Current State of Motor Cortex and deep brain stimulation for the treatment of intractable neuropathic face pain

Abstract

Intractable neuropathic face pain is a syndrome of unremitting severe pain that stems from abnormal nociceptive processing at various levels of the trigeminal system. Treatment of this debilitating condition has long presented a challenge for physicians due to the refractoriness to standard pharmacologic therapies. With few viable treatment options available surgical procedures such motor cortex stimulation (MCS) and Deep brain stimulation (DBS) provide additional treatment options. The authors present a review of the current literature and practices regarding patient selection criteria, potential mechanism of action, surgical technique, and outcome of patients with neuropathic face pain treated with MCS and DBS.

Introduction

Intractable neuropathic face pain is a syndrome of severe constant, throbbing or burning pain in the distribution of the trigeminal nerve. Common etiologies of the pain can include injury to the nerve from surgical procedures, facial trauma, stroke, and post-herpetic neuralgia. The disorder is often refractory to most pain medications. Current pharmacologic treatment continues to include regimen of anticonvulsant and antidepressant drugs. With few effective therapies available, Motor cortex stimulation (MCS) and Deep Brain stimulation (DBS) have shown promise as potential surgical treatment options to provide pain relief.

The ability of electrical stimulation of the motor cortex to produce analgesia was first observed by Penfield in the 1930s during intraoperative electrical stimulation in epilepsy patients [1]. However, it was not until the early 1990s that Tsubokawa et al. [2, 3] published outcomes from their case series of patients implanted with a motor cortex stimulator for the treatment of intractable pain. Since then, MCS for chronic pain syndromes has grown, with variable clinical results [4]. Similarly, Deep Brain Stimulation (DBS) of the sensory thalamus, periaqueductal (PAG), or periventricular grey (PVG) has also been employed in the treatment of intractable pain syndromes. Although multicenter trials have been attempted to determine the efficacy, it is still undetermined the precise value of DBS in the treatment of chronic pain [5][6].

Here, we provide an overview of the current status of MCS and DBS in the treatment of intractable neuropathic facial pain, describing the patient selection, preoperative evaluation, potential mechanism of action, surgical technique, and outcome.

Patient Selection and Preoperative Evaluation

Currently, no standard inclusion or exclusion criteria exist for patients undergoing either MCS or DBS for chronic pain. A comprehensive evaluation including a detailed history, physical examination, is important in determining which patients would be appropriate for the procedure as well as provide baseline values to measure the degree of pain reduction post-operatively. Assessment of the type and intensity of pain can be done with tools such as the Visual Analog Scale (VAS), the McGill Pain Questionnaire, the Quality of Life Inventory, or the Health Status Questionnaire 2.0. [12]. A pain journal maintained by the patient to characterize the nature, intensity, distribution of pain becomes an invaluable tool in assisting with classification of face pain. Imaging studies (Head MRI or CT) are completed to exclude other etiologies.

Facial pain classifications have been developed based on information provided from patients. Classification is intended to provide a systematic framework to better understand and treat facial pain syndromes. Typical trigeminal neuralgia has been described as episodic, sharp, shock-like face pain in one or more of the three trigeminal nerve distributions. Pain occurs in bursts, often triggered by facial activities such as talking or brushing teeth. In contrast, atypical face pain is described as constant, aching, burning, or throbbing pain or any face pain that does not fit the classic clinical picture of typical trigeminal neuralgia. Burchiel et al. developed a classification system to provide a standardized means to accurately diagnose the patient’s condition and offer further information about natural history and treatment options (see table 1). A classification system facilitates improved communication between specialties and consistency for clinical trials

Table 1.

Burchiel Face Pain Classification

• Type 1 and Type 2	• Typical Trigeminal Neuralgia Spontaneous Episodic (Type 1) or Constant (Type 2)
• Type 3	• Trigeminal Neuropathic pain Results from Unintentional Injury to Trigeminal Nerve from Trauma or Surgery
• Type 4	• Trigeminal Deafferentation Pain Results from Intentional Injury to Trigeminal Nerve by surgeries intended to treat TGN
• Type 5	• Symptomatic Trigeminal Pain from Multiple Sclerosis
• Type 6	• Post Herpetic Neuralgia that occurs after outbreak of Herpes Zoster typically affecting the 1st division of the nerve
• Type 7	• Chronic Face pain and somatoform pain disorder. Pain typically bilateral and extends beyond margins of the trigeminal nerve.

As with other surgical interventions, efficacy and outcome also rely on social and emotional stability and support systems available to the patient. Evaluations by a pain psychiatrist could assist patients to maintain realistic expectations and to identify psychosocial stressors. Further, because neuromodulation may act on the limbic system altering the suffering aspect of pain, depression could alter outcome [13]. In addition, stress management therapy and development of coping skills are suggested for these patients especially if the stressor is one that is not likely to change with surgery, such as job dissatisfaction or marital problems.

Interestingly, high-frequency sub threshold repetitive transcranial magnetic stimulation (rTMS) of the motor cortex has been shown to be able to produce analgesic effects in patients with chronic pain and has been suggested to be useful in identifying patients who may benefit from MCS. However, the clinical application of rTMS for patient selection for MCS has not been clearly demonstrated and needs further evaluation.

In an effort to identify which patients with central pain syndromes could benefit from neuromodulation, several groups have developed testing protocols with various drugs. For example, Yamamoto et al. [9] used morphine, thiamylal and ketamine tests to correlate pharmacological characteristics and the effects of chronic motor cortex stimulation therapy. The study employed 39 central post-stroke pain patients who had intractable hemibody pain. The long-term follow-up results of MCS revealed that thiamylal and ketamine-sensitive and morphine-resistant cases experienced long-lasting pain reduction. They concluded that pharmacological classification of central post-stroke pain by the morphine, thiamylal and ketamine tests could be useful for predicting the outcome of motor cortex stimulation therapy. In addition, Saitoh et al. [10] infused phentolamine, lidocaine, ketamine, thiopental, morphine, and a placebo before electrodes implantation. They found a positive response to ketamine to be a good prognostic indicator of response to neuromodulation.

Motor Cortex Stimulation Mechanism of Action

There is much speculation as to the exact mechanism of action of MCS. There is debate as to whether it acts at the cortical level or at the level of pyramidal neurons and their efferents [16, 17]. This debate most likely stems from the fact that the primary motor cortex is known to inhibit the primary somatosensory cortex, the ventral posterior thalamus and the spinothalamic tract [18]. There are highly organized, reciprocal pathways between M1 and S1 that carry primarily non-noxious information, and it has been suggested that MCS works via these pathways to restore the inhibition of hyperactive nociceptors and produce its analgesic effect [19, 20]. Further, It is known that the somatosensory system can attenuate the output of nociceptive neurons [14]. With deafferentation this attenuation is lost, leading to aberrant connections, reduced spatial discrimination and a divergence of excitation which manifests clinically as abnormal sensory phenomena such as hyperalgesia and allodynia [15]. When this system is damaged or destroyed, normal non-painful stimuli can elicit pain. Stimulation of these damaged afferents can reestablish the inhibition of the nociceptive fibers. It is this reasoning that led Tsubokawa and colleagues to attempt to treat chronic pain by the stimulation of the primary somatosensory cortex (S1), although surprisingly it was stimulation of the primary motor cortex (M1) that produced a greater analgesic effect. [3] This may be due to more effective stimulation of the sensory cortex via synaptic connections than via direct somatic depolarization of the neurons. There are extensive cortico-cortical projections from primary motor to primary sensory cortex, and many of these axons travel in Layer I, the most superficial cortical layer, making them easily accessible to stimulation.

The analgesic effect of MCS is delayed from hours to days in some cases, arguing against a direct inhibitory effect on S1 accounting for its mechanism, and its analgesic effects extend for hours after its discontinuation. Furthermore, the effect occurs below motor threshold, arguing against the requirement for, at least layer V pyramidal cell depolarization, and favoring more superficial axonal depolarization as the medium of the analgesia. The established involvement of the NMDA receptor system suggests a mechanism involving synaptic plasticity, which is concordant with the time course of its onset and offset.

In addition to these changes, numerous PET studies have found changes in cerebral blood flow (CBF) to many areas including the ipsilateral thalamus, Periaqueductal and Periventricular gray (PAG/PVG), anterior cingulate cortex (ACC), orbitofrontal cortex and brainstem with analgesic effects corresponding closest to changes in CBF of the anterior cingulated gyrus [18, 21–24]. Current evidence suggests the activation of a functional network for pain control that includes the ACC, orbitofrontal cortex, medial thalamus, and PAG/PVG. For example, Peyron et al [25], observed activation in the anterior middle cingulate cortex (aMCC), which is anatomically connected to the primary motor cortex [26], as well as in the pregenual ACC (pgACC), which is activated with medial prefrontal Cortices in pain control. Interestingly, it has been demonstrated that brain areas activated by MCS have connections with the pgACC, orbitofrontal cortex, and insula [27, 28], suggesting the existence of a functional network of pain control activated by MCS.

Another mechanism that has been suggested for the pain relief obtained with MCS involves the endogenous opioid system. Maarawi et al. [29] recently demonstrated that MCS produced an enhanced secretion of endogenous opioids, particularly in the aMCC and PAG, which correlated with pain relief. Also, the areas in which CBF is increased with MCS are known to have a high density of opioid receptors.

Surgical Technique

The surgical technique for MCS has evolved from that first used by Tsubokawa et. al. Most centers utilize image guidance either with CT or MRI to localize the region of face pain, anterior to the central sulcus at the level of the inferior frontal sulcus. This information is loaded into a neuronavigation workstation and used to direct the most appropriate location for the incision and craniotomy. Local or general anesthesia may be used. After completing the craniotomy, the central sulcus must be identified as well as the cortical region representing the hand. This can be accomplished intraoperatively with somatosensory evoked potentials (SSEPs) (median nerve, N20 – P20 phase shift) followed by cortical mapping. Recently preoperative functional MRI (fMRI) for tongue tapping and face brushing has been implemented to localize the desired target. Data is merged with preoperative imaging in the neuronavigation workstation to guide the surgical procedure (Figure 1).

Figure 1.

Model of the motor cortex showing motor cortex with lead localized to the area of the motor cortex representing the face. Green represents area of somatosensory cortex activated with face brushing. Purple represents electrode contacts.

Most centers position the grid in the epidural space, however, some (including Mayo clinic), place the electrodes in the subdural space. The advantages of epidural space placements include lower operative risk and shorter operative time. Disadvantages include higher required stimulus intensities resulting in shorter battery life and limitation of stimulation intensities due to pain evoked by dural pain fibers. For these reasons, some centers, including Mayo Clinic, routinely place the stimulating electrodes in the subdural space. Following placement of the electrode, the leads are tunneled, externalized, and connected to an external stimulus generator for trial stimulation monitoring in the intensive care unit. All patients undergo postoperative spiral CT scan to localize the position of the test grid. This can be merged with preoperative fMRI data to determine accuracy of grid placement relative to the activated facial area (Figure 1).

Trial stimulation typically lasts 2–4 days with a goal of 50% reduction in reported pain level. The patient maintains the pain journal during this period to provide a guide for response to changes in stimulation parameters. Original parameters used at Mayo Clinic are 4 contacts along the posterior motor cortex negative, 4 contacts along the anterior motor cortex positive, pulse width of 450 μs, rate of 40 Hz, and amplitude of 4.0 V. This is the highest yield arrangement, from there the grid is explored with better results moving anterior than posterior. We have found that the fMRI appears quite accurate in identifying the facial region of the motor strip gauged by suprathreshold stimulation parameters. Seizures are a risk in this situation and often times the most effective stimulus amplitude is just below seizure threshold. We often pretreat our patient with fosphenytoin because of this risk.

If successful with the patient reporting 50% reduction in pain often documented with the use of the VAS, the patient would return to the operating room for permanent implantation of a four contact RESUME electrode (Medtronic, Inc., Minneapolis, MN, USA) centered over the most effective leads of the trial grid and connected to an internal pulse positioned in the subclavicular region.

Alignment of the RESUME leads with the grid electrodes is facilitated by intraoperative photographs taken during grid placement.

There is much variability among the stimulation protocols. A recent review of the current literature found stimulation protocols with rates of 15–130 Hz, pulse widths of 60–500 μsec and amplitudes of .5–10.5 mA [22]. There is also some debate as to whether the stimulation should be continuous or episodic. Advocates of episodic stimulation point to the fact that MCS has been shown to have analgesic effects for hours after stimulation has stopped. Regardless of the exact stimulation protocol used, the analgesic effect is always achieved below the motor threshold, and increased voltage may even cause intolerable sensory effects. [18] At our institution we employ cycling mode stimulation with 0.1 seconds on alternating with 0.1 seconds off, 100 Hz frequency.

Patient Follow-Up, Outcomes, and Complications

The reported patient outcomes following MCS have varied widely. This may be due to the fact that inclusion criteria for patients selected for MCS vary widely. In addition, the follow up period has varied considerably from study to study. In two separate studies, Meyerson et al. [30, 31] followed nine patients with trigeminal neuropathic pain, with follow up time varying between 8 and 40 months. Of these patients, 6 had pain relief greater than 60%, with 2 achieving 100% pain relief. In two studies by Nguyen et al. [32, 33], 12 patients suffering from trigeminal neuropathic pain underwent MCS and over the course of follow up (mean was 27.3 months) 8 had 70–100% relief. In a study by Brown and Pilitsis [4], 8 of 10 patients suffering from facial pain underwent permanent MCS implantation with 75% obtaining pain reduction over a follow up period ranging from 3–24 months. Nuti et al [34] treated 31 patients with neuropathic pain with MCS. At one month, 52% of the patients had pain relief greater than 40%. Additionally, 35.5% of the patients had stopped medical treatment altogether and 16% decreased their regimen. In a more recent study, Velasco et al [35] used MCS to treat 11 patients with neuropathic pain, 8 of whom underwent permanent implantation. At one year follow-up, all 8 patients had at least 40% pain reduction (range 40–86%). Table 2 shows the overall results for several recent studies of MCS for the treatment of neuropathic pain.

Table 2.

Recent Patient Outcomes using MCS or DBS for the treatment of Neuropathic Pain^*

Study	Number of Patients	Implantation Site	Mean Follow-Up (mth)	Mean Pain Relief (%)
Velasco et al. 2008	8	Motor Cortex	12	63.25
Nuti et al. 2005	31	Motor Cortex	1	39.2
Brown and Pilitsis 2005	8	Motor Cortex	10	75
Pereira et al. 2007	3	VPL/PVG	27.3	37
Owen et al. 2006	15	VPL/PVG	12	48.8
Rasche et al. 2006	6	VPM/PVG	30	45.8

^*This indicates only the patients with neuropathic pain; individual studies may have included more patients.

Of the few reports of complications from MCS, seizures have been reported. Some patients may experience seizures during the testing period and with subsequent changes in programming parameters. The amplitudes found to induce seizures have a lower threshold of approximately 6V, with seizures becoming relatively common beginning at 9V [36]. Thus, seizures can be avoided by keeping stimulation parameters below this range as well as administering anti-epileptic drugs. There has been some concern about adverse cognitive effects since MCS seems to work via brain structures that are also involved in cognitive functions such as attentional processes. A study by Montes et al. [37] revealed that MCS might interfere with simple cognitive processes.

Many MCS patients report decrease in the efficacy of the stimulation in follow up. Readjustment of the stimulation parameters often results in a restoration of the analgesia, but is not true for all patients. It is not known why this occurs, but further study of this might lead to the revelation of the underlying mechanisms of MCS as well as a solution to this effect.

Deep Brain Stimulation Mechanism of Action

DBS for pain has been used since the 1950’s when the caudate and thalamus were targeted in chronic pain patients [38]. Since no conclusive results were obtained from multicenter trials in the 1990’s [5], DBS has been used less frequently. However, there is still much to learn about this technique and its usefulness in treating intractable neuropathic pain.

The actual therapeutic mechanisms of DBS are not known. Recent studies have begun to shed more light on its likely mechanisms. In the case of stimulation of the PVG/PAG, one potential mechanism is the release of endogenous opioids. This is supported by studies which indicate that analgesia produced by stimulation of this area is blocked by administration of naloxone [39, 40]. Stimulation of the PVG might also alter the activity of ascending pain pathways involved in the emotional response to pain. This idea comes from fMRI studies that show activation in the thalamus medial dorsal nucleus, which has connections with the cingulated cortex and is associated with the limbic cortex [41]. Pereira et al [42] showed increased rCBF in the region between the PVG and thalamus in patients with stimulation of the VPL thalamus and/or PVG. This area contains the centromedian parafascicular complex, which is involved in pain processing [43], and the zona incerta which has been implicated in nociception. [44] They also found that there was a reduction in rCBF in neocortical areas, including the anterior cingulate cortex, in patients with dual stimulation of the VPL and PVG. This led to the conclusion that increased thalamic activity reduces neocortical pain processing via an inhibitory gating process. From the results of this and other similar studies [45, 46], it seems that DBS might work on the same functional network mentioned above for MCS, but via a different mechanism.

Surgical Technique

The DBS surgical strategy for the treatment of neuropathic facial pain is to place an electrode in the VPM thalamus with or without concomitant placement of a second electrode in the PAG/PVG. The actual surgical procedure is somewhat variable from institution to institution. At Mayo Clinic, the Leksell (Elekta) stereotactic head frame is placed under local anesthesia. The base of the frame is aligned with the orbitomeatal line to parallel the inter commissural line. A T1-wieghted and MPRAGE with contrast MRI sequences are utilized to identify the anterior commissure (AC), posterior commissure (PC), and the inter commissural line (ICL). Well-established x, y, and z target coordinates, relative to the ICL, are used for planning electrode placement. For example, the coordinates for VPM are X= 10–12 mm lateral to midline, Y= 3–5 mm anterior to PC, Z= 0 – (−2) below ICL/PVG X= 2 mm lateral to third ventricular wall, Y= 2–3 mm anterior to PC, and Z= 2 mm above or below the ICL. [47] Commercially available planning software may be used to determine the target coordinates and entry point for a safe electrode trajectory that avoids blood vessels and ventricles.

The patient is then returned to the operating room, where, under sterile conditions and local anesthesia, the surgery commences. The patient is awake, so that verbal feedback may be obtained during the surgery and general anesthetics suppress normal neuronal firing necessary for electrophysiological recordings. Using a high speed drill, burr holes are placed at the predetermined entry point. Refinement of electrode placement is performed through electrophysiological recordings with micro- and macro stimulation. [47, 48] Confirmation of accurate electrode placement is performed first with intraoperative fluoroscopy and then postoperative MRI or CT. The electrode leads are then tunneled and externalized for a trial period of stimulation.

Trial stimulation is carried out in the intensive care unit for 2 – 5 days with a goal of 50% reduction in reported pain. Narcotics are withheld during this period. Variable combinations of contacts and stimulation parameters are used. Stimulus-evoked symptoms for PAG/PVG DBS may include a sensation of warmth, weightlessness, and dizziness or anxiety and a sense of panic. Thalamic stimulation may produce paresthesias in the face or exacerbate their pain with suprathreshold stimulation. [47] Electrodes placed in both the sensory thalamus and the PAG/PVG have resulted in a greater analgesic effect than electrodes in either area alone. [6]

If the trial stimulation is deemed successful the patient returns to the operating room for internalization of electrode leads and placement of a pulse generator. Common stimulation parameters include, frequencies 5 to 100 Hz, amplitude 1 to 8 volts, and pulse widths 0.1 to 0.8 ms when intermittent stimulation was utilized. [6]

Patient Follow-Up, Outcomes and Complications

Following the failure of the clinical trials reported in 2001 [5], DBS for pain has been somewhat overshadowed by MCS, but it is still an option that deserves more research and development. Recent results have shown that DBS for intractable neuropathic pain shows promise. In a recent trial of 15 patients with post-stroke neuropathic pain who underwent DBS of the VPL thalamus and PVG, 12 proceeded to full implantation with an overall VAS score reduction of 48.8% with an average follow up period of 27 months [48]. In addition to the VAS scores, 7 of the 12 completely stopped analgesics and the remaining 5 switched from a regular opiate regimen to “as-required” non-opiates. In another study by Pereira et al [42], 3 patients with intractable neuropathic pain underwent DBS of the VPL thalamus, PVG, or both, respectively. At a one-year follow up, there was an average VAS score reduction of 37.3%.

In a larger study by Rasche et al. [47], 56 patients with neuropathic and mixed nociceptive/neuropathic pain underwent DBS of the somatosensory thalamus and the PVG. This study was unique in that a double-blind evaluation was employed prior to implantation of the stimulation device to determine the effect of each electrode on its own and both together with various parameters. There were 6 patients with trigeminal neuropathic pain/dysesthesia dolorosa, half of which had either no response or very little response (see table 2).

Conclusion

The results of MCS and DBS as treatment for intractable neuropathic face pain are variable, but promising. Many important questions remain regarding these techniques. A major issue is a lack of standardized and accepted pre- and post-operative evaluation, and defined inclusion and exclusion criteria for patient selection. The surgical technique varies from institution to institution and a consensus is yet to be reached on factors such as optimal electrode placement and stimulation parameters. Given the dire nature of intractable neuropathic face pain, the lack of effective therapy, and reported efficacy of neuromodulation surgery, it is reasonable to continue to offer DBS or MCS in the carefully chosen patient.