Neuromodulation: Technology at the Neural Interface (onlinelibrary.wiley.com) DOI: 10.1111/ner.12209
FROM THE EDITOR-IN-CHIEF
Motor Cortex Stimulation for Chronic Pain: Panacea or Placebo?
In this issue, Sachs and coworkers (1) report and carefully examine their negative experience with motor cortex stimulation (MCS) for the treatment of chronic pain. This highlights an ongoing controversy in the field of brain neuromodulation; while there exists a large body of literature reporting the significant efficacy of MCS for chronic pain therapy, several investigators have more recently discussed their frustration with the long-term efficacy of MCS. Is MCS a panacea for neuropathic pain syndromes such as anesthesia dolorosa and central poststroke pain, or is this merely a placebo effect? Those of us involved in the clinical care of refractory chronic pain patients need to more thoroughly examine this controversy and provide direction for further research and clinical practice. Tsubokawa et al. first reported chronic stimulation of the precentral cortex for the treatment of pain in 1991 (2,3). Interestingly, stimulation of the motor cortex gave better results than stimulation of the sensory cortex, the latter of which caused some patients’ pain to worsen. A number of reports have followed describing the use of MCS for intractable pain syndromes including poststroke pain, phantom limb pain, spinal cord injury pain, postherpetic neuralgia, and neuropathic pain of the limbs or face (4). MCS has shown particular promise in the treatment of trigeminal neuropathic pain and central pain syndromes such as poststroke thalamic pain syndrome for which there are few other
Figure 2. Transdural bipolar stimulation mapping of the motor cortex to confirm proper site for electrode placement.
effective treatments (2,3,5–14). Based upon these reports, poststroke pain responds well to MCS, with approximately twothirds of reported patients achieving adequate relief. Several studies have reported excellent results of using MCS for the treatment of trigeminal neuropathic pain, with 75% to 100% of patients achieving good to excellent pain relief (8,10,15–17).
SURGICAL TECHNIQUE FOR MCS
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Figure 1. Craniotomy performed with stereotactic guidance over the motor cortex. Note the exposed dura, which is not opened during the procedure.
For the contemporary MCS procedure, most clinicians prefer stereotactic functional MRI imaging (fMRI) to localize the area of the motor cortex representing the contralateral painful body region (18– 21). MRI without functional information can be used, however, to provide anatomic guidance alone (5,10,19,22–25). Most investigators perform a small craniotomy for electrode placement (8–10,16) under either local (6–10,14–17,21,26–28) or general anesthetic (5,11,12,19,20,22,25,29), replacing the earlier burr hole technique. Image-guided neuronavigation is used to precisely center the skin incision and craniotomy over the motor cortex target (10,19–22). Electrophysiologic monitoring and stimulation are then performed. The central sulcus is identified by recording brain surface electrical activity using an epidural grid electrode. N20/P20 evokedpotential waveform phase reversal is used to locate the central
LEVY of the motor threshold as a guide. Many investigators begin by stimulating the cortex at 20% of the motor threshold and, if no pain relief is noted, increasing stimulation by 20% increments until pain relief is reported or to a maximum of 80% of motor threshold. Others use fixed stimulus intensities in their trials. If patients obtain sufficient pain relief during the trial, they are returned to the operating room, and the electrode is connected to an implanted pulse generator, usually placed subcutaneously over the pectoralis muscle.
REPORTED COMPLICATIONS OF MCS Figure 3. Epidural motor cortex-stimulating electrodes sutured to the dura prior to replacement of the cranial bone flap.
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sulcus. The cortex is stimulated, usually through the dura, and both somatosensory evoked potentials and electromyogram are monitored to precisely locate the area of the motor cortex that corresponds to the pain region. Electrode strips are then placed over the center of this target. Nearly all investigators place the electrodes epidurally, although subdural placement has been described (23,30). Some investigators prefer to place the electrode strips perpendicular to the precentral gyrus, while others prefer a parallel orientation; no clear evidence exists to favor one technique over another. Some investigators prefer the use of two side-by-side fourcontact electrode strips, while other investigators have evaluated an implantable electrode grid designed specifically for MCS (Keravel, personal communication). Motor threshold testing is often carried out in the operating room (5,6,9,13,31), and, in awake patients, some implanters evaluate the effect of acute stimulation on the patient’s report of pain. In light of the homonuclear representation of the body on the motor cortex, with face and arm located on its superolateral aspects, coverage of pain in these regions by MCS is relatively straightforward. With the representation of the leg extending medially into the interhemispheric fissure, however, coverage of leg pain is more challenging. Some investigators place the lead epidurally as close to midline as possible and rely upon increased stimulation intensities to drive current deeper into the leg motor cortex. Others place leads subdurally within the interhemispheric fissure to directly contact the leg motor cortex. After closure of the craniotomy, the electrode cable is usually externalized for trial stimulation. Patients then undergo a period of trial stimulation usually lasting three to seven days. Unlike other forms of neurostimulation, patients experience no stimulation-induced sensory phenomenon during MCS; only pain relief is noted if MCS is effective. There is considerable variation in the stimulation parameters used by various investigators. Reported amplitudes range from 0.5 V to 10 V, rates from 5 Hz to Figure 4. Jaimie Henderson, 130 Hz, and pulse widths from MD, John and Jene Blume— 60 μsec to 450 μsec (32). Once the Robert and Ruth Halperin Profes- pulse width and frequency have sor of Neurosurgery and been optimized, most investigators Professor, by courtesy, of Neurology at the Stanford University will increase stimulus intensities during the trial, using a percentage Medical Center. www.neuromodulationjournal.com
While a majority of studies have reported no adverse events with MCS (2,3,18,28,30,33–35), serious complications, although rare, have been reported. The surgical risks of MCS include intracranial bleeding, infection, and permanent neurological deficits (5,8,10,12,13,16,19,20,22,23). Seizure induction has been reported following MCS programming and during chronic MCS (6,11,12,15,17,19–21). While seizure induction does not necessarily lead to the development of epilepsy, there is at least one patient who developed severe epilepsy after long-term motor cortex stimulation (36).
REPORTED EFFICACY OF MCS Until now, successful treatment of facial neuropathic pain with MCS has been almost uniformly reported (8–10,15,16). A review of the literature has corroborated these results, showing that 29 of 38 (76%) reported patients with neuropathic facial pain achieved ≥50% pain relief with MCS (22). Poststroke pain responds nearly as well, with almost two-thirds of patients obtaining good to excellent relief (9,10).
“NEGATIVE” REPORTS OF MCS: THE ISSUE OF BLINDED STIMULATION In their paper in this issue, Sachs and coworkers identify three studies that are purported to demonstrate a lack of efficacy of MCS. As noted in their excellent discussion, Velasco et al. (37) prospectively evaluated eight patients with chronic unilateral neuropathic pain undergoing MCS; all had >40% reduction in pain at one year. During this year, the stimulation was turned off in a blinded manner for 30 days; all eight patients experienced statistically significant pain recurrence after turning off the stimulation. A European multinational prospective trial of MCS, closed due to slow subject accrual, enrolled 24 patients. Eleven patients underwent a fourweek blinded period randomized to “on” or “off” stimulation; none Figure 5. Takashi Tsubokawa, expressed a preference for either the MD, PhD, Professor and Chairman of the Department of Neu“on” or “off” condition (38). Nguyen rological Surgery at Nihon et al. performed a two-week trial University School of Medicine in comparing stimulation “on” and “off” Tokyo.
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FROM THE EDITOR-IN-CHIEF in a blinded fashion in 10 patients. A clear worsening of visual analogue scale score as compared with unblended was noted in both the “off”and“on”conditions (39). In 16 patients reporting successful pain relief at one year following MCS, Lefaucheur and coworkers performed an embedded one-month double-blind evaluation comparing “on” and “off” stimulation. No preference for either condition was identified (40). Sachs and coworkers conclude that while these studies suggest some true analgesic effect associated with MCS, the inconclusive results during blinded stimulation raise the possibility of placebo or other effects not directly related to the stimulation itself. While I agree with this conclusion, we must consider an equally plausible explanation, leading to a type II error. Could the 30-day window of these blinded trials be too short to eliminate the washout effect of the stimulation? Could those patients who do not appreciate a difference in pain relief between the “on”phase and the “off” phase still be experiencing the effect of prior stimulation during the blinded testing phase? More than once I have had the experience of a patient returning with complaints that their MCS has stopped providing pain relief. After taking a careful history and performing some calculations of expected battery life based upon stimulation parameters, it has become clear that the battery should have expired several months before the return of pain. More notably, pain relief returned with replacement of the pulse generator. This raises the equally likely possibility that the MCS effect, when successful, can be quite long-lasting and can thus confound clinical trials that do not take it into account.
“NEGATIVE” REPORTS OF MCS: THE ISSUE OF RTMS SCREENING OR IMPLANTED TRIALS
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CONCLUSIONS At the present time, it is unlikely that we can make any definitive conclusions as to the efficacy of MCS for chronic neuropathic pain. So I failed to answer the question I first proposed: Is MCS a placebo or a panacea? It is likely neither. The bulk of the literature suggests that MCS holds promise for patients with trigeminal neuropathic pain, poststroke pain, and pain that has failed to respond to other
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Contrary to the standard for most neurostimulation procedures for chronic pain therapy, Sachs and coworkers chose not to perform a screening trial prior to implant, at least in 12 of their 14 patients. They correctly note the difficulties and risks of performing such trial screening with implanted leads, including the need for craniotomy, postoperative pain potentially obscuring stimulation benefit, the limited time of a trial making comprehensive programming difficult, the risk of infection, and the significant resource allocation required to support this approach. They further noted that given the high trial-to-permanent-implantation ratios in most reports of MCS, this alone is unlikely to be the cause of their poor success rate. My perspective on this matter is very much different. Just as for spinal cord stimulation, I insist upon a period of trial stimulation prior to permanent device implantation for MCS. While I have not kept formal data over the years, it is my impression that only about half of my trial patients go on to permanent device implantation; certainly the trial-to-permanent ratio is far less than 100%. We have never had an infection during our five- to seven-day trial. I agree that such a trial requires a significant allocation of resources and may not be long enough to perform an ideal comprehensive trial. Nonetheless, I believe that it is preferable to simply implanting all patients with an expensive device that may not be appropriate for them. The need for significant resource allocation during these trials might be addressed by limiting such specialized procedures to regional centers which, by virtue of their volumes, can afford to provide the level of support to perform high-quality screening trials. The authors mention the possibility of trialing with noninvasive repetitive transcranial magnetic stimulation (rTMS); we and others have proposed this as well for several different MCS applications (41). While they comment that rTMS may not be sufficiently precise
for effective trialing, this does not seem to be the case. DeRidder and colleagues have reported the successful use of rTMS as a screening modality for cortical stimulation for tinnitus (42). They have furthermore used stereotactically navigated rTMS in their screening paradigm such that the precision is actually greater than that of functional MRI. There are other areas where Sachs et al. and I are in substantial agreement. Certainly, with a group as experienced as theirs, it is highly unlikely that improper patient selection led to their reported poor efficacy. I am quite certain that other experts in the field would have considered these patients as appropriate for a trial of MCS; as stated before, only their response to trial would warrant permanent implant in the hands of several expert implanters. Furthermore, improper lead location is highly unlikely to have led to their poor results. The authors provide an exhaustive and convincing discussion of their confirmation of appropriate lead placement for MCS. As they state, “postoperative image reconstructions confirmed lead positions on both sides of the central sulcus, and intraoperative neurophysiological testing confirmed somatotopically appropriate lead placement in most cases. However, sub-optimal lead location is still a possible explanation in the 5 patients in whom intraoperative muscle contractions were not elicited.” I wonder, however, whether some of the contradictory results in this field result from the possibility that our optimal target may not actually be the motor cortex representing the area of the patient’s pain. This is particularly plausible in that we do not actually understand the mechanism of action of MCS for neuropathic pain. While attractive models have been proposed to explain these effects, there is little or no experimental data to support these models. As such, the actual target may be adjacent or near what we believe to be the target, such that some of us may inadvertently stimulate the actual target while others might miss it, all the while intending to stimulate the motor cortex. We simply need more mechanistic information to make this a more robust therapy. In that many of us in the field actually use the MCS programming protocols suggested by the senior author, I also agree that inadequate programming is unlikely to explain the lack of effect reported in the present study. They have exhausted the full parameter range of the current device, including electrode selection, frequency, amplitude, and pulse width. That being said, the currently employed devices are adapted from other established neuromodulation applications (spinal cord and deep brain stimulation) and are not specifically optimized for MCS. Little do we know of the potential impact of leads specifically designed to stimulate the brain cortex, ultra-high-stimulation frequencies outside the norm for DBS currently being explored for spinal cord stimulation, nontraditional waveforms, and/or nontonic stimulation patterns such as bursting stimulation. As most thalamocortical circuits communicate via rhythmic bursting activity, DeRidder has postulated that this might be a much more effective way of normalizing abnormal brain activity.
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less invasive forms of neurostimulation. As Sachs and coworkers point out, however, all of the published reports are either retrospective or inadequately powered prospective studies. I certainly agree that the bias to publish only positive results might skew the literature to suggest a greater degree of efficacy than one might expect in general clinical practice. Certainly, no randomized controlled trials exist to confirm or refute the effectiveness of MCS. This lack of Class I data, added to the current observational data, may cause some observers to view the therapy skeptically in spite of the considerable history of clinical use. MCS is better suited to the randomized controlled research format than other forms of neurostimulation in that effective stimulation evokes no perception on the part of the patient save for pain relief. This presents researchers with a unique opportunity to perform blinded studies in which placebo effects can be assessed. Such studies could employ crossover designs to encourage enrollment and address ethical concerns related to the implantation of leads into control patients. They must however pay keen attention to the potential washout period of the stimulation effect such that the results are not open to potential criticism. The lack of randomized controlled trials may be due, in part, to the challenges of patient recruitment and monitoring and the need to assign patients to control groups, which by definition means subjecting patients to treatments that have already been unsuccessful in managing their pain. However, the risk of not performing these studies is great, because it means that both physicians and patients will lack definitive information about the efficacy of this intracranial neurostimulation therapy. This will then slow further development and limit patient access in the future. Future research into MCS should also focus in part on customizing neurostimulation technology for this application. For example, paddle leads that were originally designed for spinal cord stimulation are often employed in MCS, even though their length and intercontact distances can make them unwieldy. Additionally, these leads have a relatively narrow strip of electrodes that makes them poorly suited to cover multiple targets on the cortex. Implanters can attempt to use multiple leads to compensate for this shortcoming, but this may result in poor control over the stimulation field and possibly interference between the leads. Additionally, using a standard four-contact paddle lead to stimulate the motor cortex, as often happens in clinical practice, is not a particularly discrete way of targeting the cortical geography, and leads that allow more precise stimulation may be desired. Leads could be designed to allow for stimulation both parallel and perpendicular to the precentral gyrus, permitting the selection of the most effective stimulation targets in individual patients. They might again reveal an adjacent or nearby primary target that is much more efficacious and robust than the motor cortex target currently employed. Further research is required to determine the optimal stimulation parameters for MCS. Research should also focus on how to overcome the apparent habituation that some patients experience during the course of their MCS therapy and to determine whether this is true habituation or, possibly, the waning of a strong placebo effect. MCS for intractable pain has clearly not been rigorously studied in a prospective fashion, and these studies must be performed. There are differing opinions in the literature regarding surgical technique, programming, and patient selection. Nonetheless, MCS appears to be a relatively safe neuromodulation procedure, and the suggestion of efficacy demands that we more aggressively pursue adequately powered prospective trials and further examine the potential mechanisms of action for this potentially effective therapy. This is especially important in that the majority of patients treated with www.neuromodulationjournal.com
MCS lack other treatment alternatives and without it might be forced to suffer profoundly for the remainder of their lives. Robert M. Levy, MD, PhD Editor-in-Chief Boca Raton, Florida Neuromodulation: Technology at the Neural Interface Editorial Office: 800 Meadows Road Boca Raton, FL 33486 Email: [email protected]
REFERENCES 1. Sachs AJ, Babu H, Su Y-F, Miller KJ and Henderson JM. Lack of efficacy of motor cortex stimulation for the treatment of neuropathic pain in 14 patients. Neuromodulation: Technology at the Neural Interface 2014;17:303–311. 2. Tsubokawa T, Katayama Y, Yamamoto T, Hirayama T, Koyama S. Chronic motor cortex stimulation for the treatment of central pain. Acta Neurochir (Wein) 1991;52 (Suppl. ):137–139. 3. Tsubokawa T, Katayama Y, Yamamoto T et al. Treatment of thalamic pain by chronic motor cortex stimulation. Pacing Clin Electrophysiol 1991;14:131–134. 4. Brown JA, Barbaro NM. Motor cortex stimulation for central and neuropathic pain: current status. Pain 2003;104:431–435. 5. Carroll D, Joint C, Maartens N et al. Motor cortex stimulation for chronic neuropathic pain: a preliminary study of 10 cases. Pain 2000;84:431–437. 6. Katayama Y, Fukaya C, Yamamoto T. Poststroke pain control by chronic motor cortex stimulation: neurological characteristics predicting a favorable response. J Neurosurg 1998;89:585–591. 7. Katayama Y, Tsubokawa T, Yamamoto T. Chronic motor cortex stimulation for central deafferentation pain: experience with bulbar pain secondary to Wallenberg syndrome. Stereotact Funct Neurosurg 1994;62:295–299. 8. Nguyen JP, Keravel Y, Feve A et al. Treatment of deafferentation pain by chronic stimulation of the motor cortex: report of a series of 20 cases. Acta Neurochir (Wien) 1997;68 (Suppl. ):54–60. 9. Nguyen JP, Lefaucher JP, Le Guerinel C et al. Motor cortex stimulation in the treatment of central and neuropathic pain. Arch Med Res 2000;31:263–265. 10. Nguyen JP, Lefaucheur JP, Decq P et al. Chronic motor cortex stimulation in the treatment of central and neuropathic pain: correlations between clinical, electrophysiological and anatomical data. Pain 1999;82:245–251. 11. Saitoh Y, Shibata M, Hirano S et al. Motor cortex stimulation for central and peripheral deafferentation pain. Report of eight cases. J Neurosurg 2000;92:150–155. 12. Saitoh Y, Hirano S, Kato K et al. Motor cortex stimulation for deafferentation pain. Neurosurg Focus 2001;11:E1. 13. Smith H, Joint C, Schlugman D, Nandi D, Stein JF, Aziz TZ. Motor cortex stimulation for neuropathic pain. Neurosurg Focus 2001;11:E2. 14. Tsubokawa T, Katayama Y, Yamamoto T, Hirayama T, Koyama S. Chronic motor cortex stimulation in patients with thalamic pain. J Neurosurg 1993;78:393–401. 15. Ebel H, Rust D, Tronnier V et al. Chronic precentral stimulation in trigeminal neuropathic pain. Acta Neurochir (Wien) 1996;138:1300–1306. 16. Meyerson BA, Lindblom U, Linderoth B et al. Motor cortex stimulation as treatment of trigeminal neuropathic pain. Acta Neurochir (Wien) 1993;58 (Suppl.):150–153. 17. Rainov NG, Fels C, Heidecke V et al. Epidural electrical stimulation of the motor cortex in patients with facial neuralgia. Clin Neurol Neurosurg 1997;99:205–209. 18. Gharabaghi A, Hellwig D, Rosahl SK et al. Volumetric image guidance for motor cortex stimulation: integration of three-dimensional cortical anatomy and functional imaging. Neurosurgery 2005;57 (Suppl. 1):114–120. 19. Nuti C, Peyron R, Garcia-Larrea L et al. Motor cortex stimulation for refractory neuropathic pain: four year outcome and predictors of efficacy. Pain 2005;118:43–52. 20. Pirotte B, Voordecker P, Neugroschl C et al. Combination of functional magnetic resonance image-guided neuronavigation and intraoperative cortical brain mapping improves targeting of motor cortex stimulation in neuropathic pain. Neurosurgery 2005;56 (Suppl. 2):334–359. 21. Sharan AD, Rosenow JM, Turbay M et al. Precentral stimulation for chronic pain. Neurosurg Clin N Am 2003;14:437–444. 22. Brown JA, Pilitsis JG. Motor cortex stimulation for central and neuropathic facial pain: a prospective study of 10 patients and observations of enhanced sensory and motor function during stimulation. Neurosurgery 2005;56:290–297, discussion 290–7. 23. Saitoh Y, Kato K, Ninomiya H et al. Primary motor cortex stimulation within the central sulcus for treating deafferentation pain. Acta Neurochir 2003;87 (Suppl.):149–152. 24. Tomasino B, Budai R, Mondani M et al. Mental rotation in a patient with an implanted electrode grid in the motor cortex. Neuroreport 2005;16:1795–1800. 25. Velasco M, Velasco F, Brito F et al. Motor cortex stimulation in the treatment of deafferentation pain:localization of the motor cortex. Stereotact Funct Neurosurg 2002;79:146–167.
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FROM THE EDITOR-IN-CHIEF 26. Katayama Y, Yamamoto T, Kobayashi K, Kasai M, Oshima H, Fukaya C. Motor cortex stimulation for phantom limb pain: a comprehensive therapy with spinal cord and thalamic stimulation. Stereotact Funct Neurosurg 2001;77:159–161. 27. Rainov NG, Heidecke V. Motor cortex stimulation for neuropathic facial pain. Neurol Res 2003;25:157–161. 28. Son UC, Kim MC, Moon DE, Kang JK. Motor cortex stimulation in a patient with intractable complex regional pain syndrome type II with hemibody involvement. Case report. J Neurosurg 2003;98:175–179. 29. Roux FE, Ibarrola D, Lazorthes Y et al. Chronic motor cortex stimulation for phantom limb pain. A functional magnetic resonance imaging study: technical case report. Neurosurgery 2001;48:681–687, discussion 687–688. 30. Tani N, Saitoh Y, Hirata M, Kato A, Yoshimine T. Bilateral cortical stimulation for deafferentation pain after spinal cord injury. Case report. J Neurosurg 2004;101:687– 689. 31. Katayama Y, Yamamoto T, Kobayashi K et al. Deep brain and motor cortex stimulation for post-stroke movement disorders and post-stroke pain. Acta Neurochir 2003;87 (Suppl.):121–123. 32. Bonicalzi V, Canavero S. Motor cortex stimulation for central and neuropathic pain [letter]. Pain 2004;108:199–200. 33. Herregodts P, Stadnik T, De Ridder F et al. Cortical stimulation for central neuropathic pain: 3-D surface MRI for easy determination of the motor cortex. Acta Neurochir (Wien) 1995;64 (Suppl.):132–135. 34. Hosobuchi Y. Motor cortical stimulation for control of central deafferentation pain. Adv Neurol 1993;63:215–217.
35. Sol JC, Casaux J, Roux FE et al. Chronic motor cortex stimulation for phantom limb pain: correlations between pain relief and functional imaging studies. Stereotact Funct Neurosurg 2001;77:172–176. 36. Bezard E, Boraud T, Nguyen JP, Velasco F, Keravel Y, Gross C. Cortical stimulation and epileptic seizure: a study of the potential risk in primates. Neurosurgery 1999;45:346–350. 37. Velasco F, Arguelles C, Carrillo-Ruiz JD et al. Efficacy of motor cortex stimulation in the treatment of neuropathic pain: a randomized double-blind trial. J Neurosurg 2008;108:698–706. 38. Coffey RJ, Hamani C, Lozano AM. Evidence base: neurostimulation for pain. In: Winn HR, ed. Youmans Neurological Surgery, Vol. 2, 6th ed. Philadelphia: Elsevier, 2011. 39. Nguyen JP, Velasco F, Brugieres P et al. Treatment of chronic neuropathic pain by motor cortex stimulation: results of a bicentric controlled crossover trial. Brain Stimul 2008;1:89–96. 40. Lefaucheur JP, Drouot X, Cunin P et al. Motor cortex stimulation for the treatment of refractory peripheral neuropathic pain. Brain 2009;132 (Pt 6):1463– 1471. 41. Lefaucheur JP, Menard-Lefaucheur I, Goujon C, Keravel Y, Nguyen JP. Predictive value of rTMS in the identification of responders to epidural motor cortex stimulation therapy for pain. J Pain 2011;12:1102–1111. 42. Londero A, Langguth B, De Ridder D, Bonfils P, Lefaucheur J-P. Repetitive transcranial magnetic stimulation (rTMS): a new therapeutic approach.Neurophysiol Clin 2009;36:145–155.
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© 2014 International Neuromodulation Society
Neuromodulation 2014; 17: 295–299
FROM THE EDITOR-IN-CHIEF
Motor Cortex Stimulation for Chronic Pain: Panacea or Placebo?
In this issue, Sachs and coworkers (1) report and carefully examine their negative experience with motor cortex stimulation (MCS) for the treatment of chronic pain. This highlights an ongoing controversy in the field of brain neuromodulation; while there exists a large body of literature reporting the significant efficacy of MCS for chronic pain therapy, several investigators have more recently discussed their frustration with the long-term efficacy of MCS. Is MCS a panacea for neuropathic pain syndromes such as anesthesia dolorosa and central poststroke pain, or is this merely a placebo effect? Those of us involved in the clinical care of refractory chronic pain patients need to more thoroughly examine this controversy and provide direction for further research and clinical practice. Tsubokawa et al. first reported chronic stimulation of the precentral cortex for the treatment of pain in 1991 (2,3). Interestingly, stimulation of the motor cortex gave better results than stimulation of the sensory cortex, the latter of which caused some patients’ pain to worsen. A number of reports have followed describing the use of MCS for intractable pain syndromes including poststroke pain, phantom limb pain, spinal cord injury pain, postherpetic neuralgia, and neuropathic pain of the limbs or face (4). MCS has shown particular promise in the treatment of trigeminal neuropathic pain and central pain syndromes such as poststroke thalamic pain syndrome for which there are few other
Figure 2. Transdural bipolar stimulation mapping of the motor cortex to confirm proper site for electrode placement.
effective treatments (2,3,5–14). Based upon these reports, poststroke pain responds well to MCS, with approximately twothirds of reported patients achieving adequate relief. Several studies have reported excellent results of using MCS for the treatment of trigeminal neuropathic pain, with 75% to 100% of patients achieving good to excellent pain relief (8,10,15–17).
SURGICAL TECHNIQUE FOR MCS
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Figure 1. Craniotomy performed with stereotactic guidance over the motor cortex. Note the exposed dura, which is not opened during the procedure.
For the contemporary MCS procedure, most clinicians prefer stereotactic functional MRI imaging (fMRI) to localize the area of the motor cortex representing the contralateral painful body region (18– 21). MRI without functional information can be used, however, to provide anatomic guidance alone (5,10,19,22–25). Most investigators perform a small craniotomy for electrode placement (8–10,16) under either local (6–10,14–17,21,26–28) or general anesthetic (5,11,12,19,20,22,25,29), replacing the earlier burr hole technique. Image-guided neuronavigation is used to precisely center the skin incision and craniotomy over the motor cortex target (10,19–22). Electrophysiologic monitoring and stimulation are then performed. The central sulcus is identified by recording brain surface electrical activity using an epidural grid electrode. N20/P20 evokedpotential waveform phase reversal is used to locate the central
LEVY of the motor threshold as a guide. Many investigators begin by stimulating the cortex at 20% of the motor threshold and, if no pain relief is noted, increasing stimulation by 20% increments until pain relief is reported or to a maximum of 80% of motor threshold. Others use fixed stimulus intensities in their trials. If patients obtain sufficient pain relief during the trial, they are returned to the operating room, and the electrode is connected to an implanted pulse generator, usually placed subcutaneously over the pectoralis muscle.
REPORTED COMPLICATIONS OF MCS Figure 3. Epidural motor cortex-stimulating electrodes sutured to the dura prior to replacement of the cranial bone flap.
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sulcus. The cortex is stimulated, usually through the dura, and both somatosensory evoked potentials and electromyogram are monitored to precisely locate the area of the motor cortex that corresponds to the pain region. Electrode strips are then placed over the center of this target. Nearly all investigators place the electrodes epidurally, although subdural placement has been described (23,30). Some investigators prefer to place the electrode strips perpendicular to the precentral gyrus, while others prefer a parallel orientation; no clear evidence exists to favor one technique over another. Some investigators prefer the use of two side-by-side fourcontact electrode strips, while other investigators have evaluated an implantable electrode grid designed specifically for MCS (Keravel, personal communication). Motor threshold testing is often carried out in the operating room (5,6,9,13,31), and, in awake patients, some implanters evaluate the effect of acute stimulation on the patient’s report of pain. In light of the homonuclear representation of the body on the motor cortex, with face and arm located on its superolateral aspects, coverage of pain in these regions by MCS is relatively straightforward. With the representation of the leg extending medially into the interhemispheric fissure, however, coverage of leg pain is more challenging. Some investigators place the lead epidurally as close to midline as possible and rely upon increased stimulation intensities to drive current deeper into the leg motor cortex. Others place leads subdurally within the interhemispheric fissure to directly contact the leg motor cortex. After closure of the craniotomy, the electrode cable is usually externalized for trial stimulation. Patients then undergo a period of trial stimulation usually lasting three to seven days. Unlike other forms of neurostimulation, patients experience no stimulation-induced sensory phenomenon during MCS; only pain relief is noted if MCS is effective. There is considerable variation in the stimulation parameters used by various investigators. Reported amplitudes range from 0.5 V to 10 V, rates from 5 Hz to Figure 4. Jaimie Henderson, 130 Hz, and pulse widths from MD, John and Jene Blume— 60 μsec to 450 μsec (32). Once the Robert and Ruth Halperin Profes- pulse width and frequency have sor of Neurosurgery and been optimized, most investigators Professor, by courtesy, of Neurology at the Stanford University will increase stimulus intensities during the trial, using a percentage Medical Center. www.neuromodulationjournal.com
While a majority of studies have reported no adverse events with MCS (2,3,18,28,30,33–35), serious complications, although rare, have been reported. The surgical risks of MCS include intracranial bleeding, infection, and permanent neurological deficits (5,8,10,12,13,16,19,20,22,23). Seizure induction has been reported following MCS programming and during chronic MCS (6,11,12,15,17,19–21). While seizure induction does not necessarily lead to the development of epilepsy, there is at least one patient who developed severe epilepsy after long-term motor cortex stimulation (36).
REPORTED EFFICACY OF MCS Until now, successful treatment of facial neuropathic pain with MCS has been almost uniformly reported (8–10,15,16). A review of the literature has corroborated these results, showing that 29 of 38 (76%) reported patients with neuropathic facial pain achieved ≥50% pain relief with MCS (22). Poststroke pain responds nearly as well, with almost two-thirds of patients obtaining good to excellent relief (9,10).
“NEGATIVE” REPORTS OF MCS: THE ISSUE OF BLINDED STIMULATION In their paper in this issue, Sachs and coworkers identify three studies that are purported to demonstrate a lack of efficacy of MCS. As noted in their excellent discussion, Velasco et al. (37) prospectively evaluated eight patients with chronic unilateral neuropathic pain undergoing MCS; all had >40% reduction in pain at one year. During this year, the stimulation was turned off in a blinded manner for 30 days; all eight patients experienced statistically significant pain recurrence after turning off the stimulation. A European multinational prospective trial of MCS, closed due to slow subject accrual, enrolled 24 patients. Eleven patients underwent a fourweek blinded period randomized to “on” or “off” stimulation; none Figure 5. Takashi Tsubokawa, expressed a preference for either the MD, PhD, Professor and Chairman of the Department of Neu“on” or “off” condition (38). Nguyen rological Surgery at Nihon et al. performed a two-week trial University School of Medicine in comparing stimulation “on” and “off” Tokyo.
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FROM THE EDITOR-IN-CHIEF in a blinded fashion in 10 patients. A clear worsening of visual analogue scale score as compared with unblended was noted in both the “off”and“on”conditions (39). In 16 patients reporting successful pain relief at one year following MCS, Lefaucheur and coworkers performed an embedded one-month double-blind evaluation comparing “on” and “off” stimulation. No preference for either condition was identified (40). Sachs and coworkers conclude that while these studies suggest some true analgesic effect associated with MCS, the inconclusive results during blinded stimulation raise the possibility of placebo or other effects not directly related to the stimulation itself. While I agree with this conclusion, we must consider an equally plausible explanation, leading to a type II error. Could the 30-day window of these blinded trials be too short to eliminate the washout effect of the stimulation? Could those patients who do not appreciate a difference in pain relief between the “on”phase and the “off” phase still be experiencing the effect of prior stimulation during the blinded testing phase? More than once I have had the experience of a patient returning with complaints that their MCS has stopped providing pain relief. After taking a careful history and performing some calculations of expected battery life based upon stimulation parameters, it has become clear that the battery should have expired several months before the return of pain. More notably, pain relief returned with replacement of the pulse generator. This raises the equally likely possibility that the MCS effect, when successful, can be quite long-lasting and can thus confound clinical trials that do not take it into account.
“NEGATIVE” REPORTS OF MCS: THE ISSUE OF RTMS SCREENING OR IMPLANTED TRIALS
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CONCLUSIONS At the present time, it is unlikely that we can make any definitive conclusions as to the efficacy of MCS for chronic neuropathic pain. So I failed to answer the question I first proposed: Is MCS a placebo or a panacea? It is likely neither. The bulk of the literature suggests that MCS holds promise for patients with trigeminal neuropathic pain, poststroke pain, and pain that has failed to respond to other
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Contrary to the standard for most neurostimulation procedures for chronic pain therapy, Sachs and coworkers chose not to perform a screening trial prior to implant, at least in 12 of their 14 patients. They correctly note the difficulties and risks of performing such trial screening with implanted leads, including the need for craniotomy, postoperative pain potentially obscuring stimulation benefit, the limited time of a trial making comprehensive programming difficult, the risk of infection, and the significant resource allocation required to support this approach. They further noted that given the high trial-to-permanent-implantation ratios in most reports of MCS, this alone is unlikely to be the cause of their poor success rate. My perspective on this matter is very much different. Just as for spinal cord stimulation, I insist upon a period of trial stimulation prior to permanent device implantation for MCS. While I have not kept formal data over the years, it is my impression that only about half of my trial patients go on to permanent device implantation; certainly the trial-to-permanent ratio is far less than 100%. We have never had an infection during our five- to seven-day trial. I agree that such a trial requires a significant allocation of resources and may not be long enough to perform an ideal comprehensive trial. Nonetheless, I believe that it is preferable to simply implanting all patients with an expensive device that may not be appropriate for them. The need for significant resource allocation during these trials might be addressed by limiting such specialized procedures to regional centers which, by virtue of their volumes, can afford to provide the level of support to perform high-quality screening trials. The authors mention the possibility of trialing with noninvasive repetitive transcranial magnetic stimulation (rTMS); we and others have proposed this as well for several different MCS applications (41). While they comment that rTMS may not be sufficiently precise
for effective trialing, this does not seem to be the case. DeRidder and colleagues have reported the successful use of rTMS as a screening modality for cortical stimulation for tinnitus (42). They have furthermore used stereotactically navigated rTMS in their screening paradigm such that the precision is actually greater than that of functional MRI. There are other areas where Sachs et al. and I are in substantial agreement. Certainly, with a group as experienced as theirs, it is highly unlikely that improper patient selection led to their reported poor efficacy. I am quite certain that other experts in the field would have considered these patients as appropriate for a trial of MCS; as stated before, only their response to trial would warrant permanent implant in the hands of several expert implanters. Furthermore, improper lead location is highly unlikely to have led to their poor results. The authors provide an exhaustive and convincing discussion of their confirmation of appropriate lead placement for MCS. As they state, “postoperative image reconstructions confirmed lead positions on both sides of the central sulcus, and intraoperative neurophysiological testing confirmed somatotopically appropriate lead placement in most cases. However, sub-optimal lead location is still a possible explanation in the 5 patients in whom intraoperative muscle contractions were not elicited.” I wonder, however, whether some of the contradictory results in this field result from the possibility that our optimal target may not actually be the motor cortex representing the area of the patient’s pain. This is particularly plausible in that we do not actually understand the mechanism of action of MCS for neuropathic pain. While attractive models have been proposed to explain these effects, there is little or no experimental data to support these models. As such, the actual target may be adjacent or near what we believe to be the target, such that some of us may inadvertently stimulate the actual target while others might miss it, all the while intending to stimulate the motor cortex. We simply need more mechanistic information to make this a more robust therapy. In that many of us in the field actually use the MCS programming protocols suggested by the senior author, I also agree that inadequate programming is unlikely to explain the lack of effect reported in the present study. They have exhausted the full parameter range of the current device, including electrode selection, frequency, amplitude, and pulse width. That being said, the currently employed devices are adapted from other established neuromodulation applications (spinal cord and deep brain stimulation) and are not specifically optimized for MCS. Little do we know of the potential impact of leads specifically designed to stimulate the brain cortex, ultra-high-stimulation frequencies outside the norm for DBS currently being explored for spinal cord stimulation, nontraditional waveforms, and/or nontonic stimulation patterns such as bursting stimulation. As most thalamocortical circuits communicate via rhythmic bursting activity, DeRidder has postulated that this might be a much more effective way of normalizing abnormal brain activity.
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less invasive forms of neurostimulation. As Sachs and coworkers point out, however, all of the published reports are either retrospective or inadequately powered prospective studies. I certainly agree that the bias to publish only positive results might skew the literature to suggest a greater degree of efficacy than one might expect in general clinical practice. Certainly, no randomized controlled trials exist to confirm or refute the effectiveness of MCS. This lack of Class I data, added to the current observational data, may cause some observers to view the therapy skeptically in spite of the considerable history of clinical use. MCS is better suited to the randomized controlled research format than other forms of neurostimulation in that effective stimulation evokes no perception on the part of the patient save for pain relief. This presents researchers with a unique opportunity to perform blinded studies in which placebo effects can be assessed. Such studies could employ crossover designs to encourage enrollment and address ethical concerns related to the implantation of leads into control patients. They must however pay keen attention to the potential washout period of the stimulation effect such that the results are not open to potential criticism. The lack of randomized controlled trials may be due, in part, to the challenges of patient recruitment and monitoring and the need to assign patients to control groups, which by definition means subjecting patients to treatments that have already been unsuccessful in managing their pain. However, the risk of not performing these studies is great, because it means that both physicians and patients will lack definitive information about the efficacy of this intracranial neurostimulation therapy. This will then slow further development and limit patient access in the future. Future research into MCS should also focus in part on customizing neurostimulation technology for this application. For example, paddle leads that were originally designed for spinal cord stimulation are often employed in MCS, even though their length and intercontact distances can make them unwieldy. Additionally, these leads have a relatively narrow strip of electrodes that makes them poorly suited to cover multiple targets on the cortex. Implanters can attempt to use multiple leads to compensate for this shortcoming, but this may result in poor control over the stimulation field and possibly interference between the leads. Additionally, using a standard four-contact paddle lead to stimulate the motor cortex, as often happens in clinical practice, is not a particularly discrete way of targeting the cortical geography, and leads that allow more precise stimulation may be desired. Leads could be designed to allow for stimulation both parallel and perpendicular to the precentral gyrus, permitting the selection of the most effective stimulation targets in individual patients. They might again reveal an adjacent or nearby primary target that is much more efficacious and robust than the motor cortex target currently employed. Further research is required to determine the optimal stimulation parameters for MCS. Research should also focus on how to overcome the apparent habituation that some patients experience during the course of their MCS therapy and to determine whether this is true habituation or, possibly, the waning of a strong placebo effect. MCS for intractable pain has clearly not been rigorously studied in a prospective fashion, and these studies must be performed. There are differing opinions in the literature regarding surgical technique, programming, and patient selection. Nonetheless, MCS appears to be a relatively safe neuromodulation procedure, and the suggestion of efficacy demands that we more aggressively pursue adequately powered prospective trials and further examine the potential mechanisms of action for this potentially effective therapy. This is especially important in that the majority of patients treated with www.neuromodulationjournal.com
MCS lack other treatment alternatives and without it might be forced to suffer profoundly for the remainder of their lives. Robert M. Levy, MD, PhD Editor-in-Chief Boca Raton, Florida Neuromodulation: Technology at the Neural Interface Editorial Office: 800 Meadows Road Boca Raton, FL 33486 Email: [email protected]
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