Introduction

The pioneer neurosurgeon Lauri Laitinen once commented that “when one sets out to make a historical survey of surgical attempts to relieve the tremor and rigor in Parkinson disease, one cannot help feeling that it would have been a far easier task to list those nervous structures which have not been attacked.”^18,19 Neurosurgical attempts to relieve intractable pain mirror his wry observation; all structures from peripheral nerve through dorsal root, spinal cord, midbrain, and thalamus to cingulate cortex have been first lesioned and later electrically stimulated or perfused with analgesics or anesthetics (Fig. 22-1). Yet chronic pain continues to present a considerable burden to society, transcending many debilitating medical diseases, including cancer, stroke, trauma, and failed surgery.²⁰ Its prevalence may be over 20%.²¹

Fig. 22-1 Structures in the pain neuromatrix targeted by ablative neurosurgery (red) and electrical stimulation or neuromodulation (blue). DBS, Deep brain stimulation; PAG, periaqueductal gray.

The concept of ameliorating persistent pain by deep brain stimulation (DBS) originates from clinical studies over half a century ago. On the basis of septal self-stimulation experiments in rodents²² and reports of analgesia in patients receiving septal DBS for psychiatric disorders,^23,24 Heath and Mickle²⁵ postulated that stimulating the same area that produced pleasure might relieve pain. They successfully reduced a patient’s cancer pain over several weeks with intermittent stimulation. The findings were replicated by a case series using improved equipment a decade later.²⁶

Further impetus for DBS was provided in the mid-1960s by the theoretical paradigm shift initiated by Melzack and Wall’s gate control theory²⁷ and advances in stimulator technology. The gate control theory was translated first into implantable peripheral nerve stimulators²⁸ and then into spinal cord stimulation (SCS),²⁹ developed by Medtronic (Minneapolis, Minn) into a commercially available permanently implantable device.^30,31

Identification of the periventricular and periaqueductal gray (PVG/PAG) regions as a target for DBS has its origins in animal research. Mayer and associates³² and Reynolds and others³³ were able to perform major surgery in awake rodents using analgesia induced by PAG stimulation alone. Pain relief by PVG/PAG DBS was first reported in patients by Richardson and Akil^34–36 and then Hosobuchi, Adams, and Linchitz.³⁷ Evidence supporting ventroposterolateral and ventroposteromedial (VPL/VPM) thalamic nuclei and adjacent structures as putative targets for DBS came from ablative surgery,^38–41 leading Hosobuchi, Adams, and Rutkin⁴² to treat anesthesia dolorosa with VPM thalamic DBS. Several others pioneered thalamic DBS, including Mazars, Merienne, and Cioloca,^43,44 Mazars,⁴⁵ Mazars, Roge, and Mazars⁴⁶ and Adams and Fields who, along with Hosobuchi,^47–49 also targeted the internal capsule. Observations from inadvertent localization errors and investigations into current spread from the PVG/PAG led others to target more medial thalamic nuclei, including the centromedian-parafascicular complex (Cm-Pf).^50–53

The rapid diffusion of electrical stimulation treatments for multifarious clinical indications by the mid-1970s led the U.S. Food and Drug Administration (FDA) to sponsor a symposium to evaluate their merits.⁵⁴ Only pain treatments were documented to be both safe and effective,^55,56 albeit in an era when the long-term complications of the then recently discovered levodopa on Parkinson disease were yet to be revealed. Crucial primate investigations elucidating basal ganglia functions and presaging a renaissance in DBS for movement disorders had also not yet been undertaken.^19,57

Despite the consensus, the U.S. Medical Device Amendments of 1976 compelled the FDA to request DBS manufacturers to conduct further studies to show the benefits of DBS for pain, and an additional ruling in 1989 required clinical trials to demonstrate safety and efficacy. Two multicenter trials were conducted, first in 1976 using the Medtronic Model 3380 electrode (196 patients) and then in 1990 with the Model 3387 (50 patients) that superseded it.⁵⁸ The two studies were an amalgam of prospective case series from participating neurosurgical centers, neither randomized nor case controlled, and both suffered from poor enrollment and high attrition. Other shortcomings included heterogeneous case mixes with underspecified patient selection criteria and subjective and unblinded assessment of patient outcomes. Confounds arose from inconsistencies in deep brain sites stimulated, numbers of electrodes used per patient, and stimulation parameters chosen. Improvements made to the later Model 3387 trial included limiting deep brain sites stimulated to two per patient and using visual analog scores (VASs) to rate pain intensity for outcome assessment; but its included cases per center were tiny, with a mean of five and median of three patients treated.

Neither trial satisfied study criteria for efficacy of at least half of patients reporting at least 50% pain relief 1 year after surgery. Therefore U.S. FDA approval for analgesic DBS was not sought by the device manufacturer. However, intriguingly, the large numbers of patients lost to follow-up resulted in a steady increase with time in the proportion of patients with at least 50% pain relief; 2 years after implantation they comprised 18 out of the 30 remaining patients (60%) followed up in the Model 3380 trial and 5 out of the 10 in the Model 3387 trial (50%). Nonetheless, the trials resulted in the U.S. FDA giving DBS for pain “off-label” status, thus precluding its approval by medical insurers.^58–60 As a consequence, few clinical investigations into DBS for pain using current technology and techniques have been reported.

In the last decade to our knowledge only five centers, three European and two Canadian, have published case series of more than six patients.^1,61–69 In contrast, both other centrally implantable neurostimulation treatments for pain, SCS and motor cortex stimulation (MCS), have continued to yield research publications, albeit mostly of uncontrolled case series,^70–75 with small randomized controlled, clinical trials in SCS emerging.^76–78 Over 1300 recipients of DBS for pain have been reported^{63,64,68,69,79,80} compared to nearly 400 patients with MCS^73,81 and nearly 4000 with SCS.^74,75

Our experience is that DBS is superior to MCS for selected refractory pain syndromes.⁸² Similarly we find DBS more appropriate than SCS for certain pain etiologies, although little published data exists comparing treatments by the same surgeon in the same group of patients. Two retrospective studies from the same group have compared all three modalities of central neurostimulation, but the results are obfuscated first by different treatments trialed both between and sequentially within patients and second by limited outcome information.^83,84 A recent review has compared the three neurostimulatory therapies but did not include all contemporary DBS case series in its analysis.⁸⁵ Over the last decade we have treated over 70 patients with analgesic DBS, regularly publishing results for many implanted and amenable to follow-up.^{1,62,65,67,68} Our experience is described, and results reviewed alongside other current studies to clarify the current status of DBS for pain.

Establishing Diagnosis and Indications/Contraindications

Historically, clinical approaches to DBS have sought to categorize patients first by cause of pain and second by dichotomizing the pain into such categories as nociceptive or deafferentation, epicritic or protopathic, peripheral or central. Such distinctions are largely unhelpful to patient selection since a gathering body of human functional neuroimaging and electrophysiological evidence confirms that chronic pain arises concomitant with centrally mediated changes related to neuronal plasticity, regardless of etiology.^86–91 Thus it can be assumed that chronic pain refractory to medical treatment is largely central pain and thus neuropathic. The challenges to patient selection for DBS then become twofold: (1) the confirmation that the patient’s pain is neuropathic and neither factitious nor psychogenic, and (2) the selection of those with neuropathic pain who are likely to derive benefit from DBS.

Essential to the patient selection process is assessment by a multidisciplinary team consisting at a minimum of a pain specialist, neuropsychologist, and neurosurgeon. Comprehensive neuropsychological evaluation provides best practice in patient selection for DBS to exclude psychoses, addiction, and medically refractory psychiatric disorders and ensure minimal cognitive impairment.^92–95 Quantitative assessment of the pain and health-related quality of life should be a requirement of the preoperative patient selection process. Our preference is to use both VAS (scale of 0 to 10) to rate pain intensity and the McGill Pain Questionnaire (MPQ) for pain evaluation,^96,97 the latter giving additional qualitative information and including a quality of life assessment. We also assess quality of life using the Short Form 36 (SF-36) and VAS part of the Euroqol five-dimensional assessment tool (EQ-5D).^98–100 The patient records his or her VAS twice daily in a pain diary over a period of 12 days. The 24 VAS scores are reviewed to ensure consistency and clarified with the patient if inconsistent. The EQ-5D, SF-36, and MPQ are administered by the pain specialist before surgery. The MPQ is repeated on a separate occasion independently by the neuropsychologist and scored using the ranked pain rating index. Our experience is that certain items of the MPQ can predict a positive response to DBS. In particular, over 80% of our patients who describe burning pain have found benefit from DBS, regardless of whether VPL/VPM, PVG/PAG or both are stimulated. We have published patient data linking resolution of burning pain with blood pressure reduction and long-term PVG/PAG DBS analgesia implicating cardiovascular changes in this type of pain³ and found heart rate variability changes consistent with sympathetic suppression and/or parasympathetic augmentation by PVG/PAG DBS¹⁰¹; but further multivariate analysis of other MPQ items, other brain targets, and other measurable cardiovascular parameters are required to elucidate further the phenomenon.

The specific etiology of the chronic pain appears less important to efficacy than its symptom history, which may involve hyperalgesia, allodynia, and hyperpathia. The pain must have a definable organic origin with the patient refractory to or poorly tolerant of pharmacological treatments. Surgical treatments may have been attempted (e.g., peripheral neuroablative or decompressive procedures for trigeminal neuralgia); however, we do not consider failure of other neurostimulatory therapies a prerequisite for DBS. Our preference is to trial DBS rather than SCS or MCS in carefully selected patients wherever the etiologies of chronic pain are consistent with neuronal reorganization at multiple levels of the central neuromatrix.

The greater body of clinical studies of SCS,^71,72 coupled with ours and others’ lack of success with DBS for spinal injuries,^63,65 favors SCS over DBS as a more appropriate first-line neurostimulatory intervention for spinal cord injury when central reorganization is likely to be mostly at a spinal level. However, our experience of DBS for pain after limb or plexor injury^65,67 encourages us to consider DBS rather than SCS as first-line treatment for complex regional pain syndromes (CRPS). A 100% success rate in 13 implanted patients to date, together with a recent paradigm shift toward central brain reorganization with autonomic dysfunction as the mechanism underlying CRPS,^102–106 supports the treatment both for brachial and lumbar plexus injuries and stump pain after amputation and for phantom limb pain.

Other pain etiologies for which we and others have obtained positive outcomes using DBS are stroke^1,2; facial and head pain, including postherpetic trigeminal neuralgia and anesthesia dolorosa^62,107; multiple sclerosis⁶³; genital pain; and malignancy.^65,68 These are listed for reference by etiology with implantation success rates shown in Fig. 22-2; however, we reiterate our position that to select patients for DBS primarily by etiology rather than by findings on history and examination and use of assessment tools is to oversimplify their chronic pain and risk poor outcomes. Rather than using inflexible selection criteria, our preference in patient selection is expert opinion after multidisciplinary assessment demonstrating quantitatively severe pain refractory to medication for at least 1 year, with significantly impaired quality of life and qualitative pain suggestive of neuropathic changes without predominantly spinal involvement. We find little merit in opiate or naloxone administration to determine suitability for DBS, although an historical literature exists.⁸⁰ Medical contraindications to DBS include uncorrectable coagulopathy obviating neurosurgery and ventriculomegaly sufficient to preclude direct electrode passage to the surgical target.

Fig. 22-2 Number of patients proceeding to full implantation by etiology at Oxford 1999 to 2008. Anes. Dol., Anesthesia dolorosa; FBSS/SCI, failed back surgery syndrome/spinal cord injury; Other, other trauma, malignancy, genital pain, multiple sclerosis.

Considering cephalalgias, we have also successfully treated cluster headache with DBS of the posterior hypothalamic nuclei and investigated it using multiple translational methods as for chronic pain.^108–110 As we review comprehensively elsewhere,¹¹¹ this debilitating condition has responded impressively to DBS in our initial experience and others’ and is worthy of multicenter, randomized controlled clinical trials. Further consideration of cluster headache is beyond the scope of this review.

Anatomy

DBS targets are contralateral to the painful side of the body. Currently used sites for DBS can be divided anatomically 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/PAG) and medial thalamic Cm-Pf nuclei. Further anatomical distinction is redundant since accuracy of DBS placement for most practitioners is limited to ±2 mm at best by magnetic resonance imaging (MRI) and computerized tomography (CT) slice thickness.

Moreover, our ultimate adjustment of intracerebral electrode position is directed by awake patient reports of somesthetic localization during intraoperative stimulation. Such subjective information may alter the final electrode site by up to several millimeters from preoperative target coordinates. A guiding principle is the established somatotopic organization of the somesthetic thalamic and PVG/PAG regions. Human microelectrode studies reveal a mediolateral somatotopy in the contralateral ventroposterior thalamus, the head of the homunculus being medial and the feet lateral.¹¹² Subjective observation of a rostrocaudally inverted sensory homunculus in contralateral PVG/PAG¹¹³ has been confirmed objectively by our human macroelectrode recordings of somatosensory evoked potentials.¹¹⁴ The PVG/PAG 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, the 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 Cm-Pf 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.

Basic Science

A wealth of electrophysiological, anatomical, and radiological evidence in humans and animals, reviewed elsewhere, establishes both PVG/PAG and ventrobasal thalamus as structures important to pain perception and the pathophysiology of chronic pain syndromes.^9,115–122 The subtleties of hierarchical position and behavioral function of individual brain structures, whether sensory-discriminative, attentional, motivational-affective, or hedonic, are much debated. However, the consensus is toward a pain neuromatrix also involving spinal cord; posterior hypothalamus; amygdala; and neocortical structure, including somatosensory, insular, anterior cingulate, and prefrontal cortex. Whether pain control is top-down or bottom-up in its hierarchy is unresolved and often depends on the experimental paradigm used. Our human electrophysiological studies of neuronal coherence have used somatosensory-evoked potentials and Granger causality predictive modeling to suggest that PVG/PAG exerts ascending modulation on VPM/VPL in a bottom-up model of pain processing,¹¹⁴ a finding that functional MRI would be unable to confirm because of insufficient temporal resolution.^9,123–125

Central to the rationale for DBS is the concept of aberrant neuronal firing at the target sites concomitant with the chronic pain. Human and animal electrophysiological experiments show increased thalamic neuronal firing in pain.¹²⁶ Comprehensive reviews of electrophysiological studies conclude that the mechanisms of analgesic stimulation are not clearly delineated.^80,127–131 From insights revealed by basal ganglia microelectrode recordings and DBS for movement disorders reviewed elsewhere,^132–134 we postulate that altered rhythmic activity in VPL/VPM and PVG/PAG neurons is likely to play an important role in the pathophysiology of central pain. At either target our clinical experience is that in general DBS at lower frequencies (≤50 Hz) is analgesic and at higher frequencies (>70 Hz) hyperalgesic,^2,135,136 supporting a dynamic model whereby synchronous oscillations in discrete neuronal populations centrally modulate chronic pain perception. Therefore analgesic DBS may either disrupt pathological high-frequency synchronous oscillations or, more likely, augment pathologically diminished low-frequency synchronous oscillations in the thalamic and reticular components of a reticulothalamocorticofugal pain neuromatrix. We have shown a positive correlation between analgesic efficacy at either DBS site and the amplitude of slow frequency (<1 Hz) VPL/VPM local field potentials (LFPs),^61,137 allowing for physiologically modulated artifact.¹³⁸ We now also have early evidence that patients off DBS have characteristically enhanced low-frequency (8 to14 Hz) power spectra of both PVG/PAG and VPL/VPM LFPs when in pain.¹³⁹ Further research is required to elucidate if such neuronal signatures could aid patient selection, in particular if combined with technical advances in noninvasive functional neuroimaging and electrophysiological techniques such as single photon emission computed tomography (SPECT) and magnetoencephalography (MEG) to characterize functional neuronal connectivity.^10,11,13

The PVG/PAG is a structure optimally sited anatomically to integrate interoceptive function, both from adjacent mesencephalic cardiovascular centers and more distal pain processing areas. Its autonomic effects have been well studied in animals,^{121,140–143} and changes noted with DBS.¹³¹ We have demonstrated a positive correlation between degree of analgesia in patients receiving PVG/PAG DBS and magnitude of blood pressure reduction³ and shown that, whereas dorsal PAG stimulation can acutely elevate blood pressure, ventral stimulation reduces it.^144,145 Such findings advance investigations for objective markers of chronic pain and also potential selection of patients who may respond best to PVG/PAG DBS. Indeed our investigations into heart rate variability changes and preliminary findings from ambulatory blood pressure monitoring that such blood pressure changes are sustained may provide objective somatic measures of efficacy that correlate to subjective rating scales.^146,147 Detailed autonomic testing using such equipment as tilt-tables, Portapres, and real-time VAS recording is underway to elucidate such possibilities.

Current thinking is that ventral PVG/PAG DBS engages analgesia commensurate with passive coping behavior, whereas dorsal PVG/PAG DBS may involve “fight or flight” analgesia with associated sympathomimetic effect.³ However, evidence to substantiate the conjecture that PVG/PAG DBS acts via augmenting endogenous opioid release is contentious. The hypothesis arose from animal experiments revealing stimulation-produced analgesia reversed by naloxone^148,149 and human studies that also showed elevated levels of cerebrospinal fluid enkephalins and endorphins with DBS.^37,150,151 However, the cerebrospinal fluid measures were artifactual,^152,153 and double-blinded investigation in humans has revealed no cross-tolerance between DBS and morphine and similar reversibility between naloxone and saline placebo,¹⁵⁴ confirming others’ findings.^52,155 Our preliminary human studies agree that naloxone and placebo effects on DBS are similar, questioning an opioid-dependent mechanism. Furthermore, naloxone and saline seem to have distinct and different effects on the low-frequency power spectra of PVG/PAG and VPL/VPM LFPs, suggesting that both opioids and contextual influences can modulate neuronal responses in the pain neuromatrix independent of DBS, in agreement with the dynamic rate model proposed previously. However, naloxone can potentiate acute withdrawal and psychosis in long-term users of opiate analgesia. Thus we advise against its administration during stereotactic neurosurgical procedures in awake patients.

An obstacle yet to be surmounted in the quest to understand the mechanisms of analgesic stimulation is the lack of adequate animal models of chronic pain.^156,157 In addition to their limited homology in chronic pain paradigms, the smaller brains of rodent and murine models increase targeting inaccuracies, in particular for small brainstem structures such as PVG/PAG. Such experience emphasizes the important opportunities presented by patient-based translational research into DBS to study the mechanisms underlying its efficacious analgesia.

Guidelines

There are no recent North American guidelines for DBS for pain because of its off-label indication in the United States. We have contributed to the European Federation of Neurological Societies’ guidelines on neurostimulation therapy for neuropathic pain, which concludes that, because of the few recent case series published, DBS should be limited to specialist centers willing to study and report their outcomes.¹⁵⁸

Imaging, Equipment, and Technique

Informed written patient consent is obtained after detailed explanations of the risks and potential benefits of the procedure and counseling for its duration of approximately 2 hours under moderate sedation and local anesthesia with the head fixed and cranial stereotaxis applied (Fig. 22-3). Our operating theatre setup is shown in Fig. 22-4. A week or more before surgery, patients have a T1 weighted MRI scan. For surgery a Cosman-Roberts-Wells (CRW) base ring is applied to the patient’s head under local anesthesia. A stereotactic CT scan is then performed, and the MRI scan is volumetrically fused to it using computerized image fusion and stereotactic planning programs to eliminate spatial distortions that arise from magnetic field effects.^159,160 The coordinates for the PVG/PAG and VPL or VPM and entry trajectory are then calculated (Fig. 22-5). A frontal trajectory avoiding the lateral ventricles is preferred. DBS targets are described in the previous anatomy section.

Fig. 22-3 Deep brain stimulation for pain caseload at Oxford during the last decade showing explantation rates. These have remained constant at 23% during the last decade.

Fig. 22-4 Theater setup. During awake stereotactic surgery a portable recording rig is used for macroelectrode local field potential (LFP) recording if required. LFPs can be recorded from each of the four contacts (0 to 3) of the deep brain electrode (inset right).

Fig. 22-5 Fused T2 weighted preoperative MRI and postoperative CT images highlighted using heat mapping (axial, coronal, and sagittal clockwise from bottom left) showing left PVG/PAG electrode placement. Three-dimensional reconstruction of electrode trajectory is shown bottom right. PVG/PAG, Periventricular and periaqueductal gray.

After a 3-cm parasagittal scalp incision and separate 2.7-mm twist drill craniotomy per electrode, both VPL/VPM and PVG/PAG have been implanted to date with Medtronic Model 3387 quadripolar electrodes. PVG/PAG is implanted first; excellent intraoperative analgesia obviates implantation of a second electrode in VPL/VPM in up to half of patients, in particular those with marked thalamic damage (e.g., following stroke). Thus most of our cohorts have received PVG/PAG or dual-target DBS (Fig. 22-6). The minority who have received VPL/VPM DBS alone have either not experienced efficacy or had side effects with a trial of PVG/PAG DBS. Final electrode position is determined by intraoperative clinical assessment reliant on subjective reporting by the awake patient; microelectrode recording is not routinely used. Bipolar 5- to 30-Hz stimulation is performed initially, pulse width 100 to 450 µs, amplitude 0.1 to 3 V. VPL/VPM stimulation aims to supplant painful sensation by pleasant paresthesia, and PVG/PAG stimulation seeks to induce a sensation of warmth or analgesia in the painful area. Adjustment is primarily somatotopic so as to evoke appropriate topographic responses, but the assessor should be alert to pyramidal signs suggesting capsular involvement with VPL/VPM DBS and with PVG/PAG DBS for oscilliopsia and reports of visual disturbances caused by superior collicular involvement or facial paresthesia arising from medial lemniscus stimulation. Each electrode is fixed to the skull by a miniplate, and its leads externalized parietally via temporary extensions. Immediately after surgery a further stereotactic CT is performed and co-registered as before to confirm electrode position. MRI may be performed after surgery during the week before implantable pulse generator (IPG) insertion for further anatomical target corroboration.

Fig. 22-6 Number of patients proceeding to full implantation by etiology. PVG/PAG, Periventricular and periaqueductal gray matter.

After a week of postoperative clinical assessment, a decision is made whether to permanently implant the electrodes in a second operation under general anesthesia. They are connected to an IPG implanted subcutaneously, usually infraclavicularly or alternatively intraabdominally in subcutaneous fascia. Medtronic Synergy or Kinetra has been used to date. Our surgical technique is detailed further elsewhere.^136,161,162

Patient Management/Evaluation

All electrodes are externalized for a week of trial stimulation. During this period the patient records VAS scores at least twice daily and is kept blinded to DBS settings. Targets are trialed individually for 1 to 2 days using the stimulator parameters described to determine which settings of quadripolar electrode contact polarities confer maximum analgesia to the optimal somatic region. Monopolar stimulation is also trialed if bipolar settings fail to give pain relief. After this period both electrodes are trialed together for 1 to 2 days. If the patient is satisfied with the degree of pain relief obtained, full implantation of the efficacious electrode(s) is performed, and DBS commenced at the optimized stimulation parameters. In general, we do not decide between permanent implantation of PVG/PAG, VPL/VPM, or dual-site stimulation on any criteria other than demonstrable efficacy in each individual patient.

Another method favored for evaluating analgesia in single cases and small groups of patients is the N-of-1 trial.^162–164 A randomized, placebo-controlled intrapatient trial is conducted whereby the patient receives pairs of treatment periods during which each intervention, be it DBS on or off or different stimulation targets or parameters, occurs once. The order of treatments is randomized, and the effects of treatment or placebo can be compared between treatment periods. We have demonstrated the validity of N-of-1 trials using the VAS, and their concordance with overall MPQ has been demonstrated for VPL/VPM, PVG/PAG, and dual-target DBS.¹⁶⁵ Blinding and randomization methodologies have also been adopted by others to investigate the efficacy of thalamic DBS.⁶⁶ However, the process is labor intensive for the clinician and thus not routinely practicable with limited clinical resources.

Patients ideally leave the hospital the day after IPG implantation and we endeavor to follow their progress with clinic appointments at 1 month, 3 months, 6 months, and annually thereafter. Initially they are given a pain diary to record their VAS and stimulator settings weekly for review at follow-up. In addition to being able to switch the DBS on and off at will, they are usually only given control over its voltage, which is typically limited by the clinician to a maximum efficacious amplitude of up to 6 V.

Outcomes Evidence

Several reviews of DBS for chronic pain have been published, many expert, some commentaries, several systematic.* Our systematic searches have identified a number of primary studies.^†

^†See reference numbers 15, 34–37, 43, 45, 50, 51, 61–66, 68, 69, 82, 95, 131, 150, 151, 154, 169, and 187–209.

Published case series of at least six patients using current DBS targets are listed in Table 22-1 and their efficacy summarized. When the same authors reviewed their clinical data more than once, only their latest or largest patient series was considered. Pain relief scores showing 50% or more improvement or verbal ratings of good or excellent after surgery were considered successful outcomes, and patients not permanently implanted included as failed outcomes. However, not all authors reported such failures, leading to overestimation of efficacy in some reports. The literature is also obfuscated by varying and often simplistic or subjective outcome measures with a paucity of double-blind, placebo-controlled studies. To our knowledge only four groups have published studies of at least six patients using current standards of target localization and currently available models of deep brain stimulators in all patients with adequate follow-up and description of outcome.^63,66,68,69 All other primary studies are based on cases first implanted more than a decade ago, some using electrodes now no longer commercially available, and some targeting the internal capsule.

The etiologies and brain targets of our 66 patient-prospective case series are summarized in Figs. 22-2 and 22-6. A fifth of all patients had failed other invasive neuromodulatory treatment, including MCS, SCS, and analgesic pump implantation. Fifty-one patients (77%) gained pain relief during the week after procedure and proceeded to full DBS implantation. Mean MPQ-ranked pain indices for the cohort before and after surgery showed significant improvement (p < 0.05) in sensory domains and overall (Fig. 22-7). Average improvements in VAS for the cohort of 80% were seen at 3 months after surgery and maintained at 35% to 43% for 4 years thereafter (Fig. 22-8). VAS scores frequently did not mirror patients’ considerable subjective improvements in function and quality of life, suggesting its limitations as an assessment tool. Other explanations include emergence of a late-tolerance phenomenon or unmasking of other types or regions of pain with restoration of patient activity.

Fig. 22-7 McGill Pain Questionnaire (MPQ) ranked pain indices before and after surgery. Significant improvements (p < 0.05) are seen in the sensory domain and overall. Misc, Miscellaneous.

Fig. 22-8 Mean visual analog scores (VASs) for the Oxford cohort. Note large error bars suggestive of individual differences and limitations of this subjective rating scale as a long-term outcome assessment. Pre, Presurgery.

In December 2008 mean efficacious DBS parameters for the entire 51-patient cohort at last clinical follow-up were frequency 18.5 Hz (range 5 to 35 Hz, SD 15 Hz), pulse width 295 µs (range 90-450 µs, SD 93 µs), and amplitude 2.5 V (range 0.5 to 5.2 V, SD 1.2 V). Sixty-seven percent of patients received bipolar stimulation. Eleven patients (22% of those implanted for at least 1 year) required IPG changes, with a mean time between changes of 25 months in this minority, the mean follow-up of the remaining 78% without IPG changes being 42 months. Mean follow-up of all patients was 55 months (range 1 month to 10 years). Five patients from the cohort died of other causes more than 1 year after their surgery. Four patients developed wound infections, one resolving with antibiotics, one requiring scalp debridement, one IPG site debridement, and one complete system removal. Four patients required DBS lead replacement, two following fall-related fractures and two because of lead tethering; one patient had lead adjustment to improve efficacy. Other complications included visual disturbances in three patients with PVG/PAG DBS and one with VPL DBS and dysarthria in one patient with PVG/PAG DBS. Detailed outcomes by etiology from our patient cohort, including quality of life outcomes, are described elsewhere with comprehensive analyses also in progress.^{1,62,65,67,68,135,165}

Risk and Complication Avoidance

Specific DBS complications accounted for are stroke (<1%), seizures (<1%), hemorrhage (0.3%), death (0.1%), and the need for IPG revision surgery every 3 to 5 years because of limited battery life and infection (3%); a small proportion of cases required complete removal of the DBS system. Although our overall complication rates are lower than these percentages (e.g., 0.05% hemorrhage; 0.02% death) and IPG changes have been required in a fifth of patients receiving DBS for pain in the last decade, it appears appropriate to quote figures from prevailing published literature.^161,210,211 Patients are also counseled for the possibility that they may derive no benefit from DBS or not tolerate it well, again necessitating its removal; no specific percentage is quoted since each case is best considered individually, but analysis of our case series suggests that explantation rates caused by poor efficacy have remained constant at 23% during a decade of experience of 66 patients with refining case selection, surgery, and postoperative parameter adjustment (see Fig. 22-4).

Conclusion

Our experience of DBS for pain over the last decade has refined our practice in several clinical aspects. It has led us to use it in preference to MCS after back-to-back trials, to continue awake surgery using patient self-reports to refine targeting; to implant PVG/PAG rather than VPM/VPL first for most patients; to actively seek burning hyperesthesia and concomitant autonomic dysfunction as good prognostic indicators for the therapy aiding patient selection; to identify certain etiologies as conferring excellent outcomes; and to refine low-frequency stimulation parameters, including cycling and stimulus breaks to optimize efficacy. We have also developed multiple translational studies using invasive and noninvasive electrophysiology, functional neuroimaging, and autonomic studies aimed not just at understanding brain function and mechanisms of pain perception but at improving selection and efficacy and reducing complications of the procedure. We see several developments coming to fruition over the next 5 years.

Patient selection remains important to success in DBS for pain with objective markers of efficacy lacking preprocedure, in contrast to movement disorders. We predict that breakthroughs will arise either from intensive study of autonomic changes with PVG/PAG DBS, leading to measurable autonomic predictors of efficacy, or from noninvasive modalities such as SPECT and MEG, which may identify patients with altered activity in target brain regions in particular tests. Such findings may lead to DBS targets being chosen on an individual patient basis to optimize success.

Advances in stimulator technology such as the development of rechargeable and demand-driven stimulators may not only obviate the need for IPG replacement and thus improve cost-effectiveness but also enable demand-driven patient controlled analgesia and potentially overcome tolerance or the unmasking of other pain with successful DBS.²¹² The characterization by LFP recording in awake patients of neural signatures for pain to which such stimulators could respond forms a firm foundation for research into smart DBS for pain.¹³⁹

LFP recording and diffusion tensor imaging are beginning to objectively characterize objective somatotopy in the PVG/PAG as has previously been described in the thalamus.^112–114 Establishment of deep brain target somatotopy gives objective support to intraoperative electrode position adjustments and can enable the development of intraoperative somatosensory-evoked potential monitoring together with microelectrode or macroelectrode recording to guide electrode positioning, in particular in the anesthetized patient.

There remain groups of patients presently refractory to thalamic or PVG/PAG DBS or whose pain (e.g., whole body pain lacking distinct somatotopy or pain after spinal cord injury) makes them poor candidates for the procedure. We have successfully implanted DBS into the anterior cingulate cortex in such patients with the rationale of reducing the emotional saliency of pain perception while not seeking to alter its nociceptive component. Such work draws on a wealth of literature and our own positive clinical experience of anterior cingulotomy for cancer pain.^213,214 We expect that anterior cingulate DBS will not only become established as a viable novel target in DBS for chronic pain but that its use and related translational investigations will yield many neuropsychological insights into emotion, attention, and executive function.

Further challenges in our DBS for pain service with its international referral patterns are poor recruitment to trials and loss of patients to follow-up. History has demonstrated the potential for unconstrained application of functional neurosurgery in psychiatric disorders; thus patients must be enrolled in formal studies and not lost to clinical follow-up.²¹⁵

An admirable feature of contemporary clinical trials is the a priori standardization of clinical outcomes by collaborative multicenter groups and inclusion of quality of life measures. As DBS for chronic pain illustrates, meta-analyses and systematic reviews become hamstrung in the conclusions that can be drawn from them if the outcome measures of the primary studies analyzed are not standardized.^{80,158,162,172} Novel evidence-based methods are being considered and adapted to factor in risks of surgery such as application of a signal-to-noise ratio of treatment effect of DBS compared to expected prognosis of the chronic pain without treatment.^162,216 Treatment effects can be inferred from well-designed case series and nonrandomized cohort studies and justified when a rapid response is seen against a stable or progressively declining disease natural history using such paradigms.

As clinical indications and clinician and patient awareness of DBS continue to increase, costs of both the technology and its implantation will decrease, making the therapy more widely available. Although it is unlikely that DBS will be as widespread and inexpensive as cardiac pacemakers, it may be comparable in cost to SCS within 5 years. A priority is to demonstrate cost-effectiveness by ensuring rigorous and evidence-based studies of DBS for pain and redressing the challenges of past failed trials. A combination of tailored evidence-based methods such as N-of-1 trials and signal-to-noise ratio calculations on intensively studied small cohorts must occur alongside the coordination of multicenter clinical trials with standardized selection, implantation, and outcome data collation protocols. Only then can DBS for pain become reestablished as a widely used therapy rather than one reserved for a select handful of experienced specialist centers willing to carefully study their patients and publish their results.

Key Issues

DBS for the treatment of chronic pain refractory to drug therapy has been undertaken for half a century, but few centers have reported contemporary findings using current technology. Its use presently remains restricted to experienced, specialist centers willing to publish results, exemplifying the many challenges to demonstrating evidence of efficacy in functional neurosurgery.

DBS for pain is typically used when all other treatment has failed or is inadequate. This context should be taken into account in evaluating outcomes. Alongside a move to multicenter clinical trials, intrapatient N-of-1 trials and signal-to-noise evidence-based methodology can be applied to DBS for pain to yield robust measures of efficacy from intensively studied case series.

Our experience over a decade of DBS for pain in 66 patients emphasizes symptomatology rather than etiology in patient selection but reveals positive outcomes after stroke and excellent outcomes for pain after amputation, plexopathies, and head and face pain, including anesthesia dolorosa and postoperative pain.

PVG/PAG and VPL/VPM remain our targets of choice in DBS for intractable pain, with PVG/PAG assessed first and anterior cingulate cortex DBS considered in refractory or selected cases.

As with other neuromodulatory therapies, DBS efficacy declines with time when measured by VAS alone, suggesting either a tolerance or unmasking phenomenon likely to be common in neuropathic pain and that may be overcome by stimulation parameter alteration or deramping.

Translational insights from invasive electrophysiology, MEG, SPECT, DTI, and autonomic testing aim to advance our understanding of DBS for intractable pain and improve patient selection, surgical targeting, and efficacy alongside advances in DBS technology such as the prospect of demand-driven “smart” stimulation.

Disclosure

The authors acknowledge financial support from the UK Medical Research Council, Wellcome Trust, Norman Collisson Foundation, Charles Wolfson Charitable Trust and Oxford Comprehensive Biomedical Research Center.