Effect of Thalamic Deep Brain Stimulation on Lower Urinary Tract Function

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1 european urology 53 (2008) available at journal homepage: Neuro-urology Effect of Thalamic Deep Brain Stimulation on Lower Urinary Tract Function Thomas M. Kessler a, Fiona C. Burkhard a, Sebastian Z Brun a, Alexander Stibal b, Urs E. Studer a, Christian W. Hess c, Alain Kaelin-Lang c, * a Department of Urology, University of Bern, Inselspital, Bern, Switzerland b Department of Neurosurgery, University of Bern, Inselspital, Bern, Switzerland c Department of Neurology, University of Bern, Inselspital, Bern, Switzerland Article info Article history: Accepted July 9, 2007 Published online ahead of print on July 18, 2007 Keywords: Thalamic deep brain stimulation Essential tremor Lower urinary tract function Urodynamics Abstract Objective: The precise mechanisms underlying cerebral regulation of lower urinary tract function are still poorly understood. In patients with disabling essential tremor (ET) refractory to pharmacotherapy, thalamic deep brain stimulation (DBS) is an effective treatment for tremor control. Here, we evaluated the effect of thalamic DBS on urodynamic parameters in patients with ET. Patients and methods: We investigated seven patients (two females, five males) with ET mo after implantation of DBS leads into the ventral intermediate nucleus of the thalamus. We compared urodynamic parameters during thalamic DBS (ON state) and 30 min after turning the stimulator off (OFF state). Results: In the ON compared with the OFF state, there was a significant decrease in bladder volume at first desire to void (median, 218 ml vs. 365 ml, p = 0.031), at strong desire to void (median, 305 ml vs. 435 ml, p = 0.031), and at maximum cystometric capacity (median, 345 ml vs. 460 ml, p = 0.016). No significant differences between the ON and OFF state were detected for changes in detrusor pressure during filling cystometry, bladder compliance, maximum detrusor pressure, detrusor pressure at maximum flow rate, maximum flow rate, voided volume, and postvoid residual. Conclusions: Thalamic deep brain stimulation resulted in an earlier desire to void and decreased bladder capacity, suggesting a regulatory role of the thalamus in lower urinary tract function. Therefore, the thalamus may be a promising target for the development of new therapies for lower urinary tract dysfunction. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. Part of this work was presented as a poster during the 22nd Annual Congress of the European Association of Urology, Berlin, Germany, March 2007 (Eur Urol Suppl 2007;6:166 [abstract no. 576]). * Corresponding author. Department of Neurology, University of Bern, Inselspital, 3010 Bern, Switzerland. Tel ; Fax: address: alain.kaelin@dkf.unibe.ch (A. Kaelin-Lang) /$ see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 608 european urology 53 (2008) Introduction The afferent routes from the lower urinary tract to the brain and their precise role in regulating urinary storage and voiding are not fully understood. Important regions for the central regulation of lower urinary tract function are located in the pons, the pontine storage centre, and the pontine micturition centre [1,2]. Sensory input from the lower urinary tract mainly ascends to the periaqueductal gray (PAG) that serves as a relay centre for afferent information through its direct connexions with the pons and higher centres [3]. The thalamus itself is another important station between the PAG and several cortical regions including the prefrontal cortex, which helps in deciding whether it is appropriate or not to void [3]. Essential tremor (ET) is a motor disorder of unknown origin. Neuropathological studies suggest an important role of the cerebellum in ET [4,5]. In patients with disabling ET refractory to pharmacotherapy, thalamic deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus [6] is a safe and effective treatment [7]. The high-frequency stimulation used in thalamic DBS is assumed to primarily act by inhibiting neural structures and has largely replaced the previously performed lesioning procedure at the same thalamic site, even though additional excitatory phenomena of DBS are also possible. The function of the VIM nucleus of the thalamus is generally considered to be that of a relay station for the sensomotor pathways connecting cerebellar and somatosensory afferents with the motor and premotor cortex [6]. ET is not known to induce lower urinary tract symptoms (LUTS) or neuropathological changes in the thalamus. Consequently, DBS in patients with ET offers the unique opportunity to investigate the role of the VIM nucleus in lower urinary tract function. Therefore, we evaluated the effect of thalamic DBS on urodynamic parameters in patients with ET. 2. Patients and methods We prospectively evaluated 7 patients (2 females, 5 males; median age, 66 yr; range, 53 82) with ET mo after DBS lead implantation into the VIM nucleus of the thalamus. Two patients had unilateral DBS; the remaining patients had bilateral thalamic DBS. The tremor was successfully controlled in all patients. The study protocol was approved by the local ethics committee. All patients provided written informed consent. All patients completed the validated International Prostate Symptom Score (IPSS) questionnaire, which is used to assess LUTS in both women and men [8,9], immediately before the urodynamic study with the stimulator turned on. A urological evaluation including medical history, neurourological examination, urinalysis, and urine culture was performed. Patients then underwent two urodynamic investigations during chronic stimulation (ON state) and two urodynamic investiga- Table 1 Urodynamic parameters during ON and OFF thalamic deep brain stimulation state per patient Pt 1 a,b Pt 2 b Pt 3 Pt 4 a Pt 5 c Pt 6 Pt 7 a,c Storage phase of the bladder Bladder volume at first desire to void (ml) 236/ / /400 50/50 368/ / /200 Bladder volume at strong desire to void (ml) 335/ / /480 50/50 480/ / /295 Maximum cystometric capacity (ml) 438/ / /515 60/70 490/ / /345 Change in detrusor pressure during filling 3/4 3/3 4/5 2/2 7/6 4/4 4/4 cystometry (cm H 2 O) Bladder compliance (ml/cm H 2 O) 146/ /154 74/103 30/35 70/90 125/156 68/86 Detrusor overactivity No/no No/no No/no Terminal with incontinence/ terminal with incontinence No/no No/no Phasic without incontinence/ phasic without incontinence Voiding phase of the bladder Maximum detrusor pressure (cm H 2 O) 49/57 65/55 49/47 78/70 50/45 71/57 53/58 Detrusor pressure at maximum 38/39 38/45 45/41 65/59 44/44 52/40 47/55 flow rate (cm H 2 O) Maximum flow rate (ml/s) 12/17 11/9 10/11 4/4 19/21 12/12 6/8 Voided volume (ml) 435/ / /500 45/60 490/ / /265 Postvoid residual (ml) 3/10 110/240 18/15 15/10 0/5 0/10 70/80 Pelvic floor electromyographic activity a Patients 1, 4, and 7 complained about lower urinary tract symptoms. b Patients 1 and 2 are females; other patients are males. c Patients 5 and 7 had unilateral thalamic deep brain stimulation; other patients had bilateral thalamic deep brain stimulation.

3 european urology 53 (2008) Table 2 Comparison of urodynamic parameters between ON and OFF thalamic deep brain stimulation state using the Wilcoxon signed rank test Median ON (range) Median OFF (range) p Storage phase of the bladder Bladder volume at first desire to void (ml) 218 (50 368) 365 (50 435) * Bladder volume at strong desire to void (ml) 305 (50 480) 435 (50 580) * Maximum cystometric capacity (ml) 345 (60 500) 460 (70 625) * Change in detrusor pressure during filling cystometry (cm H 2 O) 4 (2 7) 4 (2 6) 0.99 Bladder compliance (ml/cm H 2 O) 74 (35 146) 103 (35 156) 0.31 Voiding phase of the bladder Maximum detrusor pressure (cm H 2 O) 53 (49 78) 57 (45 70) 0.38 Detrusor pressure at maximum flow rate (cm H 2 O) 45 (38 65) 44 (39 59) 0.99 Maximum flow rate (ml/s) 11 (4 19) 11 (4 21) 0.31 Voided volume (ml) 278 (45 500) 440 (60 615) 0.06 Postvoid residual (ml) 15 (0 110) 10 (5 240) 0.09 * Statistically significant results. tions 30 min after turning off the stimulator (OFF state) according to Schäfer et al s good urodynamic practices [10]. The bladder was filled with isotonic saline at a speed of 25 ml/min. Urodynamic investigations assessed parameters of both the storage (bladder volume at first desire to void, bladder volume at strong desire to void, maximum cystometric capacity, change in detrusor pressure during filling cystometry, bladder compliance, detrusor overactivity) and voiding (maximum detrusor pressure, detrusor pressure at maximum flow rate, maximum flow rate, voided volume, postvoid residual, pelvic floor electromyographic activity) phases as shown in Tables 1 and 2. All methods, definitions, and units conform to the standards recommended by the International Continence Society [11]. Values from the two consecutive urodynamic investigations performed in each patient with the stimulator in the same setting (either ON or OFF state) were averaged for further analysis because there was no significant difference in the urodynamic parameters between the two investigations. Statistical analyses were performed with the Wilcoxon signed rank test. A p value <0.05 was considered significant. 3. Results At the time of urodynamic investigation, three patients (patients 1, 4, and 7; Table 1) complained of LUTS: The IPSS for symptoms was 14, 18, and 15, respectively, and 4, 4, and 3 for quality of life, respectively, indicating moderate lower urinary tract dysfunction. The remaining four patients were free of LUTS (IPSS for symptoms 10, IPSS for quality of life 2). Two patients (patients 1 and 2, Table 1) had pathological voiding urodynamic parameters and two (patients 4 and 7, Table 1) had both pathological storage and voiding urodynamic parameters in all examinations. In one patient (patient 3, Table 1), turning off the stimulator resulted in isation of pathological storage urodynamic parameters. The remaining two patients (patients 5 and 6, Table 1) had storage and voiding urodynamic parameters in all examinations. Fig. 1 Thalamic deep brain stimulation had a significant effect on bladder volume at first and at strong desire to void and at maximum cystometric capacity.

4 610 european urology 53 (2008) Overall, in the ON compared with the OFF state (Tables 1 and 2), we did note a significant decrease in bladder volume at first desire and at strong desire to void, and at maximum cystometric capacity (Fig. 1). This effect was less evident in the three patients with LUTS (patients 1, 4, and 7). In the urologically asymptomatic patient with unilateral thalamic DBS (patient 5), this effect was remarkably lower than in the three urologically asymptomatic patients with bilateral thalamic DBS (patients 2, 3, and 6). All other parameters assessed did not differ significantly between the ON and OFF state. However, there was a trend for thalamic DBS-induced changes in voided volume and postvoid residual (Table 2). 4. Discussion To our knowledge, the present study is the first to evaluate the effect of thalamic DBS on urodynamic parameters. When the stimulator was turned on, urodynamic sensory parameters (bladder volume at first desire and at strong desire to void, and at maximum cystometric capacity) decreased significantly. Turning off the stimulator resulted in isation of pathological storage urodynamic parameters in one patient. However, whether these stimulation-related urodynamic changes are of clinical relevance remains to be clarified with further studies. Since the urodynamic investigations were always performed in the ON and then in the OFF state, the question of a potential sequence bias may be raised. However, this bias is unlikely because no significant differences were found between the two consecutive investigations performed with the stimulator in the same setting (either ON or OFF state). Independent of the presence or absence of LUTS, thalamic DBS induced a decrease in urodynamic sensory parameters in all patients. Although the number of patients was too small to allow for statistical subanalysis, these parameters had a tendency to decrease less in the three patients with LUTS compared with the three urologically asymptomatic patients with bilateral thalamic DBS. Why thalamic DBS in patients with LUTS seems to have less effect on urodynamic sensory parameters cannot be determined by this study. However, it may be attributed to LUTS-induced neuroplasticity in the afferent pathway. Similar adaptive changes due to plasticity of bladder afferents have been suggested in patients with bladder outlet obstruction [12]. Moreover, a slighter decrease in storage parameters was found in the urologically asymptomatic patient with unilateral thalamic DBS compared with the three urologically asymptomatic patients with bilateral thalamic DBS. This finding is consistent with the motor findings in patients with ET in whom bilateral thalamic DBS tends to have a more powerful effect than unilateral stimulation on axial tremor control [13]. Further examinations will be needed to assess whether bilateral stimulation may also have a greater effect than unilateral stimulation on lower urinary tract function. DBS is an effective treatment for various movement disorders including Parkinson s disease, ET, and dystonia. In patients with Parkinson s disease, subthalamic DBS (in contrast to thalamic DBS in patients with ET) was shown to have an effect on lower urinary tract function: In the ON state, a significant increase in bladder volume at first desire to void and at maximum cystometric capacity was found [14 16], and a significant improvement in storage symptoms was reported [17]. However, the interpretation of these results is hampered by the fact that Parkinsonian patients suffer from autonomic signs and symptoms. In contrast to Parkinson s disease, ET is a motor disorder without known urological symptoms. The ventrolateral thalamus was found to be a major relay site for visceral somatosensory information ascending to the cerebral cortex in animals [18] and was seen to be activated during the storage phase of the bladder in a positron emission tomography study in humans [19]. Since the effect of thalamic DBS on tremor is similar to that of a stereotactic lesion of the VIM nucleus, we hypothesise that DBS disrupts information processing between the thalamus and the cerebral cortex. Decreased bladder volumes at first desire and at strong desire to void, and at maximum cystometric capacity in the ON state of DBS imply that thalamic stimulation influences the afferent sensory input, resulting in a decreased sensory threshold of the bladder for filling. However, the exact thalamic region receiving visceral sensory inputs from the lower urinary tract is unknown in humans. It is conceivable that the VIM nucleus itself or an adjacent area of the ventrolateral thalamus also processes visceral information in humans like in animals. Suprapontine cerebrovascular lesions often lead to an overactive detrusor with increased bladder sensation and decreased maximum cystometric capacity [20]. This result is consistent with our findings, although detrusor overactivity was not induced by thalamic DBS. In addition, urodynamic studies of stroke patients with cerebrovascular lesions restricted to the thalamus have demonstrated sphincter function [21], which is in accord with our results.

5 european urology 53 (2008) It may be postulated that the effect of thalamic DBS on lower urinary tract function is due to motor rather than sensory pathways: Thalamic DBS may increase the bladder tonus consecutively, leading to a decrease in bladder volumes at first desire and at strong desire to void, and at maximum cystometric capacity. However, lower or equal bladder tonus (ie, smaller or no changes in detrusor pressure during filling cystometry) in the ON compared with the OFF state in all but one patient does not support this theory. Since our results are derived from a small number of patients, further important differences may have failed to be detected. Indeed, there was a trend for thalamic DBS-induced changes in voided volume and postvoid residual. Changes in bladder capacity will induce changes in voided volume and/or postvoid residuals. However, for a definitive statement concerning these parameters, a larger cohort would be required. In addition, the time between DBS lead implantation and urodynamic investigation varied widely so that an influence related to the duration of stimulation cannot be excluded. 5. Conclusions Thalamic deep brain stimulation resulted in an earlier desire to void and decreased bladder capacity, suggesting a regulatory role of the thalamus in lower urinary tract function. Therefore, the thalamus may be a promising target for the development of new therapies for lower urinary tract dysfunction, especially in patients with reduced/absent bladder sensation and/or increased bladder capacity. Conflicts of interest The authors have nothing to disclose. Acknowledgements Financial support was provided by the Inselspital, University Hospital Bern, Switzerland. The valuable help of Professor Brigitte Schurch (Spinal Cord Injury Centre, University of Zürich, Switzerland) in critically reading this manuscript is gratefully acknowledged. References [1] Blok BF, Willemsen AT, Holstege G. A PET study on brain control of micturition in humans. Brain 1997;120: [2] Blok BF, Sturms LM, Holstege G. Brain activation during micturition in women. Brain 1998;121: [3] Kavia RB, Dasgupta R, Fowler CJ. Functional imaging and the central control of the bladder. J Comp Neurol 2005;493: [4] Louis ED, Vonsattel JP, Honig LS, Ross GW, Lyons KE, Pahwa R. Neuropathologic findings in essential tremor. Neurology 2006;66: [5] Louis ED, Vonsattel JP, Honig LS, et al. Essential tremor associated with pathologic changes in the cerebellum. Arch Neurol 2006;63: [6] Weigel R, Krauss JK, Jones EG. Anatomie und Nomenklatur der Basalganglien und des Thalamus. In: Krauss JK, Volkmann J, editors. Tiefe Hirnstimulation. Darmstadt: Steinkopff Verlag Darmstadt; p [7] Lee JY, Kondziolka D. Thalamic deep brain stimulation for management of essential tremor. J Neurosurg 2005;103: [8] Madersbacher S, Pycha A, Klingler CH, Schatzl G, Marberger M. The International Prostate Symptom score in both sexes: a urodynamics-based comparison. Neurourol Urodyn 1999;18: [9] Boyle P, Robertson C, Mazzetta C, et al. The prevalence of lower urinary tract symptoms in men and women in four centres. The UrEpik study. BJU Int 2003;92: [10] Schäfer W, Abrams P, Liao L, et al. Good urodynamic practices: uroflowmetry, filling cystometry, and pressure-flow studies. Neurourol Urodyn 2002;21: [11] Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21: [12] Chai TC, Gray ML, Steers WD. The incidence of a positive ice water test in bladder outlet obstructed patients: evidence for bladder neural plasticity. J Urol 1998;160: [13] Lyons KE, Pahwa R. Deep brain stimulation and essential tremor. J Clin Neurophysiol 2004;21:2 5. [14] Finazzi-Agro E, Peppe A, D Amico A, et al. Effects of subthalamic nucleus stimulation on urodynamic findings in patients with Parkinson s disease. J Urol 2003;169: [15] Seif C, Herzog J, Van Der Horst C, Schrader B, Volkmann J, Deuschl G, et al. Effect of subthalamic deep brain stimulation on the function of the urinary bladder. Ann Neurol 2004;55: [16] Herzog J, Weiss PH, Assmus A, et al. Subthalamic stimulation modulates cortical control of urinary bladder in Parkinson s disease. Brain 2006;129: [17] Winge K, Nielsen KK, Stimpel H, Lokkegaard A, Jensen SR, Werdelin L. Lower urinary tract symptoms and bladder control in advanced Parkinson s disease: Effects of deep brain stimulation in the subthalamic nucleus. Mov Disord 2007;22: [18] Robbins MT, Uzzell TW, Aly S, Ness TJ. Characterization of thalamic neuronal responses to urinary bladder distention, including the effect of acute spinal lesions in the rat. J Pain 2006;7:

6 612 european urology 53 (2008) [19] Matsuura S, Kakizaki H, Mitsui T, Shiga T, Tamaki N, Koyanagi T. Human brain region response to distention or cold stimulation of the bladder: a positron emission tomography study. J Urol 2002;168: [20] Wein AJ. Neuromuscular dysfunction of the lower urinary tract and its managementin: Walsh PC, Retik AB, Vaughan ED, et al, editors. Campbell s urology, vol. 2. WB Saunders; p [21] Burney TL, Senapati M, Desai S, Choudhary ST, Badlani GH. Acute cerebrovascular accident and lower urinary tract dysfunction: a prospective correlation of the site of brain injury with urodynamic findings. J Urol 1996;156: Editorial Comment on: Effect of Thalamic Deep Brain Stimulation on Lower Urinary Tract Function Francisco Cruz Hospital S Joao, Faculty of Medicine of Porto and IBMC of Porto, Portugal cruzfjmr@med.up.pt The study by Kessler and coworkers [1] showed that high-frequency electrical stimulation of the ventral intermediate nucleus of the thalamus decreased the volume to first desire to void, to strong desire to void, and to maximal cystometric capacity in patients with essential tremor. Because the disease does not affect bladder function, most probably electrical stimulation created an ab outflow from the thalamus to the cerebral cortex, which enhanced the sensation of bladder filling during cystometry. These results must be taken with caution because they were obtained from only seven patients and in some of them the cystometric parameters obtained during and without thalamic stimulation were very close or even identical. Nevertheless, they show that the thalamus relays sensory information arising from the bladder before spinning it up to the cerebral cortex. This is not completely new. The thalamus is a major relay station for somatic and visceral sensory input. In the rat, thalamic neurons responded in a graded manner to urinary bladder distention [2]. In humans, positron emission tomography of the brain detected thalamic activation when the bladder was distended to its maximal capacity [3]. Based on these data, can one speculate that the thalamus is the origin of symptoms such as urgency in overactive bladder (OAB) or bladder pain in interstitial cystitis, either by modulating bladder input or by enhancing thalamocortical input? A full answer to this question will require further studies to evaluate thalamic function in patients with OAB and interstitial cystitis. Can one speculate, based on these data, that the thalamus will emerge as a target for treatment of lower urinary tract symptoms such as urinary urgency and bladder pain? Inhibition of sensory input at the thalamus could, in theory, prevent bladder sensory input from ascending to the cortex and give rise to unpleasant bladder sensations. Selective pharmacologic inhibitory modulation of sensory input in the thalamus may, however, be difficult to achieve due to the ubiquity of the neurotransmitters released by inhibitory thalamic interneurons, the most important being g-aminobutyric acid (GABA). As an alternative, one could envisage bladder sensory input from entering the thalamus. Neurosurgeons have tried with variable success to treat intractable pelvic pain by interrupting the spinothalamic tract. This is out of question in the treatment of OAB or interstitial cystitis. Again, selective pharmacologic approaches to blockade spinothalamic tract neurons may not be viable. Most fibers entering the thalamus release glutamate, which binds to metabotropic and inotropic glutamate receptors. Unfortunately, these receptors are widespread throughout the entire brain. Unless an up-regulation or down-regulation of one of the numerous glutamate receptor subtypes is demonstrated in the thalamus of patients with urinary urgency or bladder pain, a specific blockade seems of questionable application. In conclusion, further investigation on this matter is critical if the authors want to look to the present results as something more than a mere curiosity. References [1] Kessler TM, Burkhard FC, Z Brun S, et al. Effect of thalamic deep brain stimulation on lower urinary tract function. Eur Urol 2008;53: [2] Robbins MT, Uzzell TW, Aly S, Ness TJ. Characterization of thalamic neuronal responses to urinary bladder distention, including the effect of acute spinal lesions in the rat. J Pain 2006;7: [3] Matsuura S, Kakizaki H, Mitsui T, Shiga T, Tamaki N, Koyanagi T. Human brain region response to distention or cold stimulation of the bladder: a positron emission tomography study. J Urol 2002;168: DOI: /j.eururo DOI of original article: /j.eururo