Chlorprothixene

Facial neuralgia is the last common pathway for a variety of pathological conditions with different etiology. Neuropathic facial pain is often refractory to routine medical or surgical treatments. We present here a long-term follow-up of two patients with unilateral facial neuropathic pain due to idiopathic trigeminal neuropathy or to surgical trauma to the glossopharyngeal nerve, respectively. These patients have been treated by other modalities for several years without obtaining satisfactory pain relief Electrical stimulation of the motor cortex (MCS) with a quadripolar electrode contralateral to the painful area of the face was attempted in both cases for control of the facial pain, and resulted in immediate analgesia with more than 50% pain reduction. During a follow-up period of 72 months, a sufficient (> 50%) and stable analgesic effect of MCS was observed. These cases are discussed and the recent literature on MCS is reviewed in an attempt to identify indications for MCS as well as key structures in the brain for mediating the MCS effect. [Neurol Res 2003; 25: 157-161]

Keywords: Electrical stimulation; facial pain; glossopharyngeal neuralgia; motor cortex; trigeminal neuropathy

INTRODUCTION

There is evidence to indicate that electrical stimulation of the motor cortex (MCS) is effective in certain forms of neuropathic pain, the principal indications being central pain and trigeminal neuralgia1-3. Tsubokawa et al.4-6 first reported on MCS for treatment of neuropathic pain of central (thalamic) origin in humans. Their work was preceded by studies on electrical stimulation in the animal and human brain and was based on the hypothesis that electric impulses inhibit deafferented nociceptive neurons in the cerebral cortex7,8. During the last decade, several investigators concentrated their efforts on understanding and explaining the effector mechanisms of MCS and on evaluating its therapeutic potential in different normal and pathological conditions9-13. Clinical efficacy was demonstrated in series of cases without the development and acceptance of a model for the underlying physiological processes14-16.

Recently, patients with post-stroke movement disorders and phantom limb pain were successfully treated with MCS17-19. No reliable predictors for treatment outcome seemed to exist in all these patients, although there were some trends, at least in central pain cases, towards better outcome in patients with less neurological deficits at baseline20. The largest series of patients with central post-stroke pain are those reported by Nguyen et al.3 and Katayama et al.20, in which the overall response to MCS varies between 40% and 70%. Although only less than 50 patients with trigeminal neuropathy have been reported in the literature, the clinical results in such patients tend to be somewhat better than in cases with central pain21.

The majority of patients with central pain as well as with trigeminal neuropathy present also with allodynia and dysesthesia. In several studies it has been reported that this also may be markedly relieved by MCS2,13,21,22.

Despite increasing numbers of clinical studies, MCS should still be regarded as an experimental treatment modality under investigation. The surgical procedure for implanting intracranial stimulation electrodes is less invasive to the patient, but may be demanding to the surgeon since the positioning and the anchorage of the MCS electrode appear to be critical21. The aid of CT or MRI and peri-operative electrophysiological control is necessary to obtain a safe and effective implantation of the intracranial electrode23. Also optimal stimulation schemes and parameters vary considerably between the studies.

This study describes the treatment and long-term follow-up of two patients with chronic facial pain treated by MCS and compares these cases with other published case series.

PATIENTS AND METHODS

Implantation technique and stimulation device

CT and MRI scans are taken before electrode implantation to exclude intracranial pathological conditions and to aid in localization of the central sulcus. A 5 cm oval craniotomy is carried out under light sedation and local anesthesia over the contralateral parietal lobe. The exact position of the Rolandic fissure (central sulcus) is located epidurally by means of median nerve SSEP9. A flat quadripolar lead (Resume(R), Medtronic, Inc., Minneapolis, MN, USA) is placed across the central sulcus and located in such a way as to cover cortical areas representing the face (somatotopic orientation). Intra-operative test stimulation is carried out by a screening device (Medtronic 8214 screener) with 50-- 100 Hz frequency, 200 msec impulse width, and 2-- 8 mA intensity. Electrode polarity may vary in individual cases. Patients are asked to report vibrating or tingling sensations in the painful face area, stimulation above the threshold of muscle contractions is to be avoided. Pain sensation is tested in the affected facial areas and subjectively reported by the patient according to a 1-10 visual analog scale (VAS). The post-operative test phase is continued for at least two weeks, and if there is at least 50% pain reduction on the VAS and objective reduction of facial allodynia, a permanent impulse generator (IPG, Itrel III, Medtronic Inc.) is implanted.

Case 1

A 60-year-old Caucasian female with a long-standing history of right-sided V^sub 1^ and V^sub 2^ trigeminal neuropathy and chronic pain. Her initial presentation was with paroxysmal burning and lancinating pain attacks in the affected dermatomes, tactile allodynia and hyperesthesia, and pain-related contractions of the mimic muscles (hemifacial spasm). She was treated with opioid and nonopioid analgesics, with neuroleptic drugs such as chlorprothixene and promethazine, and with anti-- epileptics such as carbamazepine and phenobarbital. Carbamazepine was the only drug able to sufficiently relieve the symptoms, but tolerance developed quickly. Doses of up to 1600 mg daily provoked unacceptable side effects and had to be significantly reduced. Neurovascular decompression of the trigeminal nerve root was carried out, but resulted in only a short period of pain reduction. Percutaneous thermocoagulation of the Gasserian ganglion followed and, because of recurrent pain, was carried out repeatedly. With all these treatment modalities, no sufficient long-term pain relief could be achieved, and MCS was considered an option worth exploring.

During test stimulation, sufficient electrically induced analgesia was achieved only slightly below the threshold for facial muscle stimulation. At 0.6 V, there was no sensory perception and virtually no analgesic effect. At 6.4V, electrically induced paresthesias covered the painful areas and a substantial part of the upper face. Test MCS reduced subjective pain perception from a pre-stimulation mean VAS value of 7 (range 6-10) to a mean value of 3 (range 2-5), and a permanent IPG was implanted two weeks after the first procedure.

Best long-term results were obtained with intermittent 100 Hz/300 msec stimulation at 7.5-8.5 V, which was switched hourly on or off, respectively. About 6-9 h of stimulation in 24 h were recorded during long-term follow-up, most of the stimulation time during the hours of daily activity. Development of 'tolerance' against MCS necessitated current increase of up to 9.5 V and occurred repeatedly, but was easily reversed by temporary deactivation of the MCS device for three days followed by usage at low current values. There were no hardware complications. Because of the relatively high energy consumption the IPG battery could not last long and the device had to be replaced under local anesthesia every 10-12 months.

This patient was followed for 72 months and her MCS system was still in use. There is no concomitant medication apart from anti hypertensive drugs. No seizures or other side effects of the electric stimulation have been noted.

Case 2

This 43-year-old Caucasian female underwent cervical lymph node biopsy for atypical cervical lymphadenitis. The right glossopharyngeal nerve was damaged during surgery (although not completely severed) and the patient complained of pain as early as a few weeks after biopsy. She reported short intermittent attacks of lancinating and burning pain in the right half of the tongue and the throat, which was clinically diagnosed as the rather rare condition of iatrogenic glossopharyngeal neuropathy. There was a significant amount of tactile allodynia in the mouth during meals causing avoidance of hard foods. Pain attacks lasted for 1-2 h and were accompanied by spasms of the mimic musculature on the right side.

She was unsuccessfully treated by surgical re-exploration of the submandibular neck triangle, by percutaneous anesthetic infiltrations, by oral analgesics and neuroleptics (including carbamazepine, phenytoin, and phenobarbital), and by transcutaneous electric stimulation (TENS).

Test MCS immediately rendered the patient almost pain-free, reducing the initial VAS of 8 points (range 7-- 10) to 2 points (range 1-4). Long-term stimulation settings were 100 Hz frequency, 400 msec pulse width, and 5-6 V intensity. The patient used her fully implantable stimulator device (Itrel III, Medtronic Inc.) for 6-- 7 h daily and was able to return to work. She was followed for 69 months without hardware related complications apart from IPG exchange under local anesthesia. Approximately three months after the initial MCS system implantation, a single epileptic seizure occurred during stimulation. No previous history of epilepsy was known, and no further seizures occurred during the follow-up, thus making an MCS related causality rather unlikely. No focus could be identified on regular subsequent EEGs.

DISCUSSION

In the presented two cases of refractory facial neuropathic pain, treatment by MCS resulted in sustained long-term analgesic effect. Insufficient analgesia by barbiturates or opiates did not predict the effect of MCS. Relationship between electrode polarity and localization of electric paresthesias was noted in both cases. No major permanent complications related to the procedure or the MCS itself were registered. A single epileptic seizure with unclear causality occurred months after the implantation of the MCS system.

Tsubokawa et al.4 published the earliest reports on electrical stimulation of the primary motor cortex in patients with deafferentation pain secondary to benign CNS lesions. They placed the stimulation electrode over the cortical area producing the best motor response in the painful area at the lowest possible threshold. Eight of their 12 patients responded well and experienced long-- term analgesia. Unlike our cases, the pain of the patients who responded to stimulation was typically barbiturate-- sensitive and morphine-resistant4-6,24. Migita et al.12 reported a lacking correlation between response to medication and effect of transcranial electromagnetic stimulation, but hypothesized that a temporary analgesia in response to transcranial magnetic stimulation may be rather predictive for the later analgetic response to MCS.

The early Japanese experience with MCS in various central pain conditions showed that pain inhibition usually occurred at high intensity just below the threshold for muscle contraction. Also no analgesic effect was noted if the postcentral (sensory) gyrus was stimulated instead of the precentral motor area4-6,24. Furthermore, all patients with a good pain relief reported tingling or vibrating sensations (electrically induced paresthesias) in the painful area. Our experience confirms the presence of paresthesia and/or muscle twitching as a prerequisite for sufficient analgesia. Meyerson et al.2, however, did not observe electrically induced sensations during stimulation, although their trigeminal neuralgia patients treated with MCS experienced good pain relief. What these authors confirmed was the principle of somatotopic orientation of MCS by the observation that different coupling of electrodes produces analgesia in different parts of the face.

Applying electrical current to the motor cortex may result in a more generalized and even bilateral stimulation of the brain. Chiappa et al.10 used transcranial magnetic stimulation and were able to prove the transcallosal spread of electrically induced neuronal alterations by surface recordings from the opposite motor cortex in humans.

During the last five years, further studies on electrical stimulation of the motor cortex were published. Patients with deafferentation pain of central or peripheral origin, and those with neuropathic pain were most frequently chosen for MCS. Also the physiological mechanisms of MCS were investigated by functional imaging techniques.

MCS in chronic deafferentation pain and acquired

movement disorders

Saitoh et al.16 tested MCS in four patients with thalamic pain and in four patients with peripheral deafferentation pain due to amputation or plexus injury. These authors obtained useful (excellent to fair) pain reduction in all patients with pain of peripheral origin and stated in addition that there was no correlation between pharmacological response to analgesics and effectiveness of MCS. Katayama et al.17,19 analyzed the effects of MCS in groups of patients with post-stroke movement disorders and pain, and found that stimulation is effective for both conditions. More than half of the patients showed good control of hemiathetosis or tremor, some of them also reporting subjective improvement in motor performance, apparently due to attenuation of rigidity. The same group published another study20 trying to identify factors predicting favorable response to MCS in patients with post-stroke pain. In 48% of patients, excellent or good long-term pain control was achieved. Satisfactory pain control was obtained in 73% of patients without motor weakness in the painful area, but in only 15% of those with moderate to severe motor deficits. Analgesia was achieved in 70% of patients with inducible muscle contractions in the painful areas, but in only 9% of those without inducible muscle contraction. No significant relationship was observed between pain control and sensory symptoms, such as hyperpathia or allodynia, or between the analgesic effect of MCS and stimulation-induced paresthesia.

Yamamoto et al.24 used a different approach to investigate the response of central post-stroke pain syndromes to MCS. Morphine, thiamylal, or ketamine were given to patients and the analgesic effects of the drugs were compared with the presence or absence of MCS-induced analgesia. In this study of 39 post-stroke pain patients, brain lesions were subdivided in those of thalamic or suprathalamic origin according to the results of neuraxial scanning showing morphological changes in the brain. Based on pharmacological assessments, there was no obvious difference between thalamic and suprathalamic pain. Thiamylal and ketamine-sensitive and morphine-resistant cases displayed long-lasting pain reduction after MCS while the remaining patients did not. Although the authors conclude that pharmacological classification of central post-stroke pain could be useful for predicting the effects of MCS, evidence is rather scarce and there are no further prospective randomized studies to confirm this statement. The issue of predictive factors for MCS response is therefore still open and there is no substantial evidence to support the prognostic importance of clinical, neuroradiological, or functional testing prior to MCS treatment. Also the type of underlying pathological condition cannot be reliably correlated to MCS effects.

MCS in chronic neuropathic pain

Carroll et al.1 reported long-term benefit from MCS in 50% of the treated patients. Most of the responders suffered from post-stroke or phantom limb pain. Drouot et al.22 studied predictive factors in patients with drug-- resistant chronic neurogenic pain. All patients with normal nonnociceptive thermal thresholds, and 50% of these with altered thresholds within the painful area benefited from MCS. In the good responders with altered thresholds, the latter were improved by switching on the MCS, unlike the case in nonresponders. The authors proposed that preserved nonnociceptive sensory modalities within the painful area or improvable abnormal sensory thresholds correlated with response to MCS.

Nguyen et al.13 treated by MCS 20 patients with trigeminal or peripheral neuropathy or deafferentation pain. In this inhomogeneous patient population including chronic pain syndromes secondary to peripheral nerve injury or spinal cord injury, long-term pain relief was achieved to a varying degree in more than half of all patients. The stimulation electrode was localized in accordance with the somatotopic organization of the motor cortex. In a later study3 by the same group, the long-term follow-up was reported in 32 patients with refractory central or peripheral neuropathic pain treated by MCS. Substantial pain relief was seen in 77% of patients with central pain and in 75% of those with neuropathic facial pain. In addition, none of the MCS patients developed epileptic seizures due to the electric stimulation, which is one of the feared complications of MCS.

There are no clinical studies on intrinsic or external factors predisposing to or directly causing seizures during MCS. One animal study28 investigated normal primates and tested some of the more frequently used MCS parameters in regard to epileptic behavior or abnormal electroencephalographic activity. Stimulation current intensity over the threshold for inducing muscle contractions induced reversible epileptic seizures, but did not alter the epileptic threshold, since intermittent light stimulation immediately after provoked seizures elicited no abnormal electroencephalographic activity.

Ebel et al.14 reported seven cases of MCS for severe trigeminal neuropathic pain including anesthesia dolorosa and post-herpetic neuralgia. In one case, a focal seizure occurred during test stimulation and was clearly related to the MCS. Maximal analgesia was achieved in all cases at intensity just below the threshold for producing motor effects. A good to excellent pain relief was initially reported by all patients, but was maintained in the long term (up to two years) only by 50% of them. There were no identifiable factors predicting response to MCS.

Functional investigation of MCS effects

Peyron et al.25 studied the effects of MCS in refractory post-stroke pain by somatosensory evoked potentials (SSEP) and PET. MCS-induced analgesia was somatotopically distributed according to the cortical localization of the electrode. One patient had a satisfactory long-- lasting pain control, while the other experienced less marked and only transient pain relief. Cerebral blood flow (CBF) as measured by PET increased during MCS in the ipsilateral thalamus, cingulate gyrus, orbito-frontal cortex, and brainstem. CBF increase in brainstem structures was greater and lasted longer in the good responder compared with the poor responder. This study indicated that MCS effects might be related to increased synaptic activity in thalamus and brainstem leading to inhibitory control on descending pain pathways and to depression of nociceptive reflexes.

A later functional study by Garcia-Larrea et al.26 on regional CBF (rCBF) changes under MCS basically confirmed the above findings. Significant increase in rCBF was observed in the lateral ipsilateral thalamus, and much less increase was observed in the anterior cingulate, insula, and upper brainstem. Thalamic and also cingulate rCBF increased to a greater extent in patients with good clinical results, indicating that MCS may influence also the affective-emotional component of chronic pain. Another recent study from the same group23 corroborated the notion that the thalamus is the key structure mediating functional MCS effects. The authors proposed a functional model of MCS action, whereby activation of thalamic nuclei connected with the motor cortex leads to synaptic events in the medial thalamus, anterior cingulate and upper brainstem, the latter producing descending inhibition of pain and subsequent attenuation of spinal reflexes. Additional cingulate/orbitofrontal activation by MCS influences the affective-emotional component of chronic pain. Interestingly, none of the above studies obtained data suggesting direct somatosensory cortex activation by MCS.

Roux et al.18 used functional magnetic resonance imaging (fMRI) to guide electrode placement and to study effects of MCS in phantom limb pain. Activation of the sensorimotor cortex was seen on fMRI during imagination of phantom limb movements and inhibition occurred during MCS. Inhibition of contralateral sensorimotor areas was also detected. Despite the anecdotal character of the evidence, the authors stated that fMRI data might be useful in MCS electrode placement for this indication.

Hanajima et al.27 studied MCS by direct cortical recordings during placement of MCS electrodes and found that single electrical stimuli could elicit short latency motor evoked potentials or facilitate active motoneurons in the contralateral limb. Single cortical stimuli could result in inhibition of voluntarily activated motoneurons. The inhibition was larger with cathodal than with anodal monopolar stimulation. The authors concluded that MCS appears to activate axons in the cortex, which excite both corticospinal neurons and inhibitory neurons.

In summary, our patients treated with MCS fit well into the indications and results for this technique cited by other authors. While refractory trigeminal neuropathy comprises a large proportion of published data, our patient with iatrogenic glossopharyngeal neuropathy has no equivalents in the literature. We were not able to identify prognostic or predictive factors for the success of the MCS. However, even in much larger studies, there was no significant correlation between clinical or experimental parameters and outcome. Unlike cases in other studies14, our patients maintained the long-term analgesic response to MCS and the efficacy of MCS was not lost over time. No side effects due to the MCS were recorded.

All these facts are sufficient to support the case of MCS as analgesic treatment for various chronic pain syndromes of central and peripheral origin. Being minimally invasive and nondestructive, MCS should be performed prior to central neuroablative procedures. However, most of the supporting evidence available at present stems from retrospective studies or from series of cases. Prospective investigations with larger and more homogeneous patient groups have to be carried out in order to produce the evidence needed for broad acceptance of MCS and for integration of this novel technique in the clinical routine.

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Nikolai G. Rainov* and Volkmar Heidecke^

*Department of Neurological Science, University of Liverpool, and the Walton Centre for Neurology and Neurosurgery NHS Trust, Liverpool, UK, ^Department of Neurosurgery, Martin-Luther-University, Halle, Germany

Correspondence and reprint requests to: Nikolai G. Rainov, MD, DSc, The University of Liverpool, Department of Neurological Science, and The Walton Centre for Neurology and Neurosurgery NHS Trust, Clinical Sciences Centre for Research and Education, Lower Lane, Liverpool L9 7LJ, UK. [rainov@liv.ac.uk] Accepted for publication October 2002.

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