centers have critical contribution to fine regulation of the voiding process. However, more extensive investigations are needed to reach comprehensive understanding of all central neural programs controlling micturition as our current knowledge is limited to identifying major brain regions with a few pathologic cases.

NOTES

Grant/Fund Support
This work was supported by the Korea Health Technology R&D Project (HI15C2854) through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea.
Conflict of Interest
The authors have no potential conflict of interest relevant to this article to report.
AUTHOR CONTRIBUTION STATEMENT
·Full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis: KO Cho
·Study concept and design: HJ Jang, KO Cho
·Acquisition of data: HJ Jang, KO Cho
·Drafting of the manuscript: HJ Jang, MJ Kwon, KO Cho
·Critical revision of the manuscript for important intellectual content: HJ Jang, KO Cho
·Obtained funding: KO Cho
·Study supervision: KO Cho

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Fig. 1.
Brain and spinal networks involved in the regulation of bladder filling and voiding. (A) Major brain regions responsible for micturition are marked on the horizontal section (left) and the sagittal section (right) of the brain. (B) Brain and spinal networks involved in the late phase of bladder filling are shown schematically. Thickness of lines roughly represents the relative strength of signal. Dark grey and grey rectangles in periaqueductal gray represent the contribution of signal inputs from prefrontal cortex and the bladder, respectively. (C) Brain and spinal networks involved in the initiation of voiding are shown schematically. Thickness of lines roughly represents the relative strength of signal. Dark grey and grey rectangles in PAG represent the contribution of signal inputs from PFC and the bladder, respectively. Note the change in relative contribution of signal inputs from the PFC.
inj-1836040-020f1.tif
Table 1.
Urinary dysfunction in patients with epilepsy
Case No. Age (yr) Sex Urinary symptom Seizure focus by EEG monitoring CT or MRI Treatment Classification of epilepsy Reference number
1 42 Male Enuresis (incontinence) Right frontal region Not indicated Not indicated Juvenile myoclonic epilepsy [23]
2 41 Female Urinary urge Left temp oral region Left hippocampal atrophy Not indicated Temporal lobe epilepsy [24]
3 32 Female Urinary urge Right temporal region Right hippocampal atrophy Not indicated Temporal lobe epilepsy [24]
4 14 Male Urinary urge Right temporal region Normal Not indicated Temporal lobe epilepsy [24]
5 25 Female Urinary urge Right temporal region Bilateral hippocampal atrophy Not indicated Temporal lobe epilepsy [24]
6 44 Male Urinary urge Right temporal region Right temporal focal cortical dysplasia Not indicated Temporal lobe epilepsy [24]
7 61 Male Urinary urge Temporal region, nonlateralized Right hippocampal atrophy Not indicated Temporal lobe epilepsy [24]
8 19 Female Urinary urge Left temp oral region Cortical dysplasia of the left temporal lobe Left temporal lobectomy Temporal lobe epilepsy [25]
9 64 Male Urinary retention Frontotemporal region Old ischemic lesions in left occipital lobe, right basal ganglia, and pons Diazepam Stroke-induced epilepsy [26]
10 56 Male Urinary retention Bitemporal region Brain atrophy with no focal lesion Diazepam Not classified [26]
11 35 Male Urinary retention Not indicated Normal Diazepam Not classified [26]

EEG, electroencephalogram; CT, computed tomography; MRI, magnetic resonance imaging.

Table 2.
Micturition-induced reflex epilepsy
Case No. Age (yr) Sex Stimuli Seizure focus by EEG monitoring CT or MRI Treatment Developmental disorder Reference number
1 7 Male Micturition Left frontotemporal region Normal Valproic acid Mental retardation, microcephaly [27]
2 5 Male Micturition, immersion of feet in hot water Central midline region (C3 and Cz) Normal Valproic acid, carbamazepine Mental retardation [28]
3 12 Female Micturition, emotional response to prayer Anterior cingulate cortex Normal No treatment Developmental delay [29]
4 8 Female Micturition Frontal region Normal Phenytoin Normal [30]
5 6 Female Micturition, defecation Frontal and central region Normal Clobazam, phenytoin Delay in language development [31]
6 14 Male Micturition Right anterior temporal and temporal region Not indicated Primidone Normal [32]
7 21 Female Micturition Left frontal region Normal Lamotrigine Normal [33]
8 11 Female Micturition Bilateral occipital region Normal Clobazam ADHD, developmental delay [34]
9 6 Male Micturition Central midline region (Cz) Normal Not indicated Not indicated [35]

EEG, electroencephalogram; CT, computed tomography; MRI, magnetic resonance imaging; ADHD, attention deficit hyperactivity disorder.

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