Clinical Study Stereotact Funct Neurosurg 2015;93:199–205 DOI: 10.1159/000375177
Received: September 3, 2014 Accepted after revision: January 13, 2015 Published online: April 21, 2015
Long-Term Follow-Up of Motor Cortex Stimulation for Neuropathic Pain in 23 Patients Philipp J. Slotty a, c Wilhelm Eisner d Christopher R. Honey c Christian Wille b Jan Vesper a
a
Department of Stereotactic and Functional Neurosurgery, Medical Faculty, Heinrich Heine University, Düsseldorf, and b Neurosurgical Outpatient Department, Neuss, Germany; c Division of Neurosurgery, Department of Surgery, University of British Columbia, Vancouver, B.C., Canada; d Department of Neurosurgery, Leopold Franzens University, Innsbruck, Austria
Abstract Background: Motor cortex stimulation (MCS) is being offered to patients suffering from neuropathic pain. Outcome prediction, programming and especially sustaining a longterm treatment effect represent major challenges. We report a retrospective long-term analysis of our patients treated with MCS over a median follow-up of 39.1 months. Objectives: To investigate the time course of the treatment effect in MCS for neuropathic pain. Methods: Twenty-three closely followed patients treated with MCS were retrospectively analyzed. Reduction in pain measured on a visual analogue scale (VAS) was defined as the primary outcome parameter. VAS pain level and adverse events were documented at the 1-, 3-, 6-, 12-, 18- and 24-month follow-ups. Results: The mean VAS under best medical treatment was 7.8 (SD 1.2, range 5–9) with escalation to 9.3 (SD 0.9, range 6–10) when the patients’ medications were missed or delayed. About half of the patients (47.8%) experienced a satisfactory (>50%) reduction in pain during the first month of treatment. The best treatment results were seen at the 3-month follow-up
© 2015 S. Karger AG, Basel 1011–6125/15/0933–0199$39.50/0 E-Mail [email protected] www.karger.com/sfn
(mean VAS 4.8, SD 1.9, –37.2% compared to baseline). A decline in the treatment effect was generally observed at the subsequent follow-up assessments. Six patients had their devices explanted during the follow-up period due to loss of treatment effect. Conclusions: In this study, MCS failed to provide long-term pain control for neuropathic pain. Many aspects of MCS still remain unclear, especially the neural circuits involved and their response to long-term stimulation. Means must be developed to overcome the problems in this promising technique. © 2015 S. Karger AG, Basel
Introduction
Motor cortex stimulation (MCS) is being offered to patients suffering from different neuropathic pain disorders including atypical facial pain, trigeminal deafferentation pain, thalamic poststroke pain and peripheral neuropathic pain resistant to medical and adjuvant treatment [1–4]. Despite being under investigation for more than 20 years, no accepted treatment guidelines exist regarding patient selection, surgical technique, the use of trial stimulation or stimulation parameters. Also, no randomized multicenter trials have been published. Clinical knowlPhilipp J. Slotty, MD Gordon and Leslie Diamond Health Care Centre Vancouver General Hospital 8101-2775 Laurel Street, Vancouver, BC, V5Z 1M9 (Canada) E-Mail slotty @ hhu.de
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Key Words Neuropathic pain · Motor cortex stimulation · Neuromodulation
Table 1. Patient characteristics and course of treatment
Patient Age, No. years
Gender
Condition
Time to surgery, months
VAS prior to surgery
Length of follow-up
VAS last follow-up, cm
Explanted
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
F M F F F M F M M F F F F M M F F M F M M M M
PSP PA TDP CRPS SCI SCI PSP TDP PSP PSP PSP PSP CRPS PA PA PSP PSP PA PSP SCI PSP SCI PSP
50 80 82 104 28 24 58 83 36 42 42 37 36 108 153 19 47 10 144 40 33 176 60
6 5 8 9 8 9 9 9 7 7 6 9 6 8 6 8 9 8 9 9 7 9 7
26 32 28 35 18 24 33 22 39 27 31 25 26 58 28 38 42 106 62 52 35 65 50
6 6 7 9 10 9 8 9 7 5 3 9 7 6 5 4 6 8 3 9 7 8 7
– – – 14 – 19 – – 12 – – 14 – – – 26 39 – – 8 27 65 –
67 29 62 53 65 49 75 79 62 43 39 72 36 35 35 49 43 49 79 31 77 37 54
Comments/salvage treatment
cm/pf DBS cm/pf DBS
i.t. drug pump (morphine)
cm/pf = Centromedian/parafascicular thalamus; CRPS = complex regional pain syndrome; DBS = deep brain stimulation; F = female; i.t. = intrathecal; M = male; PA = plexus avulsion; PSP = poststroke pain; SCI = (incomplete) spinal cord injury; TDP = trigeminal deafferentation pain.
200
Stereotact Funct Neurosurg 2015;93:199–205 DOI: 10.1159/000375177
especially sustaining a long-term treatment effect represent major challenges. We report a retrospective long-term analysis of our patients treated with MCS over a median follow-up of 39.1 months.
Material and Methods Twenty-three patients treated with MCS for chronic neuropathic pain syndromes of different etiologies were retrospectively analyzed. All patients were treated at two large European tertiary care neuromodulation centers and were closely followed. Reduction in pain measured on a visual analogue scale (VAS) on each follow-up was defined as the primary outcome parameter. VAS pain level and adverse events were documented at the 1-, 3-, 6-, 12-, 18- and 24-month follow-ups. Last follow-up was defined as the last patient contact and was not necessarily the 24-month visit. Detailed data for each follow-up are given in table 1. The study protocol was approved by the institutional ethics review board (record No. 4243).
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edge of MCS therefore derives mainly from published individual cases, case series and personal experiences [5, 6]. Only 2 well-designed evidence class III studies and about 20 evidence class IV series, most of them describing MCS for facial neuropathic pain and poststroke pain, have been published. Even less data are available concerning MCS for complex region pain syndromes or injuries to the brachial plexus or spinal cord. A 50% reduction in pain severity, commonly accepted as successful treatment in neuromodulation for pain, is reported in about 45– 70% of patients depending on the condition treated. These rather low success rates have been accepted, as MCS is commonly used in patients failing multiple other treatment modalities. Loss of treatment effect over time requiring complex and repeated reprogramming is a common experience in these patients and has already been reported in early investigations of this technique [2, 4, 7, 8]. Although the surgical planning and technique are straightforward, outcome prediction, programming and
Color version available online
7
6
5
VAS last follow-up
VAS 24-month follow-up
VAS 18-month follow-up
VAS 12-month follow-up
VAS 6-month follow-up
VAS 3-month follow-up
VAS 1-month follow-up
4 VAS best medical treatment
Fig. 1. Mean pain levels measured by VAS scores at different times
of follow-up.
Twenty-three patients implanted between 2002 and 2011 were included in this study. Patients presented with a mean VAS under best medical treatment of 7.8 (SD 1.2, range 5–9) with escalation to 9.3 (SD 0.9, range 6–10) when their medications were missed or delayed. The mean duration from the causal event (e.g. stroke in patients treated for poststroke pain) to surgery was 64.8 months (SD 44.9, range 10–176), the mean follow-up was 39.1 months (SD 19.6, range 18–106), and the mean age at implantation was 53 years (range 29–79) with a gender ratio of 1.1 in favor of men. About half of the patients (47.8%) experienced a satisfactory (>50%) reduction in pain during the first month of treatment. The VAS mean dropped by 34.8% from 7.8
(SD 1.2) to 5.0 (SD 2.0) after the first month. The best treatment results were seen at the 3-month follow-up (mean VAS 4.8, SD 1.9, –37.2% compared to baseline; fig. 1). A decline in the treatment effect was generally observed at the subsequent follow-up assessments. Statistically significant differences in pain compared to baseline were present at all time points up to 18 months but not at the 24-month follow-up (fig. 2). Detailed statistics on the development of pain during the course of treatment are given in table 2. Overall, 6 patients had their devices explanted during the follow-up period due to loss of treatment effect. Two patients treated for poststroke pain (No. 1 and No. 10) reported a significant improvement of their tremor as well as pain during effective MCS. These additional beneficial effects of MCS have been previously described [10]. Three patients had a single seizure during extensive reprogramming to regain the treatment effect, but required no medication. A significant mean reduction in the pain level was observed at the last follow-up at a mean of 39 months following implantation (mean VAS 6.87, p = 0.031). At this point, 6 patients included in the analysis had their device explanted. Three of them were undergoing alternative invasive treatment (deep brain stimulation in 2 cases and intrathecal morphine in 2 case).
Long-Term Motor Cortex Stimulation Outcome
Stereotact Funct Neurosurg 2015;93:199–205 DOI: 10.1159/000375177
Results
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Surgical Methods MCS electrodes were placed epidurally using stereotactic guidance through a mini craniotomy (approximately 4 × 4 cm). Intraoperative functional localization of the motor strip was provided by somatosensory evoked potentials of the median nerve (phase reversal, N20) if available [9]. In patients suffering from complete plexus avulsion, only anatomical orientation was used. In 20 patients, two 4-contact paddle leads (Resume 3587A, Medtronic Inc., Minn., USA) were used, and in 3 cases 16-contact leads (Specify 5-6-5, Medtronic Inc., Minn., USA) were used. Electrodes were placed parallel with and covering the precentral gyrus and sutured to the external layer of the dura. Postoperatively, the final electrode position was confirmed by fusing a postoperative CT with the preoperative MRI. In all patients, unblinded trial stimulation including multiple reprogramming sessions if necessary was performed for 5–7 days. A single focal motor seizure during trial stimulation occurred in 3 patients. Patients were allowed to change stimulation intensity by themselves within predefined limits. A pain reduction of >30% was considered successful during the trial. Depending on the site and year of surgery, Itrel 2, Itrel 3 or RestoreUltra implantable neurostimulators (Medtronic Inc.) were used.
8
VAS pain level (cm)
Statistical Methods Data on patient outcome and adverse events were collected locally by the participating centers during patient interviews, and additional data were collected from medical records when required. Only patients successfully trialed and implanted with an MCS system were included in this analysis (see table 1 for demographic details). Statistical analysis was performed using IBM SPPS Statistics 19 (IBM Cooperation, USA). A Kolmogorov-Smirnov test resulted in a nongaussian distribution for VAS data; therefore, a Friedman screening test was performed followed by a Wilcoxon rank-sum test for post hoc paired intergroup comparison. If not stated otherwise, follow-up pain scores were compared with best medical treatment directly prior to surgery. The level of significance stipulated was p < 0.05 (p < 0.01 was considered highly significant).
Color version available online
10
VAS pain level (cm)
8
6
4
2
VAS last follow-up
VAS 24-month follow-up
VAS 18-month follow-up
VAS 12-month follow-up
VAS 6-month follow-up
VAS 3-month follow-up
times of follow-up, whiskers representing the minimum/maximum and the circle representing the extreme.
VAS 1-month follow-up
Fig. 2. Box plots of VAS scores at different
VAS off medication
VAS best medical treatment
0
Table 2. Course of pain control during follow-up
Follow-up, months
Remaining patients, n
Overall responders, n
Responders TDP, n
Responders PSP, n
Responders PA, n
Responders CRPS, n
Responders SCI, n
Explanted, n
1 3 6 12 18 24
23 21 21 18 15 15
11 (48) 10 (44) 8 (35) 7 (30) 6 (26) 1 (4)
2 (100) 1 (50) 1 (50) 1 (50) – –
4 (36) 4 (36) 5 (46) 4 (36) 4 (36) 1 (9)
3 (75) 2 (50) 1 (25) 1 (25) 1 (25) –
0 (0) 1 (50) – – – –
2 (50) 2 (50) 1 (25) 1 (25) 1 (25) –
– – – 1 (4) 4 (17) 5 (22)
Treatment response is defined as a 50% pain reduction measured by VAS compared to best medical treatment prior to surgery; percentages, given in parentheses, apply for the individual condition. CRPS = Complex regional pain syndrome; PA = plexus avulsion; PSP = poststroke pain; SCI = (incomplete) spinal cord injury; TDP = trigeminal deafferentation pain.
There are two main results from this analysis: (1) the best treatment results were seen at 3 months following implantation and (2) despite good initial response to MCS, the treatment effect was subsequently lost with only 1 responder at the 24-month follow-up. This study was not intended to investigate the surgical approach used or the overall efficacy of MCS but rather to share the authors’ experience regarding long-term out202
Stereotact Funct Neurosurg 2015;93:199–205 DOI: 10.1159/000375177
come. Good clinical results were observed in the early phase of stimulation, and we therefore consider the surgical technique to have been performed correctly. The loss of treatment effect after an initially good response is not uncommon and has been described by Tsubokawa et al. [1, 2] in their early papers on MCS. They reported a loss of treatment effect in 37% of patients being treated for poststroke pain over 2 years [2]. A significant risk of overestimating the positive effect of MCS exists, as most publications on this topic only Slotty/Eisner/Honey/Wille/Vesper
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Discussion
changing the electrode configuration (sometimes as easy as inversing polarity) hints at changes in the brain and its susceptibility to electrical stimulation. Scarring of the electrode has been observed and described as a common problem in long-term MCS, but scarring followed by impedance changes and changes to the shape of the electrical field would not easily be reversible by reprogramming. Effects of scarring should be easily overcome by increasing the voltage, and it is an uncommon observation that the desired stimulation voltage cannot be reached due to voltage limitations of the stimulator. More often, voltages cannot be increased to effective levels without inducing seizures, or higher voltages do not result in a regaining of the treatment effect at all. The spread of current into adjacent cortex susceptible to seizures limits the effectiveness. This effect might be overcome by antiepileptic drugs in some patients. Another effect possibly playing a role in loss of treatment benefit is the spread of current into the somatosensory cortex. Direct sensory cortex stimulation is known to induce pain at voltages much lower than the ones used in MCS. With decreasing efficacy in MCS followed by an increase in voltage to regain the treatment effect, currents might spill into the sensory cortex and actually cause pain. Continuous stimulation has been shown to result in periods of neural inhibition of increasing duration over time in a rat model by Butovas and Schwarz [22]. This effect could not be overcome by increased stimulation intensity, and high stimulation intensities might eventually facilitate habituation and loss of treatment effect. Therefore, defining the lowest effective voltage may be crucial. We believe that the effective voltage can be calculated as a percentage of the motor threshold (defined as the voltages which cause motor twitching) for an individual patient and that the motor threshold could itself be used as a surrogate parameter for adaptation. Settings at the lowest effective voltage might delay or even prevent adaption. Additionally, several psychological factors have to be taken into account. A significant placebo effect might take place and be responsible for the early success rates. Superimposed depressive disorders can influence the experience of pain and might be partly responsible for the loss of treatment effect. Patients who experienced an early reduction in pain (e.g. from VAS 8 to VAS 4) may be initially pleased with their therapy. After 2 subsequent years of constant pain, however, they may report this new level of pain as an ‘8’ because they have forgotten how severe the original pain was. Besides the inherent limitation of a retrospective study design, some additional aspects limit the explanatory
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cover a short follow-up, and reports on long-term outcome are rare. During the early course of treatment, the loss of effect can usually be overcome by intensive reprogramming, in most cases by increasing the voltage or changing the electrode configuration [11]. No detailed data on reprogramming cycles and voltages are available in the patients presented in this series, but extensive reprogramming was repeatedly performed in all patients. In the authors’ experience, ‘desperate measures’ such as stimulation holidays may restore treatment efficacy but will only delay, not prevent, the final loss of efficacy. The effectiveness of stimulation holidays in regaining treatment effect and the quite rapid loss of treatment effect observed in some patients is a strong argument against the theory that scarring around the electrode is responsible for the loss of overall efficacy. MCS is thought to inhibit thalamic sensory nuclei via corticothalamic pathways and enhance activity of neurons in the periaqueductal gray involved in pain processing and modulation [12–14]. Without doubt, this only represents two possible explanations since the electrical fields applied epidurally likely result in an activation of multiple systems and tracts yet to be identified. Changes in regional cerebral blood flow indicating an activation of other areas known to be involved in pain processing (e.g. the cingulate gyrus) have been demonstrated during active stimulation [15]. Activation of intracortical horizontal fibers and interneurons by MCS has recently also been proposed, and effects on systems involved in pain processing can be traced downstream to the spinal dorsal horn [16, 17]. These observations have not yet resulted in the construction of a global theory of the mechanism of action of MCS. The complexity is increased by the fact that some of these observations were based on functional imaging in humans, whereas others were based on microelectrode recordings in animals. Additionally, the individual neurophysiological response will most likely differ depending on the condition treated or animal model studied. Similar complexity applies to the role of neural plasticity, investigated in transcranial direct current stimulation and under discussion to additionally influence treatment efficacy in MCS [18, 19]. There are several possible explanations for the longterm loss of efficacy of MCS in our patients. Abundant cortical plasticity has been well described in patients suffering from chronic pain, and these changes might well be involved in the loss of treatment efficacy of MCS over time [20, 21]. The repeated need for reprogramming with the ability to regain efficacy by pausing stimulation and
power of this survey: (1) limited information was available on medication, disease progression, comorbidities and especially stimulation parameters, and (2) the group investigated was heterogeneous regarding their underlying condition and included some conditions rarely treated with MCS (e.g. spinal cord injury). Conversely, conditions such as atypical facial pain or trigeminal deafferentation pain, commonly reported to have a favorable response to MCS, were underrepresented in our study group. The percentage of early treatment success seen in the less frequently described indications was comparable to other conditions treated, as were long-term results. Nevertheless, the overall numbers are too small for subgroup analysis regarding differences in outcome for different conditions. MCS is frequently the only treatment option available for patients considered untreatable by standard medical means, and the problems regarding this technique have to be overcome. This most importantly requires a better understanding of the mechanism of action, of the spread of the current in the brain, the neural tissue’s reaction to long-term electrical stimulation and the influence of body position and overall level of cerebral activity on MCS. Besides this need for a better understanding of MCS indications, programming and mechanism of action, salvage therapies for nonresponders or patients suffering from loss of treatment effect have to be investigated. Deep brain stimulation and intrathecal drug pumps were used in the patients described. Cerebral or spinal lesioning (e.g. thalamotomy or trigeminal nucleotractotomy, dorsal root entry zone rhizotomy) have been successfully used in the past and might be reconsidered in these patients. These findings and the similar results recently published by Sachs et al. [23] also cast doubt on the effectiveness of trial stimulation, whether blinded or not. Short-
term response does not seem to predict long-term effectiveness and might merely be a suitable tool to determine correct electrode placement. Changes regarding pain control after stimulation adjustment usually take days to become apparent, and the anatomical and physiological changes in the temporal vicinity of surgery might influence results. Large prospective trials on MCS are complex to design, mainly due to the relatively low patient numbers, the heterogeneity of the underlying conditions, multiple variables within the conditions themselves and, as we now know, the long follow-up required to determine treatment success. Some of these clinical questions might be answered by including more patients in the analysis. Efforts are therefore being made to build a European MCS registry to collect data on these patients centrally (personal communication, 2013).
Conclusions
In this study, MCS failed to provide long-term pain control for neuropathic pain of different origins. Many aspects of MCS still remain unclear, especially the neural circuits involved and their response to long-term stimulation. The body of evidence currently supports the adaptation of the neural structures involved to be responsible for the loss of efficacy in chronic MCS. Means must be developed to overcome the problems in this promising technique. Disclosure Statement J.V., C.W. and W.E. disclose consulting fees from Medtronic. P.J.S. and C.R.H. disclose no conflict of interest. This study was not externally funded.
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Received: September 3, 2014 Accepted after revision: January 13, 2015 Published online: April 21, 2015
Long-Term Follow-Up of Motor Cortex Stimulation for Neuropathic Pain in 23 Patients Philipp J. Slotty a, c Wilhelm Eisner d Christopher R. Honey c Christian Wille b Jan Vesper a
a
Department of Stereotactic and Functional Neurosurgery, Medical Faculty, Heinrich Heine University, Düsseldorf, and b Neurosurgical Outpatient Department, Neuss, Germany; c Division of Neurosurgery, Department of Surgery, University of British Columbia, Vancouver, B.C., Canada; d Department of Neurosurgery, Leopold Franzens University, Innsbruck, Austria
Abstract Background: Motor cortex stimulation (MCS) is being offered to patients suffering from neuropathic pain. Outcome prediction, programming and especially sustaining a longterm treatment effect represent major challenges. We report a retrospective long-term analysis of our patients treated with MCS over a median follow-up of 39.1 months. Objectives: To investigate the time course of the treatment effect in MCS for neuropathic pain. Methods: Twenty-three closely followed patients treated with MCS were retrospectively analyzed. Reduction in pain measured on a visual analogue scale (VAS) was defined as the primary outcome parameter. VAS pain level and adverse events were documented at the 1-, 3-, 6-, 12-, 18- and 24-month follow-ups. Results: The mean VAS under best medical treatment was 7.8 (SD 1.2, range 5–9) with escalation to 9.3 (SD 0.9, range 6–10) when the patients’ medications were missed or delayed. About half of the patients (47.8%) experienced a satisfactory (>50%) reduction in pain during the first month of treatment. The best treatment results were seen at the 3-month follow-up
© 2015 S. Karger AG, Basel 1011–6125/15/0933–0199$39.50/0 E-Mail [email protected] www.karger.com/sfn
(mean VAS 4.8, SD 1.9, –37.2% compared to baseline). A decline in the treatment effect was generally observed at the subsequent follow-up assessments. Six patients had their devices explanted during the follow-up period due to loss of treatment effect. Conclusions: In this study, MCS failed to provide long-term pain control for neuropathic pain. Many aspects of MCS still remain unclear, especially the neural circuits involved and their response to long-term stimulation. Means must be developed to overcome the problems in this promising technique. © 2015 S. Karger AG, Basel
Introduction
Motor cortex stimulation (MCS) is being offered to patients suffering from different neuropathic pain disorders including atypical facial pain, trigeminal deafferentation pain, thalamic poststroke pain and peripheral neuropathic pain resistant to medical and adjuvant treatment [1–4]. Despite being under investigation for more than 20 years, no accepted treatment guidelines exist regarding patient selection, surgical technique, the use of trial stimulation or stimulation parameters. Also, no randomized multicenter trials have been published. Clinical knowlPhilipp J. Slotty, MD Gordon and Leslie Diamond Health Care Centre Vancouver General Hospital 8101-2775 Laurel Street, Vancouver, BC, V5Z 1M9 (Canada) E-Mail slotty @ hhu.de
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Key Words Neuropathic pain · Motor cortex stimulation · Neuromodulation
Table 1. Patient characteristics and course of treatment
Patient Age, No. years
Gender
Condition
Time to surgery, months
VAS prior to surgery
Length of follow-up
VAS last follow-up, cm
Explanted
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
F M F F F M F M M F F F F M M F F M F M M M M
PSP PA TDP CRPS SCI SCI PSP TDP PSP PSP PSP PSP CRPS PA PA PSP PSP PA PSP SCI PSP SCI PSP
50 80 82 104 28 24 58 83 36 42 42 37 36 108 153 19 47 10 144 40 33 176 60
6 5 8 9 8 9 9 9 7 7 6 9 6 8 6 8 9 8 9 9 7 9 7
26 32 28 35 18 24 33 22 39 27 31 25 26 58 28 38 42 106 62 52 35 65 50
6 6 7 9 10 9 8 9 7 5 3 9 7 6 5 4 6 8 3 9 7 8 7
– – – 14 – 19 – – 12 – – 14 – – – 26 39 – – 8 27 65 –
67 29 62 53 65 49 75 79 62 43 39 72 36 35 35 49 43 49 79 31 77 37 54
Comments/salvage treatment
cm/pf DBS cm/pf DBS
i.t. drug pump (morphine)
cm/pf = Centromedian/parafascicular thalamus; CRPS = complex regional pain syndrome; DBS = deep brain stimulation; F = female; i.t. = intrathecal; M = male; PA = plexus avulsion; PSP = poststroke pain; SCI = (incomplete) spinal cord injury; TDP = trigeminal deafferentation pain.
200
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especially sustaining a long-term treatment effect represent major challenges. We report a retrospective long-term analysis of our patients treated with MCS over a median follow-up of 39.1 months.
Material and Methods Twenty-three patients treated with MCS for chronic neuropathic pain syndromes of different etiologies were retrospectively analyzed. All patients were treated at two large European tertiary care neuromodulation centers and were closely followed. Reduction in pain measured on a visual analogue scale (VAS) on each follow-up was defined as the primary outcome parameter. VAS pain level and adverse events were documented at the 1-, 3-, 6-, 12-, 18- and 24-month follow-ups. Last follow-up was defined as the last patient contact and was not necessarily the 24-month visit. Detailed data for each follow-up are given in table 1. The study protocol was approved by the institutional ethics review board (record No. 4243).
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edge of MCS therefore derives mainly from published individual cases, case series and personal experiences [5, 6]. Only 2 well-designed evidence class III studies and about 20 evidence class IV series, most of them describing MCS for facial neuropathic pain and poststroke pain, have been published. Even less data are available concerning MCS for complex region pain syndromes or injuries to the brachial plexus or spinal cord. A 50% reduction in pain severity, commonly accepted as successful treatment in neuromodulation for pain, is reported in about 45– 70% of patients depending on the condition treated. These rather low success rates have been accepted, as MCS is commonly used in patients failing multiple other treatment modalities. Loss of treatment effect over time requiring complex and repeated reprogramming is a common experience in these patients and has already been reported in early investigations of this technique [2, 4, 7, 8]. Although the surgical planning and technique are straightforward, outcome prediction, programming and
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6
5
VAS last follow-up
VAS 24-month follow-up
VAS 18-month follow-up
VAS 12-month follow-up
VAS 6-month follow-up
VAS 3-month follow-up
VAS 1-month follow-up
4 VAS best medical treatment
Fig. 1. Mean pain levels measured by VAS scores at different times
of follow-up.
Twenty-three patients implanted between 2002 and 2011 were included in this study. Patients presented with a mean VAS under best medical treatment of 7.8 (SD 1.2, range 5–9) with escalation to 9.3 (SD 0.9, range 6–10) when their medications were missed or delayed. The mean duration from the causal event (e.g. stroke in patients treated for poststroke pain) to surgery was 64.8 months (SD 44.9, range 10–176), the mean follow-up was 39.1 months (SD 19.6, range 18–106), and the mean age at implantation was 53 years (range 29–79) with a gender ratio of 1.1 in favor of men. About half of the patients (47.8%) experienced a satisfactory (>50%) reduction in pain during the first month of treatment. The VAS mean dropped by 34.8% from 7.8
(SD 1.2) to 5.0 (SD 2.0) after the first month. The best treatment results were seen at the 3-month follow-up (mean VAS 4.8, SD 1.9, –37.2% compared to baseline; fig. 1). A decline in the treatment effect was generally observed at the subsequent follow-up assessments. Statistically significant differences in pain compared to baseline were present at all time points up to 18 months but not at the 24-month follow-up (fig. 2). Detailed statistics on the development of pain during the course of treatment are given in table 2. Overall, 6 patients had their devices explanted during the follow-up period due to loss of treatment effect. Two patients treated for poststroke pain (No. 1 and No. 10) reported a significant improvement of their tremor as well as pain during effective MCS. These additional beneficial effects of MCS have been previously described [10]. Three patients had a single seizure during extensive reprogramming to regain the treatment effect, but required no medication. A significant mean reduction in the pain level was observed at the last follow-up at a mean of 39 months following implantation (mean VAS 6.87, p = 0.031). At this point, 6 patients included in the analysis had their device explanted. Three of them were undergoing alternative invasive treatment (deep brain stimulation in 2 cases and intrathecal morphine in 2 case).
Long-Term Motor Cortex Stimulation Outcome
Stereotact Funct Neurosurg 2015;93:199–205 DOI: 10.1159/000375177
Results
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Surgical Methods MCS electrodes were placed epidurally using stereotactic guidance through a mini craniotomy (approximately 4 × 4 cm). Intraoperative functional localization of the motor strip was provided by somatosensory evoked potentials of the median nerve (phase reversal, N20) if available [9]. In patients suffering from complete plexus avulsion, only anatomical orientation was used. In 20 patients, two 4-contact paddle leads (Resume 3587A, Medtronic Inc., Minn., USA) were used, and in 3 cases 16-contact leads (Specify 5-6-5, Medtronic Inc., Minn., USA) were used. Electrodes were placed parallel with and covering the precentral gyrus and sutured to the external layer of the dura. Postoperatively, the final electrode position was confirmed by fusing a postoperative CT with the preoperative MRI. In all patients, unblinded trial stimulation including multiple reprogramming sessions if necessary was performed for 5–7 days. A single focal motor seizure during trial stimulation occurred in 3 patients. Patients were allowed to change stimulation intensity by themselves within predefined limits. A pain reduction of >30% was considered successful during the trial. Depending on the site and year of surgery, Itrel 2, Itrel 3 or RestoreUltra implantable neurostimulators (Medtronic Inc.) were used.
8
VAS pain level (cm)
Statistical Methods Data on patient outcome and adverse events were collected locally by the participating centers during patient interviews, and additional data were collected from medical records when required. Only patients successfully trialed and implanted with an MCS system were included in this analysis (see table 1 for demographic details). Statistical analysis was performed using IBM SPPS Statistics 19 (IBM Cooperation, USA). A Kolmogorov-Smirnov test resulted in a nongaussian distribution for VAS data; therefore, a Friedman screening test was performed followed by a Wilcoxon rank-sum test for post hoc paired intergroup comparison. If not stated otherwise, follow-up pain scores were compared with best medical treatment directly prior to surgery. The level of significance stipulated was p < 0.05 (p < 0.01 was considered highly significant).
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VAS pain level (cm)
8
6
4
2
VAS last follow-up
VAS 24-month follow-up
VAS 18-month follow-up
VAS 12-month follow-up
VAS 6-month follow-up
VAS 3-month follow-up
times of follow-up, whiskers representing the minimum/maximum and the circle representing the extreme.
VAS 1-month follow-up
Fig. 2. Box plots of VAS scores at different
VAS off medication
VAS best medical treatment
0
Table 2. Course of pain control during follow-up
Follow-up, months
Remaining patients, n
Overall responders, n
Responders TDP, n
Responders PSP, n
Responders PA, n
Responders CRPS, n
Responders SCI, n
Explanted, n
1 3 6 12 18 24
23 21 21 18 15 15
11 (48) 10 (44) 8 (35) 7 (30) 6 (26) 1 (4)
2 (100) 1 (50) 1 (50) 1 (50) – –
4 (36) 4 (36) 5 (46) 4 (36) 4 (36) 1 (9)
3 (75) 2 (50) 1 (25) 1 (25) 1 (25) –
0 (0) 1 (50) – – – –
2 (50) 2 (50) 1 (25) 1 (25) 1 (25) –
– – – 1 (4) 4 (17) 5 (22)
Treatment response is defined as a 50% pain reduction measured by VAS compared to best medical treatment prior to surgery; percentages, given in parentheses, apply for the individual condition. CRPS = Complex regional pain syndrome; PA = plexus avulsion; PSP = poststroke pain; SCI = (incomplete) spinal cord injury; TDP = trigeminal deafferentation pain.
There are two main results from this analysis: (1) the best treatment results were seen at 3 months following implantation and (2) despite good initial response to MCS, the treatment effect was subsequently lost with only 1 responder at the 24-month follow-up. This study was not intended to investigate the surgical approach used or the overall efficacy of MCS but rather to share the authors’ experience regarding long-term out202
Stereotact Funct Neurosurg 2015;93:199–205 DOI: 10.1159/000375177
come. Good clinical results were observed in the early phase of stimulation, and we therefore consider the surgical technique to have been performed correctly. The loss of treatment effect after an initially good response is not uncommon and has been described by Tsubokawa et al. [1, 2] in their early papers on MCS. They reported a loss of treatment effect in 37% of patients being treated for poststroke pain over 2 years [2]. A significant risk of overestimating the positive effect of MCS exists, as most publications on this topic only Slotty/Eisner/Honey/Wille/Vesper
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Discussion
changing the electrode configuration (sometimes as easy as inversing polarity) hints at changes in the brain and its susceptibility to electrical stimulation. Scarring of the electrode has been observed and described as a common problem in long-term MCS, but scarring followed by impedance changes and changes to the shape of the electrical field would not easily be reversible by reprogramming. Effects of scarring should be easily overcome by increasing the voltage, and it is an uncommon observation that the desired stimulation voltage cannot be reached due to voltage limitations of the stimulator. More often, voltages cannot be increased to effective levels without inducing seizures, or higher voltages do not result in a regaining of the treatment effect at all. The spread of current into adjacent cortex susceptible to seizures limits the effectiveness. This effect might be overcome by antiepileptic drugs in some patients. Another effect possibly playing a role in loss of treatment benefit is the spread of current into the somatosensory cortex. Direct sensory cortex stimulation is known to induce pain at voltages much lower than the ones used in MCS. With decreasing efficacy in MCS followed by an increase in voltage to regain the treatment effect, currents might spill into the sensory cortex and actually cause pain. Continuous stimulation has been shown to result in periods of neural inhibition of increasing duration over time in a rat model by Butovas and Schwarz [22]. This effect could not be overcome by increased stimulation intensity, and high stimulation intensities might eventually facilitate habituation and loss of treatment effect. Therefore, defining the lowest effective voltage may be crucial. We believe that the effective voltage can be calculated as a percentage of the motor threshold (defined as the voltages which cause motor twitching) for an individual patient and that the motor threshold could itself be used as a surrogate parameter for adaptation. Settings at the lowest effective voltage might delay or even prevent adaption. Additionally, several psychological factors have to be taken into account. A significant placebo effect might take place and be responsible for the early success rates. Superimposed depressive disorders can influence the experience of pain and might be partly responsible for the loss of treatment effect. Patients who experienced an early reduction in pain (e.g. from VAS 8 to VAS 4) may be initially pleased with their therapy. After 2 subsequent years of constant pain, however, they may report this new level of pain as an ‘8’ because they have forgotten how severe the original pain was. Besides the inherent limitation of a retrospective study design, some additional aspects limit the explanatory
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cover a short follow-up, and reports on long-term outcome are rare. During the early course of treatment, the loss of effect can usually be overcome by intensive reprogramming, in most cases by increasing the voltage or changing the electrode configuration [11]. No detailed data on reprogramming cycles and voltages are available in the patients presented in this series, but extensive reprogramming was repeatedly performed in all patients. In the authors’ experience, ‘desperate measures’ such as stimulation holidays may restore treatment efficacy but will only delay, not prevent, the final loss of efficacy. The effectiveness of stimulation holidays in regaining treatment effect and the quite rapid loss of treatment effect observed in some patients is a strong argument against the theory that scarring around the electrode is responsible for the loss of overall efficacy. MCS is thought to inhibit thalamic sensory nuclei via corticothalamic pathways and enhance activity of neurons in the periaqueductal gray involved in pain processing and modulation [12–14]. Without doubt, this only represents two possible explanations since the electrical fields applied epidurally likely result in an activation of multiple systems and tracts yet to be identified. Changes in regional cerebral blood flow indicating an activation of other areas known to be involved in pain processing (e.g. the cingulate gyrus) have been demonstrated during active stimulation [15]. Activation of intracortical horizontal fibers and interneurons by MCS has recently also been proposed, and effects on systems involved in pain processing can be traced downstream to the spinal dorsal horn [16, 17]. These observations have not yet resulted in the construction of a global theory of the mechanism of action of MCS. The complexity is increased by the fact that some of these observations were based on functional imaging in humans, whereas others were based on microelectrode recordings in animals. Additionally, the individual neurophysiological response will most likely differ depending on the condition treated or animal model studied. Similar complexity applies to the role of neural plasticity, investigated in transcranial direct current stimulation and under discussion to additionally influence treatment efficacy in MCS [18, 19]. There are several possible explanations for the longterm loss of efficacy of MCS in our patients. Abundant cortical plasticity has been well described in patients suffering from chronic pain, and these changes might well be involved in the loss of treatment efficacy of MCS over time [20, 21]. The repeated need for reprogramming with the ability to regain efficacy by pausing stimulation and
power of this survey: (1) limited information was available on medication, disease progression, comorbidities and especially stimulation parameters, and (2) the group investigated was heterogeneous regarding their underlying condition and included some conditions rarely treated with MCS (e.g. spinal cord injury). Conversely, conditions such as atypical facial pain or trigeminal deafferentation pain, commonly reported to have a favorable response to MCS, were underrepresented in our study group. The percentage of early treatment success seen in the less frequently described indications was comparable to other conditions treated, as were long-term results. Nevertheless, the overall numbers are too small for subgroup analysis regarding differences in outcome for different conditions. MCS is frequently the only treatment option available for patients considered untreatable by standard medical means, and the problems regarding this technique have to be overcome. This most importantly requires a better understanding of the mechanism of action, of the spread of the current in the brain, the neural tissue’s reaction to long-term electrical stimulation and the influence of body position and overall level of cerebral activity on MCS. Besides this need for a better understanding of MCS indications, programming and mechanism of action, salvage therapies for nonresponders or patients suffering from loss of treatment effect have to be investigated. Deep brain stimulation and intrathecal drug pumps were used in the patients described. Cerebral or spinal lesioning (e.g. thalamotomy or trigeminal nucleotractotomy, dorsal root entry zone rhizotomy) have been successfully used in the past and might be reconsidered in these patients. These findings and the similar results recently published by Sachs et al. [23] also cast doubt on the effectiveness of trial stimulation, whether blinded or not. Short-
term response does not seem to predict long-term effectiveness and might merely be a suitable tool to determine correct electrode placement. Changes regarding pain control after stimulation adjustment usually take days to become apparent, and the anatomical and physiological changes in the temporal vicinity of surgery might influence results. Large prospective trials on MCS are complex to design, mainly due to the relatively low patient numbers, the heterogeneity of the underlying conditions, multiple variables within the conditions themselves and, as we now know, the long follow-up required to determine treatment success. Some of these clinical questions might be answered by including more patients in the analysis. Efforts are therefore being made to build a European MCS registry to collect data on these patients centrally (personal communication, 2013).
Conclusions
In this study, MCS failed to provide long-term pain control for neuropathic pain of different origins. Many aspects of MCS still remain unclear, especially the neural circuits involved and their response to long-term stimulation. The body of evidence currently supports the adaptation of the neural structures involved to be responsible for the loss of efficacy in chronic MCS. Means must be developed to overcome the problems in this promising technique. Disclosure Statement J.V., C.W. and W.E. disclose consulting fees from Medtronic. P.J.S. and C.R.H. disclose no conflict of interest. This study was not externally funded.
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