Tara Renton

Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density.

Bone is a dynamic tissue that is subject to the balanced processes of bone formation and bone resorption. Imbalance can give rise to skeletal pathologies with increased bone density. In recent years, several genes underlying such sclerosing bone disorders have been identified. The LDL receptor-related protein 5 (LRP5) gene has been shown to be involved in both osteoporosis-pseudoglioma syndrome and the high-bone-mass phenotype and turned out to be an important regulator of peak bone mass in vertebrates. We performed mutation analysis of the LRP5 gene in 10 families or isolated patients with different conditions with an increased bone density, including endosteal hyperostosis, Van Buchem disease, autosomal dominant osteosclerosis, and osteopetrosis type I. Direct sequencing of the LRP5 gene revealed 19 sequence variants. Thirteen of these were confirmed as polymorphisms, but six novel missense mutations (D111Y, G171R, A214T, A214V, A242T, and T253I) are most likely disease causing. Like the previously reported mutation (G171V) that causes the high-bone-mass phenotype, all mutations are located in the aminoterminal part of the gene, before the first epidermal growth factor-like domain. These results indicate that, despite the different diagnoses that can be made, conditions with an increased bone density affecting mainly the cortices of the long bones and the skull are often caused by mutations in the LRP5 gene. Functional analysis of the effects of the various mutations will be of interest, to evaluate whether all the mutations give rise to the same pathogenic mechanism.

Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score.

Burning mouth syndrome (BMS) is often an idiopathic chronic and intractable pain condition, affecting 1.5-5.5% of middle-aged and elderly women. We have studied the heat and capsaicin receptor TRPV1, and its regulator nerve growth factor (NGF), in BMS. Patients with BMS (n=10) and controls (n=10) were assessed for baseline and post-topical capsaicin pain scores, and their tongue biopsies immunostained for TRPV1, NGF, and structural nerve markers neurofilament and peripherin. Nerve fibres penetrating the epithelium were less abundant in BMS (p<0.0001), indicating a small fibre neuropathy. TRPV1-positive fibres were overall significantly increased in BMS (p=0.0011), as were NGF fibres (p<0.0001) and basal epithelial cell NGF staining (p<0.0147). There was a significant correlation between the baseline pain score and TRPV1 (p=0.0143) and NGF fibres (p=0.0252). A significant correlation was observed between baseline and post-capsaicin pain (p=0.0006). Selective TRPV1 and NGF blockers may provide a new therapy for BMS.

Managing iatrogenic trigeminal nerve injury: a case series and review of the literature

This study describes the management of 216 patients with post-traumatic iatrogenic lingual nerve injuries (LNIs; n=93) and inferior alveolar nerve injuries (IANI; n=123). At initial consultation, 6% IANI and 2% LNI patients had undergone significant resolution requiring no further reviews. Reassurance and counselling was adequate management for 51% IANI and 55% LNI patients. Systemic or topical medication was offered as pain relief to 5% of patients. Additional cognitive behaviour therapy (CBT) was offered to 8% of patients. Topical 5% lidocaine patches reduced pain and allodynia in 7% of IANI patients, most often used without any other form of management. A small percentage of IANI patients (4%) received a combination of therapies involving CBT, surgery, medication and 5% lidocaine patches. Exploratory surgery improved symptoms and reduced neuropathic area in 18 LNI and 15 IANI patients resulting in improved quality of life. In conclusion, the authors suggest a more diverse and perhaps holistic strategy for management of patients with iatrogenic trigeminal nerve injuries and recommend pragmatic assessment criteria for measurement of treatment success in these patients.

Case studies on implant removal influencing the resolution of inferior alveolar nerve injury

Introduction Nerve injury during implant placement is a preventable, serious complication with major medico-legal implications. The incidence of implant related inferior alveolar nerve (IAN) injuries varies from 0-40%. This article presents four cases of IAN injury following mandibular implant placement with early removal, referred to the oral surgery department, Kings College Hospital, London.Objectives To assess sensory disturbance and recovery in patients with implant related IAN injury and assess whether early removal of the implants promotes neural recovery. To present recommendations on how to best deal with suspected/actual nerve injuries and prevent their occurrence.Methods Over the last two years, four patients referred for specialist opinion to the oral surgery department were identified as having sustained implant related IAN injury with early removal (18 hours to four days post-injury). Data were collected by referral to health records.Results All patients suffered from numbness of the affected inferior alveolar dermatome with three out of four cases also experiencing some form of neuropathic pain. Cases 1 and 2, who had their implants removed at 18 and 36 hours post-injury respectively, regained almost complete sensory recovery. Case 1 also had adjunctive NSAID and steroid therapy. Cases 3 and 4 suffered complete numbness in the inferior alveolar dermatome and did not experience any improvement in sensation following removal of their implants at two and four days post-injury respectively. Both patients with significant persistent neuropathy (Cases 3 &4) reported functional problems.Conclusion This cohort of patients may demonstrate that early removal of implants associated with IAN injury (less than 36 hours post-injury) may assist in minimising or even resolution of IAN neuropathy. Adjunctive corticosteroid and high dose non-steroidal anti-inflammatory therapy also appears effective. Implant related IAN injury is a preventable, elective procedure and a suggested protocol of management of suspected injuries, for dental practitioners, is presented.

Oral surgery: Factors predictive of difficulty of mandibular third molar surgery

Aim Historically the difficulty of third molar surgery has been judged using radiologically assessed dental factors specifically tooth morphology and position. This study investigated additional factors that have a bearing on the difficulty of extraction.Study design A prospective study undertaken by three clinical assistant grade surgeons who removed 354 single mandibular third molar teeth under day case anaesthesia over the 4-year period (1994–1998).Method Data relating to patient, dental and surgical variables were collected contemporaneously as the patients were treated. The difficulty of extraction was estimated by the surgeons pre-operatively using dental radiographic features and compared by the same surgeon within the actual surgical difficulty encountered at surgery. Operation time strongly related to both pre and post treatment assessments of difficulty and proved to be the best measure of surgical difficulty.Results Univariate analysis identified increased patient age, ethnic background, male gender, increased weight, bone impaction, horizontal angulation, depth of application, unfavourable root formation, proximity to inferior alveolar canal and surgeon as factors increasing operative time. Multivariate analysis showed that increasing age (P = 0.014), patient weight (P = 0.024), ethnicity (P = 0.019), application depth (P = 0.001), bone impaction (p=0.008) and unfavourable root formation (P = 0.009) were independent predictors for difficulty of extraction.Conclusions Half of the six independent factors that predicted surgical difficulty of third molar extraction were patient variables.

Sodium channel Nav1.8 immunoreactivity in painful human dental pulp

BackgroundThe tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 (SNS1/PN3) is expressed by nociceptors and may play a role in pain states.MethodsUsing specific antibodies for immunohistochemistry, we studied Nav1.8 – immunoreactivity in human dental pulp in relation to the neuronal marker neurofilament. Human tooth pulp was extracted from teeth harvested from a total of twenty-two patients (fourteen without dental pain, eight patients with dental pain).ResultsFibres immunoreactive for Nav1.8, were significantly increased on image analysis in the painful group: median (range) Nav1.8 to Neurofilament % area ratio, non-painful 0.059 (0.006–0.24), painful 0.265 (0.13–0.5), P = 0.0019.ConclusionNav1.8 sodium channels may thus represent a therapeutic target in trigeminal nerve pain states.

Trigeminal nerve injuries in relation to the local anaesthesia in mandibular injections

Objective This study reports the signs and symptoms that are the features of trigeminal nerve injuries caused by local anaesthesia (LA).Methods Thirty-three patients with nerve injury following LA were assessed. All data were analysed using the SPSS statistical programme and Microsoft Excel.Results Lingual nerve injury (LNI; n = 16) and inferior alveolar nerve injury (IANI; n = 17) patients were studied. LNI were more likely to be permanent. Neuropathy was demonstrable in all patients with varying degrees of paraesthesia, dysaesthesia (in the form of burning pain) allodynia and hyperalgesia. All injuries were unilateral. A significantly greater proportion of LNI patients (75%) had received multiple injections, in comparison to IANI patients (41%) (p <0.05). Fifty percent of patients with LNI reported pain on injection. The presenting signs and symptoms of both LNI and IANI included pain. These symptoms of neuropathy were constant in 88% of the IANI group and in 44% of LNI patients. Functional difficulties were different between the LNI and IANI groups, a key difference being the presence of severely altered taste perception in nine patients with LA-induced LNI.Conclusions Chronic pain is often a symptom after local anaesthetic-induced nerve injury. Patients in the study population with lingual nerve injury were significantly more likely to have received multiple injections compared to those with IANI.

Beyond Patient Reported Pain: Perfusion Magnetic Resonance Imaging Demonstrates Reproducible Cerebral Representation of Ongoing Post-Surgical Pain

Development of treatments for acute and chronic pain conditions remains a challenge, with an unmet need for improved sensitivity and reproducibility in measuring pain in patients. Here we used pulsed-continuous arterial spin-labelling [pCASL], a relatively novel perfusion magnetic-resonance imaging technique, in conjunction with a commonly-used post-surgical model, to measure changes in regional cerebral blood flow [rCBF] associated with the experience of being in ongoing pain. We demonstrate repeatable, reproducible assessment of ongoing pain that is independent of patient self-report. In a cross-over trial design, 16 participants requiring bilateral removal of lower-jaw third molars underwent pain-free pre-surgical pCASL scans. Following extraction of either left or right tooth, repeat scans were acquired during post-operative ongoing pain. When pain-free following surgical recovery, the pre/post-surgical scanning procedure was repeated for the remaining tooth. Voxelwise statistical comparison of pre and post-surgical scans was performed to reveal rCBF changes representing ongoing pain. In addition, rCBF values in predefined pain and control brain regions were obtained. rCBF increases (5–10%) representing post-surgical ongoing pain were identified bilaterally in a network including primary and secondary somatosensory, insula and cingulate cortices, thalamus, amygdala, hippocampus, midbrain and brainstem (including trigeminal ganglion and principal-sensory nucleus), but not in a control region in visual cortex. rCBF changes were reproducible, with no rCBF differences identified across scans within-session or between post-surgical pain sessions. This is the first report of the cerebral representation of ongoing post-surgical pain without the need for exogenous tracers. Regions of rCBF increases are plausibly associated with pain and the technique is reproducible, providing an attractive proposition for testing interventions for on-going pain that do not rely solely on patient self-report. Our findings have the potential to improve our understanding of the cerebral representation of persistent painful conditions, leading to improved identification of specific patient sub-types and implementation of mechanism-based treatments.

Post-implant neuropathy of the trigeminal nerve. A case series.

Background The incidence of implant-related inferior alveolar nerve injuries (IANI) is steadily increasing within the UK population.Aims This study prospectively reviewed thirty cases (35% male; 65% female) of implant-related IANI seen in a specialist nerve injury clinic.Methods Neurosensory examinations were carried out to ascertain a quantifiable rating of the perception, pain profiling and functional difficulties. Data were analysed using SPSS software.Results Patients were aware of signing consent forms for the surgery in 11 cases and 8 of those felt they were not explicitly warned about nerve injury. Over 70% of patients were referred after six months post injury. Implant surgery planning involved intra-oral films only (30%), CBCT (10%), dental pantomograph (50%) and long cone peri-apical radiographs (48%). However, no radiographic evidence pre- or postoperatively was provided by the referring practitioner in 15% of cases. Intra-operative problems included bleeding and neurological symptoms. Proximity of the implant bed or implant to the inferior alveolar canal was evident radiographically. This showed contact with roof inferior alveolar nerve canal in 44% of cases, protrusion into the canal in 20% of cases, crossing of the canal in 20% cases and distance in one case, presumed to be due to local anaesthetic injury. All patients presented with a demonstrable neuropathy, which included neuropathic pain (50%) that interfered with speaking, kissing and socialising.Conclusions Consent, preoperative planning and appropriate referral were inadequate in provision of mandibular implants in this patient group. Recommendations have been proposed to improve practice and possible novel strategies are suggested for the prevention and improved management of these complications.

Mandibular fracture osteosynthesis: a comparison of three techniques

The authors report on a retrospective study of 205 consecutive patients at the Maxillofacial Unit of The Royal Melbourne Hospital to assess if adherence to Champys principles in placement of miniplates in mandibular fractures minimises morbidity. 205 well documented cases of mandibular fractures treated with internal fixation, January 1985 to April 1990 were studied. The patients were assigned into three groups according to the type of fixation; 83 patients had miniplate fixation according to Champys principles, 40 patients had miniplate fixation ignoring Champys principles, 82 patients had transosseous wire (TOW) fixation. Outcome was measured by preoperative variables (age, gender, mechanism of fracture, site and number of fractures, nerve function, associated injuries and treatment delay) and postoperative variables (duration of admission, duration of intermaxillary fixation (IMF), malocclusion, infection, dehiscence, union, removal of fixation and nerve function which were assessed and compared. The results show that the preoperative variables were statistically similar in all groups. The postoperative variables indicated a statistically higher complication rate for the transosseous wire group compared with the miniplate groups, and morbidity was reduced in the group following Champys principles. The morbidity rates in this study compare favourably with other studies even though the patients in this study had a much higher incidence of multiple fractures. Titanium miniplates appear as effective as miniplates constructed of other materials used in previous studies, especially when Champys principles are followed.