Long-term Outcomes of Deep Brain Stimulation for Neuropathic Pain
Boccard, Sandra G.J. PhD*,‡,§; Pereira, Erlick A.C. MRCS*,§; Moir, Liz RGN§; Aziz, Tipu Z. DMedSci§; Green, Alexander L. MD§
‡Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom
§Oxford Functional Neurosurgery and Experimental Neurology Group, Nuffield Departments of Clinical Neuroscience and Surgery, University of Oxford, United Kingdom
Correspondence: Sandra G.J. Boccard, PhD, Department of Neurosurgery, Level 3, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU, UK. E-mail: firstname.lastname@example.org
* These authors contributed to this manuscript equally.
Received April 16, 2012
Accepted October 19, 2012
BACKGROUND: Deep brain stimulation (DBS) to treat neuropathic pain refractory to pharmacotherapy has reported variable outcomes and has gained United Kingdom but not USA regulatory approval.
OBJECTIVE: To prospectively assess long-term efficacy of DBS for chronic neuropathic pain in a single-center case series.
METHODS: Patient reported outcome measures were collated before and after surgery, using a visual analog score, short-form 36-question quality-of-life survey, McGill pain questionnaire, and EuroQol-5D questionnaires (EQ-5D and health state).
RESULTS: One hundred ninety-seven patients were referred over 12 years, of whom 85 received DBS for various etiologies: 9 amputees, 7 brachial plexus injuries, 31 after stroke, 13 with spinal pathology, 15 with head and face pain, and 10 miscellaneous. Mean age at surgery was 52 years, and mean follow-up was 19.6 months. Contralateral DBS targeted the periventricular gray area (n = 33), the ventral posterior nuclei of the thalamus (n = 15), or both targets (n = 37). Almost 70% (69.4%) of patients retained implants 6 months after surgery. Thirty-nine of 59 (66%) of those implanted gained benefit and efficacy varied by etiology, improving outcomes in 89% after amputation and 70% after stroke. In this cohort, >30% improvements sustained in visual analog score, McGill pain questionnaire, short-form 36-question quality-of-life survey, and EuroQol-5D questionnaire were observed in 15 patients with >42 months of follow-up, with several outcome measures improving from those assessed at 1 year.
CONCLUSION: DBS for pain has long-term efficacy for select etiologies. Clinical trials retaining patients in long-term follow-up are desirable to confirm findings from prospectively assessed case series.
ABBREVIATIONS: DBS, deep brain stimulation
EQ-5D, EuroQol-5D questionnaire
IPG, implantable pulse generator
MPQ, McGill pain questionnaire
PVG, periventricular gray region
SD, standard deviation
SF-36, short-form 36-question quality-of-life survey
VAS, visual analog score
VPL, ventral posterior lateral thalamic nuclei
VPM, ventral posterior medial thalamic nuclei
Neuropathic pain was recently redefined as pain caused by a lesion or disease of the somatosensory system.1 Its symptom severity and duration are often greater than for other types of chronic pain.2 For patients experiencing neuropathic pain, neurosurgery offers several treatments.
Deep brain stimulation (DBS) is an invasive neurosurgical intervention established in movement disorders reported also to improve symptoms of epilepsy, Tourette syndrome, obsessive-compulsive disorders, depression, and cluster headache.3 The concept of relieving persistent pain by DBS is half a century old and precedes gate-control theory. After rodent self-stimulation experiments and reported analgesia in patients receiving septal DBS,4,5 malignant pain was ameliorated by intermittent stimulation by 1960.6,7 Rodent stimulation experiments suggested periventricular (PVG) and periaqueductal gray regions as DBS targets,8 findings translated to humans in the 1970s.9,10 Evidence supporting ventral posterior lateral and medial (VPL/VPM) thalamic nuclei and adjacent structures as putative targets for limb and head pain, respectively, came from ablative surgery,11 leading anesthesia dolorosa to be treated first by intermittent, then chronic thalamic DBS.12-14 Pioneers also targeted the internal capsule and more medial thalamic nuclei.15,16 Physiological coherence between PVG and VPL/VPM has also led to implantation of both structures together to synergize analgesia.17
Two multicenter trials of DBS for pain were conducted to seek US Food and Drug Administration approval, the first in 1976 by using the Medtronic model 3380 electrode (196 patients) and the second in 1990 with the model 3387 (50 patients) that superseded it.18 These trials were an amalgam of prospective case series, neither randomized nor case-controlled, suffering from poor enrollment and high attrition. Neither trial satisfied efficacy criteria of at least half of patients reporting at least 50% pain relief 1 year after surgery. US Food and Drug Administration approval was therefore not sought. However, vast loss of patients to follow-up resulted in a steady increase with time in the proportion of patients with ≥50% pain relief; 2 years after implantation they comprised 18 of the 30 remaining patients (60%) followed up in the model 3380 trial and 5 of the 10 in the model 3387 trial (50%). Nonetheless, pain was decreed “off label,” precluding approval by medical insurers. Consequently, few surgeons report DBS for pain by using current technology and techniques, and fewer regions approve it.19,20
We describe a prospective cohort study of 12-year duration evaluating the outcomes of DBS for chronic neuropathic pain from a single center. Improvements in patient-reported outcome measures of pain and quality of life are analyzed and challenges discussed, including patient selection, deep brain target choice, optimizing efficacy, and overcoming tolerance.
PATIENTS AND METHODS
Patients were referred by clinicians nationally to a single-center multidisciplinary team consisting of pain specialists, neuropsychologists, and neurosurgeons. Neuropsychological evaluation excluded psychiatric disorders and ensured minimal cognitive impairment. A definable organic origin for pain was sought, with the patient refractory to or poorly tolerant of pharmacological treatments. Surgical treatments may have been attempted. Neuropathic pain refractory to medicines for at least 2 years together with the absence of surgical contraindications such as coagulopathy or ventriculomegaly permitted application for treatment funding. Informed consent was obtained from all patients proceeding to surgery, and the study was approved by the local ethics committee.
DBS of either PVG or VPL/VPM or both targets was performed. Patients were counseled for the possibility that they may derive no benefit from DBS or not tolerate it well, necessitating its removal. The surgical technique is detailed elsewhere.21-23 For surgery, a Cosman-Roberts-Wells base ring (Radionics Inc, Burlington, Massachusetts) was applied to the patient's head under local anesthesia. A stereotactic computed tomography (CT) scan was performed with preoperative magnetic resonance imaging (MRI) volumetrically fused to it. DBS targets were contralateral to the painful side (Figure 1). Sites for DBS might be divided functionally first into somesthetic regions of the ventrobasal thalamus (VPL/VPM) and second into more medial regions surrounding the third ventricle and aqueduct of Sylvius, including the gray matter (PVG) and medial thalamic centromedian and parafascicular nuclei.
A guiding principle in awake electrode targeting is the established somatotopic organization of the somesthetic thalamic and PVG regions. Human microelectrode studies reveal a mediolateral somatotopy in the contralateral ventroposterior thalamus, the head of the homunculus being medial and the feet lateral.24 Subjective observation of a rostrocaudally inverted sensory homunculus in contralateral PVG25 has been confirmed objectively by our human macroelectrode recordings of somatosensory-evoked potentials.26
The PVG target is found at a point 2 to 3 mm lateral to the third ventricle at the level of the posterior commissure, 10 mm posterior to the midcommissural point. Its pertinent anatomical boundaries in the midbrain include the medial lemniscus laterally, superior colliculus inferoposteriorly, and the red nucleus inferoanteriorly. Sensory thalamic targets are found 10 to 13 mm posterior to the midcommissural point and from 5 mm below to 2 mm above it. The VPM is targeted for facial pain only and found midway between the lateral wall of the third ventricle and the internal capsule, the arm area of VPL is 2 to 3 mm medial to the internal capsule, and the leg area of VPL 1 to 2 mm medial to the internal capsule. The sensory thalamus is bordered by centromedian and parafascicular nuclei medially, the internal capsule laterally, the thalamic fasciculus, zona incerta, and subthalamic nucleus inferiorly, the thalamic nucleus ventralis intermedius anteriorly, and the pulvinar thalamic nucleus posteriorly.
Targets were implanted with either Medtronic model 3387 (Medtronic Inc, Minneapolis, Minnesota) quadripolar electrodes with 0.5-mm contacts 1.5 mm apart, or St Jude Medical 6143 (St Jude Medical, St Paul, Minnesota) with 1.5-mm contacts 1.5 mm apart. PVG was usually implanted first with intraoperative sensation obviating implantation of a second electrode in VPL/VPM. Final electrode position was determined by intraoperative clinical assessment reliant upon subjective reporting by the awake patient rather than microelectrode recording. Tactile stimulation of the painful body part was performed intraoperatively to augment pain and assess response if necessary.
At either target during surgery, DBS at lower frequencies (≤50 Hz) was analgesic and higher frequencies (>70 Hz) hyperalgesic. Stimulation of 5 to 50 Hz was performed initially, pulse width 200 to 450 μs, amplitude 0.5 to 5 V. VPL/VPM stimulation aimed to supplant painful sensation by pleasant paresthesias and PVG stimulation to induce a sensation of warmth or analgesia in the painful body area. Adjustment was primarily somatotopic, with the assessor alert to pyramidal signs suggesting capsular involvement with VPL/VPM, and with PVG for oscillopsia and reports of visual disturbances caused by superior collicular involvement or facial paresthesia arising from medial lemniscus stimulation. Electrode leads were externalized parietally via temporary extensions, and electrode position was confirmed by postoperative stereotactic CT fused to preoperative MRI.
After a week of postoperative clinical assessment with continuous stimulation and titration of its parameters to optimize analgesia, a decision was made whether to permanently implant the electrodes under general anesthesia. They were connected to an implantable pulse generator (IPG; Medtronic Synergy, Kinetra, Activa PC or Activa RC, or St Jude Brio) implanted in the chest or abdomen.
During postoperative assessment, each patient recorded visual analog scores (VAS) at least twice daily at set times while blinded to DBS settings. Targets were trialed individually then together for 1 to 2 days, each using the analgesic stimulation parameters to determine which electrode contacts conferred maximum analgesia. VAS were averaged for the trial week and compared with preoperative scores to assess for improvement. The decision to proceed to implantation of the IPG was made for each individual patient, guided by the multidisciplinary team.
Patients ideally left the hospital a day after IPG implantation with progress followed by clinic appointments at approximately 5 weeks, 3 months, 6 months, then yearly thereafter. Initially, they were given a pain diary to record their VAS and stimulator settings weekly for review at follow-up. Continuous stimulation rather than on-demand was encouraged, but, in addition to being able to switch the DBS on and off at will, they were usually only given control over its voltage, which was typically limited by the clinician to a maximum amplitude of 4 V.
Quantitative assessment of the pain and health-related quality of life were performed before surgery and as above. Both VAS (scale 0-10) to rate pain intensity and the McGill pain questionnaire (MPQ) were used,27 the former having anchors of “no pain” (0) and “the worst pain you can imagine” (10), and the latter giving additional qualitative information in domains of “sensory,” affective, “evaluative,” and “miscellaneous” pain severity. Patients recorded VAS twice daily in a pain diary for 14 days. The 28 VAS scores were reviewed to ensure consistency, and the mean was then calculated. MPQs were also completed before and after surgery and analyzed by using the ranked pain rating index.27
Patients completed a short-form 36-question quality-of-life (SF-36) health survey and EuroQol-5D (EQ-5D) quality-of-life questionnaire alongside the pain questionnaires. SF-36 responses were regrouped into 8 domains of physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. Results were scored by online tools.28 Norm-based scores allowed comparison between studies. SF-36 scores ranged from 0, an extreme dysfunction or symptom severity, to 100, an optimal function. The health state of patients was evaluated by EQ-5D. Its 2 sections evaluate, first, the health state in 5 dimensions (mobility, self-care, usual activities, pain, and anxiety) and, second, on a “health” VAS, with “0” being the worst state they can imagine and 100 the best. EQ-5D scores were calculated as detailed elsewhere.29
Because pain assessments were repeated measures throughout the follow-up, pre- and postoperative scores were compared for each group of patients by using a general linear mixed model, with a P value of <.05 taken as statistically significant and <.01 taken as highly significant.
One hundred ninety-seven patients with chronic neuropathic pain were prospectively evaluated for the suitability of DBS during 12 years from May 1999 to August 2011. Fifty-six (28%) were unable to secure UK National Health Service funding for the treatment, 29 (15%) declined surgery, 15 (8%) had medical contraindications to surgery, 7 (4%) were deemed psychologically unsuitable, and 3 (2%) were deemed not to be refractory to pharmacotherapy at the time of assessment. Eighty-five (43%) patients therefore proceeded to DBS.
Sixty men (71%) and 25 women (29%) had a mean age of 51.8 (standard deviation [SD] 13.3) years. Nine patients were amputees who were experiencing phantom limb or stump pain (1 arm and 8 legs, 1 bilateral leg receiving bilateral DBS), 7 had complete brachial plexus injuries without cervical nerve root avulsion, 31 experienced poststroke pain, 13 had pain after spinal damage of various causes (failed back surgery, arteriovenous malformation, syringomyelia, trauma, and transverse myelitis), 15 others had cephalgia (head and face pain of different causes including anesthesia dolorosa), and 10 had miscellaneous etiologies such as genital pain and multiple sclerosis (“Other”).
Of the 85 patients operated on, 74 (87%) felt sufficient analgesia for IPG implantation. The 11 (13%) unsuccessful etiologies were poststroke (4/31; 13%), spinal (2/15; 13%), cephalgia (1/15; 7%), and miscellaneous (4/10; 40%). Fifteen of 74 implanted patients (20%) were excluded from analysis because of insufficient data. Reasons for the loss of long-term data included subsequent dementia, emigration, refusal to attend appointments, and death from other causes (usually cardiovascular or cancer). Fifty-nine patients' long-term outcomes were therefore analyzed (Figure 2). These comprised 9 after amputation (15%), 6 brachial plexus (10%), 23 poststroke (38%), 7 after spinal damage (12%), 11 cephalgia (18%), and 3 miscellaneous (5%) (Table 1). There were no statistical differences found between baseline pain scores and etiologies.
Of the 59 patients with implanted DBS, 39 patients (66.1%) sustained a global improvement of their EQ-5D health state at follow-up (Table 2). The success of DBS varied by etiology, ranging from 50% after brachial plexus injury to 89% after amputation (Table 2). Considering this 39-patient group, demographics were similar to the overall 85-patient cohort operated on: 28 (72%) were male with a mean age at surgery of 52.1 years (SD 13.3). Mean follow-up of outcomes was 27.9 months for this subgroup. Twenty-two of 39 (56.4%) patients were followed up for 2 years or more, and 14 of 39 (38.4%) were followed up for 4 years or more.
Figure 3 and Table 3 summarize pain and quality-of-life outcomes for the 39-patient cohort. At 3 months after surgery, VAS was improved by 50.3% (SD 27.1, P < .001), SF-36 improved by 38.7% (SD 66.8, P < .02), MPQ improved by 38.1% (SD 54.7, P < .001), EQ-5D improved by 27.2% (SD 20.4, P < .001), and health state improved by 73.8% (SD 96.8, P = .001). Throughout the first year, mean pain relief remained similar (Figure 3). VAS was improved by 45.8% (SD 25.1, P < .001), SF-36 by 26.6% (SD 45.8, P < .001), MPQ by 24.1% (SD 50.6, P < .01), EQ-5D by 20.3% (SD 30.0, P < .001), and health state by 76.1% (SD 109.2, P < .001) (Table 3).
DBS efficacy varied by etiology for both pain outcomes and quality-of-life measures (Table 4). For example, excellent pain relief at 1 year after surgery was seen for cephalgia in VAS (59.4%) and SF-36 (77.6%), whereas pain after spinal pathology improved best in VAS (63.0%) and MPQ (71.1%).
Comprehensive long-term outcome measures were available for almost all patients retained in follow-up (Figure 4), and showed sustained analgesia with a moderate reduction in efficacy for some outcome measures, yet an improvement in quality of life as measured by SF-36. Four years after DBS, VAS was still improved by 36% (SD 39.2, P = .002), SF-36 by 34% (SD 34.3, P < .4), MPQ by 38.3% (SD 35.4, P < .3), EQ-5D by 20.0% (SD 40.5, P < .4), and health state by 49.6% (SD 117.0, P = 1) (Table 5).
Twenty-one patients (53.8%) received PVG stimulation only, 5 (12.8%) had stimulation of VPL/VPM, and 13 (33.3%) kept stimulation of both targets. Efficacy differences were not statistically significant. Mean stimulation parameters for PVG were 22.8 Hz (SD 11.4), 193.8 μs (SD 104.5), and 2.3 V (SD 1.1), and for VPL/VPM they were 32.7 Hz (SD 17.5), 202.1 μs (SD 103.3), and 3.0 V (SD 1.3). Twenty-five of 60 patients (42%) required IPG changes, and 11 of 60 (18%) had lead revisions, 4 after lead breakages following falls, and 7 due to loss of analgesic effect despite stimulation cycling or breaks. Other complications included 1 lead erosion requiring removal and 7 infections, 2 successfully treated by antibiotics and 5 of 74 (7%) requiring device removal.
We describe here the largest open-label, prospective study of DBS for pain published in the past 5 years, only 1 other of similar size having been published in the past 15 years, albeit with less detailed outcomes.30 The cohort presented here is significant, comprising approximately 5% of a largely historical global literature of less than 1500 reported cases.22,23,31 It also uses current DBS technologies and current standards of neuroimaging and stereotactic surgery.
We recently summarized elsewhere all published peer-reviewed clinical outcomes data in DBS for pain case series comprising at least 6 patients.22,23 Since Mazars and coworkers’, Richardson and Akil's, and Hosobuchi and Adams's pioneering studies and their long-term follow-up published in the 1970s and 1980s,9,10,32,33 only about 20 groups worldwide reported long-term efficacy in up to 83% of patients with a follow-up of up to 6 years. Just 5 centers published results in the past decade.30,31,34-36 Not all authors reported their failed trials that obviated full device implantation, however, leading to overestimation of efficacy in some reports. The literature is obfuscated by varying and simplistic outcome measures that preclude meaningful meta-analysis, such as verbal self-reports comprising only 3 or 5 categories. The latest revision of the definition of neuropathic pain also leads us to consider all patients in this study receiving DBS as having neuropathic pain.1 Here, we did not distinguish between different deep brain targets based on literature reviews suggesting their relative efficacy for neuropathic and nociceptive pain, respectively, choosing instead to frequently trial both targets during the same awake procedure if the first target tried did not have an effect.31,37
Outcomes by etiology from our patient cohort have been previously published elsewhere,22,23,38-43 in particular, by etiology to illustrate the different etiologies of chronic neuropathic pain amenable to DBS that include cranial and facial pain,39,44 poststroke pain,42 brachial plexus injury,45 and amputation pain.35,38 One criticism of this approach has been the occasional repetition of patient data serving multiple purposes in several clinical publications, making results difficult to follow.46 However, we present here a complete summary of a complete case series wherein certain previously reported trends persist, such as excellent initial efficacy in pain after amputation and stroke and sustained analgesia in cephalgia and spinal pathologies, and an overall efficacy (67%) emerges. We previously characterized the heterogeneous cephalgia subgroup by etiology and stroke subgroup by anatomy elsewhere.39,42 Our experience overall guides us, in general, toward implanting PVG first, seeking subjective reporting of pleasant warmth intraoperatively, and proceeding to VPL DBS if it cannot be obtained. For head and face pain, we target VPM first assessing for intraoperative paresthesia.
Several limitations of the study that mirror those of the 1990s Medtronic trials are apparent18: lack of randomization or case controls, poor enrollment (selection excluding patients on clinical grounds together with refusal of funding for patients despite clinical selection), and high attrition (loss to follow-up). Other shortcomings prevalent in the field of neuromodulation for chronic pain included heterogeneous case mixes with underspecified patient selection criteria and unblinded assessment of patient self-reported outcomes. Deep brain sites stimulated and stimulation parameters also varied.
An alternative to DBS is motor cortex stimulation.47 It confers analgesia in two thirds of patients, comparable in efficacy to DBS. Our experience has been that DBS is superior to motor cortex stimulation for selected refractory pain syndromes,48 and more appropriate than spinal cord stimulation for certain refractory pain etiologies in which the neuroplasticity may be predominantly cerebral rather than spinal. One group's retrospective studies have compared all 3 modalities of central neurostimulation, but the results are limited by different treatments trialed both between and sequentially within patients and by limited outcome information.49,50 Differences in efficacy between treatment modalities may reflect surgeon expertise and refinement of particular techniques.
Although the analgesic mechanisms of DBS are unknown, aberrant rhythmic activity in VPL/VPM and PVG neurons is likely to play an important role in pain pathophysiology. Patients in pain have characteristically enhanced low-frequency (8-15 Hz) power spectra of both PVG and VPL/VPM deep brain macroelectrode local field potentials.51 Further research is required to elucidate if such neuronal signatures could aid patient selection or enable smart demand-driven stimulation, in particular, if combined with technical advances in noninvasive electrophysiological techniques to characterize functional neuronal connectivity.52-54 PVG DBS also affects autonomic function.55-58 These translational investigations advance the search for biomarkers to optimize the therapy. Some debate exists over whether PVG DBS stimulates adjacent central thalamic and parafascicular nuclei alongside adjacent medial structures such as reticular thalamus.59-61 A complete discussion is beyond the scope of this outcomes article, but it raises intriguing questions about whether PVG DBS activates a more medial pain-processing pathway incorporating emotional valence or acts via more lateral somatosensory thalamic nociceptive mechanisms. We suggest that the picture is more complex and that ventral and dorsal PVG regions may contribute to distinct analgesic streams.58
Both contemporary and older case series,62 including ours, suggest that at least a quarter of patients successful during trial stimulation do not experience long-term success beyond 1 year after surgery. One reason may be the loss of patients at follow-up, making reaching statistical significance more challenging. The challenges are to identify predictors of long-term efficacy and investigate tolerance. Progressive increases of stimulus amplitude have proven unhelpful.63 Our experience is that tolerance is often overcome by subtle alterations of either pulse width, frequency, or both, or, failing that, breaks in stimulation. Importantly, the patients in the failed Medtronic trials and many other case series also received episodic cycling DBS, whereas our patients receive continuous stimulation. Nevertheless, a subgroup remains either tolerant long-term or demonstrates progressive reductions in efficacy. Hypotheses include, first, that patients genuinely become tolerant to the treatment; second, that a particular pain characteristic is reduced but others unmasked become worse over time64; and, third, that chronic pain exhibits disease progression concomitant with increasing severity despite DBS, as has been demonstrated in tremor.65 Advances in stimulator technology such as the development of demand-driven stimulators may not only reduce energy usage and IPG replacement, but also enable patient-controlled analgesia and potentially overcome aspects of tolerance.
Neuromodulation for neuropathic pain has positive experiences among physicians, high patient expectations, and positive case series, yet few randomized, controlled, clinical trials.66,67 We encourage continued trials of the therapy from our prospective case-series experience.
The authors are supported by the Norman Collisson Foundation, Oxford NIHR BRC, UK MRC, Charles Wolfson Charitable Trust and EPSRC. The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
The authors thank Dr Carlo Chiorri, PhD, Lecturer in Psychometrics at the University of Genoa, Italy (DISFOR, Department of Educational Sciences, Psychology Unit) for assistance in statistical analyses.
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An indirect way to judge the usefulness of a therapeutic modality may be the fact that, despite multiple equivocal, or even negative, clinical evidence, the modality survives and becomes more sophisticated and refined. Many readers would remember the story of extracranial-intracranial (EC-IC) bypass procedure that was expected to die off after publication of a negative large-scale study. Similarly, albeit for different reasons, in the domain of functional neurosurgery, many may recall the predicted demise of pallidotomy because of the introduction of levodopa, or the entire field of psychiatric neurosurgery owing to ethical concerns and suboptimal outcomes. None of this, however, actually happened, and just like EC-IC bypass surgery was reborn with better indications and improved surgical techniques, the pallidotomy came back and evolved into current approaches of deep brain stimulation (DBS), and even neurosurgery for psychiatric conditions survived in a few dedicated institutions and is now in the center of attention of functional neurosurgeons.
DBS for pain is yet another example of a surgical modality that was expected to disappear after publication of several very disappointing studies. And even though it became essentially forbidden from regulatory point of view in the United States, neurosurgical centers outside the United States are still using it – perhaps supporting the unique value this modality offers in otherwise intractable clinical conditions. Some of these centers, like this group from Oxford led by Prof. Aziz, not only “keep the fire burning” but also put in an effort to analyze their clinical results, refine technical nuances, and create an algorithm in patient and target selection.
The authors of this study share their 12-year experience in DBS for pain presenting the largest contemporary series of 85 operated patients. Despite heterogeneous indications, the article gives a general overview of clinical and technical results. This information may help the surgeons – and the patients – in gauging their expectations related to the procedural effectiveness and long-term outcome.
It appears that with 13% trial failure rate and 18% loss of follow-up, the documented success of this approach in terms of quality of life is not 66% (39/59) but rather 46% (39/85). More importantly, in the cohorts of cephalgia, pain of spinal origin and brachial plexus injury, the final success rate was lower (6/15 – 40%, 4/13 – 31%, and 3/7 – 43%, respectively), whereas in the group of poststroke pain, DBS produced documented improvement in more than half of the patients (16/31 – 52%) and postamputation pain and phantom limb patients had the best chances of getting better (8/9 – 89%).
In the absence of serious complications and surgical mortality, these results should definitely stimulate development of new multicenter prospective studies so the modality may be reconsidered for regulatory approval. The important questions that have to be answered are: may this single-center experience be reproduced in other institutions? Should DBS for pain be offered more frequently to those with higher chances of improvement, such as poststroke or postamputation chronic pain sufferers? Should different deep cerebral structures be selectively targeted in specific clinical situations? And finally, with the understandable reluctance of Medtronic to repeat much needed multicenter prospective study, will the other companies be interested in pursuing this important and potentially large clinical DBS indication?
Konstantin V. Slavin
The present manuscript is a timely summary of the authors’ work who have been continuing to perform thalamic deep brain stimulation (DBS) for neuropathic pain over the decades. They clearly show that also nowadays it is worthwhile to consider thalamic DBS for refractory pain. It may be concluded that thalamic DBS most likely is heavily underused, and that it has been abandoned before it reached maturity in many countries when FDA approval was not granted in the United States in the 1980s and 1990s. Thalamic stimulation for pain has still been performed, however, in few centers worldwide, mainly in Europe and in Asia.
Will this manuscript stimulate to consider a renaissance of thalamic DBS for neuropathic pain? Hopefully, it will re-direct attention and the interest to further study this underused therapeutic option and its potentials and beneficial use in more patients. Even with new drugs such as gabapentin and pregabalin many patients with neuropathic pain cannot be treated satisfactorily either because of insufficient efficacy or because of side effects.
While any pain perception ultimately must pass through thalamic relais, it is quite unclear, however, which thalamic nuclei would be the optimal targets for chronic stimulation. In particular, the periventricular grey may not be the actual site of action in electrodes which are placed medially in the thalamus. The effect of stimulation might be mediated as well via other structures in this region, in particular the centrolateral nucleus or the center median-parafascicular nucleus, while there is also interest in the ventromedial nucleus (Jeanmonod et al, 1996; Blomqvist et al, 2000; Weigel and Krauss, 2004).1-3
It will be important to have further data on the issue of thalamic DBS for neuropathic pain, also from other groups who still perform this procedure in order to shed more light on this underinvestigated topic in the future.
Joachim K. Krauss
1. Blomqvist A, Zhang ET, Craig AD. Cytoarchitectonic and immunohistochemical characterization of a specific pain and temperature relay, the posterior portion of the ventral medial nucleus, in the human thalamus. Brain. 2000;123(Pt 3):601–619. PubMed | CrossRef Cited Here... |
2. Jeanmonod D, Magnin M, Morel A. Low-threshold calcium spike bursts in the human thalamus. Common physiopathology for sensory, motor and limbic positive symptoms. Brain. 1996;119(Pt 2):363–375. PubMed | CrossRef Cited Here... |
3. Weigel R, Krauss JK. Center median-parafascicular complex and pain control: review from a neurosurgical perspective. Stereotactic Funct Neurosurg. 2004;82(2-3):115–126. PubMed | CrossRef Cited Here... |
Deep brain stimulation; Pain; Periventricular gray; Quality of life; Ventroposterolateral thalamus
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