According to the definition by the International Association for the Study of Pain, neuropathic pain is that initiated or caused by a primary lesion or dysfunction of the nervous system. 1 Its treatment is very arduous. Medications and psychotherapy are often insufficient to reduce the pain to a bearable level. In some well-defined circumstances, functional neurosurgery may provide a solution.
Before surgery is indicated, and in the choice of the most appropriate procedure for a particular patient with neuropathic pain, the anatomical and physiologic mechanisms at the origin of the pain must be analyzed carefully. The neurosurgeon dealing with the difficult problems of pain surgery needs a solid knowledge of the pathophysiology of neuropathic pain.
MECHANISMS OF NEUROPATHIC PAIN
This short summary of the knowledge on neuropathic pain is derived from extensive data published over the past 20 years. The corresponding references are not mentioned here, not only because they are so numerous but also because this article focuses on the surgical procedures for neuropathic pain.
Pathologic Mechanisms in Primary Afferent Neurons
Abnormal Nociceptor Sensitization
After injury, primary afferent nociceptors can be sensitized and may acquire ongoing spontaneous discharges, a lowered activation threshold, and increased response to suprathreshold stimuli. In addition, the C-fiber nociceptors that survive a partial nerve injury may acquire noradrenergic sensitivity and contribute to causalgic phenomena.
Damaged Primary Afferent Axons and Ectopic Discharges
After peripheral axotomy, the regenerating sprouts of primary afferent nociceptors and low-threshhold mechanoreceptors acquire abnormalities that produce ectopic discharges. The generation of ectopic discharges at the site of stump neuromas after amputation or complete nerve transection has been well documented by microneurographic recordings.
It is important to know that primary afferent sprouts are present in many nontraumatic conditions. For instance, after herpes zoster invasion, when regenerating sprouts attempt to reinnervate, they are likely to be trapped in intraneural scars. Such neuromas-in-continuity can also be present in cases of subtotal nerve trauma, especially after crush and stretch injuries.
An extensive literature from animal experiments describes the formation of abnormal electrical connections between adjacent axons that have been demyelinated. These connections may be responsible for the so-called ephaptic (“cross-talk”) phenomenon and the “crossed after-discharge” phenomenon, which occur because the sprouts of primary afferent neurons with damaged peripheral axons can be made to discharge by the discharge of other afferents.
Also, locally demyelinated axons can give rise to “reflected” impulses, which propagate both ortho-and antidromically. This is likely able to produce a dysesthetic “buzzing” sensation.
Dorsal Root Ganglion Discharges
The abnormalities detected in the sprouts of axotomized primary afferent neurons are also expressed at the level of their cell bodies in the dorsal root ganglion (DRG).
It is now clear that continued (or even de novo) ectopic discharges from the DRG may explain cases in which pain is not eliminated by excision of the neuroma(s), without the need of postulating any central mechanism.
Anatomical and Neurochemical Changes in the Central Nervous System After Peripheral Nerve Injury
Lesions in the peripheral nervous system can be at the origin of secondary changes inside the central nervous system (CNS), especially the dorsal horn, where primary afferents terminate. It has been demonstrated that the intraspinal terminal arbors of axotomized primary afferents sprout and invade new territories within the dorsal horn. Axotomized afferents cease making their normal neuropeptides (e.g., substance P, calcitonin gene–related peptide) and begin making different ones (e.g., neuropeptide Y, galanin, vasoactive intestinal polypeptide). There is a dramatic upregulation of early immediate gene regulation (e.g., C-fos) in intrinsic spinal neurons that suggests an important and prolonged response of second-order neurons to changes in their input. The exact significance of such neurochemical changes that follow peripheral nerve injury is not well known, but they may have central consequences that are of potential pathophysiologic importance.
Central Hyperexcitability Caused by C-Nociceptor Discharge and NMDA Excitotoxicity
C-nociceptor discharge produces a central state of hyperexcitability whereby wide dynamic range neurons show increased discharges when their receptive fields (RFs) are stimulated by pinching or gentle brushing. In addition, the size of cell RFs is enlarged. These electrophysiologic changes are associated with exaggerated nocifensive withdrawal reflexes, which are indicative of perceptual hyperalgesia.
This hyperexcitability involves activity at glutaminergic synapses of the N-methyl-2-aspartate (NMDA) type. High levels of activity in these synapses produce excitotoxic insults in dorsal horn neurons. The phenomenon can be detected anatomically by the appearance of transsynaptic degenerative changes in spinal neurons in the laminae of dorsal horns I through III.
Once initiated, central hyperexcitability may be maintained and modulated by a source of ongoing nociceptor discharge. Multiple mechanisms may produce the maintaining nociceptor drive. For example, in sympathetically maintained pain, the nociceptors may themselves be driven by activity in sympathetic afferents, whereas in sympathetically independent pain, the nociceptor discharge may be caused by spontaneous ectopic discharge from nociceptor sprouts in a neuroma or by essentially normal nociceptor input from poorly healed tissue damage.
Deafferentation of Spinal Neurons After Dorsal Root Damage
Interruption of the dorsal root produces deafferentation of spinal cord neurons. This is usually the result of traumatic avulsion or vertebral fracture. Deafferented spinal neurons acquire abnormal spontaneous patterns of discharge. This discharge is of high frequency and appears in one of two patterns: long trains of fairly regular discharge, and paroxysmal burst discharges. Spontaneous discharges are found in cells in both the superficial and the deep laminae of spinal gray. Some dorsal horn neurons within the deafferented segments may have stimulus-evoked responses. They are supposed to have acquired a “new” RF, which encompasses skin along the borders of the area innervated by the cut roots. The cells with new RFs usually respond to innocuous tactile stimuli; very few respond to noxious stimulation.
Hyperactivity has been recorded in the dorsal horn of patients with deafferented spinal cord during surgical procedures. 2–5
The presence of spontaneous bursting discharge in neurons of the somatosensory thalamus and cortex has been confirmed in both anesthetized and unanesthetized animals with multiple dorsal root transections. The thalamic abnormalities appear to be expressed considerably later than the spinal phenomena, and the cortical abnormalities begin later than those in the thalamus. This temporal progression suggests an evolution of pathologic mechanisms, with the possibility that the pathologic change in the spine generates that in the thalamus, and change in the thalamus, in turn, generates that in the cortex. It is possible that the thalamocortical abnormal activity becomes independent of input from the spinal cord. This might be a cause of failure of pain surgery in the deafferented spinal cord segments if surgery is performed too late.
Abnormalities After CNS Injury
Abnormal spontaneous and evoked pain, and dysesthesias, may appear after injury to the spinal cord, brainstem, thalamus, and—although more rarely—cortex. 6 Careful sensory testing and imaging techniques have led to the conclusion that there is a common feature to most patients with “central” pain, namely, damage to some part of the spinoreticulothalamic system. 7
In patients with central pain, neurons in the ventrobasal thalamus—in that part of the body map representing the patient's anesthetic area—usually do not have detectable RFs. By contrast, neurons with RFs lying around the border of the anesthetic area have RFs larger than normal. Many of the patient's thalamic neurons have spontaneous high-frequency burst discharges (a rare finding in the normal patient and very different from the spontaneous regular discharge of 10 Hz of the normal thalamus).
Microstimulation in the vicinity of neurons without RFs frequently produces painful sensations, often similar to the patient's clinical pain. They are believed to arise from the anesthetic area, contrarily to normal patients in whom there is no pain but only paresthesia.
Complexity of Mechanisms
Pain after injury to the nervous system is complex. Even the distinction between neuropathic pain and nociceptive pain is not easy to determine. The latter is the pain perceived through nociceptors preferentially sensitive to a noxious stimuli or to a stimulus that would become noxious if prolonged.
In cancer pain, which is ordinarily thought to be caused by nociceptive mechanisms (e.g., inflammation, nerve compression), true neuropathic mechanisms may supervene by infiltration of nerve fibers, leading to deafferentation.
Nociceptive mechanisms may influence the functioning of nerve trunks. As a matter of fact, pseudoneuropathic pain can be generated by the activation of the “nervi nervorum” in the surrounding connective tissue of the nerve by ongoing tissue damage (e.g., inflammation, tumor, or trauma). 8 An inflammatory response may release eicosanoids sensitizing the axonal membranes of the sensory fibers that then become susceptible to innocuous stimuli. 9 The pain is perceived along the course of the nerve, as it is in sciatica after disc protrusion, and is aggravated by mechanical stretch, e.g., straight leg raising.
If neuropathic pain is accompanied by symptoms of dysregulation of the sympathetic nervous system, it is referred to as complex regional pain syndrome.
Noradrenergic sensitization of primary afferent nociceptors with artifical coupling to afferent sympathetic fibers 10 has led to the concept that these types of pain are, at least partially, sympathetically maintained.
In a given diagnostic category, neuropathic pain may have multiple mechanism, even in an individual patient. 11 In addition, the responsible mechanisms may alter over time. Because the several types of neuropathic pain possess distinct mechanisms, each one may require a specific treatment.
Importance of Animal Models for Studying Neuropathic Pain
There is no doubt that knowledge obtained from animal models is of prime importance to a better understanding of human neuropathic pain. Before 1980, almost all studies of chronic neurogenic pain were carried out on intact animals, which severely hampered generalizing the results from experimental conditions to the clinic. The only models attempting to create neuropathic pain were the deafferented spinal cord model 12 and, for peripheral nerve, the neuroma 13 and the axotomized 14 models. Because these models were insufficient to study all the various aspects of the mechanisms of neuropathic pain, several laboratories began to develop a diversity of animal models in an attempt to reproduce most of the pathologic situations observed in humans.
The main animal models of neuropathic pain syndromes, together with their corresponding reference numbers, are given here.
Several animal models have been developed to study the mechanisms produced by lesions in the peripheral nerve, the DRG, or the dorsal root. These include axotomies of the peripheral nerve. Such axotomies result in a self-mutilation of the denervated paw (i.e., autotomy). 13–16 The question has been raised whether autotomy after axotomy is caused by neuropathic pain or anesthesia and/or the trophic disturbances created by the peripheral nervous system lesions. 15 Increased expression of Na+ channels in regenerating afferent nociceptor fibers may lead to spontaneous ectopic discharges. 16
Chronic constriction injury of the nerve17 is created by tying four loose ligatures around the sciatic nerve at the thigh. This was the first injury model of this type. It displays thermal (cold) allodynia and hyperalgesia.
Partial nerve ligation18 also creates a partial injury of the sciatic nerve at the thigh level and produces a partial crush injury. It gives signs of tactile allodynia.
Infusion of acidified saline around the nerve19 produces heat hyperalgesia without mechanical allodynia. There is inflammation of the nerve sheath with little or no damage to axons within the nerve.
A photochemical lesion of the nerve created by low-power laser irradiation 20 induces a local photochemical reaction followed by wallerian degeneration.
Models studying the DRG 21–24 show that an injury or a chronic constriction of the sciatic nerve produces a spontaneous ectopic discharge originating in the DRG within hours of the lesion, with spontaneous discharge from the sprouts appearing several days later. 22
Some models have reproduced pathologic changes in the spinal dorsal roots by the use of compression, 25 ligation, 26 or irritation. 27
Also, animal models have been developed to study changes in the CNS, especially the dorsal horn, after injury of the peripheral nervous system. 28–31 Structural reorganization of the dorsal horn by central sprouting of myelinated afferents around unmyelinated C fibers in lamina II may lead to hyperexcitability of the primary sensory neurons and loss of the central inhibitory effect by myelinated fibers. 29
Animal models have been used to study deafferentation of the spinal cord that leads to hyperactivity/hypersensitivity of the dorsal horn. 12,32
Models of pain from spinal cord origin have used nonselective lesions:33–38 a crush of the cord, 33 a hemisection of the cord, 34 and an ischemic lesion created by use of the laser photochemical effects. 35 A photochemically induced spinal cord lesion produced mechanical allodynia. 36 Another lesion was created by the injection of a glutamatergic agonist.) 38
Other models of pain from spinal cord origin have used selective lesions on tract(s). 39–41
Additionally, models of pain from brain origin have been produced. 42,43
DECISION MAKING FOR INDICATION FOR NEUROSURGERY IN NEUROPATHIC PAIN
Neuropathic pain is generally considered to be refractory to opioids as well as to ordinary analgesic treatments. Some relief can be obtained with anticonvulsants (e.g., carbamazepine, clonazepam, valproate, gabapentin) and tricyclic antidepressants (e.g., amitriptyline, imipramine, desipramine, clomipramine). 44,45 When all medical therapies have failed, functional neurosurgery may be indicated in well-selected cases.
The neurosurgical methods to be considered are (1) modulative, by using electrostimulation or implanted drug delivery systems, and (2) ablative, by making selective therapeutic lesions in well-defined and identified targets demonstrated to sustain pain mechanisms.
The decision to propose neurosurgery is always difficult to make, and the choice of the best procedure to perform is often arduous. We have learned from our 30-year experience that consideration of the topographic level of the causal lesion is of prime importance for choosing the most appropriate target. It is the most important prerequisite for increasing the likelihood that any surgical analgesic procedure will be effective (Fig. 1).
Decision Making for Pain Caused by Peripheral Nerve Lesions (
When the causal lesion concerns a sensory nerve (especially if the lesion is small and in the distal part of the nerve) and if there is a reasonable evidence that the pain is related to scar tissue adhesions and/or the formation of a true neuroma, a direct surgical approach to the lesion site for anatomical treatment can be justified. The nerve is freed. If there is a neuroma, it is resected, and the proximal stump is ligated and protected.
When the lesion involves a large sensory nerve (especially in its proximal part) or a mixed nerve trunk, a similar strategy can be adopted, but even more prudently because of the greater functional importance of such nerves. When there is no argument for anatomical treatment (freeing of the nerve, resection of a neuroma), peripheral nerve stimulation by external transcutaneous nerve stimulation, or direct peripheral nerve stimulation if the nerve is deeply situated, or the more commonly used dorsal column stimulation (DCS) may be indicated.
When several nerves are involved, DCS at the corresponding spinal cord segments is the first choice because it is conservative. If DCS fails, lesioning surgery in the dorsal root entry zone (DREZ) may be considered but—in our experience—only if the main components of pain are of the paroxysmal and/or the allodynic types.
A type II complex regional pain syndrome (i.e., causalgia) may accompany peripheral nerve lesions, especially when they are severe. The presence of type II complex regional pain syndrome does not modify the above guidelines.
Decision Making for Pain Caused by Plexus or Root Lesions (
When the pain is related to plexus and/or root lesions, it is of prime importance to determine the exact location of the lesion—whether it is distal or central to the DRG—as well as the completeness or not of the anatomical-functional interruption of the radicular fibers (notably the large caliber primary afferents). This can be assessed by studying the nerve conduction velocity and the somatosensory evoked potentials (SEP).
If interruption is central and total, DCS cannot be effective because of the degeneration of the axons of the DRG cells all along the spinal cord, up to their brainstem relay nuclei. If neurostimulation is applied, the target should be the contralateral thalamic somatosensory nucleus (ventroposterolateral nucleus) using stereotactic deep brain stimulation. An alternative solution may be neurostimulation of the precentral (motor) cortex, using extradural precentral cortical stimulation (PCS).
In true deafferentation pain syndromes, known to be accompanied by hyperactivity of the dorsal horn cells, such as those occurring after brachial plexus avulsion (or, less frequently, lumbosacral avulsion) or after cauda equina injury, surgical lesioning of the DREZ may be particularly effective on all types of pain components.
In postherpetic pain, which corresponds to lesions both of the dorsal ganglion cells (and related axons going to and running through the spinal cord) and of the dorsal horn itself, DCS can be tried if enough dorsal column fibers are still functional. This can be assessed by SEPs. Surgery in the DREZ may be especially indicated when the main components of pain are of the paroxysmal and/or the allodynic types.
Decision Making for Pain Caused by Spinal Cord Lesions (
When pain is below the lesion, DCS can be effective only if the corresponding dorsal column(s) retain sufficient functional value. If the territory below the lesion is totally anesthetic, DCS will not work. As a matter of fact, if the dorsal columns are totally interrupted, electrodes—even if implanted above the lesion—cannot stimulate the contained lemniscal fibers, (which are the target of DCS), because of their degeneration up to their brainstem relay nuclei. Imaging and measurement of SEPs may be useful to check integrity of the dorsal columns. When pain is in the territory corresponding to the lesioned (injured) segments of the spinal cord, DCS may be effective on that pain, but only if the large-caliber segmental primary afferents (i.e., the lemniscal fibers) are still at least partially functional.
The same differentiation of pain between its segmental and its infralesional components is mandatory when DREZ surgery is being considered. In our experience, surgery in the DREZ is effective only on the pain corresponding to the lesioned segments—the so-called segmental pain—probably because generators are located in the dorsal horn of the concerned segments. Conversely, pain in the territory below the lesion is not influenced by DREZ surgical lesions, even if performed at the corresponding medullary levels.
Decision Making for Pain Caused by Brain Lesions (
This type of pain is classically not accessible to neurosurgical procedures. Nevertheless, some attempts are under evaluation, especially deep brain stimulation of the thalamic sensory ventroposterolateral nucleus and the newly introduced PCS. Preliminary studies favor use of the latter for persistent pain after stroke or trigeminal neuropathic pain.
This discussion will mainly consider spinal cord stimulation (SCS), which aims at enhancing the inhibitory control exerted on pain by the large primary afferent fibers. This procedure is widely used in most of the neurosurgical institutions. We shall also discuss the newly introduced motor cortex stimulation method, which we prefer to call precentral cortical stimulation (PCS) because the involvement of the motor system itself has not been proven and may not even exist at all. We shall not go into details of deep brain stimulation of the thalamic nuclei, as later methods have not often been used; moreover, we do not have personal experience with it.
Intrathecal morphine therapy is currently used for cancer pain. Its indication for neuropathic pain is controversial, and we do not have experience with it; therefore, we shall not take up the subject of morphine therapy for neuropathic pain. The use of clonidine and tizanidine has been attempted, but has not entered so far into current practice. Intrathecal baclofen, which is largely used for treating hyperspasticity, especially of spinal origin, has been reported to be effective in some cases of neuropathic pain, but this application is still being investigated.
Most of the ablative techniques must be reserved for cancer pain, and then only under limited conditions: for patients with a probability of survival time >1 year, in good general condition, and with pain in a restricted area caused by a rather limited lesion in extent. At present, only surgery in the DREZ target is currently used for neuropathic pain, but here also under very precise circumstances and with limited criteria.
Spinal Cord Stimulation
The neurophysiologic effects of electrostimulation of large primary afferents on the control mechanisms of nociception in the spinal cord were clearly demonstrated by animal experiments as early as the 1970s. 46–49 Soon thereafter, the results obtained in large series of patients with persistent pain and treated by transcutaneous electroneurostimulation (TENS) or spinal cord stimulation (SCS) demonstrated the clinical efficacy of electrostimulation of primary afferent neurons at the level of the peripheral nerves or the spinal roots and/or spinal cord. However, the question whether electrostimulation of these (lemniscal) fibers acts exclusively by a true neurophysiologic effect, or at least partly through a superimposed placebo effect that hampers evaluation, because the patient experiences paresthesia when using the stimulation, has remained debatable for many years. Evidence of objective modifications on spinal responses to noxious stimuli during SCS or TENS would therefore be important. Recordings of the RIII flexion reflexes in the hamstring muscles in response to nociceptive stimuli applied to the (sensory) sural nerve were carried out for this purpose by Garcia-Larrea et al. 50 These authors found a stimulation-related depression of the nociceptive reflex during SCS or TENS, especially when these methods were clinically effective (Fig. 2).
Before SCS is considered, TENS with the electrodes placed extracutaneously over the corresponding peripheral nerves should be tried first. Transcutaneous electroneurostimulation has the same theoretical rationale as stimulation of the spinal cord, i.e., closing the gate at the dorsal horn level. However, a peripheral axonal blockade might play an important role in alleviating pain of peripheral origin with peripheral electrostimulation. 51,52 Our experience of TENS in >2,000 patients was that relief is the more effective and long lasting when (1) the pain was of peripheral origin, (2) the nerve to be stimulated lay superficially under the skin (i.e., was well accessible to the electrical current delivered by the TENS electrodes), and (3) the electrodes were applied proximally to the causative lesion. No effect was achieved when stimulation was not able to elicit paresthesia covering the whole painful territory. 53
Our experience concerning SCS in a series of 180 patients is that bipolar electrostimulation is less likely than monopolar stimulation to provoke uncomfortable and even sometimes unbearable paresthesia and twitches in nonappropriate territories by diffusion of current to the neighboring sensory and motor rootlets, respectively. In their recent article on the predictors of success of epidural spinal cord stimulation, Kumar et al. 54 showed that programmable multipolar (Medtronic Inc., Minneapolis, MN, Quadripolar, Pisces, or Resume) systems had a significantly greater clinical reliability than unipolar systems (Medtronic, Inc., Minneapolis, MN, Sigma Pisces) (P < 0.001).
We found that the best location of the electrodes was just at the upper level of the spinal cord segments corresponding to the painful territory. For reaching this goal, we found easier to insert the electrodes through an open interlaminar approach rather than percutaneously, which proved more hazardous.
The most important articles reporting large experiences consider failed back syndromes with radicular pain as a good indication for SCS. 55–62 Kumar et al., 54 in their recent review of the literature (2,426 patients undergoing implantation) concluded that “cases with pain due to failed back syndrome, multiple sclerosis, reflex sympathetic dystrophy, peripheral neuropathy, peripheral vascular diseases, showed good responses after successful implantations.” They also reviewed the possible prognostic factors other than the type of pain syndrome. They did not find any significant role of age or sex. Unilaterality of pain (previously reported to respond to treatment better than bilateral pain) was not found a significant factor by these authors, nor was the number of previous operations, but a long duration of pain before SCS surgery emerged as a poor prognostic factor.
The common experience of most surgical teams dealing with SCS is that the method is effective only if paresthesias are induced and if they cover the whole painful territory. In our experience, this can be achieved only when two conditions are fulfilled: when enough valid dorsal column fibers up to the brainstem are present and, of course, if location of the electrodes is appropriate.
The first condition is a prerequisite for deciding to undertake SCS. In a retrospective study of our series, we found that SCS was not effective when primary afferent neurons were interrupted at the radicular level centrally to the DRG or when there was a complete interruption of them at the spinal cord level 63,64 (Fig. 3).
When it is not possible from clinical examination and imaging to determine the functionality of the dorsal column fibers between the dorsal ganglion and the cuneate gracilis relay nuclei at the brainstem level, recordings of SEPs are useful as an ancillary tool for patient selection by allowing assessment of the functional status of the lemniscal system. Clinical failure of SCS attributed to so-called malposition of the electrodes may be, in some cases, simply caused by a wrong appraisal of functionality of dorsal column fibers. 65 The proportion of cases with clinical efficacy has been shown to increase dramatically if patients are strictly selected on the basis of a careful assessment of the lemniscal system, using SEP recordings if necessary 66 (Fig. 4).
In difficult cases, a percutaneous stimulation test for a few days, before implantation is decided on, can be usefully associated with recordings of the (nociceptive) RIII flexion reflexes, because RIII depression during stimulation has been significantly associated with good efficacy of SCS 50,67 (Fig. 5).
Finally, if large primary afferent neurons up to the brainstem nuclei are not functional, supraspinal targets may be chosen at the level of the deep brain structures, especially at the thalamic sensory relay nucleus 68 or the precentral cortex. 69
For neuropathic pain, the deep brain stereotactic targets used are the nucleus ventralis posteromedialis for the face and the nucleus ventralis posterolateralis for the upper and lower extremities. According to a literature review, 63 the results are better for pain in the territories of the neck and the face than in those of the peripheral nerves and the spinal cord. The most common indications are postherpetic neuralgia and anesthesia dolorosa.
Precentral (Motor?) Cortical Stimulation
Because stimulation of central motor fibers was shown to inhibit afferent transmission in the dorsal horn as early as 1957 by Lindblom and Ottoson 70 and in 1962 by Andersen et al., 71 motor stimulation of the pyramidal tract at the level of the internal capsule was applied to produce analgesic effects in humans in 1974 by Adams et al. 72 The use of motor cortex stimulation to control central pain was introduced by Tsubokawa and coworkers especially for poststroke pain in 1991, 69 by Meyerson et al. for trigeminal neuropathic pain in 1993, 73 and by Katayama et al. for Wallenberg syndrome in 1994. 74
In spite of encouraging results, the mechanisms of PCS have not yet been elucidated. In a recent study, Katayama et al. 75 observed that a high degree of corticospinal impairment may be a predictor of poor efficacy. Tsubokawa et al. 76 have suggested that in cases of thalamic pain, PCS ensures activation of the rostral preserved nonnociceptive functional zones via backward excitation of axons connecting primary somatosensory and motor areas. Experimental data also point to the thalamus as a possible target of PCS, because this procedure is able to attenuate thalamic electrophysiologic hyperactivity after spinothalamic transection in cats. 77 Whatever the mechanisms underlying the clinical effects of PCS, they are likely to be mediated by regional changes in synaptic activity—and thus of cerebral blood flow, which can be measured in humans using positron emission tomography. 78,79 In these latter studies on patients, cerebral blood flow was observed to increase during PCS in the ventrolateral and medial thalamus ipsilateral to stimulation, in the orbitofrontal and anterior cingulate gyri, the anterior insula/medial temporal lobe, and the upper brainstem near the periaqueductal gray. According to Garcia-Larrea et al., 80 these findings suggest that PCS could (1) influence the affective emotional component of chronic pain by way of cingulate/orbitofrontal effects and (2) lead to descending inhibition of pain impulses by activation of the brainstem.
The surgical technique consists of a small craniotomy performed in front of the estimated area of the motor cortex, determined at first by using the conventional method of the coronal suture landmarks (Figs. 6 and 7). In patients whose somatosensory potentials are preserved, the location of the central sulcus is then confirmed from phase reversal of the N20 wave of the SEP recorded from the electrode applied extradurally. When the recording electrode is moved from the postcentral to the precentral gyrus, the N20 becomes positive (i.e., P20). Precentral identification can also be performed by use of the electrostimulator. According to Tsubokawa et al., 76 the best location and orientation of the electrode array correspond to the site where the bipolar stimulation produces muscle twitches in the painful area with the lowest threshold. When SEPs are not present, identification of the central sulcus can be guided by magnetic resonance imaging neuronavigation. After location in the appropriate place, the electrode array is tightly sutured on the dural surface, and the stimulation system is internalized. In the following days, the parameters for chronic stimulation are chosen so that the pain is inhibited for the lowest intensity possible by adjusting the frequency at the optimum value (between 25 and 60 Hz). In all patients, pulse width is constantly at 60 milliseconds. Intensity must always be restricted to a level lower than the threshold of muscle twitches and paresthesia (between 1.5 and 4.5 volts). Cycle periods of stimulation are 30 minutes on and 90 minutes off.
The results in 127 operations have been reported 73,74,76,81–85 (Table 1). Eighty-six patients had pain after brain stroke; in 29 it corresponded to trigeminal neuropathic pain, and in 12 it was of miscellaneous origins. Pain relief >50% was obtained after 1-year follow-up in two thirds of cases in patients with poststroke pain and at the same rate in patients with neuropathic trigeminal pain. In most patients, relief persisted on long-term follow-up, i.e., 1 to 6 years (average 2 years), according to the patients.
In our own series of 20 patients followed up for >1 year after surgery 86 (Figs. 8 and 9), pain relief was >80% in 5 patients and between 80% and 50% in 7.
In all series, complications were limited to occasional epileptic seizures by the time intensity parameters were adjusted.
In conclusion, preliminary experience in PCS encourages us to recommend this method for treating poststroke pain and trigeminal pain of neuropathic origin. Further studies are in progress to better evaluate the long-term efficacy of this technique and to investigate whether other types of pain can be favorably influence by this technique.
Dorsal Root Entry Zone Lesions
In the 1960s, several neurophysiologic investigations showed that the dorsal horn is the first, and an important, level of modulation for pain sensation. This was popularized in 1965 through the gate control theory, 87 which drew neurosurgeons' attention to this area as a possible target for augmentative (spinal cord stimulation) and ablative pain surgery. In 1972, we undertook anatomical studies and preliminary surgical trials in the human DREZ to determine whether a destructive procedure using a microsurgical technique was feasible. 88,89
Because the first results in malignancies (mainly the Pancoast syndrome) were encouraging, in the next 2 years we attempted the procedure in patients with neuropathic pain syndromes, namely those associated with paraplegia in December 1972, amputation in July 1973, and brachial plexus avulsion in January 1974. Soon there after (September 1974), Nashold and his group began to develop DREZ lesions, using radio-frequency thermocoagulation as the lesion maker in the substantia gelatinosa of the dorsal horn 90 and later in the whole DREZ, 91 especially for pain caused by brachial plexus avulsion. More recently, DREZ procedures have been performed by use of the laser by Levy et al. 92 and Powers et al. 93 and by use of an ultrasound probe by Kandel et al. 94 and Dreval, 95 as well as for pain caused by brachial plexus avulsion.
The Microsurgical DREZotomy procedure
The procedure consists of a longitudinal incision of the dorsolateral sulcus, ventrolaterally at the entrance of the rootlets into the sulcus, and microbipolar coagulations performed continuously inside the sulcus, down to the apex of the dorsal horn, along all the spinal cord segments selected for surgery. The lesion, which penetrates the lateral part of the DREZ and the medial part of the tract of Lissauer (TL), extends down to the apex of the dorsal horn, which can be recognized by its brown-gray color. The average lesion is 2 mm to 3 mm deep and is made at a 35° angle medially and ventrally (Fig. 10).
In patients with conserved dorsal roots and remaining sensory functions, the procedure is presumed to preferentially destroy the nociceptive fibers grouped in the lateral bundle of the dorsal rootlets, as well as the excitatory medial part of the TL. In addition, the upper layers of the dorsal horn are destroyed if microbipolar coagulations are made inside the dorsal horn to suppress the hyperactive neurons. 3,4. The procedure aims at preserving, at least, partially the inhibitory structures of the DREZ (i.e., the lemniscal fibers reaching the dorsal column, as well as their recurrent collaterals to the dorsal horn and the SG propriospinal interconnecting fibers running through the lateral part of the TL). This method, the microsurgical DREZotomy (MDT), was conceived with a view to preventing complete abolition of tactile and proprioceptive sensations and avoiding deafferentation phenomena. 96 Of paramount importance, selection of the site and extent of the DREZ lesion must take into account the shape, width, and depth of the TL and of the dorsal horn (Fig. 11). Detailed descriptions of the procedure have been previously published 97–99 and will be only summarized here.
Operative Procedure at the Cervical Level.
The prone position with the head and neck flexed in the so-called Concorde position has the advantage of avoiding brain collapse caused by cerebrospinal fluid depletion. A hemilaminectomy, generally from C4 to C7, with preservation of the spinous processes, allows sufficient exposure to the posterolateral aspect of the cervical spinal cord segments that correspond to the upper limb innervation, that is, the rootlets of C5 to T1 (T2). After the dura and the arachnoid are opened longitudinally, the exposed roots are identified.
Microsurgical lesions are performed at the selected levels, that is, those that correspond to the pain territory. The technique is summarized and illustrated in Figure 12. The incision is made with a microknife. Then, microcoagulations are made in a chain (i.e., dotted) manner. Each microcoagulation is performed by short (a few seconds), low-intensity, bipolar electrocoagulation with a special sharp bipolar forceps. The depth and extent of the lesion depend on the degree of the desired therapeutic effect and the preoperative sensory status of the patient.
For pain caused by brachial plexus avulsion, after incision of the dorsolateral sulcus, dotted microcoagulations inside the dorsal horn (at least 3 mm in depth from the surface of the cord) are performed with the sharp graduated bipolar forceps, at the level of the avulsed roots. Selective ventrolateral DREZ lesions are extended to the root remaining above and below. In brachial plexus avulsion, dissection of the spinal cord is sometimes difficult to achieve safely because of scar tissue adhering to the cord. Atrophy and/or gliotic changes at the level of the avulsed roots can make identification of the dorsolateral sulcus hazardous. In such cases, it is necessary to start from the roots remaining above and below. The presence of tiny radicular vessels that enter the cord may help determine the site of the sulcus. Yellow areas corresponding to old hemorrhages on the surface of the cord and/or microcavities in the depth of the sulcus and the dorsal horn provide some guidance for tracing the sulcomyelotomy. When the dorsolateral sulcus is difficult to find, intraoperative monitoring of SEPs evoked by stimulation of the tibial nerve is especially helpful for preserving the ascending dorsal column fibers.
Operative Procedure at the Lumbosacral Level.
The patient is positioned prone on thoracic and iliac supports, and the head is placed 20 cm lower than the level of the surgical wound to minimize the intraoperative loss of cerebrospinal fluid. The desired vertebral level is identified with lateral radiographs that include the S1 vertebra. After the laminectomy—either bilateral or unilateral, according to pain topography—is completed, the dura and arachnoid are opened longitudinally, and root level is identified, if necessary by electrical stimulation and/or surface spinal cord SEPs. 100,101
Microsurgical DREZotomy at the lumbar and sacral levels follows the same principles as at the cervical level. The technique is summarized and illustrated in Figure 13. It is important to emphasize that at the lumbosacral level, MDT can be difficult and dangerous because of the rich vasculature of the conus. The posterolateral spinal artery courses along the posterolateral sulcus. Its diameter is between 0.1 mm and 0.5 mm, and it is fed by the posterior radicular arteries and joins caudally with the descending anterior branch of the Adamkiewicz artery through the conus medullaris anastomotic loop of Lazorthes. This artery has to be preserved by being freed from the sulcus.
The Radio-Frequency Thermocoagulation Procedure
In 1976, Nashold and his group published a method using RF thermocoagulation to destroy hyperactive neurons in the substantia gelatinosa 90; in 1979 they applied the technique to the whole DREZ region 91 In 1981, 102 the technique was modified to produce less extensive lesioning, so that the risk of encroachment on the neighboring corticospinal tract and dorsal column is minimized. In the modified technique, the lesion is made with a 0.5-mm insulated stainless steel electrode, with a tapered noninsulated 2-mm tip, designed and manufactured by Radionics, Inc (Cambridge, MA).
For treatment of pain after brachial plexus avulsion, the electrode penetrates the dorsolateral sulcus to a depth of 2 mm at an angle of 25° to 45° in the lateral-medial direction. A series of RF coagulations is made under a current of 35 mA to 40 mA (not >75°C) for 10 to 15 seconds. The RF lesions are spaced at 2-to 3-mm intervals along the longitudinal extent of the dorsolateral sulcus. The lesion observed under magnification is seen as a circular whitened area, which extends 1 to 2 mm beyond the tip of the electrode.
In a recent publication, Nashold and Nashold emphasized the importance of impedance measurements during surgery for accuracy of the lesioning. 103 Before and after each lesion, the impedance has to be measured. It is usually <1,200 ohms in damaged spinal cord. The authors state that as the transition from injured parenchyma into more normal tissue is made, impedance readings should increase and eventually reach normal levels of 1,500 ohms. The authors use these figures as a guide to stop the lesion making at the desired point.
DREZ Procedures with the Laser Beam
Levy et al. in 1983 92 and Powers et al. in 1984 93 advocated CO2 and argon laser, respectively, as lesion makers. According to the description of Levy et al., the pulse duration of the CO2 laser is 0.1 seconds, and the power is adjusted to ∼20 W, so that one or two single pulses create a 2-mm depression at a 45° angle in the DREZ. The lesions are probed with a microinstrument marked in 1-mm increments to ensure that the depth of the lesions (1–2 mm) is adequate.
Intraoperative observations in humans and experimental studies comparing DREZ lesions performed by RF thermocoagulation with those made by various laser beams 104 showed that the laser lesions were generally more circumscribed and less variable. However, Walker et al. 105 reported on the danger of creating extensive damage and syrinx cavities with the CO2 laser. In a well-documented study evaluating the effects in dog spinal cord of DREZ lesions with RF or CO2 (or Yag laser), Young (personal communication 1988) observed that the size and extent of the lesion was related primarily to the magnitude of power used to make the lesion. They showed that if the procedures are performed with proper parameters, the lesions could be successfully localized to the DREZ, including layers I through VI of the dorsal horn, and spare the dorsal column and the corticospinal tract, using any of the three techniques. The main difference was that with laser, the lesion was V-shaped, with the maximum width at the surface, whereas with RF it tended to be more spherical. The same glial reactions were observed with both methods in animals followed over a long period of time.
Young 106, in a series of patients, made a comparative analysis of RF and CO2 laser procedures. With RF, 39 of 58 patients (67%) reported good results (pain regressed by ≥50%), and with the CO2 laser, 9 of 20 patients (45%) reported good results. Postoperative complications with RF were noted in 26% of patients and with CO2 laser in 15%.
The Ultrasonic DREZ Procedure
This procedure was developed by Kandel et al. 94 and Dreval 95 in Moscow. It has been mostly used for pain caused by brachial plexus avulsion. According to Dreval, the technique consists of a continuous longitudinal opening of the dorsolateral sulcus at the level of the avulsed roots to the depth of the microcavities and the changed spongy cord tissue. At the same time, ultrasonic destruction of the pathologically affected tissues is made. The lesion is strictly in the projection of the dorsolateral sulcus at an angle of 25° medially and ventrally. The depth of the microcavities is the main criterion of the depth of the lesioning. After ultrasonic DREZsulcomyelotomy, the gray color of the dorsal horn is well seen in the depth of the opened dorsolateral sulcus. The vessels crossing the sulcus are kept intact. The ultrasonic lesions are produced at a working frequency of 44 kHz, and the amplitude of ultrasonic oscillation is 15 μm to 50 μm. The lesions are placed in a chainlike manner along the sulcus.
The indications for surgery in the DREZ correspond to well-defined and topographically limited forms of severe neuropathic pain.
Indications for Surgery in the DREZ
- 1. All the authors experienced in pain surgery, and using DREZ procedures whatever their modality may be, agree that DREZ operations are effective for pain developing after brachial plexus avulsion. We believe that the DREZ lesion must not be limited to the avulsed segments but has to be extended to the adjacent remaining roots, especially if their level corresponds to the painful territory.
- Our results with the microsurgical DREZotomy technique in patients followed up for >1 year are summarized in Figure 14.
- The long-term results in our series agree with those in the literature. The group at Duke University has reported a success rate of 54% in a series of 39 patients operated on with the RF thermocoagulation technique. 107 The Queen Square group in London 108,109, in a series of 44 patients treated also with thermocoagulation, obtained a 68% success rate. Rath et al. in Germany 110 reported a 61% rate of success in 13 cases also treated with RF thermocoagulation. Dreval 95 has reported a 87% success rate in 127 patients in whom the DREZ lesions were performed by use of a special small ultrasonic probe.
- A review and analysis of the literature concerning postoperative complications with RF or laser DREZ procedures for brachial plexus avulsion 111 showed corticospinal and/or dorsal column deficits (more or less severe) in 0% to 10% of patients with the laser and in ≤50% with the RF technique.
- 2. DREZ lesions may be indicated for pain caused by spinal cord and/or cauda equina lesions. Most patients who underwent DREZ surgery for spinal cord or cauda equina lesions corresponded to spine injuries. 110–114 Nashold's group has reported in detail their results in several publications. 112,113 In our series of 44 cases, long-term good results amounted to 68%.
- Because in our series a majority of the trauma patients did not have a complete treatment for their vertebral fracture(s) at the time of the injury, MDT was preceded by a long dissection of the dura from the surrounding epidural fibrosis, a delicate freeing of the cord and/or the roots from adhesive arachnoiditis, and an eventual freeing of the neural structures from residual bone fragments occupying the subdural space. This preparatory approach was performed in about half of the patients as the first step of the whole operation. In the other half, because the approach was particularly long and bloody—especially when metallic rods had to be removed—it was the first part of a two-stage operation, the second stage being done ∼1 week later.
- Our experience is that MDT performed for pain associated with spinal cord lesions is effective only in patients whose pain has a radiculometameric distribution, that is, the pain corresponding to the level and extent of the spinal cord lesion. Pain in the territory below the lesion, especially in the perineosacral area, is not favorably influenced even if DREZ surgery is performed in the lower medullary segments. This is particularly true when the pain consists of a permanent burning sensation and is located in a infralesional totally anesthetic area.
- Therefore, MDT must be reserved for pain syndromes that are related to the injured medullary segments and the adjacent ones if modified by consecutive pathologic processes (cavitation, gliosis, arachnoiditis). In patients with incomplete paraplegia, DREZ lesions must be performed not too deeply to avoid additional neurologic deficits. By contrast, in patients with complete motor and sensory deficits below the lesion, MDT can be done extensively on the selected segments. The best indications for DREZ surgery are the same as those for cordectomy, i.e., traumatic lesions of the spine below T10 (conus medullaris), especially when pain is in the legs rather than in the perineum.
- Pain caused by lesions of the cauda equina can also be favorably influenced by MDT performed on the corresponding spinal cord segments.
- 3. When pain is caused by peripheral nerve injuries is not relieved by transcutaneous neurostimulation or spinal cord stimulation, MDT may be considered. This group of pain patients consisted of 38 cases in our series. Our experience is that MDT can be indicated when the predominant component of pain is of the paroxysmal type (electrical flashing pain), corresponds to allodynia, or both. Good results can also be achieved in severe posttraumatic causalgic syndromes with disabling hyperpathia; the pain and also the vasomotor disturbances can be favorably influenced. In patients without neurologic deficit, the DREZ lesion must not be too long and deep, so that the tactile and proprioceptive sensory capacities can be at least partially retained and uncomfortable paresthesias avoided.
- 4. After limb amputation, two main types of pain, which may coexist, can be encountered: pain in the phantom limb and pain in the stump. If spinal cord stimulation fails, DREZ surgery can be considered. Phantom limb pain is generally relieved when rootlets are found avulsed. Pain in the stump is inconstantly influenced; better results are obtained when the pain is of the paroxysmal and/or allodynic type.
- 5. A DREZ operation of the microsurgical type can be also considered for severe occipital neuralgia or unbearable laterocervical pain. Surgery is performed at the C2–C3 medullary segments. At this level, the procedure is quite easy through a C2 hemilaminectomy. The results in our three such cases were good. In the series of 11 cases published by Dubuisson, 115 the effects of the operation were also good.
- 6. The results of surgery in the DREZ for postherpetic pain have been reported by a few groups. 110,116 Our experience of MDT for postherpetic neuralgias in 10 cases is that only superficial pain located in the affected dermatome(s) is significantly improved, especially when it is of the allodynic type. The permanent (burning and/or aching) deep component is generally unrelieved and can even be aggravated, the patient experiencing additional constrictive sensations after operation. Before deciding for DREZ surgery in patients with postherpetic neuralgia, even when it is unbearable, one must be very cautious. Although no death or postoperative neurologic complication occurred in this group in our series, it is necessary to emphasize the possible vital risks in these patients, who are often elderly and psychologically impaired. Besides, when the thoracic spinal cord is the target, because at this particular level the dorsal horn is very narrow and deeply situated, encroachment on the corticospinal tract laterally and on the dorsal column medially may happen. Whatever the topographic level of the pain may be, the exact clinical identification of the root(s) corresponding to the herpetic lesions is difficult. At operation, the observation of atrophy and a grayish color in the concerned root(s) can be helpful.
In conclusion, if the selection of candidates for surgery is rigorous, DREZ lesions can achieve good pain relief. Figure 15 shows how surgery in the DREZ takes place within the frame of the neurosurgical repertoire for neuropathic pain.
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