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Stereotactic bilateral anterior cingulotomy for intractable pain
Journal of Clinical Neuroscience (2005) 12(8), 886–890 0967-5868/$ - see front matter ª 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2004.11.018
Clinical study
Stereotactic bilateral anterior cingulotomy for intractable pain Chun Po Yen1 MD, Sui Sum Kung2 MD, Yu Feng Su1 MD, Wei Chen Lin3 MD, Shen Long Howng1 MD PhD, Aij Lie Kwan1 MD PhD 1 Department of Neurosurgery, Kaohsiung Medical University Hospital, 2Department of Neurosurgery, Yuan’s General Hospital, 3Department of Radiology, Kaohsiung Medical University Hospital; Kaohsiung, Taiwan
Summary To document the value of cingulotomy for pain relief, a series of 22 patients with medically intractable pain, including 15 with cancer pain and seven with non-cancer pain, underwent stereotactic bilateral anterior cingulotomy, between August 2001 and December 2002. Of the 15 patients with cancer pain, significant or meaningful pain relief was achieved in 67% of patients at one month follow-up, which decreased to 58% at three months and 50% at six months. Of the seven patients with intractable pain from non-neoplastic origin, four achieved significant pain relief, one obtained meaningful relief, and two reported no change at one year follow-up. There was no surgical mortality or permanent neurological morbidity. Two patients developed transient confusion and another two had mild gastrointestinal bleeding. No clinically evident personality or emotional changes were noted. However, subtle cognitive impairment, especially attentional deficits, were detected through detailed neuropsychological evaluation. ª 2005 Elsevier Ltd. All rights reserved. Keywords: cingulotomy, cognitive function, magnetic resonance imaging, pain, stereotaxis
INTRODUCTION Pain is the most common complaint of patients seeking medical attention. Pharmacological or medical treatment is usually firstline management. For patients with severe persistent pain caused by underlying neoplastic or neuropathic etiologies, opioids usually constitute the major treatment, but most patients fail to achieve adequate relief and side-effects arise with high doses. When patients are unresponsive to conservative therapies, they are referred to surgeons, especially neurosurgeons. In the neurosurgeon’s armamentarium, decompressive surgery with or without reconstruction is often the first choice, which directly treats the etiology of the pain and may restore normal anatomy and function. If this goal cannot be achieved, neuroablative or neuromodulating procedures are alternatives whereby a destructive lesion is created or a stimulating electrode placed along the presumed afferent pathway of pain, in the hope of interrupting the transmission of pain sensation.1–3 Neuroablative procedures targeting a variety of brain sites have long been performed by neurosurgeons to alleviate the suffering of patients with intractable pain. Destructive lesions placed in the frontal lobe, postcentral gyrus, thalamus4–7 and components of the limbic system, particularly the cingulate gyrus8–13 have been reported to be effective to varying degrees. Unfortunately, the usefulness of these procedures is limited by cardiopulmonary risks and the need for general anesthesia. As a consequence, intracranial lesioning has been performed as the last resort. With the
Abbreviations: CT, computerized tomography, FBSS, failed back urgery syndrome, KPS, Karnofsky performance status, MR, magnetic resonance, VAS, visual analog scale Received 28 September 2004 Accepted 10 November 2004 Correspondence to: Aij-Lie Kwan, 100, Tzyou 1st Road, Kaohsiung, Taiwan 807. Tel.: +886 7 3215049; Fax: +886 7 3215039; E-mail: [email protected]
886
refinement of stereotactic equipment and accurate lesion localization guided by MR imaging, intracranial ablative surgeries can now be performed more precisely, safely and less invasively under local anesthesia.10–13 Cingulotomy was previously performed for psychiatric disorders such as anxiety, depression and obsessive-compulsive disorders, but has also been advocated for the management of pain.14,15 Although several studies proved its efficacy,9–13 controversy still exists because of its destructive nature and uncertain mechanism. In this study, we present our experience with cingulotomy for pain management with emphasis on patient selection, outcomes and complications.
PATIENTS AND METHODS Patient demographics Between August 2001 and December 2002, a consecutive series of 22 patients (mean age 58.3 years; range 35–79) underwent stereotactic bilateral anterior cingulotomy under the guidance of MRI for intractable pain (Table 1). Fifteen patients with end-stage malignancy suffered from severe persistent pain predominantly from widespread metastases, whereas the remaining seven patients had intractable chronic pain attributed to various benign etiologies. Before being referred to surgery, medical treatment with non-steroid anti-inflammatory agents, non-narcotic analgesics and antidepressants had been tried by primary care physicians or pain experts without success. All of these patients had been receiving large doses of narcotics either orally or by continuous intravenous infusion. However, patients still reported a pain score of nine or 10 on a 10-point VAS. Of the 15 patients with cancer pain, there were ten men and five women. All patients had terminal illnesses associated with systemic malignancies, including four with lung cancer, two with breast cancer, two with hepatocellular carcinoma, two with mesothelioma, one each with thyroid, esophageal, and ureteral cancer, one with lymphoma, and one with an unknown primary. Most
Bilateral anterior cingulotomy for intractable pain 887
Table 1 Characteristics of patients undergoing cingulotomy Patients with cancer pain
Patients with non-cancer pain
Age mean (range)
58.8 (41–79) years
57.3 (35–74) years
Sex (male/female)
10/5
3/4
Duration of pain mean (range)
9.9 (2–23) months
24.6 (12–48) months
Pre-operative KPS mean (range)
50 (30–70)
58.6 (40–70)
Follow-up mean (range)
10 (1–22) months
19 (10–24) months
Cause of pain
Lung cancer 4 Breast cancer 2 Hepatocellular carcinoma 2 Mesothelioma 2 Thyroid cancer 1 Esophageal cancer 1 Ureteral cancer 1 Lymphoma 1 Unknown primary 1
Diabetic neuropathy 2 FBSS 2 Spinal cord injury 2 Trigeminal neuralgia 1
patients experienced excruciating severe pain, mainly consequent to widespread bony metastases and had been treated with high dose opiates either orally or parenterally for more than one month. Two patients with mesothelioma involving the chest wall had received repeated peripheral nerve blocks. Another two patients had intraventricular narcotic infusion. The mean age was 58.8 years (range 41–79). The mean preoperative period of pain was 9.9 months. Average preoperative KPS was 50 (range: 30–70). Another seven patients (three men, four women) suffered from pain of non-neoplastic conditions, including two with diabetic neuropathy, two with FBSS, two with limb pain following spinal fracture and spinal cord injury and one with recurrent trigeminal neuralgia. These patients had received at least one year of medical treatment before undergoing cingulotomy. Two cases with FBSS had received two and three surgeries each to correct their lumbar spine problems. Both cases with antecedent spinal cord injury also had previous decompression and fusion in the cervical spine and thoracic spine, respectively. The patient with trigeminal neuralgia had received two microvascular decompressions; during the second surgery the patient had a brainstem stroke from vascular injury. The mean age in this group was 57.3 years (range: 35–74). The average chronicity of pain was 24.6 months. Preoperative KPS was 58.6 (range: 40–70). Aside from thorough examinations by neurosurgeons, patients were also evaluated by neurologists and psychiatrists to rule out any previous or existing neurocognitive and psychiatric disorders. Although most of them had been afflicted by long-standing severe pain and exhibited some degree of depression or anxiety, none were diagnosed with major psychiatric disorders that excluded them as candidates for cingulotomy. Patients and families were fully notified about the possible benefits and potential risks of the procedure and informed consent was obtained.
holes trephined 2 cm lateral to the midline, lesioning of the targets was made with radiofrequency thermocoagulation using a thermocoupled bipolar lesion electrode with a diameter of 2 mm using 80 for 80 seconds. A single lesion was created in the majority of patients. In some cases, a larger, segmented cingulate gyrus necessitated two continuous lesions with one placed 3 mm above the other to ensure a good coverage of the anterior cingulate region.
Surgical techniques
RESULTS
A Leksell stereotactic frame was applied to the patient’s head under local anesthesia. MRI was obtained in the coronal plane with 3 mm-thick sections without a gap. We used non-enhanced T1weighted images for target localization. The target slice was selected as 24 mm posterior to the anterior tip of the lateral ventricle. On the target slice, the coordinates of the fiducials were determined and the center of each cingulate gyrus in both hemispheres was identified as a target point. The coordinates of targets as well as the entry points through the skull were computed. The patient was then transferred to the operating suite. Through burr ª 2005 Elsevier Ltd. All rights reserved.
Postoperative follow-up Postoperative CT scan or MRI was performed to confirm the location of lesions within two weeks of surgery (Fig. 1). A VAS was utilized to evaluate the severity of pain before surgery, at the first week, one month and three months after surgery and thereafter at three month intervals. Even though all patients had been explained that surgery, instead of eliminating their pain sensation, may just modulate their perception of pain, they invariably expected pain relief after surgery. To avoid this bias, the pain relief reported on the first day after surgery was not considered. Families were also asked about changes in emotions and personality during the follow-up period. For those cases operated after 2002, more detailed neuropsychological tests was performed perioperatively. However, only five patients had complete evaluation because the tests were sometimes too tedious for these already debilitated patients, due to severe pain or somnolence caused by large doses of narcotics. To evaluate the efficacy of pain relief, surgical results were arbitrarily defined as ‘‘significant improvement’’ if the postoperative pain score decreased by 50% or more on the VAS: ‘‘definite, slight but meaningful improvement’’ with a decrease of 25–50%; and ‘‘little or no improvement’’ with a decrease of less than 25%.
Results for patients with cancer pain Of the 15 patients with cancer pain, eight (53%) reported significant pain relief in the first week after surgery, four (27%) reported meaningful relief and three (20%) reported little or no improvement (Table 2). At one month follow-up, three patients who initially experienced significant pain relief reported that the efficacy attenuated. One patient reported the pain relief became less significant and two reported the pain returned to the same status as before surgery. Four patients with slight but meaningful Journal of Clinical Neuroscience (2005) 12(8), 886–890
888 Yen et al.
Fig. 1 Coronal (A) and sagittal (B) T1-weighted MRI one week after cingulotomy showing one radiofrequency lesion in the left cingulate gyrus and two consecutive lesions in the right, segmented cingulate gyrus with accompanying perilesional edema. This patient suffered from metastatic bone pain which was completely eliminated after surgery and the effect remained for 20 months.
Table 2 Rating of early and late results of cingulotomy for pain Disease category
Time of rating
No. of patients
Amount of pain relief >75%
25–75%
<25%
Cancer pain
1 1 3 6
week month months months
15 15 12 10
8 5 4 2
(53%) (33%) (33%) (20%)
4 5 3 3
(27%) (33%) (25%) (30%)
3 5 5 5
(20%) (33%) (42%) (50%)
Non-cancer pain
1 week 1 month 3 months 6 months 12 months
7 7 7 7 7
6 5 4 4 4
(86%) (71%) (57%) (57%) (57%)
1 0 1 1 1
(14%) (0%) (14%) (14%) (14%)
0 2 2 2 2
(0%) (29%) (29%) (29%) (29%)
pain relief initially still reported some degree of improvement. Those who did not benefit from surgery from the outset did not attain any delayed effect at one month evaluation or during later follow-up. At three-months evaluation, 12 patients survived, in whom four (33%) reported significant pain relief, three (25%) reported meaningful relief, and five (42%) reported no improvement. Ten patients survived longer than six months; two of them (20%) had significant pain relief, three (30%) had meaningful relief and five (50%) had little or no improvement. Results for patients with non-cancer pain Among seven patients with non-cancer pain, two cases of FBSS attained significant pain relief immediately after cingulotomy. One of them reported recurrent pain with the same intensity as compared with preoperative status a few days after surgery and the other reported the effect waned progressively but the pain was still moderately relieved during later follow-up. One patient with pain following spinal cord injury achieved slight pain relief initially but reported recurrence of pain at one-month follow-up. The other patient with limb pain following spinal cord injury, the two patients with diabetic neuropathy and the one patient with recurrent trigeminal neuralgia, responded to cingulotomy fairly Journal of Clinical Neuroscience (2005) 12(8), 886–890
well and maintained significant improvement of pain at followup of 12, 20, 23, and 12 months respectively. Factors influencing results of pain relief The overall average follow-up in this series was 12.9 months (range: 1–24). At the end point of evaluation (last available follow-up), nine patients (41%) had pain relief of more than 50%, six (27%) had pain relief between 25% and 50% and seven (32%) had pain improvement of less than 25%. Higher KPS score and longer duration of pain before cingulotomy correlated with better pain relief by univariate analysis. The other factors such as age, gender, cause of pain and follow-up period did not correlate with the outcome. Those who achieved some degree of pain relief also reported improved daily activities, and some of these even returned to work. Complications and adverse effects of surgery No surgical mortality in this series was noted. There was no obvious flattening of affect or change of personality immediately after surgery. Some patients experiencing significant pain relief after surgery actually became euphoric and more talkative as compared ª 2005 Elsevier Ltd. All rights reserved.
Bilateral anterior cingulotomy for intractable pain 889
with their preoperative state. Two patients developed transient confusion and recovered within in a few days. Another two patients suffered from mild upper gastrointestinal bleeding which soon subsided with medical treatment. There were no clinically observable neurological or cognitive deficits in our series. An adequate neuropsychological evaluation was not available but the preliminary data from five patients did reveal some attentional impairment at the early postoperative stage. DISCUSSION The cingulate gyrus, as a part of the limbic system, does not aid in differentiation of the various types of pain sensation but is more specifically involved in the emotional reaction to pain.8 Foltz and White in 1962 reported a series of 16 patients with pain treated with cingulotomy based on the belief that surgery did not change the sensation of pain per se but modified patients’ reactions to it.8 They concluded that the effectiveness of the surgery depended primarily on the personality and emotional reactivity of the patient. Over the years, lesioning of the cingulate gyrus, originally used in the management of psychiatric patients, has been used in the management of patients with refractory pain and proved to be effective in selected patients. Although experimental and functional imaging studies have shown a direct role of the cingulate gyrus in processing of nociceptive information, the mechanism of pain relief by cingulotomy is not clearly understood.16–19 Cingulotomy was once performed via open surgery. However, for terminally ill cancer patients and those incapacitated by chronic pain, general anesthesia and a major neurosurgical procedure is inappropriate. After the introduction of stereotactic techniques, cingulate lesions could be performed under local anesthesia and the attendant mortality and morbidity lowered significantly. Previous stereotactic methods using ventriculography were indirect and cumbersome for lesion localization. The discomfort and complications associated with ventriculography are also well documented.13,14 A large lesion was usually necessary to ensure adequate cingulate region coverage by this indirect method. Under the guidance of MRI, the target can be directly visualized and the size of the lesion can be tailored according to the size, shape and location of the cingulate gyri, which are usually asymmetric from patient-to-patient and even differ from sideto-side in the same patient.12,13,20 Accordingly, a circumscribed radiofrequency lesion can be created to ablate the anterior cingulate regions without extensive damage to the adjacent frontal cortex, which to our understanding might decrease untoward side-effects. However, the efficacy with a more limited lesion demands further investigation. Hurt and Ballantine reported a large series of patients undergoing cingulotomy for persistent pain.9 In 32 patients with cancer pain, 66% obtained some degree of pain relief although this was not maintained over a long time. They attributed the recurrence of pain to new sources of stimuli that might not be affected by prior cingulate lesions. In the same study, 66% of 34 patients with pain of non-neoplastic origin also obtained some degree of pain relief throughout the long-term follow-up of up to nine years. Wilkinson et al. also reported a series of 18 patients in whom 72% obtained pain improvement.13 In our experience, 66% of patients with cancer pain reported definite improvement of pain at one month follow-up, which decreased to 55% and 50% at three months and six months, respectively. The experience with benign pain is limited but 71% of patients had long-term pain relief. Some conclusions can be drawn from our series. Firstly, patients who did not benefit from cingulotomy immediately after ª 2005 Elsevier Ltd. All rights reserved.
surgery and those who only benefited temporally did not attain any delayed effect during later follow-up. This result is different from that of Wilkinson et al.13 In their series, the pain relief achieved was ‘‘temporally bimodal’’. Secondly, the placebo effect cannot be neglected. Although the effect of cingulotomy for pain relief was not emphasized before surgery, patients still expected that the procedure would ameliorate their suffering to some extent. The remarkably high percentage of patients reporting significant or meaningful pain relief within the first few days post-surgery substantiate this point. Thirdly, pain relief could be long-lasting. This is true for both patients with neoplastic or non-neoplastic pain. Rarely has mortality been reported since the introduction of modern stereotactic methods. Neurological morbidity associated with cingulotomy is also uncommon, and mostly secondary to bleeding. Compared with the lesions created for pallidotomy or thalamotomy, a larger lesion is always produced to cover the whole cingulum and even the cingulate cortex. The relatively large lesion with the attendant peri-lesional edema may incur complications: aphasia, confusion, and incontinence.12,13 Despite strong evidence showing correlation of the cingulate cortex with various neurocognitive functions, outcome studies have generally not indicated significant cognitive disturbances after surgery.13,21 This conclusion however, is usually derived from subjective clinical observation by clinicians or families. Detailed neurocognitive studies, although limited, definitely reveal some subtle abnormalities such as attentional impairment and deficit of response selection in addition to the well-known ‘‘frontal-type’’ syndrome of apathy, and decreased activity and spontaneity.22–24 Although cingulotomy provides dramatic results in selected patients with intractable pain, controversy as to its employment for pain management remains.13,25 The exact mechanism of cingulotomy to relieve pain is unclear. Even considered as a surgery for pain rather than a psychosurgery, the affective response of cingulotomy seems to play a key role in modulation of the painful sensation and the psychological aspects of pain experience. For patients with cancer pain, the recurrence of pain is another problem. Pain relief with ablative procedures in this category of patients is typically short-lived, although the pain is somewhat different in quality and location. It is not certain whether the later recurrence of pain results from late failure of cingulotomy or generation of new metastatic foci. 9,26 Therefore, cingulotomy is best considered in terminally ill patients with limited life expectancy. Another great concern associated with ablative procedures is the risk of developing deafferentation pain which is especially true for patients with pain of benign origin. Even though no deafferentation pain following cingulotomy has been reported in the literature so far, the possibility of developing deafferentation pain after other neuroablative procedures is well established. Patients with persistent pain are desperate to seek any means to alleviate their suffering. Before utilization of any neuroablative procedures for pain management, a thorough preoperative evaluation of the patient’s neurological and psychological condition, as well as consideration of other non-destructive management modalities, is necessary. We understand that there are limitations in our study. A small number of patients with limited follow-up and no control group make it impossible to draw any definite conclusion. An oversimplified scale for the evaluation of pain is inaccurate and biased. Lack of complete neuropsychological testing may also underestimate the impact on cognitive functioning. Although it is premature to deny the value of this neuroablative procedure, a carefully performed prospective study is warranted. Journal of Clinical Neuroscience (2005) 12(8), 886–890
890 Yen et al.
CONCLUSION Management of pain is a formidable challenge for all clinicians taking care of patients with advanced cancers or those incapacitated by chronic intractable pain. MRI guided cingulotomy is a relatively simple procedure that can be accomplished under local anesthesia with little discomfort or risk to the fragile patient. Rather than a treatment of last resort, the procedure should be considered an adjunct to the multidisciplinary management of patients with severe intractable pain. Although most of the neuroablative procedures are outdated and have been replaced by neuromodulating procedures, considering the limited life expectancy of terminally ill cancer patients as well as the need for improved costcontainment, a reappraisal of the role of neuroablative procedures is needed. In the setting of intractable pain from benign origin, possible cognitive complications associated with destructive lesions in the brain cannot be underestimated. The possible deficits must be weighed against the potential pain relief.
REFERENCES 1. Sweet WH. Pain – old and new methods of study and treatment. Acta Neurochir Suppl (Wien) 1995; 64: 83–87. 2. Davis KD, Lozano AM, Tasker RR, Dostrovsky JO. Brain targets for pain control. Stereotact Funct Neurosurg 1998; 71: 173–179. 3. Meyerson BA. Neurosurgical approaches to pain treatment. Acta Anaesthesiol Scand 2001; 45: 1108–1113. 4. White JC, Sweet WH, Hackett TP. Radiofrequency leukotomy for relief of pain: coagulation of medial frontal white fibers in stages by means of inlying electrodes. Arch Neurol 1960; 2: 317–330. 5. White JC. Modifications of frontal leukotomy for relief of pain and suffering in terminal malignant disease. Ann Surg 1962; 156: 394–403. 6. Hariz MI, Bergenheim AT. Thalamic stereotaxis for chronic pain: ablative lesion or stimulation? Stereotact Funct Neurosurg 1995; 64: 47–55. 7. Ohye C. Stereotactic treatment of central pain. Stereotact Funct Neurosurg 1998; 70: 71–76. 8. Foltz EL, White Jr LE. Pain ‘‘relief’’ by frontal cingulumotomy. J Neurosurg 1962; 19: 89–100. 9. Hurt RW, Ballantine Jr HT. Stereotactic anterior cingulate lesions for persistent pain: A report on 68 cases. Clin Neurosurg 1974; 21: 334–351.
Journal of Clinical Neuroscience (2005) 12(8), 886–890
10. Hassenbusch SJ, Pillay PK, Barnett GH. Radiofrequency cingulotomy for intractable cancer pain using stereotaxis guided by magnetic resonance imaging. Neurosurgery 1990; 27: 220–223. 11. Pillay PK, Hassenbusch SJ. Bilateral MRI-guided stereotactic cingulotomy for intractable pain. Stereotact Funct Neurosurg 1992; 59: 33–38. 12. Wong ET, Gunes S, Gaughan E, et al. Palliation of intractable cancer pain by MRI-Guided cingulotomy. Clin J Pain 1997; 13: 260–263. 13. Wilkinson HA, Davidson KM, Davidson RI. Bilateral anterior cingulotomy for chronic noncancer pain. Neurosurgery 1999; 45: 1129–1134. 14. Ballantine Jr HT, Cassidy WL, Flanagan NB, Marino Jr R. Stereotaxic anterior cingulotomy for neuropsychiatric illness and intractable pain. J Neurosurg 1967; 26: 488–495. 15. Ballantine Jr HT, Bouckoms AJ, Thomas EK, Giriunas IE. Treatment of psychiatric illness by stereotactic cingulotomy. Biol Psychiatry 1987; 22: 807–819. 16. Talbot JD, Marrett S, Evans AC, Meyer E, Bushnell MC, Duncan GH. Multiple representations of pain in human cerebral cortex. Science 1991; 251: 1355–1358. 17. Casey KL, Minoshima S, Berger KL, Koeppe RA, Morrow TJ, Frey KA. Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli. J Neurophysiol 1994; 71: 802–807. 18. Vogt BA, Derbyshire S, Jones AK. Pain processing in four regions of human cingulate cortex localized with co-registered PET and MR imaging. Eur J Neurosci 1996; 8: 1461–1473. 19. Lenz FA, Rios M, Zirh A, Chau D, Krauss G, Lesser RP. Painful stimuli evoke potentials recorded over the human anterior cingulate gyrus. J Neurophysiol 1998; 79: 2231–2234. 20. Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995; 118: 279–306. 21. Sharma T. Absence of cognitive deficits from bilateral cingulotomy for intractable pain in humans. Tex Med 1973; 69: 79–82. 22. Cohen RA, Kaplan RF, Zuffante P, et al. Alteration of intention and self-initiated action associated with bilateral anterior cingulotomy. J Neuropsychiatry Clin Neurosci 1999; 11: 444–453. 23. Cohen RA, Kaplan RF, Moser DJ, Jenkins MA, Wilkinson H. Impairments of attention after cingulotomy. Neurology 1999; 53: 819–824. 24. Cohen RA, Paul R, Zawacki TM, Moser DJ, Sweet L, Wilkinson H. Emotional and personality changes following cingulotomy. Emotion 2001; 1: 38–50. 25. Meyerson B. Bilateral anterior cingulotomy for chronic noncancer pain. Neurosurgery 1999; 45: 1135–1136 (comment). 26. Nagaro T, Adachi N, Tabo E, Kimura S, Arai T, Dote K. New pain following cordotomy: clinical features, mechanisms, and clinical importance. J Neurosurg 2001; 95: 425–431.
ª 2005 Elsevier Ltd. All rights reserved.
Clinical study
Stereotactic bilateral anterior cingulotomy for intractable pain Chun Po Yen1 MD, Sui Sum Kung2 MD, Yu Feng Su1 MD, Wei Chen Lin3 MD, Shen Long Howng1 MD PhD, Aij Lie Kwan1 MD PhD 1 Department of Neurosurgery, Kaohsiung Medical University Hospital, 2Department of Neurosurgery, Yuan’s General Hospital, 3Department of Radiology, Kaohsiung Medical University Hospital; Kaohsiung, Taiwan
Summary To document the value of cingulotomy for pain relief, a series of 22 patients with medically intractable pain, including 15 with cancer pain and seven with non-cancer pain, underwent stereotactic bilateral anterior cingulotomy, between August 2001 and December 2002. Of the 15 patients with cancer pain, significant or meaningful pain relief was achieved in 67% of patients at one month follow-up, which decreased to 58% at three months and 50% at six months. Of the seven patients with intractable pain from non-neoplastic origin, four achieved significant pain relief, one obtained meaningful relief, and two reported no change at one year follow-up. There was no surgical mortality or permanent neurological morbidity. Two patients developed transient confusion and another two had mild gastrointestinal bleeding. No clinically evident personality or emotional changes were noted. However, subtle cognitive impairment, especially attentional deficits, were detected through detailed neuropsychological evaluation. ª 2005 Elsevier Ltd. All rights reserved. Keywords: cingulotomy, cognitive function, magnetic resonance imaging, pain, stereotaxis
INTRODUCTION Pain is the most common complaint of patients seeking medical attention. Pharmacological or medical treatment is usually firstline management. For patients with severe persistent pain caused by underlying neoplastic or neuropathic etiologies, opioids usually constitute the major treatment, but most patients fail to achieve adequate relief and side-effects arise with high doses. When patients are unresponsive to conservative therapies, they are referred to surgeons, especially neurosurgeons. In the neurosurgeon’s armamentarium, decompressive surgery with or without reconstruction is often the first choice, which directly treats the etiology of the pain and may restore normal anatomy and function. If this goal cannot be achieved, neuroablative or neuromodulating procedures are alternatives whereby a destructive lesion is created or a stimulating electrode placed along the presumed afferent pathway of pain, in the hope of interrupting the transmission of pain sensation.1–3 Neuroablative procedures targeting a variety of brain sites have long been performed by neurosurgeons to alleviate the suffering of patients with intractable pain. Destructive lesions placed in the frontal lobe, postcentral gyrus, thalamus4–7 and components of the limbic system, particularly the cingulate gyrus8–13 have been reported to be effective to varying degrees. Unfortunately, the usefulness of these procedures is limited by cardiopulmonary risks and the need for general anesthesia. As a consequence, intracranial lesioning has been performed as the last resort. With the
Abbreviations: CT, computerized tomography, FBSS, failed back urgery syndrome, KPS, Karnofsky performance status, MR, magnetic resonance, VAS, visual analog scale Received 28 September 2004 Accepted 10 November 2004 Correspondence to: Aij-Lie Kwan, 100, Tzyou 1st Road, Kaohsiung, Taiwan 807. Tel.: +886 7 3215049; Fax: +886 7 3215039; E-mail: [email protected]
886
refinement of stereotactic equipment and accurate lesion localization guided by MR imaging, intracranial ablative surgeries can now be performed more precisely, safely and less invasively under local anesthesia.10–13 Cingulotomy was previously performed for psychiatric disorders such as anxiety, depression and obsessive-compulsive disorders, but has also been advocated for the management of pain.14,15 Although several studies proved its efficacy,9–13 controversy still exists because of its destructive nature and uncertain mechanism. In this study, we present our experience with cingulotomy for pain management with emphasis on patient selection, outcomes and complications.
PATIENTS AND METHODS Patient demographics Between August 2001 and December 2002, a consecutive series of 22 patients (mean age 58.3 years; range 35–79) underwent stereotactic bilateral anterior cingulotomy under the guidance of MRI for intractable pain (Table 1). Fifteen patients with end-stage malignancy suffered from severe persistent pain predominantly from widespread metastases, whereas the remaining seven patients had intractable chronic pain attributed to various benign etiologies. Before being referred to surgery, medical treatment with non-steroid anti-inflammatory agents, non-narcotic analgesics and antidepressants had been tried by primary care physicians or pain experts without success. All of these patients had been receiving large doses of narcotics either orally or by continuous intravenous infusion. However, patients still reported a pain score of nine or 10 on a 10-point VAS. Of the 15 patients with cancer pain, there were ten men and five women. All patients had terminal illnesses associated with systemic malignancies, including four with lung cancer, two with breast cancer, two with hepatocellular carcinoma, two with mesothelioma, one each with thyroid, esophageal, and ureteral cancer, one with lymphoma, and one with an unknown primary. Most
Bilateral anterior cingulotomy for intractable pain 887
Table 1 Characteristics of patients undergoing cingulotomy Patients with cancer pain
Patients with non-cancer pain
Age mean (range)
58.8 (41–79) years
57.3 (35–74) years
Sex (male/female)
10/5
3/4
Duration of pain mean (range)
9.9 (2–23) months
24.6 (12–48) months
Pre-operative KPS mean (range)
50 (30–70)
58.6 (40–70)
Follow-up mean (range)
10 (1–22) months
19 (10–24) months
Cause of pain
Lung cancer 4 Breast cancer 2 Hepatocellular carcinoma 2 Mesothelioma 2 Thyroid cancer 1 Esophageal cancer 1 Ureteral cancer 1 Lymphoma 1 Unknown primary 1
Diabetic neuropathy 2 FBSS 2 Spinal cord injury 2 Trigeminal neuralgia 1
patients experienced excruciating severe pain, mainly consequent to widespread bony metastases and had been treated with high dose opiates either orally or parenterally for more than one month. Two patients with mesothelioma involving the chest wall had received repeated peripheral nerve blocks. Another two patients had intraventricular narcotic infusion. The mean age was 58.8 years (range 41–79). The mean preoperative period of pain was 9.9 months. Average preoperative KPS was 50 (range: 30–70). Another seven patients (three men, four women) suffered from pain of non-neoplastic conditions, including two with diabetic neuropathy, two with FBSS, two with limb pain following spinal fracture and spinal cord injury and one with recurrent trigeminal neuralgia. These patients had received at least one year of medical treatment before undergoing cingulotomy. Two cases with FBSS had received two and three surgeries each to correct their lumbar spine problems. Both cases with antecedent spinal cord injury also had previous decompression and fusion in the cervical spine and thoracic spine, respectively. The patient with trigeminal neuralgia had received two microvascular decompressions; during the second surgery the patient had a brainstem stroke from vascular injury. The mean age in this group was 57.3 years (range: 35–74). The average chronicity of pain was 24.6 months. Preoperative KPS was 58.6 (range: 40–70). Aside from thorough examinations by neurosurgeons, patients were also evaluated by neurologists and psychiatrists to rule out any previous or existing neurocognitive and psychiatric disorders. Although most of them had been afflicted by long-standing severe pain and exhibited some degree of depression or anxiety, none were diagnosed with major psychiatric disorders that excluded them as candidates for cingulotomy. Patients and families were fully notified about the possible benefits and potential risks of the procedure and informed consent was obtained.
holes trephined 2 cm lateral to the midline, lesioning of the targets was made with radiofrequency thermocoagulation using a thermocoupled bipolar lesion electrode with a diameter of 2 mm using 80 for 80 seconds. A single lesion was created in the majority of patients. In some cases, a larger, segmented cingulate gyrus necessitated two continuous lesions with one placed 3 mm above the other to ensure a good coverage of the anterior cingulate region.
Surgical techniques
RESULTS
A Leksell stereotactic frame was applied to the patient’s head under local anesthesia. MRI was obtained in the coronal plane with 3 mm-thick sections without a gap. We used non-enhanced T1weighted images for target localization. The target slice was selected as 24 mm posterior to the anterior tip of the lateral ventricle. On the target slice, the coordinates of the fiducials were determined and the center of each cingulate gyrus in both hemispheres was identified as a target point. The coordinates of targets as well as the entry points through the skull were computed. The patient was then transferred to the operating suite. Through burr ª 2005 Elsevier Ltd. All rights reserved.
Postoperative follow-up Postoperative CT scan or MRI was performed to confirm the location of lesions within two weeks of surgery (Fig. 1). A VAS was utilized to evaluate the severity of pain before surgery, at the first week, one month and three months after surgery and thereafter at three month intervals. Even though all patients had been explained that surgery, instead of eliminating their pain sensation, may just modulate their perception of pain, they invariably expected pain relief after surgery. To avoid this bias, the pain relief reported on the first day after surgery was not considered. Families were also asked about changes in emotions and personality during the follow-up period. For those cases operated after 2002, more detailed neuropsychological tests was performed perioperatively. However, only five patients had complete evaluation because the tests were sometimes too tedious for these already debilitated patients, due to severe pain or somnolence caused by large doses of narcotics. To evaluate the efficacy of pain relief, surgical results were arbitrarily defined as ‘‘significant improvement’’ if the postoperative pain score decreased by 50% or more on the VAS: ‘‘definite, slight but meaningful improvement’’ with a decrease of 25–50%; and ‘‘little or no improvement’’ with a decrease of less than 25%.
Results for patients with cancer pain Of the 15 patients with cancer pain, eight (53%) reported significant pain relief in the first week after surgery, four (27%) reported meaningful relief and three (20%) reported little or no improvement (Table 2). At one month follow-up, three patients who initially experienced significant pain relief reported that the efficacy attenuated. One patient reported the pain relief became less significant and two reported the pain returned to the same status as before surgery. Four patients with slight but meaningful Journal of Clinical Neuroscience (2005) 12(8), 886–890
888 Yen et al.
Fig. 1 Coronal (A) and sagittal (B) T1-weighted MRI one week after cingulotomy showing one radiofrequency lesion in the left cingulate gyrus and two consecutive lesions in the right, segmented cingulate gyrus with accompanying perilesional edema. This patient suffered from metastatic bone pain which was completely eliminated after surgery and the effect remained for 20 months.
Table 2 Rating of early and late results of cingulotomy for pain Disease category
Time of rating
No. of patients
Amount of pain relief >75%
25–75%
<25%
Cancer pain
1 1 3 6
week month months months
15 15 12 10
8 5 4 2
(53%) (33%) (33%) (20%)
4 5 3 3
(27%) (33%) (25%) (30%)
3 5 5 5
(20%) (33%) (42%) (50%)
Non-cancer pain
1 week 1 month 3 months 6 months 12 months
7 7 7 7 7
6 5 4 4 4
(86%) (71%) (57%) (57%) (57%)
1 0 1 1 1
(14%) (0%) (14%) (14%) (14%)
0 2 2 2 2
(0%) (29%) (29%) (29%) (29%)
pain relief initially still reported some degree of improvement. Those who did not benefit from surgery from the outset did not attain any delayed effect at one month evaluation or during later follow-up. At three-months evaluation, 12 patients survived, in whom four (33%) reported significant pain relief, three (25%) reported meaningful relief, and five (42%) reported no improvement. Ten patients survived longer than six months; two of them (20%) had significant pain relief, three (30%) had meaningful relief and five (50%) had little or no improvement. Results for patients with non-cancer pain Among seven patients with non-cancer pain, two cases of FBSS attained significant pain relief immediately after cingulotomy. One of them reported recurrent pain with the same intensity as compared with preoperative status a few days after surgery and the other reported the effect waned progressively but the pain was still moderately relieved during later follow-up. One patient with pain following spinal cord injury achieved slight pain relief initially but reported recurrence of pain at one-month follow-up. The other patient with limb pain following spinal cord injury, the two patients with diabetic neuropathy and the one patient with recurrent trigeminal neuralgia, responded to cingulotomy fairly Journal of Clinical Neuroscience (2005) 12(8), 886–890
well and maintained significant improvement of pain at followup of 12, 20, 23, and 12 months respectively. Factors influencing results of pain relief The overall average follow-up in this series was 12.9 months (range: 1–24). At the end point of evaluation (last available follow-up), nine patients (41%) had pain relief of more than 50%, six (27%) had pain relief between 25% and 50% and seven (32%) had pain improvement of less than 25%. Higher KPS score and longer duration of pain before cingulotomy correlated with better pain relief by univariate analysis. The other factors such as age, gender, cause of pain and follow-up period did not correlate with the outcome. Those who achieved some degree of pain relief also reported improved daily activities, and some of these even returned to work. Complications and adverse effects of surgery No surgical mortality in this series was noted. There was no obvious flattening of affect or change of personality immediately after surgery. Some patients experiencing significant pain relief after surgery actually became euphoric and more talkative as compared ª 2005 Elsevier Ltd. All rights reserved.
Bilateral anterior cingulotomy for intractable pain 889
with their preoperative state. Two patients developed transient confusion and recovered within in a few days. Another two patients suffered from mild upper gastrointestinal bleeding which soon subsided with medical treatment. There were no clinically observable neurological or cognitive deficits in our series. An adequate neuropsychological evaluation was not available but the preliminary data from five patients did reveal some attentional impairment at the early postoperative stage. DISCUSSION The cingulate gyrus, as a part of the limbic system, does not aid in differentiation of the various types of pain sensation but is more specifically involved in the emotional reaction to pain.8 Foltz and White in 1962 reported a series of 16 patients with pain treated with cingulotomy based on the belief that surgery did not change the sensation of pain per se but modified patients’ reactions to it.8 They concluded that the effectiveness of the surgery depended primarily on the personality and emotional reactivity of the patient. Over the years, lesioning of the cingulate gyrus, originally used in the management of psychiatric patients, has been used in the management of patients with refractory pain and proved to be effective in selected patients. Although experimental and functional imaging studies have shown a direct role of the cingulate gyrus in processing of nociceptive information, the mechanism of pain relief by cingulotomy is not clearly understood.16–19 Cingulotomy was once performed via open surgery. However, for terminally ill cancer patients and those incapacitated by chronic pain, general anesthesia and a major neurosurgical procedure is inappropriate. After the introduction of stereotactic techniques, cingulate lesions could be performed under local anesthesia and the attendant mortality and morbidity lowered significantly. Previous stereotactic methods using ventriculography were indirect and cumbersome for lesion localization. The discomfort and complications associated with ventriculography are also well documented.13,14 A large lesion was usually necessary to ensure adequate cingulate region coverage by this indirect method. Under the guidance of MRI, the target can be directly visualized and the size of the lesion can be tailored according to the size, shape and location of the cingulate gyri, which are usually asymmetric from patient-to-patient and even differ from sideto-side in the same patient.12,13,20 Accordingly, a circumscribed radiofrequency lesion can be created to ablate the anterior cingulate regions without extensive damage to the adjacent frontal cortex, which to our understanding might decrease untoward side-effects. However, the efficacy with a more limited lesion demands further investigation. Hurt and Ballantine reported a large series of patients undergoing cingulotomy for persistent pain.9 In 32 patients with cancer pain, 66% obtained some degree of pain relief although this was not maintained over a long time. They attributed the recurrence of pain to new sources of stimuli that might not be affected by prior cingulate lesions. In the same study, 66% of 34 patients with pain of non-neoplastic origin also obtained some degree of pain relief throughout the long-term follow-up of up to nine years. Wilkinson et al. also reported a series of 18 patients in whom 72% obtained pain improvement.13 In our experience, 66% of patients with cancer pain reported definite improvement of pain at one month follow-up, which decreased to 55% and 50% at three months and six months, respectively. The experience with benign pain is limited but 71% of patients had long-term pain relief. Some conclusions can be drawn from our series. Firstly, patients who did not benefit from cingulotomy immediately after ª 2005 Elsevier Ltd. All rights reserved.
surgery and those who only benefited temporally did not attain any delayed effect during later follow-up. This result is different from that of Wilkinson et al.13 In their series, the pain relief achieved was ‘‘temporally bimodal’’. Secondly, the placebo effect cannot be neglected. Although the effect of cingulotomy for pain relief was not emphasized before surgery, patients still expected that the procedure would ameliorate their suffering to some extent. The remarkably high percentage of patients reporting significant or meaningful pain relief within the first few days post-surgery substantiate this point. Thirdly, pain relief could be long-lasting. This is true for both patients with neoplastic or non-neoplastic pain. Rarely has mortality been reported since the introduction of modern stereotactic methods. Neurological morbidity associated with cingulotomy is also uncommon, and mostly secondary to bleeding. Compared with the lesions created for pallidotomy or thalamotomy, a larger lesion is always produced to cover the whole cingulum and even the cingulate cortex. The relatively large lesion with the attendant peri-lesional edema may incur complications: aphasia, confusion, and incontinence.12,13 Despite strong evidence showing correlation of the cingulate cortex with various neurocognitive functions, outcome studies have generally not indicated significant cognitive disturbances after surgery.13,21 This conclusion however, is usually derived from subjective clinical observation by clinicians or families. Detailed neurocognitive studies, although limited, definitely reveal some subtle abnormalities such as attentional impairment and deficit of response selection in addition to the well-known ‘‘frontal-type’’ syndrome of apathy, and decreased activity and spontaneity.22–24 Although cingulotomy provides dramatic results in selected patients with intractable pain, controversy as to its employment for pain management remains.13,25 The exact mechanism of cingulotomy to relieve pain is unclear. Even considered as a surgery for pain rather than a psychosurgery, the affective response of cingulotomy seems to play a key role in modulation of the painful sensation and the psychological aspects of pain experience. For patients with cancer pain, the recurrence of pain is another problem. Pain relief with ablative procedures in this category of patients is typically short-lived, although the pain is somewhat different in quality and location. It is not certain whether the later recurrence of pain results from late failure of cingulotomy or generation of new metastatic foci. 9,26 Therefore, cingulotomy is best considered in terminally ill patients with limited life expectancy. Another great concern associated with ablative procedures is the risk of developing deafferentation pain which is especially true for patients with pain of benign origin. Even though no deafferentation pain following cingulotomy has been reported in the literature so far, the possibility of developing deafferentation pain after other neuroablative procedures is well established. Patients with persistent pain are desperate to seek any means to alleviate their suffering. Before utilization of any neuroablative procedures for pain management, a thorough preoperative evaluation of the patient’s neurological and psychological condition, as well as consideration of other non-destructive management modalities, is necessary. We understand that there are limitations in our study. A small number of patients with limited follow-up and no control group make it impossible to draw any definite conclusion. An oversimplified scale for the evaluation of pain is inaccurate and biased. Lack of complete neuropsychological testing may also underestimate the impact on cognitive functioning. Although it is premature to deny the value of this neuroablative procedure, a carefully performed prospective study is warranted. Journal of Clinical Neuroscience (2005) 12(8), 886–890
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CONCLUSION Management of pain is a formidable challenge for all clinicians taking care of patients with advanced cancers or those incapacitated by chronic intractable pain. MRI guided cingulotomy is a relatively simple procedure that can be accomplished under local anesthesia with little discomfort or risk to the fragile patient. Rather than a treatment of last resort, the procedure should be considered an adjunct to the multidisciplinary management of patients with severe intractable pain. Although most of the neuroablative procedures are outdated and have been replaced by neuromodulating procedures, considering the limited life expectancy of terminally ill cancer patients as well as the need for improved costcontainment, a reappraisal of the role of neuroablative procedures is needed. In the setting of intractable pain from benign origin, possible cognitive complications associated with destructive lesions in the brain cannot be underestimated. The possible deficits must be weighed against the potential pain relief.
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ª 2005 Elsevier Ltd. All rights reserved.