Original Paper
Urologia Internationalis
Received: December 21, 2012 Accepted: March 23, 2013 Published online: July 9, 2013
Urol Int 2013;91:417–422 DOI: 10.1159/000350940
Overactive Bladder and Pontine Reticular Formation Orhan Ünal Zorba a Serkan Kırbaş b Hakkı Uzun a Mehmet Çetinkaya c Kadir Önem d Mehmet Murat Rifaioğlu e Departments of a Urology and b Neurology, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize, c Department of Urology, Faculty of Medicine, Muğla University, Muğla, d Department of Urology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, and e Department of Urology, Faculty of Medicine, Mustafa Kemal University, Antakya, Turkey
Key Words Overactive bladder · Pons · Reticular formation · Blink reflex
mation-originated pathology. Additional studies on other reticular formation-mediated reflexes are needed to reveal possible dysfunction of reticular formation. Copyright © 2013 S. Karger AG, Basel
Abstract Background: The etiology of overactive bladder (OAB) remains unclear. Observed neurogenic factors in the literature are limited to suprapontine or spinal pathologies. The blink reflex is a useful tool in the evaluation of brainstem functions. Blink reflex latency times were evaluated in order to reveal pathology in the brainstem. Methods: A total of 60 women, 30 patients with idiopathic OAB and 30 healthy controls, were enrolled in the study. Blink reflex latency times were analyzed by electrical stimulation of the supraorbital nerve. Two responses in the orbicularis oculi muscle, early ipsilateral response (R1) and late bilateral response (R2) latency times, were recorded. Results: Mean ages of the patients and controls were 51.9 ± 5.3 and 49.2 ± 6.2 years, respectively. R2 latency times were significantly higher in patients than in controls. However, R1 latency times were similar between the two groups. Conclusions: The results of the study suggest a significant relation between late blink latency times and OAB. An oligosynaptic path via the trigeminal nuclei is responsible for R1; however, R2 response is relayed through the reticular formation. Stimulation of pontine reticular formation inhibits micturition contraction. In some patients, idiopathic OAB may result from reticular for-
© 2013 S. Karger AG, Basel 0042–1138/13/0914–0417$38.00/0 E-Mail [email protected] www.karger.com/uin
Introduction
Three main factors have been proposed regarding the cause of overactive bladder (OAB): myogenic, neurogenic and urotheliogenic. Most of the observed neurogenic factors in the literature are limited to suprapontine or spinal pathologies. To our knowledge, there are only a few studies evaluating brainstem structures in OAB [1–3]. One of the most frequent motor actions that we do in everyday life is blinking, which is organized by brainstem structures. The blink reflex can be analyzed by electromyography (EMG) with electrostimulation of the supraorbital nerve. The afferent limb of the reflex travels in the ophthalmic division of the trigeminal nerve, known as ‘the supraorbital nerve’. The supraorbital nerve can be stimulated by surface electrodes during EMG. The facial nerve subserves the efferent limb. Reflex responses from the inferior portion of both orbicularis oculi muscles may be recorded simultaneously by surface electrodes. Reflex blinking is usually employed in the clinical neurophysiology laboratory for the assessment of not only conduction Orhan Ünal Zorba Recep Tayyip Erdoğan Üniversitesi Tıp Fakültesi, Üroloji AD TR–53100 Rize (Turkey) E-Mail zorbaunal @ gmail.com
along the reflex arc, but also to demonstrate many functions that are either integrated in or mediated by the brainstem structures [4, 5]. Anatomical and physiological studies have shown that the micturition reflex is dependent on neural circuitry in the brainstem called pontine micturition center (PMC) or M region in the dorsolateral pontine tegmentum, activating micturition. The pontine storage center is also called L region and inhibits micturition to maintain urine storage. Micturition contractions can also be inhibited by the stimulation of the rostral part of the pontine reticular formation [6]. The L region is located at the pontine tegmental reticular formation. These regions have been demonstrated neurophysiologically in the cat [7] and by imaging studies in humans [8]. The reticular formation is a network of loosely packed multipolar neurons located inside the brainstem, from the mesencephalon through the pons to the medulla oblongata. The reticular formation provides a transition between ascending and descending motor and sensory pathways [9]. It helps to automatically regulate heart rate variability, breathing and the process of digestion. In addition, the reticular formation also helps to regulate the processes of micturition and defecation [10]. It also regulates brainstem reflexes like those of blinking, masseter and pharyngeal [9, 11]. In this study, using standard electrodiagnostic methods, we evaluated blink reflex latency times by stimulation of the supraorbital nerve, leading to orbicularis oculi muscle contraction via the facial nerve in patients with OAB and healthy controls, in order to reveal pathology that may be attributed to the brainstem structure related to both micturition and blink reflex. Subjects and Methods In this case-control study, a total of 60 women, 30 patients with idiopathic OAB and 30 healthy controls, were enrolled. The patients’ medical history was obtained and physical examinations (including neurologic examination) were performed. Complete blood count, serum electrolyte, vitamin B12, glucose, urea, creatinine and liver enzyme analyses as well as urinalysis and uroflowmetry were performed on both healthy controls and patients. The study patients met the criteria for OAB as defined by the 2003 International Continence Society criteria [12] and had an OAB-validated 8-question screener score >8 [13]. All patients had frequency and nocturia >7 and >1, respectively. All had previously provided a urination pattern detailing the time and volume of each urination over at least 3 days. The control subjects were chosen from former ureteral stone patients with no new stone in the urinary tract. Also, the control subjects had no documented urinary tract anomaly causing stone formation or as a result of stone
418
Urol Int 2013;91:417–422 DOI: 10.1159/000350940
passage. None of the control subjects had voiding difficulty, urgency, incontinence, frequency or nocturia. The neurologist was blinded to whether the patients were cases or controls. Exclusion criteria were (1) OAB symptoms with stress urinary incontinence (stress incontinence was verified by stress test), (2) pelvic organ prolapse, (3) any condition that can disrupt the brainstem reflex, such as cranial nerve lesions, cerebrovascular disease or disease associated with neuropathy or being treated with drugs recognized as potentially causing neuropathy, (4) abnormal neurological examination findings, (5) history of pelvic surgery, (6) alcohol use, (7) anticholinergic medication or (8) any abnormality determined by the aforementioned blood and urine analyses. During the EMG recording, patients and controls were supine on a bed in a warm room with eyes slightly closed. The left and right supraorbital nerves were percutaneously stimulated with bipolar surface electrodes located above the eyebrow where the supraorbital nerve emerges from the skull. The reflex responses were recorded using two surface electrodes located on the cheekbone overlaying the orbicularis oculi muscle in line with the pupil in forward gaze to record the response of the muscle. The EMG signal was then conducted to the recording equipment. The reference electrode was placed on the lateral surface of the nose and a ground electrode was placed at an electrically inactive site such as the arm. A blink’s EMG amplitude is rarely more than a few hundred microvolts; because of this, recording conditions should improve the flow of current from the skin surface to the electrodes. The skin is prepared by removing makeup and dead skin cells to reduce the impedance between the skin and the electrode gel. After preparation of the skin, an EMG technician massaged electrode gel as a thin layer on the recording site. The electrical stimulation of the supraorbital nerve elicits two responses in the orbicularis oculi muscle, the early ipsilateral response (R1) and the late bilateral response (R2) (fig. 1). Stimulus duration was 0.1–0.2 ms and the intensity of the stimulus was set to 100 mV/division and always under the pain threshold, in order to evoke early R1 and late R2 responses and simultaneously to avoid any activation of nociceptive afferents. The EMG signals were amplified with a frequency response of 20 Hz to 3 kHz, which allowed accurate analyses of short latency responses. The latency times of both the R1 and R2 reflex responses were measured from the stimulus artifact to the initial response of the orbicularis oculi muscle. The subjects had no auditory or visual prepulse stimulation. All subjects gave their informed consent to the experimental procedures, which were approved by the local ethics committee and conducted in accordance with the regulations laid down in the Declaration of Helsinki. Statistical analysis was performed using Student’s t test. The software used for all statistical evaluations was PASW 18.0.0 Statistics program (SPSS Inc., Chicago, Ill., USA).
Results
Mean ages of the OAB patients and control subjects were 51.9 ± 5.3 and 49.2 ± 6.2 years, respectively. There was no significant difference in the demographic and clinical data of patients and controls (table 1). Zorba/Kırbaş/Uzun/Çetinkaya/Önem/ Rifaioğlu
Blink reflex – analysis
Trig supraorbital
0.5 mV/D R1 R2
(stim) Right Amplif.1
Amplif.2
27.6 mA 0.2 ms 1 Hz
10 ms/D R1 = 10.5 ms R2 = 39.3 ms
R2
Left
R2 = 36.7 ms
Note : 0.5 mV/D
Amplif.1
10 ms/D R2
Right
R2 = 39.7 ms R1
R2
(stim) Left Amplif.2
R1 = 10.8 ms R2 = 41.0 ms
Fig. 1. Early (R1) and bilateral late respons-
es (R2) of the blink reflex on the electromyogram of a patient with OAB syndrome.
Early blink latency times were similar in both groups bilaterally. All of the late blink latency times were significantly higher in patients with OAB than in controls (p = 0.001) (table 2). Figure 2 represents the latency times for the study and control group, with 95% confidence interval (as darker bars) and range. The values were significantly higher in the OAB group for late latency times (p = 0.001).
Note :
Table 1. Clinical data of the OAB and the control group
Age, years Height, m Weight, kg BMI, kg/m2 Menopause, n (%) Nocturia Frequency OAB score
OAB
Control
p
51.9±5.3 1.59±0.1 76.8±16.3 30.2±6.5 15 (50) 3.2±1.1 9±1.4 22.8±4.9
49.2±6.2 1.60±0.1 75.5±12.0 29.2±4.3 14 (47) 0.1±0.3 3.6±0.9 1.76±1.73
0.074 0.322 0.733 0.477 0.796 0.001 0.001 0.001
Discussion BMI = Body mass index.
The finding of this study is a strong association between increase in late blink reflex latency time (R2) and OAB, which may be attributed to a disorder in a brainstem structure that can mediate both late blink reflex and micturition, resulting in OAB and increased late blink latency time. The blink reflex can be evoked or modulated by nontrigeminal inputs; these are called somatosensory, acoustic, photic blink reflex and prepulse inhibition [11]. Connectivity to other neurons in the pons makes the blink reflex an ideal parameter to check pontine structures. There are various studies showing blink reflex as a useful tool in the evaluation of brainstem functions [4, 5, 9, 14, 15]. Abnormal blink reflex may be the expression of a dysfunction located in the pons, which is why we preferred the blink reflex in order to evaluate the pontine structures in OAB patients. Overactive Bladder and Pontine Reticular Formation
Table 2. Latency times (ms) of blink reflex in the OAB and the
control group
RR1 RR2i RR2c LR1 LR2i LR2c
OAB
Control
p
11.6±1.2 37.3±2.0 37.4±1.9 11.9±1.0 37.1±2.2 37.4±1.9
11.2±1.3 31.5±1.6 32.7±1.9 11.2±1.0 32.2±1.8 33.1±2.2
0.163 0.001 0.001 0.064 0.001 0.001
RR1 = Early right ipsilateral response; RR2i = late right ipsilateral response; RR2c = late right contralateral response; LR1 = early left ipsilateral response; LR2i = late left ipsilateral response; LR2c = late left contralateral response.
Urol Int 2013;91:417–422 DOI: 10.1159/000350940
419
45
40
40 RR2c
RR2i
45
35
30
25
35
30
Control
25
OAB
45
45
40
40
35
30
25
Control
OAB Group
LR2c
LR2i
Group
35
30
Control
OAB Group
25
Control
Group
OAB
Fig. 2. Plots comparing late blink latency times for the study and control groups. RR2i = Late right ipsilateral re-
sponse; RR2c = late right contralateral response; LR2i = late left ipsilateral response; LR2c = late left contralateral response.
The centers involved in the control of micturition, the M and L region, are in the dorsolateral pontine tegmentum and lie in close anatomical proximity to the regions responsible for coordinating the blink reflex. To our knowledge, there is only one study showing connectivity between the PMC and blink reflex neurons; Dauvergne et al. [14] demonstrated terminal boutons in the PMC from the sensory trigeminal complex. Additionally, there are also other studies showing anatomical proximity between regions of blink reflex and the PMC [16, 17]. Retrograde tracer injections in the facial nucleus revealed several pools of neurons in the brainstem of different animals, which innervate the facial nucleus. Some of these neurons are in the ventral part of the lateral pontine tegmental field, which contains the L region [16, 17]. 420
Urol Int 2013;91:417–422 DOI: 10.1159/000350940
The aforementioned connections between the areas responsible for blink reflex and the PMC make us suspect that there may be a link between the neurons of the blink reflex and the micturition center in the pons, and this may expose these two activities to the effects of the same pathology. The reticular formation regulates brainstem reflexes and also micturition [9–11]. The pontine reticular formation can be divided into a lateral and a medial tegmental field. The L region is located more ventrally and more laterally in the pontine tegmentum than the M region, overlapping the lateral pontine tegmental reticular formation [18]. In monkeys, microstimulation of the pontine lateral tegmental field suppresses reflex blinks [19]. The lateral tegmental field also houses the premotor neurons with long descending axons to the motor neurons of the spinal cord Zorba/Kırbaş/Uzun/Çetinkaya/Önem/ Rifaioğlu
involved in micturition [10]. On the other hand, detrusor relaxation and external sphincter contraction are elicited by electrical stimulation of the lateral tegmental field of the pontine reticular formation [6, 20]. These studies suggest that the L region’s descending pathways are relayed through the lateral pontine tegmental reticular formation. Early blink reflex (R1) is relayed through an oligosynaptic path, consisting of one or two interneurons [21]; however, R2 response is relayed through a polysynaptic path, including neurons in the reticular formation [22]. For the late blink reflex response (R2) trigeminal sensory impulses are relayed by a pathway that ascends bilaterally to the facial nuclei in the pons. These trigeminofacial connections pass through the lateral pontine tegmental reticular formation [15, 23] from where the L region’s descending pathways are suggested to pass. In the present study, all of the late blink latency times (LR2i, LR2c, RR2i, RR2c) were found to be increased in patients with OAB. The early blink latency times (RR1 and LR1) were not significantly different between the groups. In the light of these neuroanatomical and possible functional relationships between blinking and micturition, assessing a significant difference in only late blink reflex latency time (R2) in the present study suggests that the increase in R2 and OAB may both originate from a brainstem structure that can mediate micturition as well as late blink reflex. This structure seems us to be pontine reticular formation. In patients with idiopathic OAB, due to unknown etiology, afferent receptors/nerves of the bladder may be activated during the storage phase and, in some individuals, this may result in M region activation leading to involuntary contractions and OAB symptoms. However, in normal subjects, there appears to be reciprocal inhibition between the M region and the L region, facilitating either micturition or urine storage [7, 17]. This intense vesical
afferent activity may be inhibited by activation of the L region and does not result in OAB symptoms. If this inhibitory effect is delayed because of a disorder in the reticular formation, subjects may experience OAB symptoms such as increased response time of the orbicularis oculi muscle to the stimulus of the supraorbital nerve (increased late blink latency time).
Conclusions
In the present study, we present new data suggesting a connection between the neurons related to late blink reflex and the L region, which may account for OAB symptoms and increased late blink latency times. The nature of this association between blink reflex and OAB is uncertain. In patients with OAB, there may be a defect in the pontine reticular formation. This pathology may affect both the blink reflex and the micturition center and lead to increased late blink latency times and OAB symptoms. In order to reveal pontine reticular formation pathology in OAB patients, studies on other pontine reticular formation-regulated reflexes are needed.
Authors’ Contributions O.Ü. Zorba: project development, data collection, data analysis, manuscript writing. S. Kırbaş: project development, data collection. H. Uzun: data collection, manuscript writing. K. Önem: data analysis, manuscript writing. M. Çetinkaya: manuscript writing. M.M. Rifaioğlu: project development, manuscript writing.
Disclosure Statement The authors declare no conflict of interest.
References 1 Griffiths D, Tadic SD, Schaefer W, et al: Cerebral control of the bladder in normal and urgeincontinent women. Neuroimage 2007;37:1–7. 2 Kuipers R, Mouton LJ, Holstege G: Afferent projections to the pontine micturition center in the cat. J Comp Neurol 2006;494:36–53. 3 Yokoyama O, Komatsu K, Ishiura Y, et al: Overactive bladder – experimental aspects. Scand J Urol Nephrol Suppl 2002;210:59–64. 4 Kimura J, Powers JM, Van Allen MW: Reflex response of orbicularis oculi muscle to supraorbital nerve stimulation. Arch Neurol 1969; 21:193–199.
Overactive Bladder and Pontine Reticular Formation
5 Shahani BT, Young RR: Human orbicularis oculi reflexes. Neurology 1972;22:149–154. 6 Kimura Y, Ukai Y, Kimura K, et al: Inhibitory influence from the nucleus reticularis pontis oralis on the micturition reflex induced by electrical stimulation of the pontine micturition center in cats. Neurosci Lett 1995;195:214–216. 7 Blok BFM, Holstege G: The central nervous system control of micturition in cats and humans. Behav Brain Res 1998;92:119–125. 8 Kavia RBC, Dasgupta R, Fowler CJ: Functional imaging and the central control of the bladder. J Comp Neurol 2005;493:27–32.
Urol Int 2013;91:417–422 DOI: 10.1159/000350940
9 Ennever JB, Horn AKE: Reticular formation: eye movements, gaze, and blinks; in Paxinos G, Mai JK (eds): The Human Nervous System. Elsevier, 2004, pp 479–510. 10 Holstege G: Descending motor pathways and the spinal motor system: limbic and nonlimbic components. Prog Brain Res 1991;87:307– 421. 11 Aramideh M, Ongerboer de Visser BW: Brainstem reflexes: electrodiagnostic techniques, physiology, normative data, and clinical applications. Muscle Nerve 2002; 26: 14–30.
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12 Abrams P, Cardozo L, Fall M, et al: The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 2003;61:37–49. 13 Coyne KS, Margolis MK, Zyczynski T, Elinoff V, Roberts R: Validation of an overactive bladder screener in a primary care patient population in the United States. Poster presented at the 34th Joint Meeting of the International Continence Society and the International UroGynecological Association, August 23–27, 2004, Paris, France. 14 Dauvergne C, Smit AE, Valla J, et al: Are locus coeruleus neurons involved in blinking? Neurosci Res 2008;61:182–191. 15 Nazlıel B, Arıkan Z, Irkeç C, et al: Blink reflex abnormalities in chronic alcoholics. Eur Neurol 2004;52:82–86.
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16 Holstege G, Tan J, van Ham JJ, et al: Anatomical observations on the afferent projections to the retractor bulb motoneuronal cell group and other pathways possibly related to the blink reflex in the cat. Brain Res 1986; 374: 321–334. 17 Holstege G, van Ham JJ, Tan J: Afferent projections to the orbicularis oculi motoneuronal cell group. An autoradiographical tracing study in the cat. Brain Res 1986;374:306–320. 18 Sakakibara R, Nakazawa K, Shiba K, et al: Firing patterns of micturition-related neurons in the pontine storage centre in cats. Auton Neurosci 2002;99:24–30. 19 Mays LE, Morisse DW: Electrical stimulation of the pontine omnipause area inhibits eye blink. J Am Optom Assoc 1995;66:419–422.
20 Griffiths D, Holstege G, Dalm E, et al: Control and coordination of bladder and urethral function in the brainstem of the cat. Neurourol Urodyn 1990;9:63–82. 21 Ongerboer de Visser BW: Anatomical and functional organization of reflexes involving the trigeminal system in man: jaw reflex, blink reflex, corneal reflex and exteroceptive suppression. Adv Neurol 1983;39:729–738. 22 Sibony PA, Evinger C: Normal and abnormal eyelid function; in Miller NR, Newman NH (eds): Clinical Neuro-Ophthalmology. Baltimore, Williams & Wilkins, 1998, pp 1509– 1592. 23 Ongerboer de Visser BW, Kuypers HGJM: Late blink reflex changes in lateral medullary lesions. An electrophysiological and neuroanatomical study of Wallenberg’s syndrome. Brain 1978;101:285–294.
Zorba/Kırbaş/Uzun/Çetinkaya/Önem/ Rifaioğlu
Copyright: S. Karger AG, Basel 2013. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Urologia Internationalis
Received: December 21, 2012 Accepted: March 23, 2013 Published online: July 9, 2013
Urol Int 2013;91:417–422 DOI: 10.1159/000350940
Overactive Bladder and Pontine Reticular Formation Orhan Ünal Zorba a Serkan Kırbaş b Hakkı Uzun a Mehmet Çetinkaya c Kadir Önem d Mehmet Murat Rifaioğlu e Departments of a Urology and b Neurology, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize, c Department of Urology, Faculty of Medicine, Muğla University, Muğla, d Department of Urology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, and e Department of Urology, Faculty of Medicine, Mustafa Kemal University, Antakya, Turkey
Key Words Overactive bladder · Pons · Reticular formation · Blink reflex
mation-originated pathology. Additional studies on other reticular formation-mediated reflexes are needed to reveal possible dysfunction of reticular formation. Copyright © 2013 S. Karger AG, Basel
Abstract Background: The etiology of overactive bladder (OAB) remains unclear. Observed neurogenic factors in the literature are limited to suprapontine or spinal pathologies. The blink reflex is a useful tool in the evaluation of brainstem functions. Blink reflex latency times were evaluated in order to reveal pathology in the brainstem. Methods: A total of 60 women, 30 patients with idiopathic OAB and 30 healthy controls, were enrolled in the study. Blink reflex latency times were analyzed by electrical stimulation of the supraorbital nerve. Two responses in the orbicularis oculi muscle, early ipsilateral response (R1) and late bilateral response (R2) latency times, were recorded. Results: Mean ages of the patients and controls were 51.9 ± 5.3 and 49.2 ± 6.2 years, respectively. R2 latency times were significantly higher in patients than in controls. However, R1 latency times were similar between the two groups. Conclusions: The results of the study suggest a significant relation between late blink latency times and OAB. An oligosynaptic path via the trigeminal nuclei is responsible for R1; however, R2 response is relayed through the reticular formation. Stimulation of pontine reticular formation inhibits micturition contraction. In some patients, idiopathic OAB may result from reticular for-
© 2013 S. Karger AG, Basel 0042–1138/13/0914–0417$38.00/0 E-Mail [email protected] www.karger.com/uin
Introduction
Three main factors have been proposed regarding the cause of overactive bladder (OAB): myogenic, neurogenic and urotheliogenic. Most of the observed neurogenic factors in the literature are limited to suprapontine or spinal pathologies. To our knowledge, there are only a few studies evaluating brainstem structures in OAB [1–3]. One of the most frequent motor actions that we do in everyday life is blinking, which is organized by brainstem structures. The blink reflex can be analyzed by electromyography (EMG) with electrostimulation of the supraorbital nerve. The afferent limb of the reflex travels in the ophthalmic division of the trigeminal nerve, known as ‘the supraorbital nerve’. The supraorbital nerve can be stimulated by surface electrodes during EMG. The facial nerve subserves the efferent limb. Reflex responses from the inferior portion of both orbicularis oculi muscles may be recorded simultaneously by surface electrodes. Reflex blinking is usually employed in the clinical neurophysiology laboratory for the assessment of not only conduction Orhan Ünal Zorba Recep Tayyip Erdoğan Üniversitesi Tıp Fakültesi, Üroloji AD TR–53100 Rize (Turkey) E-Mail zorbaunal @ gmail.com
along the reflex arc, but also to demonstrate many functions that are either integrated in or mediated by the brainstem structures [4, 5]. Anatomical and physiological studies have shown that the micturition reflex is dependent on neural circuitry in the brainstem called pontine micturition center (PMC) or M region in the dorsolateral pontine tegmentum, activating micturition. The pontine storage center is also called L region and inhibits micturition to maintain urine storage. Micturition contractions can also be inhibited by the stimulation of the rostral part of the pontine reticular formation [6]. The L region is located at the pontine tegmental reticular formation. These regions have been demonstrated neurophysiologically in the cat [7] and by imaging studies in humans [8]. The reticular formation is a network of loosely packed multipolar neurons located inside the brainstem, from the mesencephalon through the pons to the medulla oblongata. The reticular formation provides a transition between ascending and descending motor and sensory pathways [9]. It helps to automatically regulate heart rate variability, breathing and the process of digestion. In addition, the reticular formation also helps to regulate the processes of micturition and defecation [10]. It also regulates brainstem reflexes like those of blinking, masseter and pharyngeal [9, 11]. In this study, using standard electrodiagnostic methods, we evaluated blink reflex latency times by stimulation of the supraorbital nerve, leading to orbicularis oculi muscle contraction via the facial nerve in patients with OAB and healthy controls, in order to reveal pathology that may be attributed to the brainstem structure related to both micturition and blink reflex. Subjects and Methods In this case-control study, a total of 60 women, 30 patients with idiopathic OAB and 30 healthy controls, were enrolled. The patients’ medical history was obtained and physical examinations (including neurologic examination) were performed. Complete blood count, serum electrolyte, vitamin B12, glucose, urea, creatinine and liver enzyme analyses as well as urinalysis and uroflowmetry were performed on both healthy controls and patients. The study patients met the criteria for OAB as defined by the 2003 International Continence Society criteria [12] and had an OAB-validated 8-question screener score >8 [13]. All patients had frequency and nocturia >7 and >1, respectively. All had previously provided a urination pattern detailing the time and volume of each urination over at least 3 days. The control subjects were chosen from former ureteral stone patients with no new stone in the urinary tract. Also, the control subjects had no documented urinary tract anomaly causing stone formation or as a result of stone
418
Urol Int 2013;91:417–422 DOI: 10.1159/000350940
passage. None of the control subjects had voiding difficulty, urgency, incontinence, frequency or nocturia. The neurologist was blinded to whether the patients were cases or controls. Exclusion criteria were (1) OAB symptoms with stress urinary incontinence (stress incontinence was verified by stress test), (2) pelvic organ prolapse, (3) any condition that can disrupt the brainstem reflex, such as cranial nerve lesions, cerebrovascular disease or disease associated with neuropathy or being treated with drugs recognized as potentially causing neuropathy, (4) abnormal neurological examination findings, (5) history of pelvic surgery, (6) alcohol use, (7) anticholinergic medication or (8) any abnormality determined by the aforementioned blood and urine analyses. During the EMG recording, patients and controls were supine on a bed in a warm room with eyes slightly closed. The left and right supraorbital nerves were percutaneously stimulated with bipolar surface electrodes located above the eyebrow where the supraorbital nerve emerges from the skull. The reflex responses were recorded using two surface electrodes located on the cheekbone overlaying the orbicularis oculi muscle in line with the pupil in forward gaze to record the response of the muscle. The EMG signal was then conducted to the recording equipment. The reference electrode was placed on the lateral surface of the nose and a ground electrode was placed at an electrically inactive site such as the arm. A blink’s EMG amplitude is rarely more than a few hundred microvolts; because of this, recording conditions should improve the flow of current from the skin surface to the electrodes. The skin is prepared by removing makeup and dead skin cells to reduce the impedance between the skin and the electrode gel. After preparation of the skin, an EMG technician massaged electrode gel as a thin layer on the recording site. The electrical stimulation of the supraorbital nerve elicits two responses in the orbicularis oculi muscle, the early ipsilateral response (R1) and the late bilateral response (R2) (fig. 1). Stimulus duration was 0.1–0.2 ms and the intensity of the stimulus was set to 100 mV/division and always under the pain threshold, in order to evoke early R1 and late R2 responses and simultaneously to avoid any activation of nociceptive afferents. The EMG signals were amplified with a frequency response of 20 Hz to 3 kHz, which allowed accurate analyses of short latency responses. The latency times of both the R1 and R2 reflex responses were measured from the stimulus artifact to the initial response of the orbicularis oculi muscle. The subjects had no auditory or visual prepulse stimulation. All subjects gave their informed consent to the experimental procedures, which were approved by the local ethics committee and conducted in accordance with the regulations laid down in the Declaration of Helsinki. Statistical analysis was performed using Student’s t test. The software used for all statistical evaluations was PASW 18.0.0 Statistics program (SPSS Inc., Chicago, Ill., USA).
Results
Mean ages of the OAB patients and control subjects were 51.9 ± 5.3 and 49.2 ± 6.2 years, respectively. There was no significant difference in the demographic and clinical data of patients and controls (table 1). Zorba/Kırbaş/Uzun/Çetinkaya/Önem/ Rifaioğlu
Blink reflex – analysis
Trig supraorbital
0.5 mV/D R1 R2
(stim) Right Amplif.1
Amplif.2
27.6 mA 0.2 ms 1 Hz
10 ms/D R1 = 10.5 ms R2 = 39.3 ms
R2
Left
R2 = 36.7 ms
Note : 0.5 mV/D
Amplif.1
10 ms/D R2
Right
R2 = 39.7 ms R1
R2
(stim) Left Amplif.2
R1 = 10.8 ms R2 = 41.0 ms
Fig. 1. Early (R1) and bilateral late respons-
es (R2) of the blink reflex on the electromyogram of a patient with OAB syndrome.
Early blink latency times were similar in both groups bilaterally. All of the late blink latency times were significantly higher in patients with OAB than in controls (p = 0.001) (table 2). Figure 2 represents the latency times for the study and control group, with 95% confidence interval (as darker bars) and range. The values were significantly higher in the OAB group for late latency times (p = 0.001).
Note :
Table 1. Clinical data of the OAB and the control group
Age, years Height, m Weight, kg BMI, kg/m2 Menopause, n (%) Nocturia Frequency OAB score
OAB
Control
p
51.9±5.3 1.59±0.1 76.8±16.3 30.2±6.5 15 (50) 3.2±1.1 9±1.4 22.8±4.9
49.2±6.2 1.60±0.1 75.5±12.0 29.2±4.3 14 (47) 0.1±0.3 3.6±0.9 1.76±1.73
0.074 0.322 0.733 0.477 0.796 0.001 0.001 0.001
Discussion BMI = Body mass index.
The finding of this study is a strong association between increase in late blink reflex latency time (R2) and OAB, which may be attributed to a disorder in a brainstem structure that can mediate both late blink reflex and micturition, resulting in OAB and increased late blink latency time. The blink reflex can be evoked or modulated by nontrigeminal inputs; these are called somatosensory, acoustic, photic blink reflex and prepulse inhibition [11]. Connectivity to other neurons in the pons makes the blink reflex an ideal parameter to check pontine structures. There are various studies showing blink reflex as a useful tool in the evaluation of brainstem functions [4, 5, 9, 14, 15]. Abnormal blink reflex may be the expression of a dysfunction located in the pons, which is why we preferred the blink reflex in order to evaluate the pontine structures in OAB patients. Overactive Bladder and Pontine Reticular Formation
Table 2. Latency times (ms) of blink reflex in the OAB and the
control group
RR1 RR2i RR2c LR1 LR2i LR2c
OAB
Control
p
11.6±1.2 37.3±2.0 37.4±1.9 11.9±1.0 37.1±2.2 37.4±1.9
11.2±1.3 31.5±1.6 32.7±1.9 11.2±1.0 32.2±1.8 33.1±2.2
0.163 0.001 0.001 0.064 0.001 0.001
RR1 = Early right ipsilateral response; RR2i = late right ipsilateral response; RR2c = late right contralateral response; LR1 = early left ipsilateral response; LR2i = late left ipsilateral response; LR2c = late left contralateral response.
Urol Int 2013;91:417–422 DOI: 10.1159/000350940
419
45
40
40 RR2c
RR2i
45
35
30
25
35
30
Control
25
OAB
45
45
40
40
35
30
25
Control
OAB Group
LR2c
LR2i
Group
35
30
Control
OAB Group
25
Control
Group
OAB
Fig. 2. Plots comparing late blink latency times for the study and control groups. RR2i = Late right ipsilateral re-
sponse; RR2c = late right contralateral response; LR2i = late left ipsilateral response; LR2c = late left contralateral response.
The centers involved in the control of micturition, the M and L region, are in the dorsolateral pontine tegmentum and lie in close anatomical proximity to the regions responsible for coordinating the blink reflex. To our knowledge, there is only one study showing connectivity between the PMC and blink reflex neurons; Dauvergne et al. [14] demonstrated terminal boutons in the PMC from the sensory trigeminal complex. Additionally, there are also other studies showing anatomical proximity between regions of blink reflex and the PMC [16, 17]. Retrograde tracer injections in the facial nucleus revealed several pools of neurons in the brainstem of different animals, which innervate the facial nucleus. Some of these neurons are in the ventral part of the lateral pontine tegmental field, which contains the L region [16, 17]. 420
Urol Int 2013;91:417–422 DOI: 10.1159/000350940
The aforementioned connections between the areas responsible for blink reflex and the PMC make us suspect that there may be a link between the neurons of the blink reflex and the micturition center in the pons, and this may expose these two activities to the effects of the same pathology. The reticular formation regulates brainstem reflexes and also micturition [9–11]. The pontine reticular formation can be divided into a lateral and a medial tegmental field. The L region is located more ventrally and more laterally in the pontine tegmentum than the M region, overlapping the lateral pontine tegmental reticular formation [18]. In monkeys, microstimulation of the pontine lateral tegmental field suppresses reflex blinks [19]. The lateral tegmental field also houses the premotor neurons with long descending axons to the motor neurons of the spinal cord Zorba/Kırbaş/Uzun/Çetinkaya/Önem/ Rifaioğlu
involved in micturition [10]. On the other hand, detrusor relaxation and external sphincter contraction are elicited by electrical stimulation of the lateral tegmental field of the pontine reticular formation [6, 20]. These studies suggest that the L region’s descending pathways are relayed through the lateral pontine tegmental reticular formation. Early blink reflex (R1) is relayed through an oligosynaptic path, consisting of one or two interneurons [21]; however, R2 response is relayed through a polysynaptic path, including neurons in the reticular formation [22]. For the late blink reflex response (R2) trigeminal sensory impulses are relayed by a pathway that ascends bilaterally to the facial nuclei in the pons. These trigeminofacial connections pass through the lateral pontine tegmental reticular formation [15, 23] from where the L region’s descending pathways are suggested to pass. In the present study, all of the late blink latency times (LR2i, LR2c, RR2i, RR2c) were found to be increased in patients with OAB. The early blink latency times (RR1 and LR1) were not significantly different between the groups. In the light of these neuroanatomical and possible functional relationships between blinking and micturition, assessing a significant difference in only late blink reflex latency time (R2) in the present study suggests that the increase in R2 and OAB may both originate from a brainstem structure that can mediate micturition as well as late blink reflex. This structure seems us to be pontine reticular formation. In patients with idiopathic OAB, due to unknown etiology, afferent receptors/nerves of the bladder may be activated during the storage phase and, in some individuals, this may result in M region activation leading to involuntary contractions and OAB symptoms. However, in normal subjects, there appears to be reciprocal inhibition between the M region and the L region, facilitating either micturition or urine storage [7, 17]. This intense vesical
afferent activity may be inhibited by activation of the L region and does not result in OAB symptoms. If this inhibitory effect is delayed because of a disorder in the reticular formation, subjects may experience OAB symptoms such as increased response time of the orbicularis oculi muscle to the stimulus of the supraorbital nerve (increased late blink latency time).
Conclusions
In the present study, we present new data suggesting a connection between the neurons related to late blink reflex and the L region, which may account for OAB symptoms and increased late blink latency times. The nature of this association between blink reflex and OAB is uncertain. In patients with OAB, there may be a defect in the pontine reticular formation. This pathology may affect both the blink reflex and the micturition center and lead to increased late blink latency times and OAB symptoms. In order to reveal pontine reticular formation pathology in OAB patients, studies on other pontine reticular formation-regulated reflexes are needed.
Authors’ Contributions O.Ü. Zorba: project development, data collection, data analysis, manuscript writing. S. Kırbaş: project development, data collection. H. Uzun: data collection, manuscript writing. K. Önem: data analysis, manuscript writing. M. Çetinkaya: manuscript writing. M.M. Rifaioğlu: project development, manuscript writing.
Disclosure Statement The authors declare no conflict of interest.
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Copyright: S. Karger AG, Basel 2013. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
