Neurosurgical Approaches to Pain Management

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Neurosurgical Approaches to Pain Management Ahmed M. Raslan | Kim J. Burchiel

Neurosurgeons have a long history of surgically treating pain, particularly cancer pain. The notion that sectioning pain pathways could achieve pain control was first introduced by Spiller and Martin in 1912.1 This was followed by the development of a whole array of surgical procedures aimed at interrupting ascending pain signals throughout different parts of the central nervous system. Two approaches are used when targeting the brain or spinal cord to treat pain. The first, a nondestructive approach, uses either electrical stimulation of brain targets, which is thought to modulate the process of pain perception, or pharmacologic agents, which are introduced into the ventricular or intrathecal spaces to target pain-modulating receptors. Targets for electrical stimulation include the peripheral nerves, spinal cord, thalamic nuclei, periventricular gray (PVG) matter, periaqueductal gray (PAG) matter, and motor cortex. Currently, the pharmacologic agent of choice for intrathecal or intracerebroventricular (ICV) injection is morphine or other opiates. In general, nondestructive procedures are used for non–malignant-type pain; however, intrathecal opioids are also used for the treatment of cancer pain. The second, a destructive approach, is used with the goal of interrupting signals that lead to perception of pain at various levels. Neuroablation can be performed on cellular complexes, such as nuclei or gyri, or on tracts with the aim of either disrupting the ascending sensory signals or destroying the limbic pathways involved in the emotional processes associated with pain. Neurosurgical procedures for pain can be performed at the level of the nerve, spinal cord, brainstem, or cerebrum and are considered ablative or neuromodulatory. Spinal cord neuromodulatory procedures fall into two subcategories: electrical and pharmacologic. These procedures are performed by anesthesiologists and neurosurgeons and are discussed elsewhere in this textbook. We present three broad categories of neurosurgical procedures for pain: (1) cerebral neuroablation (e.g., dorsomedial thalamotomy and the caudalis dorsal root entry zone [DREZ] procedure), (2) spinal neuroablation (e.g., cordotomy, extralemniscal myelotomy, and trigeminal tractotomy), and (3) cerebral neuromodulation (electric: motor cortex stimulation [MCS] and deep brain stimulation [DBS]; and pharmacologic: ICV opioids).

are more than what could be considered of purely historical significance.

MEDIAL THALAMOTOMY Stereotactic thalamic neuroablative surgery for pain is relatively safe with respect to deep brainstem structures, and because of the wide involvement of many thalamic nuclei in pain processing, it has been considered a part of the pain surgery armamentarium.2 The first structure targeted for neuroablation was the ventral caudal (Vc) nucleus, as defined by Hassler3; however, it was soon recognized that neuroablation of the Vc nucleus was associated with significant deafferentation pain phenomena. The work of Mark and colleagues led to the belief that targeting the medial thalamic nuclei was more effective in managing pain.4 Nuclear targets for neuroablative medial thalamotomy are (1) the centralis lateralis, (2) centrum medianum, and (3) parafascicularis. Several pain syndromes, including cancer pain, central and peripheral deafferentation pain, spinal cord injury, malignancy, arthritis, and the neurogenic pains associated with Parkinson’s disease,5 have been successfully treated by medial thalamotomy. Frank and coauthors reported the overall success rate of medial thalamotomy to be 52%,6 with cancer pain being the main condition treated. Jeanmonod and coworkers7 and Young and colleagues8 used radiofrequency and Gamma Knife treatment, respectively, and reported a 60% success rate in achieving pain control. The ideal target lying between the three main medial thalamic nuclei (listed above) has yet to be determined, although the centrum medianum nucleus is the most frequently targeted. DBS of the medial nuclei does not usually produce a conscious sensory response, and lesioning does not induce sensory loss. The published literature on medial thalamotomy is inconsistent regarding the target, guidance technique, patient population, and lesioning method used. Therefore, the actual success rate of medial thalamotomy is difficult to assess. However, in general, the procedure is considered to be effective in treating nociceptive pain, with recent data pointing to some success in relieving neuropathic pain.

STEREOTACTIC CINGULOTOMY CEREBRAL NEUROABLATION Historically, many procedures fall into this category, includin­ g mesencephalotomy, pontine tractotomy, and hypophysectomy. We focus on procedures that we believe

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Cingulotomy refers to stereotactic lesioning of the anterior cingulate gyrus. Le Beau performed the first open cingulectomy to treat intractable pain in 1954.9 It is believed that cingulotomy causes relief by altering a patient’s emotional reaction to painful stimuli through interruption of the

CHAPTER 22 — NEUROSURGICAL APPROACHES TO PAIN MANAGEMENT Cerebral Neuromodulation

Cerebral Neuroablation

Deep brain stimulation

Medial thalamotomy

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Spinal Neuroablation Myelotomy

Trigeminal nucleotomy-tractotomy

Motor cortex stimulation

Cingulotomy

Cordotomy

Intraventricular opioids

DREZ

Caudalis DREZ

Not illustrated: Hypophysectomy mesencephalotomy

Hypothalamotomy pontine tractotomy

Papez circuit10 and increasing tolerance to the subjective and emotional feelings of pain.11,12 Cingulotomy is performed with standard stereotactic protocols, usually under general anesthesia. Bilateral lesions are made in the anterior aspect of the cingulate gyrus, and success of the procedure is directly related to the extent of ablation of the cingulum (Fig. 22.1).1 A suitable stereotactic cingulotomy candidate is a terminally ill patient with widespread metastatic disease that has extended to the musculoskeletal system, where intrathecal or intraventricular administration of opiates is difficult. Emotional factors associated with pain would favor selection of a stereotactic cingulotomy procedure. Of note, stereotactic cingulotomy has been used to treat nonmalignant pain with a success rate of approximately 25%.13 Stereotactic cingulotomy involves the ablation of sufficient anterior cingulate gyrus volume, which is usually achieved by producing at least two lesions with a wide–surface area, noninsulated tip electrode. The procedure is generally safe with few and minor side effects. Pillay and Hassenbusch reported on a series of 12 patients in which 7 had satisfactory pain relief.14 Cingulotomy is rarely used today, mainly because of its narrow indication, advances in the medical management of terminal cancer patients, and the widespread use of neuroaugmentive procedures.

CAUDALIS DORSAL ROOT ENTRY ZONE (BRAINSTEM LEVEL) Following the introduction of stereotaxis in the 1960s, the use of open ablative brain and brainstem surgery was almost

Figure 22.1  Diagrammatic representation of cerebral neuromodulation and neuroablation procedures and spinal neuroablation procedures. DREZ, dorsal root entry zone. (Adapted with permission from © Springer-Verlag 2007, Raslan AM, McCartney S, Burchiel KJ. Management of chronic severe pain: cerebral neuromodulatory and neuroablative approaches. Acta Neurochir Suppl. 2007;97:17-26; and Raslan AM, McCartney S, Burchiel KJ. Management of chronic severe pain: spinal neuromodulatory and neuroablative approaches. Acta Neurochir Suppl. 2007;97:33-41. With kind permission from Springer Science and Business Media.)

abandoned. Siqueira first reported performance of the caudalis DREZ procedure in two patients.15 Gorecki, Nashold, and colleagues at Duke University16,17 later adopted the technique and expanded its indications. In the caudalis DREZ procedure, the caudal portion of the spinal trigeminal nucleus, along with the overlying trigeminal tract, is destroyed. Similar to spinal DREZ surgery, the objective is to destroy the cells of second-order neurons thought to be hyperactive in trigeminal deafferentation pain, thereby achieving pain relief (see Fig. 22.1). The main indications for the caudalis DREZ procedure are ophthalmic postherpetic neuralgia and trigeminal anesthesia dolorosa. In cases of neuropathic facial pain in which all other medical and surgical modalities are ineffective, the caudalis DREZ procedure may represent a last resort. The procedure is rarely performed, and potential risks include ipsilateral limb ataxia and weakness.

SPINAL NEUROABLATION The first report of surgical disruption of spinal pain pathways was presented by Spiller and Martin in 1912.1 They sectioned the anterolateral quadrant of the spinal cord with the intention of interrupting transmission of pain signals via the spinothalamic tract (anterolateral system) and relieving pain on the contralateral side of the body, caudal to the lesion.1 Several decades ago, open surgical sectioning of the spinothalamic tract (anterolateral cordotomy) to control pain

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was a common procedure in many neurosurgical centers. The procedure was used mainly to treat somatic nociceptive pain, usually from cancer. However, factors such as the debilitated state of cancer patients resulting in poor tolerance of open spinal cord surgery, together with high complication rates, meant that the procedure was not an ideal solution to the problem of cancer pain. Currently, spinal cord targets for destructive procedures to treat pain include (1) the spinothalamic tract (anterolateral column), where destruction can alleviate somatic nociceptive pain below the level of the neck (e.g., anterolateral cordotomy); (2) trigeminal spinal nucleus, which is disrupted to treat trigeminal neuropathic pain (e.g., trigeminal tractotomynucleotomy [“caudalis DREZ”]); (3) midline ascending polysynaptic visceral pain pathway, which is used to treat visceral pain, particularly pelvic pain (i.e., midline myelotomy); and (4) the DREZ, primarily to treat deafferentation pain in the upper extremity (i.e., DREZ procedure) (see Fig. 22.1). The role of each of these procedures in contemporary surgical pain management will be reviewed.

ANTEROLATERAL CORDOTOMY Anterolateral cordotomy refers to lesioning, sectioning, or other disruption of the lateral spinothalamic tract (LST), which is located in the anterolateral quadrant of the spinal cord. The procedure was historically performed in the upper thoracic spine via an open posterior approach and, less commonly, high in the cervical spine.18 The spinal cord anterolateral ascending pain transmission system carries information about pain and temperature from one side of the body. The tract is formed by the central processes of nociceptive neurons in the dorsal horn that cross the spinal cord in the anterior commissure, ascend in the anterolateral column to the brainstem, and relay in the thalamus. Lesions of the anterolateral tract produce a contralateral deficit in pain and temperature sensation two to five segments below the level of the cordotomy. Fibers in the LST have a somatotopic arrangement, with the sacral segments arranged posterolaterally and the cervical segments anteromedially.19 The corticospinal (pyramidal) tract lies posterior to the LST with white matter in between. The ventral spinocerebellar tract overlies the LST, and a lesion that damages the spinocerebellar tract may cause ipsilateral ataxia of the arm. Autonomic pathways for vasomotor and genitourinary control and reticulospinal fibers that subserve ipsilateral automatic respiration are also part of the anterolateral quadrant of the spinal cord. A patient with hemibody somatic cancer pain localized caudal to the cervical and upper thoracic area represents the best candidate for a cordotomy procedure.20 From the beginning of the 20th century until the late 1960s to early 1970s, cordotomy was an open procedure undertaken at the mid to high thoracic levels since these sites largely avoided the complications of upper limb ataxia and sleep apnea.21 Introduction of the minimally invasive percutaneous approach for cordotomy by Mullan, Rosomoff, and their colleagues mitigated some of the neurologic risks and made it possible for the procedure to be performed on patients in poor general health.22,23 In the mid-1980s and early 1990s, advances in opioid pharmacology, as well as the introduction of reversible and testable

neuroaugmentive techniques, reduced the perceived need for spinal destructive procedures for pain control and led to a major reduction in the number of cordotomies performed by neurosurgeons worldwide. However, these neuroaugmentive procedures were expensive, particularly given the short life expectancy of many of the candidates, and were not uniformly effective. Kanpolat and coworkers first introduced the concept of computed tomography (CT)-guided cordotomy, which allowed a safer, selective, and more effective procedure.24-26 In 1995, Fenstermaker and associates27 performed anterior CT-guided lower cervical cordotomy through the disk space to avoid sleep apnea (a modification of Gildenberg and colleagues’ anterior low cervical percutaneous cordotomy).28 CT-guided cordotomy is typically performed as a percutaneous procedure via a lateral approach to the spinal cord at the level of C2. However, the anterior cervical transdiscal approach can also be used, and in a recent clinical study this approach was used to control cancer pain in six of eight patients with pulmonary-pleural malignancy while avoiding sleep apnea.29 Today, the CT-guided cordotomy procedure involves lumbar puncture and injection of a water-soluble dye into the patient’s intrathecal space. After 30 minutes, a cervical CT scan is performed. This and subsequent scans are used to direct the cordotomy electrode into the anterolateral quadrant of the ipsilateral spinal cord. The electrode is insulated throughout the entire shaft except the tip (2 mm in length and 0.3 to 0.4 mm in diameter). After measurement of the skin-dura distance and local anesthesia of the lateral cervical region, an electrode is introduced from the lateral side of the neck opposite the C2 foramen into the anterolateral quadrant of the spinal cord. To ensure complete entry into the spinothalamic tract (while avoiding the corticospinal tract), electrophysiologic testing is essential. Radiofrequency lesions are performed until adequate hypoesthesia is achieved in the contralateral hemibody or at least in the region of pain. CT-guided cordotomy has a higher success rate than do more traditional approaches, as well as fewer complications. Control of cancer pain is reportedly achieved in more than 95% of cases. Procedural complications may include weakness, hypotension, dysesthesia, mirror-image pain, ataxia, incontinence, and sleep apnea. However, contemporary CT-guided cordotomy complications tend to be both minor and transient.30 A recent evidence-based review concluded that the case for cordotomy is somewhat unique among all cancer pain procedures in that it has the most supportive evidence.31 In that review the GRADE system of recommendation was used, and a recommendation for cordotomy was given. The GRADE system produces recommendations that are independent of the level of evidence.32

TRIGEMINAL TRACTOTOMY-NUCLEOTOMY (SPINAL LEVEL) Sensory information from the 5th, 7th, 9th, and 10th cranial nerves is carried by the trigeminal tract and branches into the trigeminal tract spinal nucleus and extended caudally into the spinal cord to C2.33 The trigeminal tract is considered a target for surgically treating facial pain,34 and the history of procedures directed to this target is similar to

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cordotomy in that initial open procedures evolved toward less invasive stereotactic operations. Crue and colleagues and Hitchcock developed a stereotactic technique to lesion the trigeminal tract and nucleus via radiofrequency that was named trigeminal nucleotomy.35,36 As with CT-guided cordotomy, CT is used when performing the trigeminal tractotomy-nucleotomy (TR-NC) procedure today. Indications include anesthesia dolorosa, post-herpetic neuralgia, neuropathic facial pain, facial cancer pain, and either glossopharyngeal or geniculate neuralgia.26,37 The procedure can be considered, in some ways, a mini–caudalis DREZ procedure. The nucleus caudalis DREZ operation involves the same concept as the TR-NC procedure but includes destruction of the substantia gelatinosa (Rexed laminae II and III) of the nucleus caudalis. Pain relief from TR-NC is reported to be complete or satisfactory in 80% of cases. Complications include ataxia from injury to the spinocerebellar tract (usually temporary) and contralateral hypoalgesia if the spinothalamic tract is included in the lesion.26,36-38

EXTRALEMNISCAL MYELOTOMY The extralemniscal myelotomy (ELM) procedure was first described by Hitchcock, who initially aimed to destroy the decussating fibers of the spinothalamic tract in the anterior commissure of the spinal cord to control pain in the neck and both arms.39 ELM was achieved by creating a lesion in the central medullary region at the cervicomedullary junction. Unexpectedly, it was noted that the ELM procedure also seemed to control pain caudal to the level of the lesion. Schvarcz added the term “extralemniscal” to “myelotomy” because of the contention that the lesion incorporated an ascending polysynaptic nociceptive pathway.40 Subsequently, the presence of such a tract has been confirmed anatomically. Several authors have now presented reports of midline “punctuate” ELM via open procedures to interrupt this pathway at various spinal cord levels. The polysynaptic ascending pathway is thought to carry ­visceral nociceptive information and lies deep to the midline dorsal column.41-43 The concept of CT guidance, previously applied to cordotomy and TR-NC procedures, has also been applied to ELM by Kanpolat and colleagues, thus developing the image-guided ELM procedure used today.37 ELM is currently conceived as a pain control procedure for pain of visceral origin, including patients with pelvic malignancy, or for cancer pain in the lower part of the trunk and lower extremities with a predominant visceral pain component. The procedure appears to be safe; however, pain relief results are not as good as those achieved with cordotomy and TR-NC procedures.18

DORSAL ROOT ENTRY ZONE LESIONS With introduction of the gate control theory in the 1960s, attention was drawn to the spinal dorsal horn as the initial physiologic substrate for pain modulation.44 The dorsal horn and DREZ were then reconsidered as targets for both neuromodulation (spinal cord stimulation) and neuroablation. In 1972, Sindou45 first attempted cervical DREZ destruction for neuropathic deafferentation pain in the upper extremity secondary to brachial plexus avulsion.

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Nashold and associates soon followed and introduced the use of radiofrequency lesions to perform DREZ disruption.46 Laser and ultrasound have also been used to damage the DREZ.47,48 When large-fiber afferents (touch, position sense) in peripheral nerves or dorsal roots are altered, there is a reduction in the inhibitory control of the dorsal horn.49 This situation is presumed to result in excessive firing of the dorsal horn neurons, which is thought to be the cause of deafferentation pain and hence able to be controlled by DREZ lesioning.50 The technical details of the procedure and its variants are beyond the scope of this chapter, but DREZ lesioning is performed as an open surgical procedure under general anesthesia and oftentimes accompanied by intraoperative neurophysiologic monitoring. Surgical candidates are patients with brachial plexus avulsion, Pancoast’s tumor with brachial plexus invasion combined with a good general condition and reasonable life expectancy, pain caused by spinal cord or cauda equina lesions, and pain accompanying spasticity after plexus or cord injury.45 A general prerequisite for the DREZ procedure is a lack of functional use of the limb where the DREZ procedure is performed since complete sensory denervation of the limb will render it functionless even if there is residual motor power. When patients are carefully selected and the lesions accurately performed, the success rate can be as high as 90% (with follow-up success rates reported for up to 4 years). Complications and side effects include cerebrospinal fluid (CSF) fistula, meningitis, ataxia, increased neurologic deficits, and dysesthesias.51

CEREBRAL NEUROMODULATION ELECTRICAL NEUROMODULATION DEEP BRAIN STIMULATION Pool first observed and reported on the analgesic effects of septal stimulation in the frontal and lateral forniceal columns while performing psychosurgery in the 1950s.52 Heath and Mickle and Pool and colleagues subsequently reported the pain-relieving effect of septal and near-septal stimulation in nonpsychiatric patients.53,54 Mazars and coauthors and Reynolds first reported pain relief from thalamic stimulation in 1960.55,56 Neurostimulation of the brain to relieve pain was thus introduced decades before what has become the main contemporary indication for DBS—treatment of movement disorders.57 However, these early reports only set the stage for the eventual applications of DBS for pain relief. In the mid-1960s, Melzack and Wall’s gate theory44 provided the logical rationale for DBS of the sensory thalamus to control pain. Shortly afterward, Reynolds reported on the analgesic effect of focal brain stimulation in rats (stimulation-produced analgesia).56 In the early 1970s, Hoso­ buchi and associates58,59 and Richardson and Akil60,61 were the first to report on stimulation of the human thalamus and PVG and PAG matter for pain control. Even though stimulation of the thalamic sensory nuclei produced paresthesias in painful areas, consistent pain relief was not achieved. Similar results were produced by stimulation of the internal capsule.62,63 Stimulation of the PVG and PAG typically did not produce paresthesias but did induce a

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sense of “warmth.” Higher-intensity PVG/PAG stimulation produced unpleasant and sometimes overwhelming sensations such as impending doom or terror. The centromedianparafascicular complex was also targeted by Andy64 as a stimulation site to treat pain, and this stimulation likewise did not produce paresthesias. Despite reports describing the use of DBS to treat chronic pain in the 1970s and early 1980s, data to support the technique never reached contemporary evidentiary standards. The use of DBS for pain control has failed to gain much acceptance in the neurosurgical community, and the use of DBS electrodes as pain control implants has never achieved U.S. Federal Drug Administration (FDA) approval. The lack of data to support the procedure is due, in part, to the small number of patients treated, inconsistent target localization, heterogeneity of the pain diagnoses treated, and failure to mount a prospective randomized trial that was sufficiently powered to answer the question of efficacy. The mechanism of pain relief by DBS is poorly understood but appears to be dependent on the site. The thalamus and PVG/PAG were the most commonly65 targeted sites for DBS implants for pain. Hosobuchi and colleagues58 suggested that the pain-relieving effect of PVG and PAG stimulation might involve endogenous opioid receptors based on their studies in which it was found that the pain-relieving effect of DBS could be reversed by naloxone. Evidence to support this mechanism of action of PAG/PVG DBS is inconsistent. Some investigators supported the concept whereas others disagreed. Currently, it is postulated that the painrelieving effect of PAG/PVG DBS is due to activation of multiple supraspinal descending pain modulatory systems, both opioid and nonopioid.66 Pain relief resulting from stimulation of the ventral posterolateral (VPL) nucleus and ventral posteromedial (VPM) nucleus (Vc nucleus in the European Hassler terminology), the major sensory nuclei of the thalamus, is poorly understood. Inhibition of spinothalamic tract neurons67 and activation of dopaminergic mechanisms have both been proposed.68 The most accepted hypothesis is that thalamic stimulation activates the nucleus raphe magnus of the rostroventral medulla, which results in activation of a suprasegmental descending endogenous pain inhibition system.66 Meticulous patient selection, with classification of the pain (i.e., nociceptive or neuropathic) combined with informed DBS target selection, should help improve the outcome of DBS for pain. Clinical case series (class III evidence) observations suggest that PVG/PAG stimulation seems to be more effective in treating somatic nociceptive pain. This is consistent with the proposed opioid-mediated effect of PAG/PVG stimulation.69 It has also been suggested that VPL and VPM (Vc) stimulation is more effective in treating neuropathic pain, a gate theory–based concept.69 In the absence of controlled trials to prove efficacy, any definitive conclusions regarding the ideal target for any particular pain syndrome remains elusive. Furthermore, many patients have mixed neuropathic/nociceptive pain, which suggests that the DBS target to control pain should be individualized according to the patient. Some authors have even suggested placing two electrodes simultaneously in the sensory thalamic nucleus (Vc) and in the PVG.70 For some pain syndromes (e.g., thalamic infarction–induced pain), target selection is simpler given that thalamic stimulation is not possible.70

Chronic neuropathic pain conditions treated by DBS have included anesthesia dolorosa, post-stroke pain, thalamic pain, brachial plexus avulsion, post-herpetic neuralgia, postcordotomy dysesthesia, spinal cord injuries, and peripheral neuropathy pain. Nociceptive pain conditions treated by but not limited to DBS have included failed back surgery syndrome, osteoarthritis, and cancer pain.71 DBS for chronic pain is similar to DBS for other indications (movement disorders) in that surgeons have a number of targets that are applicable to the general problem (see Fig. 22.1). DBS target locations are often indirectly derived from the Schaltenbrand and Bailey atlas or measured directly from the patient’s CT or magnetic resonance imaging scans. The location of these targets can be confirmed intraoperatively by macrostimulation, microelectrode mapping, or intraoperative imaging. To best judge the benefits of stimulation and help fine-tune stimulation parameters following final electrode implantation, a trial period of approximately 1 week is often a prerequisite. Complications of DBS for pain relief are similar to those for movement disorders. Typically, they are related to either (1) brain injury from bleeding or inadvertent trauma as a result of electrode insertion, (2) infection, (3) hardware failure, and (4) transient site-specific side effects related to overstimulation or unintentional stimulation of neighboring areas. The later might produce diplopia, seizures, nausea, paresthesias, or headaches. Overall, DBS surgery is a safe procedure with a relatively low chance of complications or unintended neurologic sequelae. However, data to support its efficacy are sparse. Currently, DBS for pain control is an extraordinary treatment that may be applicable to only a few chronic pain conditions. DBS implantable hardware is not approved by the FDA for pain control procedures, and many insurance carriers will not authorize implantation. Given the tremendous interest in and application of DBS for movement disorders, whether DBS for pain will be substantially resurrected at some point remains to be seen. MOTOR CORTEX STIMULATION In 1954, Penfield and Jasper observed that stimulation of the precentral (motor) gyrus elicited sensory responses when the corresponding portion of the adjacent postcentral gyrus had previously been resected.72 They treated burning pain on one side of the body by postcentral gyrectomy, and when the pain recurred, they performed precentral gyrectomy, which then controlled the pain. Independently, in 1955 White and Sweet attempted surgical resection of the postcentral gyrus for relief of central pain and reported 13% pain relief.73 It was not until 1971, after publication of the gate theory in 1965, that Lende and coworkers re-explored the motor cortex as a potential site for pain control. In an attempt to treat central neuropathic facial pain74 they performed two cases of precentral and postcentral gyrectomy of the facial cortex. These reports formed the basis for establishing a linkage between the precentral and postcentral areas and pain control surgery. By the 1980s, the cumulative failure of other procedures, both modulatory and destructive, to fundamentally alter neuropathic pain made it clear that the development of an innovative methodology to surgically treat pain was critically needed. Exploration of the motor area as a target

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site was well under way. Hardy and associates stimulated the rat medial prefrontal cortex with a resultant significant elevation in nociceptive response latency.75,76 Hosobushi implanted electrodes in subcortical somatosensory areas for control of dysesthetic pain, and from this study it was concluded that somatosensory stimulation could be effective in the treatment of leg pain.77 In 1991, Tsubokawa and coworkers first introduced epidural stimulation of the motor cortex as an option to treat central deafferentation pain. His group had tried postcentral gyrus (sensory) stimulation and found that it was either ineffective or exacerbated the pain. They demonstrated that epidural MCS inhibited abnormal thalamic neuronal burst activity and increased regional blood flow to the cortex and thalamus.78 Primarily, Tsubokawa and colleagues used MCS for central deafferentation pain syndromes such as post-stroke pain.78,79 The mechanism of action of MCS is still poorly understood; however, the work of Garcia-Larrea, Peyron, and coworkers80-82 has shed some light on its mechanism of action. Positron emission tomography and electrophysiologic studies have demonstrated that MCS increases blood flow to the ipsilateral thalamus, cingulate gyrus, orbitofrontal cortex, insula, and the brainstem, with some correlation between increased thalamic and brainstem blood flow and efficacy of pain relief. The increased blood flow to the ipsilateral sensory thalamus was greater than that to the motor (ventrolateral) thalamus. It did not appear that an intact somatosensory system was absolutely necessary for the clinical benefits to be realized, an important discovery allowing the use of this technology for stroke and other deafferentation states.80-82 As with many forms of chronic stimulation, habituation seems to occur, which is more likely with the use of high-frequency stimulation. The patient selection process for MCS is of paramount importance (as it is for all pain-relieving surgeries), and in this case, the debate continues. Neuropathic pain is more responsive than nociceptive pain to this form of therapy. Attempting to predict the best candidates for MCS can be challenging, and Yamamoto and colleagues introduced a pharmacologic classification of post-stroke patients based on their pain relief response to escalating doses of both intravenous thiamylal and morphine. They concluded that patients with a good response to thiamylal or ketamine and a poor response to morphine were the best candidates for MCS.83 Several neurogenic pain syndromes have been treated by MCS, including thalamic pain, bulbar post-stroke pain (which typically occurs with “Wallenberg’s syndrome”), facial neuropathic and deafferentation pain, and phantom and brachial plexus avulsion pain.84,85 Treatment of central post-stroke pain following thalamic infarction or thalamic or putaminal bleeding by MCS was reported by Tsubokawa and colleagues to achieve good to excellent pain control in 65% of cases (follow up >12 months), with no seizures observed.78,79 Katayama and associates extended the indications to include bulbar pain secondary to “Wallenberg’s syndrome” and reported on four patients initially treated by VPL thalamic stimulation that resulted in increased pain. Three other patients were later treated by MCS, with greater than a 60% reduction in pain in two patients and greater than 40% in one patient.86 Treatment of neuropathic facial pain appears to be one of the most promising indications for MCS, which

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may be related to the breadth of facial representation over the motor cortex. Several reports include neuropathic facial pain treatment by MCS. Raslan, Ebel, Herregodts, Meyerson, Nguyen, Rainov, and their colleagues all treated trigeminal neuropathic pain with MCS and reported pain relief in approximately 60% of patients for periods of up to 12 months.85,87-92 Peripheral deafferentation pain, as well as brachial plexus avulsion pain, has also been treated by MCS, with variable results. Movement disorders are an active area of ongoing MCS research.84 MCS has been shown to produce improvement in the symptoms of thalamic hand syndrome, action tremors, intention myoclonus, and Parkinson’s disease. MCS involves the implantation of epidural electrodes over the motor cortex (see Fig. 22.1), which can be localized by either (1) radiologic landmarks of the central sulcus, (2) intraoperative somatosensory evoked potentials with observation of “phase reversal” over the central sulcus, (3) intraoperative stimulation of the cortex with concurrent electromyographic monitoring of the relevant muscle groups contralaterally, and more recently, (4) use of neuronavigation systems to localize either the central sulcus or the precentral gyrus. Some authors even recommend the use of functional magnetic resonance imaging for targeting, especially with infarctions involving the motor cortex.93 A trial period of MCS is usually required followed by implantation of a permanent system if the trial produces adequate relief. Complications of MCS include intraoperative seizures, stimulator pocket infection, epidural bleeding, subdural effusion, and “tolerance” to stimulation with diminished analgesia over time.

CEREBRAL NEUROMODULATION: PHARMACOLOGIC INTRAVENTRICULAR OPIOIDS Studies showing the direct analgesic effects of opioids applied in the ventricular region and around the medulla of the central nervous system94,95 led to the work of Leavens and coworkers in 1982,96 in which human ICV use of morphine was first reported. The profound analgesic response to intrathecal morphine coupled with its widespread clinical use for lower body pain suggested the need for more rostral injection sites to control pain involving the head, neck, and upper extremity regions. Even though cervical intrathecal opioid injection sometimes resulted in respiratory depression, it was possible to deliver a small amount of ICV morphine without respiratory dysfunction or dysautonomia. Opioid receptors are abundant around the wall of the third ventricle and aqueduct, as well as in the PVG and PAG. In Leavens and colleagues’ 1982 report, 1 mg of morphine was used to treat patients with intractable cancer pain and resulted in profound analgesia and no respiratory depression or neurologic changes.96 In a report on 82 patients, Lazorthes and associates recommended nine specific guidelines for the ICV use of morphine: (1) chronic pain secondary to inoperable malignant tumors in patients with terminal cancer; (2) pain not relieved by medical treatment and, in particular, the development of serious side effects from using oral or systemic morphine; (3) intractable bilateral, midline, or diffuse pain not appropriate for percutaneous

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PART 4 — CLINICAL CONDITIONS

or open surgical interruption of nociceptive pathways; (4) chronic pain of somatic nociceptive origin (neurogenic pain was a contraindication); (5) upper body pain secondary to cervicothoracic cancer; (6) chronic pain of the lower half of the body (subdiaphragmatic) only after failure of or contraindication to conventional intrathecal spinal opioid administration; (7) absence of general risks for complications, such as coagulation disturbances, cutaneous infection, and septicemia; (8) informed consent from the patient and family; and (9) the presence of a favorable domestic environment (e.g., physician, nurse, or family) for ambulatory surveillance and chronic ICV morphine treatment. The authors recommended that when the topography of the pain involved a transitional area (e.g., lower thoracic, diaphragmatic, or upper abdominal region), ICV morphine could be indicated if the patient failed a more standard intrathecal morphine trial.97 Surgically, the technique for implanting a chronic ICV morphine infusion system involves placement of a catheter into the lateral ventricle near the foramen of Monro to deliver drug near target receptors in the periaqueductal parenchyma of the midbrain (see Fig. 22.1). The analgesic latency of ICV morphine administration is between 15 and 30 minutes, and the effect lasts for a mean of 28 hours. Excellent or good pain relief rates range from greater than 50% to 97%, and side effects include somnolence, nausea, confusion, and respiratory depression, which are usually transient. Finally, Lazorthes and coauthors reported tolerance in 3 of 82 patients.97 The increased effectiveness of oral opioids has diminished the necessity for ICV morphine administration. However, the technique remains relatively simple and effective and is a viable option for patients with intractable pain of malignant etiology, following oral opioid failure, and when pain is diffuse or cephalic in topography.98

SUMMARY Neurosurgical procedures to treat intractable pain have gone through an evolutionary process, dictated in part by technological advances, scientific discovery, and changes in the survival rates of chronic pain patients, especially those with cancer pain. Irreversible ablative procedures are used much less frequently today, yet on occasion they remain the procedures of choice. Depending on the physiologic substrate and pain topography, multiple brain and spinal cord regions can be targeted to treat chronic pain. Today, neuromodulation by either electrical stimulation or pharmacologic manipulation is generally the preferred approach to treat chronic pain.

KEY POINTS • Neurosurgical treatments of intractable pain are usually reserved as last options for the treatment of intractable pain. • These interventions can be either ablative or neuromodulatory, which in turn could be divided into pharmacologic and electrical. • Neurosurgical procedures can be done at either a spinal or cerebral level. Spinal spinothalamic ablation (cordotomy) is the most studied and performed neurosurgical ablative procedure, and it is very effective in treating unilateral somatic cancer pain. • Opioid use has limited the indications for ablative procedures, but there are still defined but limited indications for spinal ablative procedures that are confined to cancer-related pain. • Spinal neuromodulation (i.e., spinal cord stimulation and intrathecal opioid devices) are used widely for chronic spinal pain. • Cerebral ablation of pain pathways or centers is rarely done at present. However, cerebral neuromodulation procedures such as deep brain stimulation and motor cortex stimulation have limited indications and utility that are usually related to central pain and neuropathic pain.

ACKNOWLEDGMENT The authors thank Shirley McCartney, Ph.D., for editorial assistance. SUGGESTED READINGS Hosobuchi Y. Combined electrical stimulation of the periaqueductal gray matter and sensory thalamus. Appl Neurophysiol. 1983;46:112-115. Kanpolat Y. Percutaneous cordotomy, tractotomy, and midline myelotomy: minimally invasive stereotactic pain procedures. In: Fisher W, Burchiel K, eds. Seminars in Neurosurgery: Pain Management for the Neurosurgeon. Vol. 2/3. New York: Thieme Medical; 2005:203-219. Lazorthes YR, Sallerin BA, Verdie JC. Intracerebroventricular administration of morphine for control of irreducible cancer pain. Neurosurgery. 1995;37:422-428. Raslan AM, Cetas JS, McCartney S, et al. Destructive procedures for control of cancer pain: the case for cordotomy. J Neurosurg. 2011;114:155-170. Tsubokawa T, Katayama Y, Yamamoto T, et al. Chronic motor cortex stimulation for the treatment of central pain. Acta Neurochir Suppl. 1991;52:137-139.

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