Trigeminal Injury Research Articles

Management of Traumatic Trigeminal and Facial Nerve Injuries.

In the area of craniomaxillofacial trauma, neurosensory disturbances are encountered commonly, especially with regard to the trigeminal and facial nerve systems. This article reviews the specific microanatomy of both cranial nerves V and VII, and evaluates contemporary neurosensory testing, current imaging modalities, and available nerve injury classification systems. In addition, the article proposes treatment paradigms for management of trigeminal and facial nerve injuries, specifically with regard to the craniomaxillofacial trauma setting.

Puerarin Attenuates Complete Freund's Adjuvant-Induced Trigeminal Neuralgia and Inflammation in a Mouse Model via Sirt1-Mediated TGF-β1/Smad3 Inhibition.

BackgroundPuerarin, an active compound of radix puerariae, is a major compound used in Chinese herbal medicines and it has been well known for its pharmacological effects, including antioxidant, anti‑inflammatory, neuroprotective and cardioprotective properties. The aim of the present study was to determine the role of puerarin (Pue) in complete Freund’s adjuvant (CFA)-induced trigeminal neuralgia (TN) and the effects of this compound on Sirt1 activity and on the progression of CFA-induced TN.MethodsMice were injected with CFA on the unilateral face to induce TN. A cell model of inflammation-associated TN was established by interleukin-1β (IL-1β; 10 ng/mL) and tumor necrosis factor-α (TNF-α; 50 ng/mL) stimulation of neurons. Reverse transcription-quantitative PCR and Western blot analyses were performed to analyze mRNA and protein expression levels in trigeminal ganglion and nerve cells. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining was used to determine nerve cell apoptosis following IL-1β/TNF-α or Pue treatment.ResultsPue is a conceivable Sirtuin1 (Sirt1) activator used for the prevention of trigeminal nerve injury that attenuates CFA-induced TN and inflammatory cytokine-evoked overactivation of neuronal inflammation and apoptosis. Treatment of mice with inflammatory cytokines induced upregulation of cleaved caspase-3 protein expression, which was neutralized by Pue supplementation. Both in vivo and in vitro experiments led to the conclusion that Pue modulated Sirt1 activation and repressed transforming growth factor-β1 (TGF-β1) protein expression and drosophila mothers against decapentaplegic homolog3 (Smad3) phosphorylation in order to exert neuroprotection.ConclusionThe findings suggested that Pue functioned as a potential Sirt1 activator to improve neuroinflammation-induced TN and neuronal apoptosis via the suppression of TGF-β1/Smad3 activity. The pharmacological activity of Pue provides a new perspective for the effective prevention and treatment of TN.

Orofacial Neuropathic Pain-Basic Research and Their Clinical Relevancies.

Trigeminal nerve injury is known to cause severe persistent pain in the orofacial region. This pain is difficult to diagnose and treat. Recently, many animal studies have reported that rewiring of the peripheral and central nervous systems, non-neuronal cell activation, and up- and down-regulation of various molecules in non-neuronal cells are involved in the development of this pain following trigeminal nerve injury. However, there are many unknown mechanisms underlying the persistent orofacial pain associated with trigeminal nerve injury. In this review, we address recent animal data regarding the involvement of various molecules in the communication of neuronal and non-neuronal cells and examine the possible involvement of ascending pathways in processing pathological orofacial pain. We also address the clinical observations of persistent orofacial pain associated with trigeminal nerve injury and clinical approaches to their diagnosis and treatment.

Rapamycin Accelerates Axon Regeneration Through Schwann Cell-mediated Autophagy Following Inferior Alveolar Nerve Transection in Rats

Sensory disturbance in the orofacial region owing to trigeminal nerve injury is caused by dental treatment or accident. Commercially available therapeutics are ineffective for the treatment of sensory disturbance. Additionally, the therapeutic effects of rapamycin, an allosteric inhibitor of mammalian target of rapamycin (mTOR), which negatively regulates autophagy, on the sensory disturbance are not fully investigated. Thus, we investigated the therapeutic effects of rapamycin on the sensory disturbance in the mandibular region caused by inferior alveolar nerve (IAN) transection (IANX) in rats. The expression levels of the phosphorylated p70S6K, a downstream molecule of mTOR, in the proximal and distal stumps of the transected IAN were significantly reduced by rapamycin administration to the injured site. Conversely, the increments of both Beclin 1 and microtubule-associated protein-1 light chain 3-II protein levels in the proximal and distal stumps of the transected IAN was induced by rapamycin administration. Immunohistochemical analyses revealed that Beclin 1 was located in Schwann cells in the proximal stump of the IAN. Accumulation of myelin protein zero and myelin basic protein in the proximal and distal stumps of the IAN was significantly reduced by rapamycin administration. Rapamycin administration facilitated axon regeneration after IANX and increased the number of brain-derived neurotrophic factor positive neurons in the trigeminal ganglion. Thus, recovery from sensory disturbance in the lower lip caused by IANX was markedly facilitated by rapamycin. These findings suggest that rapamycin administration is a promising treatment for the sensory disturbance caused by IANX.

Acute and Chronic Pain from Facial Skin and Oral Mucosa: Unique Neurobiology and Challenging Treatment.

The oral cavity is a portal into the digestive system, which exhibits unique sensory properties. Like facial skin, the oral mucosa needs to be exquisitely sensitive and selective, in order to detect harmful toxins versus edible food. Chemosensation and somatosensation by multiple receptors, including transient receptor potential channels, are well-developed to meet these needs. In contrast to facial skin, however, the oral mucosa rarely exhibits itch responses. Like the gut, the oral cavity performs mechanical and chemical digestion. Therefore, the oral mucosa needs to be insensitive, to some degree, in order to endure noxious irritation. Persistent pain from the oral mucosa is often due to ulcers, involving both tissue injury and infection. Trigeminal nerve injury and trigeminal neuralgia produce intractable pain in the orofacial skin and the oral mucosa, through mechanisms distinct from those seen in the spinal area, which is particularly difficult to predict or treat. The diagnosis and treatment of idiopathic chronic pain, such as atypical odontalgia (idiopathic painful trigeminal neuropathy or post-traumatic trigeminal neuropathy) and burning mouth syndrome, remain especially challenging. The central integration of gustatory inputs might modulate chronic oral and facial pain. A lack of pain in chronic inflammation inside the oral cavity, such as chronic periodontitis, involves the specialized functioning of oral bacteria. A more detailed understanding of the unique neurobiology of pain from the orofacial skin and the oral mucosa should help us develop novel methods for better treating persistent orofacial pain.

Trigeminal Nerve Repair: Is the Trigeminocardiac Reflex a Concern?

Our hypothesis is that direct manipulation of the third and second divisions of the trigeminal nerve during microneurosurgery does not affect the incidence of trigeminocardiac reflex (TCR). The purpose of this paper was to analyze the incidence of TCR events during microneurosurgery involving the second and third divisions of the trigeminal nerve. This was a retrospective cohort study of 94 patients who underwent nerve repair of the second and third divisions of the trigeminal nerve, between July 2014 and February 2021 by a single surgeon (J. Z.). The independent variables were the trigeminal nerve branch injured, the laterality of the trigeminal nerve injury, the Sunderland classification, the ASA classification, the intraoperative narcotic(s) used, and the depth of anesthesia. The dependent variables included the occurrence of intraoperative hypercapnia, hypoxia, and TCR event. Since the data was retrospective and categorical in nature, χ2 analysis was performed initially. None of the patients in this retrospective cohort demonstrated intraoperative hypercapnia, hypoxia or TCR events. Initial χ2 calculation was performed for the dependent variables with the trigeminal nerve groups (IAN, LN, and ION). The χ2 calculation [χ2 (1, n=101)] was 0.2235. The P-value was .6364. Since there was no statistical significance found, there was no further analysis of surgical and anesthesia independent variables in the data collection. The zero incidence of TCR in a large number of patients provides strong evidence supporting the rejection of the hypothesis that TCR can occur during the surgical repair of peripheral trigeminal nerves.

The effect of IL-6/Piezo2 on the trigeminal neuropathic pain.

The nature of trigeminal neuropathic pain (TN) attacks is regarded as the ignition of ectopic action potentials from the trigeminal root following vascular compression, which seemed to be related to transmembrane proteins and inflammation factors. This study focused on the mechanosensitive channel Piezo2 and cytokine IL-6.The chronic constriction injury of infraorbital nerve in SD rats was used to establish the TN model. The trigeminal ganglion was then achieved to perform immunocytochemistry studies.A significant upregulation of Piezo2 and IL-6 was showed in the TN model rats. The Piezo2 positive accounted for 72.3±9.5% in those IL-6 positive neurons. The Piezo2 co-localized with CGRP, IB4 and NF-200 but not with GFAP, which implied that it was expressed in both the C-type and the A-type neurons. After administration of GsMTx4 or anti-rat IL-6 antibody in the TN model, the dynamic allodynia and pinprick hyperalgesia scores as well as the mechanical threshold changed significantly. In the sham-operation rates, with local administration of IL-6, an upregulation of Piezo2 was also exhibited.Our study demonstrated that the up-regulation of Piezo2 in the pain afferent neurons following trigeminal nerve injury may play a role in the development of the neuralgia. Meanwhile, the expression of Piezo2 may be modulated by inflammatory cytokines, such as IL-6.

Pretreatment with High Mobility Group Box-1 Monoclonal Antibody Prevents the Onset of Trigeminal Neuropathy in Mice with a Distal Infraorbital Nerve Chronic Constriction Injury

Persistent pain following orofacial surgery is not uncommon. High mobility group box 1 (HMGB1), an alarmin, is released by peripheral immune cells following nerve injury and could be related to pain associated with trigeminal nerve injury. Distal infraorbital nerve chronic constriction injury (dIoN-CCI) evokes pain-related behaviors including increased facial grooming and hyper-responsiveness to acetone (cutaneous cooling) after dIoN-CCI surgery in mice. In addition, dIoN-CCI mice developed conditioned place preference to mirogabalin, suggesting increased neuropathic pain-related aversion. Treatment of the infraorbital nerve with neutralizing antibody HMGB1 (anti-HMGB1 nAb) before dIoN-CCI prevented both facial grooming and hyper-responsiveness to cooling. Pretreatment with anti-HMGB1 nAb also blocked immune cell activation associated with trigeminal nerve injury including the accumulation of macrophage around the injured IoN and increased microglia activation in the ipsilateral spinal trigeminal nucleus caudalis. The current findings demonstrated that blocking of HMGB1 prior to nerve injury prevents the onset of pain-related behaviors, possibly through blocking the activation of immune cells associated with the nerve injury, both within the CNS and on peripheral nerves. The current findings further suggest that blocking HMGB1 before tissue injury could be a novel strategy to prevent the induction of chronic pain following orofacial surgeries.

The α2δ-1-NMDAR1 interaction in the trigeminal ganglion contributes to orofacial ectopic pain following inferior alveolar nerve injury

Orofacial ectopic pain can often arise following nerve injury. However, the exact mechanism responsible for orofacial ectopic pain induced by trigeminal nerve injury remains unknown. The α2δ-1 and glutamate N-methyl-d-aspartic acid receptor (NMDAR) interactions have been demonstrated to participate in neuropathic pain regulation in the spinal cord. In this study, a rat model of inferior alveolar nerve transection (IANX) was used to investigate the role of α2δ-1-NMDAR1 interaction in the trigeminal ganglion (TG) in regard to the regulation of orofacial ectopic pain. Western blot (WB) analysis indicated that α2δ-1 and NMDAR1 in the TG were substantially higher in IANX rats than they were in sham/naive rats. Additionally, immunofluorescence (IF) results revealed that α2δ-1 and NMDAR1 were co-expressed and distributed within neurons and activated satellite glial cells in the TG. Co-immunoprecipitation (Co-IP) results indicated that α2δ-1-NMDAR1 complex levels in the TG were higher in IANX rats than they were in sham rats. Furthermore, the results of behavioral tests demonstrated that intra-TG injection of gabapentin (α2δ-1 inhibitory ligand) or memantine hydrochloride (NMDAR antagonist) reversed the decrease in mechanical head-withdrawal threshold (HWT) in IANX rats. Moreover, inhibition of α2δ-1 by intra-TG administration of gabapentin suppressed the upregulation of the NMDAR1 protein, and the inhibition of NMDAR by intra-TG administration of memantine hydrochloride inhibited the increased expression of α2δ-1 protein induced by IANX. In conclusion, the physical and functional interaction between α2δ-1 and NMDAR1 is critical for the development of orofacial ectopic pain, indicating that α2δ-1, NMDAR1, and the α2δ-1–NMDAR1 complex may represent potential targets for the treatment of orofacial ectopic pain.

Injuries of the Peripheral Mandibular Nerve, Evaluation of Interventions and Outcomes: A Systematic Review.

Trigeminal nerve injuries are common and there is currently no consensus on both timing and type of intervention to achieve the best outcomes. A systematic review was performed to compare the outcomes of the many different types of therapeutic interventions for nerve injury. PubMed, EBSCO, and Cochrane Review databases were used to search for studies published from January 1, 2000 to December 31, 2019. Included studies detailed treatment of an injury to peripheral branches of the trigeminal nerve, either known transection or injury causing persistent alteration in sensation. The primary outcome was functional sensory recovery via the Medical Research Council scale. Twenty studies were included, detailing outcomes of 608 subjects undergoing intervention for 622 nerve injuries. Surgical interventions were able to achieve functional sensory recovery in approximately >80% or more of the subjects. There was heterogeneity among how procedures were performed, timing to intervention, and methods of measuring recovery. The data of this study supports the ability of surgical intervention to achieve functional sensory recovery in a significant number of subjects, and found evidence for better outcomes with intervention closer to the time of injury.

Clinical characteristics and curative effect analysis of neurotrophic keratitis caused by trigeminal nerve injury

目的： 探讨三叉神经损伤引起的神经营养性角膜炎的临床特征及治疗。 方法： 回顾性系列病例研究。收集2014年1月至2020年6月山东省眼科医院收治的因三叉神经损伤导致的NK患者64例（65只眼），其中男性32例（32只眼），女性32例（33只眼），年龄（57.5±12.9）岁。分析患者发病原因、临床分期的特点，观察发病原因、发病时间与角膜病变严重程度的关系以及治疗方法及效果。 结果： 64例患者的发病原因包括颅脑肿瘤28只眼（43.08%），三叉神经痛术后13只眼（20.00%），脑卒中12只眼（18.46%），颅脑外伤5只眼（7.69%），格林-巴利综合征2只眼（3.08%），其他原因5只眼（7.69%）（皆合并面神经麻痹）。病程4 d至10年，其中病程≤1个月者28例（29只眼，44.61%），1～6个月者25例（25只眼，38.46%），>6个月者11例（11只眼，16.92%）。所有患者均有明显的角膜知觉减退。27只眼（41.54％）合并暴露性角膜炎，其中22只眼同时伴有面神经麻痹。根据Mackie临床分期，1期1只眼（1.53％），表现为眼表泪膜干燥，角膜上皮点状粗糙，睑裂暴露区明显，荧光素钠染色可见点状着色；2期14只眼（21.54％），表现为角膜中央或偏下方睑裂区上皮缺损，多呈横椭圆形，上皮缺损的边缘多增厚呈潜掘状；3期50只眼（76.92％），发生角膜中央偏下方溃疡及浸润，椭圆形最为常见。合并感染12只眼（18.46%）。药物联合手术治疗59只眼（90.76%），行永久性睑裂缝合术16只眼（27.12%），永久性睑裂缝合联合结膜瓣遮盖术15只眼（25.42%）、永久性睑裂缝合联合羊膜移植术21只眼（35.59%）、永久性睑裂缝合联合角膜移植术7只眼（11.86%），6只眼因全身情况不耐受手术或个人原因拒绝手术。术后半年内59只眼（除外6只眼放弃治疗，后失访），治愈52只眼（88.14%），治愈时间为（10.52±6.52）d。好转6只眼（10.17%），1只眼（1.69%）无效。 结论： 三叉神经损伤可引起患者角膜知觉明显减退或消失，导致症状不明显而忽略病情，临床接诊多为角膜损伤较严重的2或3期患者；近一半患者角膜炎发生于三叉神经损伤后1个月以内，需药物联合手术治疗，为治愈溃疡、防止角膜基质融解需联合永久性睑裂缝合术。（中华眼科杂志，2021，57：126-132）.

Kv4.3 Channel Dysfunction Contributes to Trigeminal Neuropathic Pain Manifested with Orofacial Cold Hypersensitivity in Rats

Trigeminal neuropathic pain is the most debilitating pain disorder but current treatments including opiates are not effective. A common symptom of trigeminal neuropathic pain is cold allodynia/hyperalgesia or cold hypersensitivity in orofacial area, a region where exposure to cooling temperatures are inevitable in daily life. Mechanisms underlying trigeminal neuropathic pain manifested with cold hypersensitivity are not fully understood. In this study, we investigated trigeminal neuropathic pain in male rats following infraorbital nerve chronic constrictive injury (ION-CCI). Assessed by the orofacial operant behavioral test, ION-CCI animals displayed orofacial cold hypersensitivity. The cold hypersensitivity was associated with the hyperexcitability of small-sized trigeminal ganglion (TG) neurons that innervated orofacial regions. Furthermore, ION-CCI resulted in a reduction of A-type voltage-gated K+currents (IA currents) in these TG neurons. We further showed that these small-sized TG neurons expressed Kv4.3 voltage-gated K+channels, and Kv4.3 expression in these cells was significantly downregulated following ION-CCI. Pharmacological inhibition of Kv4.3 channels with phrixotoxin-2 inhibited IA-currents in these TG neurons and induced orofacial cold hypersensitivity. On the other hand, pharmacological potentiation of Kv4.3 channels amplified IA currents in these TG neurons and alleviated orofacial cold hypersensitivity in ION-CCI rats. Collectively, Kv4.3 downregulation in nociceptive trigeminal afferent fibers may contribute to peripheral cold hypersensitivity following trigeminal nerve injury, and Kv4.3 activators may be clinically useful to alleviate trigeminal neuropathic pain.SIGNIFICANCE STATEMENTTrigeminal neuropathic pain, the most debilitating pain disorder, is often triggered and exacerbated by cooling temperatures. Here, we created infraorbital nerve chronic constrictive injury (ION-CCI) in rats, an animal model of trigeminal neuropathic pain to show that dysfunction of Kv4.3 voltage-gated K+channels in nociceptive-like trigeminal ganglion (TG) neurons underlies the trigeminal neuropathic pain manifested with cold hypersensitivity in orofacial regions. Furthermore, we demonstrate that pharmacological potentiation of Kv4.3 channels can alleviate orofacial cold hypersensitivity in ION-CCI rats. Our results may have clinical implications in trigeminal neuropathic pain in human patients, and Kv4.3 channels may be an effective therapeutic target for this devastating pain disorder.

How Many Oral Surgeons Does It Take to Classify a Nerve Injury?

There is inconsistency in clinical grading of peripheral trigeminal nerve (TN5) injuries that impact patient care. The study goal is to assess the current status of evaluation and classification of TN5 injuries by oral and maxillofacial surgeons (OMSs). A cross-sectional study design used an electronic survey to 100 selected OMSs to determine their clinical TN5 injury practice, including neurosensory testing, confidence level with current protocols, and evaluation and treatment of a hypothetical TN5 injury case. The target sample was enhanced to reduce type 2 error, assuming prior experience in the diagnosis and management of TN5 injuries. The sample was composed of 90 respondents. Nerve injury classification systems used by OMSs include Seddon (44%), Sunderland (70%), and Medical Research Council Scale (31%). Neurosensory testing protocols varied considerably among survey respondents. A sample case for Medical Research Council Scale grading produced inconsistent and inaccurate results. There was no consensus on TN5 injury management, and recommendations for timely nerve repair varied from 1month to up to 1year after injury. Half of the respondents stated that OMSs are not adequately prepared to assess inferior alveolar/lingual nerve injuries, and most oral-maxillofacial surgery respondents evaluate fewer than 10 TN5 injuries each year. Most OMSs (92%) have had a temporary inferior alveolar/lingual nerve injury, while 54% have had a permanent injury; of which, 21% required microsurgical repair. The majority of OMSs (74%) believed that a uniform TN5 injury classification system is needed. Within the oral-maxillofacial surgery target group experienced in evaluation of TN5 injuries, respondents do not feel confident in the assessment of these injuries. There is inconsistency in evaluation methods, and there is agreement that a unified classification system is needed for more efficient patient evaluation and reporting of outcomes in the literature. The Medical Research Council Scale and clinical neurosensory testing is preferred for evaluation of TN5 injuries.

Prevalence of iatrogenic trigeminal nerve injuries in routine dental practice in private, public, and educational clinics of Riyadh, Saudi Arabia

Background: The trigeminal nerve (V) is a critical nerve in the maxillofacial region relevant to dentistry. The nerve trifurcates into ophthalmic, maxillary, and mandibular nerves . The risk of having trigeminal nerve injuries (TNIs) is relatively high as dentists from various specialties perform trigeminal nerve blocks in routine dental practice. The causes of TNIs can be varied and broadly classified into iatrogenic and non-iatrogenic. The current study aimed to assess the prevalence of TNIs, mainly iatrogenic injuries, in Riyadh, Saudi Arabia, and examine the various dental factors associated with these types of nerve injuries. Methods: A cross-sectional study was carried out through a questionnaire. The questionnaire consisted of two major parts: demographic data and injury assessment and management. The participants were 349 in number and were dentists, interns, and dental students working in private, governmental, and educational sectors. The participants were approached by a simple random sampling technique. The reporting of the iatrogenic cases is mainly outlined. Results: Among the participants, 45.9% were dentists, 35.8% students, and 18.3% were interns. Most cases (93%, N = 44) were presented with neuropathy due to iatrogenic injury. Out of the 93% reported cases, 65.9% were related to extractions, 27.3% were associated with implants and restorative procedures, and 18.2% were related to endodontic procedures. Temporary injuries accounted for 82%, whereas permanent injuries were 18%. The inferior alveolar nerve is affected more often than the lingual nerve. Most of these injuries (70%) were referred to oral and maxillofacial surgeons for follow-up. Conclusion: An appropriate assessment, thorough history, and clinical examination would significantly help prevent TNI cases. Moreover, well documentation and prompt reporting and referral by the clinicians would ensure optimum patient care. Therefore, further studies covering the main Saudi regions other than Riyadh city are advocated to establish preventive and management protocols.

Clinical Statistics of Iatrogenic Trigeminal Nerve Injury

Clinical Statistics of Iatrogenic Trigeminal Nerve Injury

The surgical management of extra-cranial trigeminal nerve palsies: A retrospective case series

To assess for functional improvement in outcomes following supermicrosurgical restoration across a cohort of patients with a spectrum of trigeminal nerve disorders. In a retrospective case series over three years (2016-18), twenty patients were included in a cohort of trigeminal nerve palsy patients. Eleven patients with corneal anaesthesia underwent corneal neurotisation procedures and were followed up using Cochet-Bonnet aesthesiometry. Six patients with sensory trigeminal nerve injuries had direct nerve coaptation and neuroma excision. Three patients with trigeminal motor nerve palsies were followed up with photography for contour improvement. Regarding corneal neurotisation, there was evidence of significant improvement in protective corneal sensation and also blinking frequency. Regarding facial sensory disturbances, all patients had full resolution of painful trigeminal neuroma symptoms. In two cases of iatrogenic trigeminal motor palsies with contour defects, adipo-fascial variants of the superficial circumflex iliac artery (SCIP) free flap achieved excellent restoration of facial contour in lieu of facial lipofilling. In another case of a necrotising infection of the head and neck with loss of all masticatory muscles, a free functional muscle using a chimaeric vastus lateralis-ALT flap was used to restore masticatory and facial movement in a single stage procedure. Using combinations and permutations of current surgical techniques, it is possible to successfully restore both form and function for patients with sensory as well as motor trigeminal nerve palsies. This sets a precedent for the expansion of cranial nerve surgery as an evolving sub-speciality.

Effects of trigeminal nerve injury on the expression of galanin and its receptors in the rat trigeminal ganglion

In the spinal nervous system, the expression of galanin (GAL) and galanin receptors (GALRs) that play important roles in the transmission and modulation of nociceptive information can be affected by nerve injury. However, in the trigeminal nervous system, the effects of trigeminal nerve injury on the expression of GAL are controversy in the previous studies. Besides, little is known about the effects of trigeminal nerve injury on the expression of GALRs. In the present study, the effects of trigeminal nerve injury on the expression of GAL and GALRs in the rat trigeminal ganglion (TG) were investigated by using quantitative real-time reverse transcription-polymerase chain reaction and immunohistochemistry. To identify the nerve-injured and nerve-uninjured TG neurons, activating transcription factor 3 (ATF3, the nerve-injured neuron marker) was stained by immunofluorescence. The levels of GAL mRNA in the rostral half and caudal half of the TG dramatically increased after transection of infraorbital nerve (ION) and inferior alveolar nerve (IAN), respectively. Immunohistochemical labeling of GAL and ATF3 revealed that GAL level was elevated in both injured and adjacent uninjured small and medium-sized TG neurons after ION/IAN transection. In addition, the levels of GAL2R-like immunoreactivity were reduced in both injured and adjacent uninjured TG neurons after ION/IAN transection, while levels of GAL1R and GAL3R-like immunoreactivity remained unchanged. Furthermore, the number of small to medium-sized TG neurons co-expressing GAL- and GAL1R/GAL2R/GAL3R-like immunoreactivity was significantly increased after ION/IAN transection. In line with previous studies in other spinal neuron systems, these results suggest that GAL and GALRs play functional roles in orofacial neuropathic pain and trigeminal nerve regeneration after trigeminal nerve injury.

Predictors of Trigeminal Nerve Neurosensory Deficit Following Alloplastic Temporomandibular Joint Replacement

The purpose of this study was to identify factors associated with trigeminal nerve injury following alloplastic temporomandibular joint (TMJ) replacement. The sample included subjects who underwent alloplastic TMJ replacement surgery from 2010 through 2019 at the University of Texas Health Science Center at San Antonio. Operative interventions consisted of TMJ reconstruction with patient-fitted total joint replacement (TMJ TJR) either with or without orthognathic surgery. Eligible subjects included those who were evaluated for a neurosensory deficit at longest follow-up with a follow-up time of at least 6 months. The primary outcome variable was a neurosensory deficit (NSD) (i.e., trigeminal nerve sensory deficit, yes or no) defined as a score of greater than 0 on a Likert scale from 0-4 (0 = no deficit, 4 = complete deficit). Outcome variables were categorized as demographic, anatomic, and operative. Descriptive and bivariate statistics were used to identify associations between the predictor and outcome variables. P < .05 was considered statistically significant. A total of 346 joints were replaced within the defined temporal period. Of those, 176 met the necessary criteria to be included in the sample. Twenty-three subjects had unilateral TMJ TJR while 75 had bilateral replacement. Of the 98 subjects, 28 (29%) had a maxillary osteotomy in addition to the TMJ TJR. The mean age at the time of the operation was 38 + 18 years (min: 16, max: 79), and the majority of the subjects were female (n = 92, 94%). At the immediate follow-up appointment, 50 (51%) NSDs were reported, 16 of those fully recovered by the time of the longest follow-up (mean: 23 months). The maxillary division (V2) was involved in 21% (n = 7) of cases, the mandibular division (V3) in 44% (n = 15) of cases, and both divisions were involved in 35% of cases (n = 12). Specifically, the lower lip was the region most often affected. The prevalence of an NSD was significantly greater in subjects who underwent TJR with concomitant orthognathic surgery (n = 28, P = .036) compared to TJR alone (n = 70). Additionally, subjects with the diagnosis of degenerative joint disease (51%) had a statistically significant higher risk of trigeminal nerve deficits compared with all other diagnoses (P = .049). Age and gender were not statically correlated with prevalence of an NSD. Many patients undergoing alloplastic TMJ replacement who report a trigeminal nerve injury completely recover by the time of longest follow-up. A persistent NSD is associated with temporomandibular joint pathology and the extent of the operative procedure performed.

Microglia-Astrocyte Communication via C1q Contributes to Orofacial Neuropathic Pain Associated with Infraorbital Nerve Injury.

Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which promotes the activation of astrocytes, is known to be synthesized in microglia. However, it is unclear whether microglia–astrocyte communication via C1q is involved in orofacial neuropathic pain. Here, we analyzed microglia-astrocyte communication in a rat model with infraorbital nerve injury (IONI). The orofacial mechanical hypersensitivity induced by IONI was significantly attenuated by preemptive treatment with minocycline. Immunohistochemical analyses revealed that minocycline inhibited the increase in c-Fos immune-reactive (IR) cells and the fluorescence intensity of both Iba1 and glial fibrillary acidic protein (GFAP) in the Vc following IONI. Intracisternal administration of C1q caused orofacial mechanical hypersensitivity and an increase in the number of c-Fos-IR cells and fluorescence intensity of GFAP. C1q-induced orofacial mechanical hypersensitivity was completely abrogated by intracisternal administration of fluorocitrate. The present findings suggest that the enhancement in the excitability of Vc nociceptive neurons is produced by astrocytic activation via the signaling of C1q released from activated microglia in the Vc following IONI, resulting in persistent orofacial neuropathic pain.

The Trigeminal Nerve Injury.

Trigeminal nerve branches are never far from the operating field of the oral and maxillofacial surgeon. Increasingly the surgeon is required to provide accurate diagnosis and grading of trigeminal nerve injury, and surgical management by oral and maxillofacial surgeons will become common. Although trauma and ablative procedures for head and neck pathology can cause injuries, dentoalveolar surgical procedures remain an important cause of injury to the fifth cranial nerve, with the third division being the main branch affected. Oral and maxillofacial surgeons should be aware of strategies of avoiding iatrogenic injury, and know when referral and surgical management are appropriate.