Clinical Study Stereotact Funct Neurosurg 2012;90:9–15 DOI: 10.1159/000330382 Received: January 17, 2011 Accepted after revision: June 18, 2011 Published online: December 22, 2011 Impact of Ventralis Caudalis Deep Brain Stimulation Combined with Stereotactic Bilateral Cingulotomy for Treatment of Post-Stroke Pain Joo Pyung Kim Won Seok Chang Young Seok Park Jin Woo Chang Department of Neurosurgery, Severance Hospital, Brain Korea 21 Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea Key Words Ventralis caudalis ⴢ Cingulotomy ⴢ Deep brain stimulation ⴢ Post-stroke pain Abstract Stroke is the third leading cause of death worldwide. As the elderly population grows, interest in the quality of life, management and treatment of patients with post-stroke pain has grown. Pharmacological treatment is usually the first line of management in these patients. However, if medications fail to achieve appropriate pain relief, neuroablative or neuromodulating procedures are used as alternative methods to interrupt the transmission of pain. We performed unilateral ventralis caudalis deep brain stimulation combined with stereotactic bilateral cingulotomy to maximize the effects of treatment for 3 patients with intractable post-stroke pain. Copyright © 2011 S. Karger AG, Basel Materials and Methods Central post-stroke pain was first described as ‘thalamic syndrome’ by Dejerine and Roussy in 1906 [1]. It can occur following lesions anywhere along the classical spi© 2011 S. Karger AG, Basel 1011–6125/12/0901–0009$38.00/0 Accessible online at: www.karger.com/sfn Patients Between August 2007 and November 2010, 3 patients were diagnosed with post-stroke pain and underwent stereotactic bilateral cingulotomy and unilateral ventralis caudalis (Vc) DBS. One Jin Woo Chang, MD, PhD Department of Neurosurgery Yonsei University College of Medicine 134 Shinchon-Dong, Seodaemoon-Gu, Seoul 120-752 (Korea) Tel. +82 2 2228 2159, E-Mail jchang @ yuhs.ac Downloaded by: Kungliga Tekniska Hogskolan 198.143.54.65 - 1/27/2016 12:54:32 PM Introduction Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com nothalamic pathway and its corticopetal projections. Pharmacological treatment is usually attempted first for management, but if this treatment is ineffective and other causes are not found, neuroablative or neuromodulating procedures may be used to interrupt the transmission of pain. The anterior cingulate cortex is considered to be part of the limbic loop. Anterior cingulotomy has been performed for the management of some psychotic diseases and intractable pain [2, 3]. Although some studies have indicated its efficacy in relieving pain [4–7], controversy still exists because of its destructive nature and uncertain mechanism. Additionally, deep brain stimulation (DBS) of the thalamus and internal capsule was initially used for intractable pain, and is still used for thalamic and periaqueductal/periventricular gray matter stimulation. We assessed the long-term outcomes of unilateral thalamic DBS combined with stereotactic bilateral cingulotomy for patients with intractable post-stroke hemibody pain. a c b Fig. 1. Preoperative MRIs show cerebromalacia in the right temporal lobe and external capsule in patient 1 (a) and in the posterior part of the left basal ganglia in patient 2 (b). Case 3 showed cerebromalacia in the left external capsule and thalamus (c). Table 1. Summary of patient demographic data and clinical characteristics Sex Age Past medical years history Diagnosis Duration of pre-surgery years Pain location Follow-up VAS months Surgical target 1 F 49 none post-stroke 1.7 left hemibody 39 9 2 M 49 hypertension post-stroke 5 right hemibody 38 8 3 F 57 none post-stroke 2.3 right hemibody 34 8 right Vc DBS + bilateral cingulotomy left Vc DBS + bilateral cingulotomy left Vc DBS + bilateral cingulotomy 10 Stereotact Funct Neurosurg 2012;90:9–15 feelings tied by a rubber band and severe allodynia in the trunk. A visual analog scale (VAS) was used preoperatively, at 1 month (during the period under which the implantable pulse generator, IPG, was turned off), and at 6 months (period when IPG turned on), and then at the last follow-up. Inclusion Criteria The inclusion criteria included a history of medically intractable pain despite medical pharmacotherapy. All patients had experienced a hemorrhagic event, shown by an abnormal finding on MRI and PET, and exhibited normal cognitive functioning. Other causes of pain were strictly excluded by a neurologist and neurosurgeon, and surgery was considered for patients with VAS scores of higher than 7. The clinical data are summarized in table 1. Surgical Method After Leksell frame fixation (Elekta Instruments, USA), T2weighted axial, coronal, and T1-weighted axial MRI were taken Kim/Chang/Park/Chang Downloaded by: Kungliga Tekniska Hogskolan 198.143.54.65 - 1/27/2016 12:54:32 PM patient was male and the other 2 were female; their mean age was 51.7 8 4.6 years. The mean interval between stroke and pain onset was 6.3 months. The mean duration between stroke and surgery was 3.0 years. The mean follow-up period was 37 8 2.6 months. All patients had medically intractable pain and they were prescribed antidepressants and opioids for insomnia, anxiety and constant pain. Preoperative MRI showed cerebromalacia in the right temporal lobe and external capsule in patient 1, and in the posterior part of the left basal ganglia in patient 2. Case 3 displayed cerebromalacia in the left external capsule and thalamus (fig. 1). All patients showed defects on FDG-PET scans, and had intractable pain of the contralateral hemibody. The main pain pattern in patient 1 was constant, steady and burning, with throbbing, shooting and sharp pain also being observed at times. The symptoms in the lower extremities were more severe than in the upper extremities or face. Patient 2 presented with constant steady pain and occasional hyperpathia towards cold stimuli, especially in the arm. Patient 3 also complained of Color version available online Fig. 2. The targets for bilateral stereotactic cingulotomy and unilateral Vc coordinates were determined using the Surgiplan. using a 1.5-T machine (Philips MR System Achieva, The Netherlands) through continuous slices of 1 mm in thickness. After data acquisition, all images were transferred to the Leksell Surgiplan workstation (Elekta, Sweden). Under local anesthesia, using a lesion generator (RFG-3C; Radionics, USA), a 1.8-mm electrode with a 10-mm bare tip (Radionics) was inserted into the target at 85 ° C for 90 s to create radiofrequency thermocoagulation lesions. Bilateral lesions were created on either side of the anterior cingulate gyrus. The lesions were made 20 mm posterior to the frontal horn of the lateral ventricle, 2 mm above the roof of the ventricle, and 7 mm lateral to the midline. Following this, patients underwent Vc DBS via quadripolar DBS electrodes (Model 3387, Medtronic, USA). The Vc target coordinates referred to the midpoint of the anterior commissure-posterior commissure line: X = 14–17 mm lateral; Y = 2–3 mm anterior to posterior commissure; Z = 0 mm of the anterior commissure-posterior commissure line based on Schaltenbrand and Wahren anatomical reference [8] (fig. 2). The X coordinates were set to lateral 14–17 mm depending on the patient’s main symptoms. Postoperative MRI confirmed the accuracy of targeting (fig. 3). IPG was turned off. The VAS score was measured again after 6 months to determine the effect of bilateral cingulotomy plus unilateral Vc DBS. Additionally, we confirmed the long-term effect of cingulotomy plus Vc DBS at the last follow-up. The mean VAS score and improvement were 4.0 and 51.9 8 3.2%, respectively, when the IPG was turned off. All patients showed significant pain improvement at 1 day post-operation, and this improvement persisted for 1 month, indicating that cingulotomy and the insertional effect of the DBS electrode were 51.9% for post-stroke intractable pain. The mean VAS score and improvement were 2.3 and 71.8 8 8.1%, respectively, at 6 months. The best synergistic response of bilateral cingulotomy plus unilateral Vc DBS occurred after 6 months. The mean VAS score and improvement were 2.7 and 68.4 8 18.8%, respectively, at last follow-up. These results were for the long-term outcome of bilateral cingulotomy plus unilateral Vc DBS when combined with medication (table 2; fig. 4). Results DBS Combined with Cingulotomy for Post-Stroke Pain Final Stimulation Parameters and Medication The stimulation mode used for all patients was cyclic. In patient 1, the parameters used for contact were 1 and 2 as cathode and case as the anode with 1.3 V, 210 pulse width and 60 Hz; the on time was 30 min and off time was 3.5 h. In patient 2, the parameters used for contact were 0, 1 and 2 as cathode and case as the anode with Stereotact Funct Neurosurg 2012;90:9–15 11 Downloaded by: Kungliga Tekniska Hogskolan 198.143.54.65 - 1/27/2016 12:54:32 PM Periodic Neurological Outcome and Rate of Improvement All of the patients’ IPGs were turned on 1 month postoperation. The VAS score was measured before this to determine the effect of cingulotomy and the insertional effect of the DBS electrode during the period where the a c VAS score 8 6 4 2 0 Preoperative 1 month 6 months Last months Fig. 4. Periodic changes in the VAS score. The best synergic re- sponse to bilateral cingulotomy plus unilateral Vc DBS occurred at 6 months. Stereotact Funct Neurosurg 2012;90:9–15 1.5 V, 180 pulse width and 25 Hz; the on time was 30 min and off time was 2 h. In patient 3, the parameters used for contact were 0 and 1 as cathode and case as the anode with 2 V, 120 pulse width and 35 Hz; the on time was 5 min and off time was 3 h. Patients 1 and 2 used gabapentin 400 mg and gabapentin 600 mg, respectively; patient 3 did not use a particular medication. Table 2 shows the electrode contact and the parameters for each patient. Adverse Effects There were no specific complications related to surgery. In the process of adjusting the parameters, the area to be stimulated changed in patient 1. The patient complained of paresthesia and discomfort as the on time was extended, and we therefore shortened the on time and extended the off time, as for patient 3. There were no hardware-related complications. Kim/Chang/Park/Chang Downloaded by: Kungliga Tekniska Hogskolan 198.143.54.65 - 1/27/2016 12:54:32 PM 10 12 d Color version available online Fig. 3. Axial (a) and coronal (b) T2-weighted MRI after bilateral cingulotomy showing the radiofrequency lesion in the cingulate gyrus. Axial (c) and coronal (d) T2-weighted MRI after unilateral Vc DBS showing the electrode position in the Vc area. b Table 2. Periodic changes in VAS score, final stimulation parameter and current medication 1 2 3 Lesioning and insertional effect VAS at IPG off VAS at IPG on VAS at IPG on + medication at last follow-up Stimulation parameter (last follow-up) Current medication Y Y Y 4 (55.6) 4 (50) 4 (50) 2 (77.8) 3 (62.5) 2 (75) 3 (67.7) 4 (50) 1 (87.5) 1,2(–)/1.3/210/60 0,1,2(–)1.5/180/25 0,1(–)2/120/35 gabapentin 400 mg b.i.d. gabapentin 600 mg b.i.d. none Parentheses contain percentages of improvement. Cingulotomy and Insertional Effects of Electrodes The cingulate gyrus is a component of the limbic system that specifically regulates personality and emotional reactions to intractable pain. In addition, intention, self-initiated action, attention and executive function are involved. Although experimental and functional imaging studies have shown that the cingulate gyrus plays a direct role in the processing of nociceptive information [9, 10], the exact mechanism is still not clear. Coghill et al. [11] and Hsieh et al. [12] demonstrated hypermetabolism in the anterior cingulate gyrus secondary to acute noxious stimulation or processing of pain and vibration by the human brain. Davis et al. [13, 14] used functional MRI to show that a much more restricted area of the anterior cingulate gyrus was involved in the perception of acute painful stimuli and suggested activation of the anterior cingulated cortex by thalamic stimulation in patients with chronic pain. In addition, Hutchison et al. [15] identified neurons in the anterior cingulate gyrus that were responsive both to peripheral painful and noxious thermal stimuli. These nociceptive neurons, located 40 mm behind the genu of the corpus callosum, presented small receptive fields and could codify the intensity of the noxious stimuli. Application of stereotactic bilateral anterior cingulotomy was first described by Foltz and White in 1962 for treatment of pain [3]. In the past, cingulotomy was performed as ventriculography-guided cingulotomy or open surgery. However, through developments in stereotactic technique, circumscribed radiofrequency lesions can be created without extensive damage to the adjacent cortex, and mortality and morbidity have significantly decreased. Wilkinson et al. [7] reported 72% improvement in 18 patients with chronic non-cancer pain. However, Hurt and Ballantine [16] found that early pain relief was DBS Combined with Cingulotomy for Post-Stroke Pain reduced at long term follow-up, and Yen et al. [17] reported that 66% of patients with cancer pain improved 1 month post-operation, but the effect decreased to 50– 55% after 3–6 months. We do not know why the lesioning effect decreases as time goes on, but we can determine why the effects of cingulotomy for patients with obsessive-compulsive disorder or cancer pain had decreased at long-term follow-up. In addition, we combined this treatment with Vc DBS to overcome limitations of the long-term effects of cingulotomy and to induce minimal paresthesia by stimulating the sensory thalamic nucleus. Our original plan was to perform DBS in both cingula, but we were unable to do so because the national insurance of the Republic of Korea did not allow it. The primary complications of bilateral cingulotomy are aphasia, confusion, incontinence and neurocognitive disturbances [6, 7, 18]. According to Yen et al. [19], thermal lesioning can be accomplished at a temperature of 80 ° C for 80 s, leaving most neurocognitive domains unchanged. In our center, the current cingulotomy procedure is 4 lesions along 2 tracks created on either side of the anterior cingulate gyrus. However, for patients with post-stroke pain, the procedure was performed at 85 ° C for 90 s to create radiofrequency thermocoagulation lesions because of the combined Vc DBS and previous hemorrhagic history. We also expected that the effects of Vc DBS would be to moderate pain and relieve the psychological effects of pain from stereotactic cingulotomy. Hamani et al. [20] reported that the insertional effect of the DBS electrode on treatment outcomes are significant. Although it was difficult to distinguish whether the results were from cingulotomy or from the effects of electrode insertion, the VAS score in our study showed a 52% improvement in pain in the IPG off state. These findings suggest that the cingulotomy and insertional effect of DBS in the acute postoperative period are larger than we originally expected. Stereotact Funct Neurosurg 2012;90:9–15 13 Downloaded by: Kungliga Tekniska Hogskolan 198.143.54.65 - 1/27/2016 12:54:32 PM Discussion Early Bilateral Cingulotomy plus Unilateral Vc DBS Effect Lesioning and DBS studies [21, 22] of the Vc area suggest that stimulation of cells within or posteroinferior to the Vc can evoke sensations of pain, warmth or cold. Katayama et al. [23] analyzed the effects of spinal cord stimulation, DBS of Vc thalamus, and motor cortex stimulation; they found that abnormal processing of nociceptive information develops at the level of deafferentation and spreads to higher levels. Vc DBS has also been used to control peripheral deafferentation pain. According to Yamamoto et al. [24], chronic Vc DBS can restore organization and diminish phantom limb pain. The long-term outcomes of DBS are varied [25–27], but most studies show 30–60% improvement. We performed unilateral Vc DBS on the contralateral side of the painful hemibody and observed a maximal effect of 72% improvement at 6 months post-operation. We believe that the improvement rate during this period was the synergic effect of bilateral cingulotomy plus unilateral Vc DBS. stimulation was too strong over time, although the same parameters were used. Control of chronic parameters is more difficult, and more detailed studies are needed. It is possible that the plasticity of neuronal circuits plays a role in these phenomena, culminating in the adaptation of cerebral tissue to stimulation. However, we still do not know the exact mechanism underlying the effects of DBS in post-stroke patients. However, maintenance of emotional stability is a benefit of cingulotomy, and control of intractable pain by combining cingulotomy with Vc DBS allows for modulation of pathways and effective longterm pain control. The limitations of our study were that the combined surgery was performed on an experimental basis without an established protocol, and the number of subjects included was very small. We were also unable to perform DBS in the cingulum because it is not allowed by the national insurance of the Republic of Korea. Long-Term Outcomes of Bilateral Cingulotomy plus Unilateral Vc DBS Effect and Combined Medication The average pain improvement was 68.4% upon last follow-up. We observed interesting phenomena,such as changes in the location of stimulation or feelings that the We performed bilateral stereotactic cingulotomy combined with Vc thalamic DBS for patients with post-stroke hemibody pain and achieved relatively good clinical outcomes over the long-term follow-up period. 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