Keith G. Smith

Interleukin-10 reduces scarring and enhances regeneration at a site of sciatic nerve repair.

Abstract  Axonal regeneration at a site of peripheral nerve repair can be impeded by the formation of scar tissue, which creates a mechanical barrier and initiates the development of multiple branched axonal sprouts that form a neuroma. We have investigated the hypothesis that the application of a scar‐reducing agent to the nerve repair site would permit better axonal regeneration. In anaesthetised C57 Black‐6 mice, the left sciatic nerve was sectioned and immediately re‐approximated using four epineurial sutures. In five groups of eight mice, we injected transforming growth factor‐β3 (50 or 500 ng), interleukin‐10 (IL‐10) (125 or 500 ng), or saline into and around the repair site, both before and after the nerve section. Another group of eight animals acted as sham‐operated controls. After 6 weeks, the outcome was assessed by recording compound action potentials (CAPs), measuring collagen levels using picrosirius red staining, and counting the number of myelinated axons proximal and distal to the repair. CAPs evoked by electrical stimulation distal to the repair were significantly smaller in all repair groups except for the low‐dose IL‐10 group, where they were not significantly different from that in controls. The area of staining for collagen had significantly increased in all repair groups except for the low‐dose IL‐10 group, which was not significantly different from that in controls. The myelinated fibre counts were always higher distal to the repair site, but there were no significant differences between groups. We conclude that administration of a low‐dose of IL‐10 to a site of sciatic nerve repair reduces scar formation and permits better regeneration of the damaged axons.

Surgical anatomy of the buccal nerve

The buccal nerve may be damaged during surgical procedures which require an incision along the external oblique ridge of the mandible and this study was undertaken to clarify its surgical anatomy. The course and relationships of the nerve were determined in 20 formalin-fixed cadaver specimens. The number of major branches of the nerve ranged from 4 to 8 and a mean of 3 branches was present as the nerve crossed the external oblique ridge. In 14 dissections the main trunk of the nerve crossed the external oblique ridge within 3 mm of the deepest concavity, but in the other 6 it was 7-12 mm below this point. We conclude that incisions even 12 mm below the deepest concavity in the external oblique ridge could result in buccal nerve damage.

Ectopic neural activity from myelinated afferent fibres in the lingual nerve of the ferret following three types of injury

Sensory disturbances following nerve injury may result from abnormal neural activity initiated at the injury site. We have studied the activity generated in the lingual nerve after three types of injury which may have variable potentials for the initiation of sensory disturbances. We have also compared the results with those found after damage to the inferior alveolar nerve, another branch of the trigeminal nerve, to determine whether differences in nerve fibre type or location affect the level of abnormal activity. In anaesthetised adult male ferrets the left lingual nerve was either ligated and cut distally, chronically constricted, or sectioned and allowed to regenerate. Following recovery periods of 3 days-6 months, single unit electrophysiological recordings were made from central to the injury site. After all three types of injury, some of the damaged axons at the injury site developed spontaneous activity (up to 36% of units) and mechanical sensitivity (up to 35% of units). There were significantly fewer spontaneously active units after ligation than after the other two types of injury but the level of mechanical sensitivity was not significantly different between the three types of injury. There was a significant increase in the spontaneous activity between 3 weeks and later recovery periods following both ligation and section injuries, and this late increase was not seen in our previous studies on the inferior alveolar nerve. Differences in the time-course of ectopic activity in adjacent branches of the trigeminal nerve suggest that the fibre types or anatomical relationships affect the outcome of injury.

The reinnervation of the tongue and salivary glands after two methods of lingual nerve repair in the cat

The recovery of fibres in the chorda tympani after repair by epineurial suture or entubulation was investigated. The combined trunk of the chorda tympani and lingual branch of the trigeminal nerve was sectioned unilaterally, repaired using either epineurial sutures or entubulation, and allowed to recover for 12 weeks. The properties of gustatory, thermosensitive and mechanosensitive units, and the return of vasomotor and secretomotor responses were then investigated. After repair by epineurial suture, integrated whole-nerve activity recorded from the chorda tympani during stimulation of the tongue with gustatory or thermal stimuli was reduced in all areas of the tongue when compared to controls. After entubulation repair, little or no activity could be recorded. Recordings made from 57 single units in the chorda tympani after repair by epineurial suture revealed a greater proportion of purely mechanosensitive units and fewer gustatory units than in the controls. Fewer units were spontaneously active, they had lower maximum discharge frequencies, and produced fewer impulses when stimulated. Recordings made from 61 single units after repair by entubulation revealed receptor characteristics with greater differences from controls than after epineurial suture and there was only one gustatory and one thermosensitive unit. Vasomotor responses were completely restored after repair by epineurial suture, but some responses were smaller after entubulation repair. Secretomotor responses were significantly smaller after both methods of repair and there was no difference between the two groups.

The effect of triamcinolone hexacetonide on the spontaneous and mechanically-induced ectopic discharge following lingual nerve injury in the ferret.

Abstract Investigations into the aetiology of nerve injury‐induced dysaesthesia have revealed the development of spontaneous and mechanically‐induced activity from damaged axons. Pharmacological manipulation of this activity could provide a method of treatment for this intractable condition. This study has investigated the effect of a corticosteroid applied to the injury site, as these agents are known to reduce inflammation and scarring. In 24 anaesthetised adult ferrets the left lingual nerve was sectioned and the animals allowed to recover. In eight of these animals the nerve was re‐exposed under anaesthesia after 1 month and 100 μl of corticosteroid (triamcinolone hexacetonide, 20 mg/ml) was injected into and around the injury site. In eight others, 100 μl of the steroid carrier was injected, and the eight remaining animals were used as controls. In terminal experiments under general anaesthesia, 3 months after the initial injury, electrophysiological recordings were made from axons in fine filaments dissected from the nerve central to both the injury site and junction with the chorda tympani nerve. Spontaneous activity (SA) was found in approximately 13% of units in control animals, 12% following the application of steroid, and 14% in the carrier group. Mechanically‐induced activity at the injury site was found in approximately 13% of units in controls, significantly fewer after the application of steroid 4% (P<0.001) and 12% in the carrier group. These data suggest that local application of the corticosteroid triamcinolone hexacetonide could reduce the level of mechanically‐induced, but not spontaneous, dysaesthesia following lingual nerve injury.

An experimental study of lingual nerve repair using epineurial sutures or entubulation

The recovery of the mechanosensitive afferent fibres in the lingual branch of the trigeminal nerve has been studied using electrophysiological techniques in cats, after two methods of nerve repair. After nerve section the lingual nerve was repaired by either epineurial sutures or by entubulation. 12 weeks after either method of repair the properties of the regenerated fibres were significantly different from normal, but following repair with epineurial suture they were closer to normal than after repair by entubulation. After entubulation the fibres had a greater reduction in conduction velocity, a greater increase in force threshold, and the adaptation times were faster. The results suggest that epineurial suture should be preferred clinically.

The effect of delayed nerve repair on the properties of regenerated fibres in the chorda tympani

The characteristics of regenerated fibres in the chorda tympani have been investigated in cats after nerve section without repair or after section followed by nerve repair twelve weeks later. In the unrepaired group the animals were allowed to recover for twenty four weeks and after delayed repair there was a further recovery period of twelve or twenty four weeks. The properties of gustatory, thermosensitive and mechanosensitive units and the return of vasomotor and secretomotor responses were then investigated and data compared with that from normal controls and from animals which had undergone immediate nerve repair. After nerve section, integrated whole-nerve activity recorded from the chorda tympani during gustatory or thermal stimulation of the tongue was reduced when compared to controls, but there were only small differences between the repaired and unrepaired groups. Recordings made from single units in the chorda tympani revealed that more units were spontaneously active after repair (P < 0.05) and the gustatory units produced more impulses when stimulated (P < 0.005). Twelve weeks after delayed repair the units had slower conduction velocities than those in the unrepaired nerves (P < 0.001), but by twenty four weeks after repair they were significantly faster (P < 0.05). There was little difference in the level of recovery twelve weeks after immediate or delayed repair. We conclude that delayed nerve repair results in better recovery than leaving the nerve unrepaired and that a twelve week delay before repair has little effect.

The effect of nerve growth factor on functional recovery after injury to the chorda tympani and lingual nerves

Nerve growth factor (NGF) is known to ameliorate central changes and enhance the regeneration of damaged axons in the early stages after peripheral nerve injury. We have assessed the long-term outcome of placing NGF at a nerve repair site by determining the functional characteristics of several groups of sensory afferent and autonomic efferent fibres in the cat lingual nerve. Six months after entubulation repair, with or without the incorporation of NGF, the recovery of secretomotor and vasomotor efferents was determined by recording salivary flow from the submandibular gland and temperature changes on the tongue surface, each evoked by stimulation of the repaired nerve. Electrophysiological recordings from the lingual and chorda tympani nerves proximal to the repair allowed characterisation of mechanosensitive, thermosensitive and gustatory afferents. When compared with data from uninjured control animals, both repair groups showed changes in spontaneous discharge and persistent reductions in conduction velocity, receptor sensitivity, proportion of gustatory units, and rate of salivary secretion. Comparisons between the outcome of repair with or without NGF revealed few differences. In the NGF group the conduction velocity of afferents in the lingual nerve was lower, and the level of spontaneous activity was higher. However, NGF appeared to preferentially enhance the regeneration of thermosensitive afferents, suggesting that it may play a role in determining the phenotypic profile of the regenerating axonal population. This suggests that future therapeutic enhancement of regeneration after peripheral nerve injury may require a combination of factors to encourage regeneration of specific fibre groups.

Psychosocial Outcomes in Orthognathic Surgery: A Review of the Literature

Objective To identify and critically appraise the literature on the psychosocial outcomes of orthognathic surgery, reflect on the clinical and theoretical implications, and suggest avenues for future research. Design A search of the literature was completed using the databases Web of Science, MEDLINE, and PsycINFO to identify English-language articles published since January 2001 that have reported a measure of psychosocial functioning posttreatment. Results A total of 38 articles were eligible for inclusion in the review. The studies reported improvements in areas such as satisfaction with facial appearance, self-confidence, self-esteem, anxiety, and social functioning. Small percentages of patients were left dissatisfied or had difficulty adjusting to appearance change despite the absence of treatment complications. Gains in psychosocial functioning were maintained over several years, and satisfaction increased over time. Conclusions There are consistent positive outcomes reported as a result of orthognathic surgery, but conclusions are limited by methodological issues in study design such as small sample sizes, limited use of control groups, and measures that fail to tap into relevant areas of psychosocial functioning. In addition, further exploration is required of processes such as adjustment to facial change and the role of psychological support during treatment.

Correlation of Nav1.8 and Nav1.9 sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas

BackgroundVoltage-gated sodium channels Nav1.8 and Nav1.9 are expressed preferentially in small diameter sensory neurons, and are thought to play a role in the generation of ectopic activity in neuronal cell bodies and/or their axons following peripheral nerve injury. The expression of Nav1.8 and Nav1.9 has been quantified in human lingual nerves that have been previously injured inadvertently during lower third molar removal, and any correlation between the expression of these ion channels and the presence or absence of dysaesthesia investigated.ResultsImmunohistochemical processing and quantitative image analysis revealed that Nav1.8 and Nav1.9 were expressed in human lingual nerve neuromas from patients with or without symptoms of dysaesthesia. The level of Nav1.8 expression was significantly higher in patients reporting pain compared with no pain, and a significant positive correlation was observed between levels of Nav1.8 expression and VAS scores for the symptom of tingling. No significant differences were recorded in the level of expression of Nav1.9 between patients with or without pain.ConclusionsThese results demonstrate that Nav1.8 and Nav1.9 are present in human lingual nerve neuromas, with significant correlations between the level of expression of Nav1.8 and symptoms of pain. These data provide further evidence that changes in expression of Nav1.8 are important in the development and/or maintenance of nerve injury-induced pain, and suggest that Nav1.8 may be a potential therapeutic target.