Kim J. Burchiel

The effect of intravenous lidocaine, tocainide, and mexiletine on spontaneously active fibers originating in rat sciatic neuromas

&NA; The effects of intravenously administered subanesthetic concentrations of lidocaine, tocainide, and mexiletine on spontaneously active fibers (SAFs) originating in 7‐day‐old rat sciatic neuromas were studied. Control injections of normal saline caused no decrease in SAF or discharge rate. Lidocaine and tocainide given in incremental doses of 5, 10, 15, 20 and up to 25 mg/kg caused nearly all observed SAFs to stop firing. Mexiletine given in doses of 3, 5, 7, 10 and up to 15 mg/kg showed similar results at lower doses. All agents decreased the sensitivity of SAF to mechanical stimulation. No conduction blockade occurred at these doses of intravenously administered local anesthetics. The demonstrated reduction in firing rate of SAF may explain the pain relief observed in clinical trials of these orally available agents.

Pain responses to perineuromal injection of normal saline, gallamine, and lidocaine in humans.

&NA; Rat neuromas have shown an increase of spontaneously active fibers to systemically administered potassium channel blocking agents such as tetraethylammonium chloride (TEA) and gallamine. Neuroma formation and spontaneous activity have been associated with autotomy in rats and pain in humans. To evaluate the chemosensitivity of human neurons to potassium channel blocking agents, 9 subjects with neuroma pain underwent perineuromal injection in a single‐blinded fashion of normal saline, gallamine, and lidocaine. Sodium chloride had no effect on control pain levels, while gallamine significantly increased and lidocaine significantly decreased pain from control levels. Three of 4 patients with accompanying phantom limb pain noted an increase in pain after the injection of gallamine. The data suggest that peripheral input plays a modulating but not solitary role in both neuroma and phantom limb pain. Agents which increase potassium channel permeability or decrease sodium influx would be predicted to decreased perceived pain.

Spontaneous impulse generation in normal and denervated dorsal root ganglia: sensitivity to alpha-adrenergic stimulation and hypoxia.

Previous experiments indicate that after peripheral nerve lesion, two sites of spontaneous ectopic impulse generation rapidly develop: the peripheral neuroma and the region of the dorsal root ganglion (DRG). In 30 adult Sprague-Dawley rats, microfilament recordings were made from either the dorsal root of L5 or the proximal sciatic nerve. The locus of the ectopic impulse generator, spontaneous firing patterns, and response to both adrenergic and hypoxic stimulation were observed in 200 spontaneously active isolated fibers. Results indicated that after sciatic transection the neuroma and the DRG behaved as independent sources of ectopic impulse generation. Spontaneous activity originating in the neuroma was responsive to adrenergic and hypoxic stimulation in 57% and 86% of fibers tested, respectively. Spontaneous activity originating in the DRG after chronic sciatic nerve transection demonstrated a response to adrenergic stimulation in 61% of fibers tested, and all fibers showed an increase in activity during hypoxic periods. Furthermore, after acute sciatic neurotomy in otherwise normal animals, spontaneous activity originating in the DRG could be recorded in a few fibers. Likewise, 48% of those fibers showed some response to topical or systemic epinephrine administration, and hypoxia produced some degree of excitation of firing in all fibers tested. Neither epinephrine administration nor hypoxic challenge produced excitation of firing in DRG neurons with intact receptive fields in normal animals. The pharmacology of adrenergic sensitivity of spontaneously active fibers from both the neuroma and the region of the DRG indicated alpha-adrenergic specificity. Furthermore, a number of fibers exhibiting spontaneous activity from both the region of the neuroma and the DRG showed either adrenergic or hypoxic sensitivity, but not both. Thus, the mechanisms of the largely excitatory actions of alpha-agonists and hypoxia on spontaneous discharges from these sites were felt to be different. These data indicate that adrenergic and/or hypoxic responsiveness is a property of (i) otherwise normal DRG neurons which demonstrate intrinsic spontaneous firing properties, (ii) neurons in chronically denervated ganglia which exhibit spontaneous activity, and (iii) some fibers within neuromas. Normal DRG neurons with intact receptive fields do not appear to increase their firing rate in response to either hypoxia or adrenergic stimulation. These findings may be relevant to the development of chronic pain in man following peripheral nerve injury.

Spontaneous activity of primary afferent neurons in diabetic BB/Wistar rats: A possible mechanism of chronic diabetic neuropathic pain

The mechanism of painful diabetic neuropathy remains unknown. Spontaneous activity in nociceptive primary afferents has been implicated in the genesis of chronic pain due to peripheral nerve injury, and diabetic axonopathy shares some histologic features with traumatic neuropathy. We hypothesized that spontaneous hyperactivity of nociceptive neurons might represent the neurophysiologic mechanism of diabetic neuropathic pain. To test this, we examined the spontaneous activity of primary afferent axons from diabetic BB/Wistar and normal Wistar rat saphenous nerves isolated from central and peripheral connections. Microfilament recordings from diabetic nerves showed a significantly higher incidence of spontaneous discharges in comparison to normal nerves. Furthermore, this spontaneous hyperactivity occurred almost exclusively in potentially nociceptive C-fibers. We conclude that in the diabetic BB/Wistar rat, spontaneous impulses are generated in potential nociceptive primary afferent neurons, and that this may represent the mechanism of chronic diabetic neuropathic pain.

Comparison of percutaneous radiofrequency gangliolysis and microvascular decompression for the surgical management of tic douloureux

Forty-two patients with tic douloureux underwent posterior fossa craniectomy and microvascular decompression (MVD) or partial rhizotomy of the trigeminal nerve and were followed an average of 25 months after operation. Thirty-six patients were found to have anatomical distortions of the nerve by an artery, vein, bony prominence, or a combination of factors, and 30 patients (83%) of this groups hav remained pain-free postoperatively. Six patients had no discernible pathological condition at the time of operation and underwent partial trigeminal rhizotomy. No patient underwent repeated MVD or rhizotomy, although 4 patients whose pain recurred after MVD underwent rhizotomy at a second operation. Eight of the 10 patients treated by rhizotomy are currently pain-free. The overall success rate of the entire group is 90%; 2% experienced a complication, and there was 1 perioperative death. Seventy-eight patients with tic douloureux who underwent 92 percutaneous radiofrequency trigeminal gangliolysis (PRTG) procedures were evaluated on average of 56 months postoperatively. Sixty-eight per cent of these patients when evaluated 1 year postoperatively were pain-free. However, only 35% of the PRTG procedures resulted in continued pain relief 5 years after operation. Twelve of the 78 patients (15%) required repeat gangliolysis because of recurrent tic pain. Considering all 78 patients treated with 92 PRTG procedures, 64% were pain-free at follow-up examination. PRTG was associated wtih an 8% risk of complications, which included anesthesia dolorosa, corneal anesthesia with keratitis, and significant facial paresthesias. Both PRTG and MVD have advantages. MVD should be considered because: (a) it attacks what is believed to be the primary etiology of tic douloureux, (b) the trigeminal nerve is preserved, (c) postoperative pain relief dose not depend upon the production of sensory deficit, and (d) it may have a greater potential for producing long-lasting pain relief. However, PRTG has other advantages: (a) it avoids the risks of craniectomy, (b) it is repeated easily if tic pain recurs, (c) morbidity is minimal and there is essentially no risk of mortality, and (d) it is much less expensive.

Carbamazepine inhibits spontaneous activity in experimental neuromas

In eight adult Sprague-Dawley rats the effect of parenteral carbamazepine on spontaneous discharges from saphenous neuromas (7-42 days following nerve section) was tested. Intravenous carbamazepine produced immediate inhibition of spontaneous activity originating in both A-alpha/beta and A-delta fibers at doses of 2.51-11.2 (7.9 +/- 3.3) mg/kg. In four additional animals, serum levels of carbamazepine were determined following iv administration of the drug. These results indicated that ectopic spontaneous impulse generation from experimental neuromas was inhibited by carbamazepine in the range of serum concentration in which the agent is used to treat trigeminal neuralgia and other painful neuropathies in humans. This implies that the effectiveness of this agent in the treatment of these disorders may result from suppression of peripherally originating ectopic spontaneous activity.

Use of stimulation mapping and corticography in the excision of arteriovenous malformations in sensorimotor and language-related neocortex.

The excision of an arteriovenous malformation (AVM) located within eloquent neocortex presents a formidable neurosurgical challenge. Compromise of the vascular supply to normal surrounding brain or surgical trauma to essential neighboring neocortex may result in unacceptable postoperative neurological morbidity. In addition, successful removal of these lesions without the benefit of intraoperative corticography may leave in situ areas of highly epileptogenic brain, resulting in continued epilepsy. In this report, we describe eight patients who underwent craniotomy and excision of AVMs at our institutions. Six of these lesions were located in the dominant (left) hemisphere, and two were on the right. All patients underwent preoperative testing with Amytal administered via the carotid artery (Wada test). Subsequently, the patient was placed under local anesthesia, and we performed a craniotomy. Electrocorticography was used to identify epileptogenic brain in the region of the AVM and to establish after-discharge thresholds to electrical stimulation. Stimulation-mapping techniques were then used to delineate critical motor, sensory, and language areas. Trial occlusion of feeding vessels was also carried out to document postocclusion neurological deterioration, if any. At a later time, a second procedure was performed under general anesthesia to excise the lesion and any epileptogenic foci, using the cortical maps derived earlier. Using these techniques, it was possible to effect complete excision of these lesions in seven of eight patients without causing additional neurological deficits.

Intracranial pressure changes in brain-injured patients requiring positive end-expiratory pressure ventilation

In 16 patients with severe head injury and 2 patients with subarachnoid hemorrhage, positive end-expiratory pressure (PEEP) ventilation was required to maintain adequate oxygenation. The effects of PEEP on intracranial pressure (ICP) were evaluated with respect to the volume-pressure response (VPR), an indicator of intracranial compliance, and the static lung compliance (CL). Based on these parameters: (a) All 11 patients with a normal VPR (less than 2 torr) had no significant change in ICP with PEEP therapy. (b) All 5 patients with abnormal VPR and a normal CL (greater than 30 ml/cm H2O) had significantly increased ICP or decreased cerebral perfusion pressure while on PEEP. (c) Two patients with both an abnormal VPR and a decreased CL had no significant change in their ICP with PEEP. (d) Significant elevations of ICP were also seen in 4 patients with abnormal VPRs concurrent with the rapid reduction or withdrawal of PEEP ventilation. Thus, the VPR is an accurate predictor of the effects of PEEP on the ICP. In addition, however, decreased lung compliance may buffer these effects in patients who have decreased intracranial compliance. We propose that ICP monitoring and intracranial compliance determination are necessary in the management of brain-injured patients requiring PEEP ventilation.

Surgical decompression without transposition for ulnar neuropathy: factors determining outcome.

Fifty-one surgical decompressions without nerve transposition for ulnar neuropathy were performed in 46 patients. All of the patients were men with an average age of 59 years at the time of surgery. The follow-up range was between 5 and 32 months (average, 17.8 months). The disease involved the nondominant arm in 24 patients (52%) and was bilateral in 5 (11%). In 23 cases (50%), no predisposing condition could be identified, whereas 15 patients (33%) abused alcohol and 8 patients (17%) had diabetes mellitus. Fifty-seven percent of the patients helped by surgery had symptoms for less than 1 year, whereas only 30% of patients with symptoms for more than 1 year had symptomatic improvement. The relative magnitude of the slowing of ulnar nerve conduction velocity across the elbow was not significantly correlated with the success of decompression in relieving symptoms. Ulnar nerve conduction velocities across the elbow were 36.13 +/- 11.76 m/s in those responding to surgery and 38.97 +/- 13.91 m/s in those not responding (c = 0.06, dF = 50, P less than 0.3). A total of 37 patients showed symptomatic improvement after decompression. Simple decompression of the ulnar nerve was performed under local anesthesia without transposition of the nerve. In all of these cases, compression of the nerve occurred predominantly in the epicondylar groove. Narrowing of the nerve in the groove was present in 28 cases (55%); scar tissue was found adhering to the nerve in 21 cases (41%); and two pseudoneuromas were found (4%). Forty-one operations (80%) resulted in symptomatic improvement, typically noted by the patient within the first month postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic Epileptic Foci in Monkeys: Correlation Between Seizure Frequency and Proportion of Pacemaker Epileptic Neurons

A total of 1,802 neurons from 15 alert, undrugged Macaca mulatto monkeys were studied. Thirteen monkeys had chronic epilepsy induced by subpial alumina injections in precentral cortex. Precentral neurons were judged epileptic by the magnitude and variability of the percentage of interspike intervals less than 5 msec during periods when the monkeys were awake. This method of quantifying epileptic single neuron activity appears highly reliable in distinguishing epileptic neurons from precentral neurons in either normal cortex, cortex contralateral to, or within the focus. For the 13 epileptic monkeys, the relative proportion of strongly epileptic neurons found within foci was logarithmically correlated with the mean number of daily seizures. Because of the similarity between the physiology of the alumina focus in monkeys and epileptic foci in humans, these data imply that the severity of focal human epilepsy is a function of epileptic neuronal mass.