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Chronic neuropathic pain can result from nervous system injury and can persist in the absence of external stimuli. Although ongoing pain characterizes the disorder, in many individuals, the intensity of this ongoing pain fluctuates dramatically. Previously, it was identified that functional magnetic resonance imaging signal covariations between the midbrain periaqueductal gray (PAG) matter, rostral ventromedial medulla (RVM), and spinal trigeminal nucleus are associated with moment-to-moment fluctuations in pain intensity in individuals with painful trigeminal neuropathy (PTN). Since this brainstem circuit is modulated by higher brain input, we sought to determine which cortical sites might be influencing this brainstem network during spontaneous fluctuations in pain intensity. Over 12 min, we recorded the ongoing pain intensity in 24 PTN participants and classified them as fluctuating ( n  = 13) or stable ( n  = 11). Using a PAG seed, we identified connections between the PAG and emotional-affective sites such as the hippocampal and posterior cingulate cortices, the sensory-discriminative posterior insula, and cognitive-affective sites such as the dorsolateral prefrontal (dlPFC) and subgenual anterior cingulate cortices that were altered dependent on spontaneous high and low pain intensity. Additionally, sliding-window functional connectivity analysis revealed that the dlPFC-PAG connection anticorrelated with perceived pain intensity over the entire 12 min period. These findings reveal cortical systems underlying moment-to-moment changes in perceived pain in PTN, which likely cause dysregulation in the brainstem circuits previously identified, and consequently alter the appraisal of pain across time., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Meylakh et al.)

Data on the state of sense of smell in patients who had a new coronavirus infection caused by the SARS-CoV-2 virus are currently reduced because of the impairment of the olfactory nerve system. There are practically no results in studies of disorders in the trigeminal nerve system., Objective: Qualitative assessment of olfactory disorders after COVID-19 according to the system of olfactory and trigeminal nerves with a targeted assessment of the functional component of olfactory disorders., Material and Methods: We examined 40 patients aged 19 to 66 who had a coronavirus infection. All patients underwent neurological, otorhinolaryngological examinations, olfactometry, filled out the hospital anxiety and depression scale., Results: Anosmia was diagnosed in 5 (12.5%) patients, hyposmia in 21 (52.5%) patients, and normosmia in 14 (35%) patients. Formed: the 1st group - 14 patients (35%) with normogram according to olfactometry; the 2nd group - 26 patients (65%) with anosmia/hyposmia. In the 1st group, disorders of the anxiety-depressive spectrum were significantly more common. In the 2nd group, a low identification of odors was found, lying in the spectrum of fresh, sharp, unpleasant, irritating, compared with sweet and pleasant or neutral, which indicates a predominant lesion of the trigeminal system., Conclusion: In patients with complaints of impaired sense of smell after undergoing COVID-19, the possible functional nature of anosmia/hyposmia should be taken into account, which requires the referral of such patients to psychotherapeutic specialists, and the possible entry of olfactory disorders into the 'trigeminal' spectrum.

Purpose: The aim of this study is to describe techniques, results, and open issues of corneal neurotization (CN) for the treatment of neurotrophic keratopathy (NK)., Methods: An overview of the most important studies of CN is provided. The 2 main surgical approaches (namely, direct CN and indirect CN) with specific advantages and disadvantages are described. The results regarding changes of corneal sensitivity and clarity, visual acuity, and in vivo confocal microscopy metrics are summarized. Ex vivo studies with histopathology of the neurotized cornea are reported. Intraoperative and early and late postoperative complications are described along with current open issues to be further clarified., Results: Corneal sensitivity improves after both direct and indirect CN. Corneal reinnervation allows the healing of NK in almost the totality of the operated eyes, determining a corresponding improvement of corneal clarity and visual acuity. Regeneration of corneal nerve fibers is confirmed by means of either in vivo confocal microscopy or ex vivo histopathology. Few self-limiting complications are reported during the postoperative course. Current open issues concern the identification of the technique of choice, the use of autograft or allograft, and the timing of CN either when performed alone or when combined with other surgeries., Conclusions: CN represents a game-changing surgical procedure for NK, which has the potential to restore corneal sensitivity in all stages of the disease regardless of the mechanism of denervation. Further long-term results are needed to confirm its efficacy over time. The design of randomized clinical trials comparing CN with noninterventional therapies could further validate the adoption of this technique., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Infraorbital nerve-chronic constriction injury (ION-CCI) has become the most popular chronic trigeminal neuropathic pain (TNP) injury animal model which causes prolonged mechanical allodynia. Accumulative evidence suggests that TNP interferes with cognitive functions, however the underlying mechanisms are not known. The aim of this study was to investigate decision-making performance as well as synaptic and large-scale neural synchronized alterations in the spinal trigeminal nucleus (SpV) circuitry and anterior cingulate cortex (ACC) neural circuitry in male rats with TNP. Rat gambling task showed that ION-CCI led to decrease the proportion of good decision makers and increase the proportion of poor decision makers. Electrophysiological recordings showed long-lasting synaptic potentiation of local field potential in the trigeminal ganglia-SpV caudalis (SpVc) synapses in TNP rats. In this study, TNP led to disruption of ACC spike timing and basolateral amygdala (BLA) theta oscillation associated with suppressed synchronization of theta oscillation between the BLA and ACC, indicating reduced neuronal communications. Myelination is critical for information flow between brain regions, and myelin plasticity is an important feature for learning. Neural activity in the cortical regions impacts myelination by regulating oligodendrocyte (OL) proliferation, differentiation, and myelin formation. We characterized newly formed oligodendrocyte progenitor cells, and mature OLs are reduced in TNP and are associated with reduced myelin strength in the ACC region. The functional disturbances in the BLA-ACC neural circuitry is pathologically associated with the myelin defects in the ACC region which may be relevant causes for the deficits in decision-making in chronic TNP state., (© 2021 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Competing Interests: The authors report no conflicts of interest.

Trigeminal neuropathic pain (TNP) led to vital cognitive functional deficits such as impaired decision-making abilities in a rat gambling task. Chronic TNP caused hypomyelination in the anterior cingulate cortex (ACC) associated with decreased synchronization between ACC spikes and basal lateral amygdala (BLA) theta oscillations. The aim of this study was to investigate the effect of pain suppression on cognitive impairment in the early or late phases of TNP. Blocking afferent signals with a tetrodotoxin (TTX)-ELVAX implanted immediately following nerve lesion suppressed the allodynia and rescued decision-making deficits. In contrast, the TTX used at a later phase could not suppress the allodynia nor rescue decision-making deficits. Intra-ACC administration of riluzole reduced the ACC neural sensitization but failed to restore ACC-BLA spike-field phase synchrony during the late stages of chronic neuropathic pain. Riluzole suppressed allodynia but failed to rescue the decision-making deficits during the late phase of TNP, suggesting that early pain relief is important for recovering from pain-related cognitive impairments. The functional disturbances in ACC neural circuitry may be relevant causes for the deficits in decision making in the chronic TNP state.

Aims: Nod-like receptor family pyrin domain containing 3 (NLRP3) may play an important role in neuropathic pain. Treatment for trigeminal neuropathic pain remains a challenge, as common drugs either do not demonstrate beneficial therapeutic effects or induce intolerance in patients., Main Methods: In a rat model of trigeminal neuropathic pain, pain caused by the malpositioning of dental implants is similar to that experienced by humans. We used masculine Sprague-Dawley rats with inferior alveolar nerve damage as a model to investigate the differential regulation of NLRP3. First, we confirmed the level of NLRP3 in the medullary dorsal horn and variation of pain response behavior after silencing the expression of NLRP3 inflammasome bodies in rats with trigeminal neuropathic pain. Second, under localized anesthesia, we extracted the lower left second molar, implanted a micro-dental implant, and deliberately injured the inferior alveolar nerve., Key Findings: After nerve damage, the level of NLRP3-related inflammasomes was upregulated in microglia and the expression of a component of the inflammasome gradually increased during postoperative days 3-21. The suppression of adenovirus-shRNA-NLRP3 on postoperative day 1 markedly inhibited the expression of pro-inflammatory cytokines and the activation of the inflammasome and mechanical allodynia. Furthermore, it attenuated cell death in microglia, as evidenced by increased Bcl-2, Bcl-xL, Bax, and Bik expression., Significance: The level of NLRP3 in the dorsal horn is a pivotal factor in trigeminal neuropathic pain, and inhibition of the early expression of NLRP3 might serve as a potential therapeutic approach., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Significance: Ocular tilt reaction (OTR) is an abnormal eye-head postural reaction that consists of skew deviation, head tilt, and bilateral ocular torsion. Understanding of the pathway of the vestibulo-ocular reflex (VOR) is essential because this will help to localize the pathology., Purpose: The aim of this study was to report a case of OTR with contralateral internuclear ophthalmoplegia (INO) and fifth and seventh cranial nerve palsies., Case Report: A 51-year-old gentleman with underlying diabetes mellitus presented with sudden onset of diplopia for 3 days. On examination, his visual acuity was 20/30 bilaterally without a relative afferent pupillary defect. He had a right OTR consisting of a right head tilt, a skew deviation with a left eye hypertropia, and bilateral ocular torsion (right excyclotorsion and left incyclotorsion) with nystagmus. He also had a left adduction deficit and right abduction nystagmus consistent with a left INO. Ocular examination revealed evidence of proliferative diabetic retinopathy bilaterally. Two days after the initial presentation, the patient developed left seventh and fifth cranial nerve palsies. MRI showed left pontine infarction and multiple chronic lacunar infarctions. There was an incidental finding of a vascular loop compression on cisternal portions of the left trigeminal, facial, and vestibulocochlear nerves. Antiplatelet treatment was started on top of a better diabetic control. The diplopia was gradually resolved with improved clinical signs. In this case, the left pontine infarction had likely affected the terminal decussated part of the vestibulocochlear nerve from the right VOR pathway, medial longitudinal fasciculus, and cranial nerve nuclei in the left pons., Conclusions: The OTR can be ipsilateral to the lesion if the lesion is before the decussation of the VOR pathway in the pons, or it can be contralateral to the lesion if the lesion is after the decussation. In case of an OTR that is associated with contralateral INO and other contralateral cranial nerves palsy, a pathology in the pons that is contralateral to the OTR should be considered. Neuroimaging study can hence be targeted to identify the possible cause.

Objective: To characterize the frequency and patterns of optic, trigeminal, and facial nerve involvement by neuroimaging and electrophysiology in IgG4 anti-neurofascin 155 antibody-positive (NF155 + ) chronic inflammatory demyelinating polyneuropathy (CIDP)., Methods: Thirteen IgG4 NF155 + CIDP patients with mean onset age of 34 years (11 men) were subjected to neurological examination, blink reflex, and visual-evoked potential (VEP) testing, and axial and/or coronal T2-weighted head magnetic resonance imaging (MRI)., Results: Among 13 patients, facial sensory impairment, facial weakness, and apparent visual impairment were observed in three (23.1%), two (15.4%), and two (15.4%) patients, respectively. All 12 patients tested had blink reflex abnormalities: absent and/or delayed R1 in 11 (91.7%), and absent and/or delayed R2 in 10 (83.3%). R1 latencies had strong positive correlations with serum anti-NF155 antibody levels (r = 0.9, P ≤ 0.0001 on both sides) and distal and F wave latencies of the median and ulnar nerves. Absent and/or prolonged VEPs were observed in 10/13 (76.9%) patients and 17/26 (65.4%) eyes. On MRI, hypertrophy, and high signal intensity of trigeminal nerves were detected in 9/13 (69.2%) and 10/13 (76.9%) patients, respectively, whereas optic nerves were normal in all patients. The intra-orbital trigeminal nerve width on coronal sections showed a significant positive correlation with disease duration., Interpretation: Subclinical demyelination frequently occurs in the optic, trigeminal, and facial nerves in IgG4 NF155 + CIDP, suggesting that both central and peripheral myelin structures of the cranial nerves are involved in this condition, whereas nerve hypertrophy only develops in myelinated peripheral nerve fibers., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Painful traumatic trigeminal neuropathy (PTTN) may occur following major craniofacial or oral trauma, or may be subsequent to relatively minor dental interventions. Following injury, pain may originate from a peripheral nerve, a ganglion, or from the central nervous system. In this review, we focus on molecular mechanisms of pain resulting from injury to the peripheral branch of the trigeminal nerve. This syndrome has been termed painful traumatic trigeminal neuropathy (PTTN) by the International Headache Society and replaces previous terms including atypical odontalgia, deafferentation pain, traumatic neuropathy and phantom toothache. We emphasize the scientific evidence supporting the events purported to lead to PTTN by reviewing the pathophysiology of PTTN based on relevant animal models. Additionally, we briefly overview clinical correlates and pathophysiological manifestations of PTTN., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To evaluate the efficacy and safety of topical cenegermin (recombinant human nerve growth factor) in patients with neurotrophic keratopathy., Design: Multicenter, randomized, double-masked, vehicle-controlled trial., Participants: Patients with neurotrophic persistent epithelial defect with or without stromal thinning., Methods: The NGF0214 trial, conducted among 11 sites in the United States, randomized 48 patients 1:1 to cenegermin 20 μg/ml or vehicle eye drops, 6 drops daily for 8 weeks of masked treatment. Follow-up was 24 weeks. Safety was assessed in all patients who received study drug. Efficacy was assessed by intention to treat., Main Outcome Measures: The primary end point was healing of the neurotrophic lesion (persistent epithelial defect or corneal ulcer) after 8 weeks of masked treatment. Masked central readers measured neurotrophic lesions in randomized clinical pictures, then assessed healing status conventionally (<0.5 mm of fluorescein staining in the greatest dimension of the lesion area) and conservatively (0-mm lesion staining and no other residual staining). Secondary variables included corneal healing at 4 weeks of masked treatment (key secondary end point), overall changes in lesion size, rates of disease progression, and changes in visual acuity and corneal sensitivity from baseline to week 8., Results: Conventional assessment of corneal healing showed statistically significant differences at week 8: compared to 7 of 24 vehicle-treated patients (29.2%), 16 of 23 cenegermin-treated patients (69.6%) achieved less than 0.5 mm of lesion staining (+40.4%; 95% confidence interval [CI], 14.2%-66.6%; P = 0.006). Conservative assessment of corneal healing also reached statistical significance at week 8: compared to 4 of 24 vehicle-treated patients (16.7%), 15 of 23 cenegermin-treated patients (65.2%) achieved 0 mm of lesion staining and no other residual staining (+48.6%; 95% CI, 24.0%-73.1%; P < 0.001). Moreover, the conservative measure of corneal healing showed statistical significance at week 4 (key secondary end point). Compared to vehicle, cenegermin-treated patients showed statistically significant reductions in lesion size and disease progression rates during masked treatment. Cenegermin was well tolerated; adverse effects were mostly local, mild, and transient., Conclusions: Cenegermin treatment showed higher rates of corneal healing than vehicle in neurotrophic keratopathy associated with nonhealing corneal defects., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Aim: To report clinical outcomes and evidence of corneal innervation in patients with neurotrophic keratopathy (NK) treated with minimally invasive corneal neurotisation (MICN) using a sural nerve graft and donor sensory nerves from the face., Methods: Patients undergoing MICN at The Hospital for Sick Children, Toronto, Canada were prospectively recruited. Data on central corneal sensation (CCS, measured with Cochet-Bonnet aesthesiometer), best-corrected visual acuity (BCVA) and corneal epithelial integrity were collected. In four patients who subsequently underwent keratoplasty, immunohistochemical analysis was performed on the corneal explants. One patient underwent magnetoencephalography (MEG) after MICN to characterise the neurophysiological pathways involved., Results: Between November 2012 and February 2017, 19 eyes of 16 patients underwent MICN. Mean follow-up was 24.0±16.1 months (range, 6-53). Mean CCS significantly improved from 0.8±2.5 mm to 49.7±15.5 mm at final follow-up (p<0.001). Mean BCVA remained stable, and the number of episodes of corneal epithelial defects after MICN was significantly reduced compared with the year leading up to the procedure (21% vs 89%, respectively; p<0.0001). In the four eyes that underwent keratoplasties after MICN, all transplants fully re-epithelialised and regained sensation subsequently. Immunohistochemistry of the corneal explants demonstrated evidence of corneal reinnervation. In one patient who was 8 months after MICN, novel neuroactivity was detected on MEG in the ipsilateral somatosensory cortex on mechanical stimulation of the reinnervated cornea., Conclusions: By providing an alternative source of innervation, MICN improves corneal sensation and stabilises the corneal epithelium, permitting optical keratoplasty for patients with NK-related corneal opacity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Trigeminal-targeted treatments (TTTs), the most specific and selective therapeutic migraine approach to date, are effective in approximately 60% of patients regardless of treatment type or mechanism, at least if used alone. Sixty percent is also the proportion of migraineurs who develop migraine-like episodes following experimental intravenous administration of trigeminal neuropeptides and roughly 60% is the percentage of patients with a unilateral migraine tracing the area of cutaneous distribution of the trigeminal ophthalmic branch. Hence, mechanisms other than the trigeminovascular activation are probably involved in the 40% of migraineurs who do not respond to TTTs. A closer cooperation between clinical and basic neuroscientists is needed to explore migraine models because only a careful appraisal of migraine endophenotypes may help to unravel their underlying multifaceted pathophysiological machinery., (© 2019 American Headache Society.)

Purpose: This study aimed to characterize the sensory profile of patients with post-implant trigeminal neuropathy and identify the association between subjective symptoms and objective signs including psychophysical testing and radiographic imaging. This study further evaluated to the association between quantitative sensory testing (QST)/qualitative sensory testing (QualST) and the severity of nerve injury graded by radiographic imaging. Materials and methods: This retrospective study included 34 patients diagnosed with post-implant trigeminal neuropathy. Data on the neuropathic pain symptom inventory (NPSI), thermal and electric QST, bedside QualST, and cone beam computed tomography (CBCT) was collected and the association between these variables were analysed. Results: Numbness was the most common subjective symptom and evoked pain was the most frequent neuropathic pain. There was no significant correlation between negative and positive symptoms. Spearman's rank correlation analyses indicated that objective findings including QST/QualST correlated with a sensory loss profile rather than a gain of function profile. Moderate positive correlations between some positive symptoms and the score of QualST were observed. The Mann-Whitney U test showed that subjective symptoms did not differ according to the severity of nerve damage according to CBCT, but the electric QST and QualST was discriminative. Conclusions: This study suggests that QST/QualST associated with the severity of nerve damage according to CBCT might be useful in assessing numbness in patients with negative and positive symptoms after implant surgery, but may be of marginal utility in the evaluation of neuropathic pain within the limitation of this cross-sectional study with small sample size.

Trigeminal nerve pathology can lead to sensory and motor dysfunction to structures of the head that are easily recognized. The trigeminal nerve is a conduit for the distribution of postganglionic parasympathetic innervation to structures of the head. Parasympathetic innervation to the salivary glands is provided by preganglionic parasympathetic neurons of the facial and glossopharyngeal nerves. Postganglionic axons course with branches of the mandibular branch of the trigeminal nerve to reach the salivary glands. Denervation of the salivary glands impacts glandular function, leading to a reduction in the volume and composition of the saliva produced. Saliva plays an important role in oral health. Poor oral health has widespread systemic implications. This article describes a group of dogs with unilateral or bilateral dysfunction of the trigeminal nerve and/or its branches. In all dogs, an accumulation of thick, foamy saliva was observed accumulating in the dorsal aspect of the caudal oral cavity on the ipsilateral side to the affected nerve. In dogs with magnetic resonance imaging (MRI), there was a reduction in size based on the largest cross-sectional area measurement and an increase in mean signal intensity of the salivary glands ipsilateral to the affected nerves compared to the glands on the normal side. The authors hypothesize that the abnormal saliva and MRI changes observed were consequent to parasympathetic denervation of the salivary glands. The recognition of this clinical observation is the first step in understanding the impact that denervation has on salivation and ultimately on overall oral and systemic health in dogs.

Neuropathic pain represents a challenge to clinicians because it is resistant to commonly prescribed analgesics due to its largely unknown mechanisms. Here, we investigated a descending dopaminergic pathway-mediated modulation of trigeminal neuropathic pain. We performed chronic constriction injury of the infraorbital nerve from the maxillary branch of trigeminal nerve to induce trigeminal neuropathic pain in mice. Our retrograde tracing showed that the descending dopaminergic projection from hypothalamic A11 nucleus to spinal trigeminal nucleus caudalis is bilateral. Optogenetic/chemogenetic manipulation of dopamine receptors D1 and D2 in the spinal trigeminal nucleus caudalis produced opposite effects on the nerve injury-induced trigeminal neuropathic pain. Specific excitation of dopaminergic neurons in the A11 nucleus attenuated the trigeminal neuropathic pain through the activation of D2 receptors in the spinal trigeminal nucleus caudalis. Conversely, specific ablation of the A11 dopaminergic neurons exacerbated such pain. Our results suggest that the descending A11-spinal trigeminal nucleus caudalis dopaminergic projection is critical for the modulation of trigeminal neuropathic pain and could be manipulated to treat such pain.

Corneal neurotisation describes surgical restoration of nerve growth into the cornea to restore corneal sensation and trophic function. It represents an exciting and effective emerging treatment for neurotrophic keratopathy. Techniques described to date involve either direct nerve transfer or an interpositional nerve graft coapted to a healthy donor nerve. We review the experience to date with particular emphasis on a detailed review of techniques, outcomes and current thoughts., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Previous experimental studies assessing corneal nerves as a measure of the severity of diabetic peripheral neuropathy have yielded discordant results; this may have been due to the effect of the short duration of the induced diabetes. We investigated whether increases in the duration of hyperglycemia result in the development of corneal lesions in a mouse model of alloxan (AL)- or streptozotocin (STZ)-induced type 1 diabetes. We further determined whether corneal nerve fiber density, intraepidermal nerve fiber density (IENFD), and sural nerve morphology can be used as morphologic markers of diabetic peripheral neuropathy in rodent models., Methods: A total of 30 female ICR mice were divided into three groups: those with STZ-induced (STZ group) and AL-induced (AL group) diabetes, and a control group. Hyperglycemia was maintained in diabetic mice for 35 weeks. Animals were euthanized at 41 weeks of age., Results: Subbasal nerve plexus density (SBNPD) and terminal epithelial nerve density (TEND) in the cornea, as well as IENFD, were significantly lower, and mean sural nerve axon sizes were smaller in mice in the STZ and AL groups than in the control group. There were significant correlations between IENFD and SBNPD, and between IENFD and TEND., Conclusions: These results indicate that the TEND and SBNTD of the cornea may be useful morphologic markers for diabetic peripheral neuropathy.

Purpose: Corneal neurotization is a novel surgical procedure to reinnervate the cornea in patients with neurotrophic keratopathy (NK). We developed a rat model of NK and corneal neurotization to further investigate corneal neurotization as a treatment to improve maintenance and healing of the corneal epithelium., Methods: Thy1-GFP+ Sprague Dawley rats were used to develop the model. Corneal denervation was performed via stereotactic electrocautery of the ophthalmomaxillary branch of the trigeminal nerve. Corneal neurotization was performed by guiding donor sensory axons from the contralateral infraorbital nerve into the cornea via two nerve grafts. Corneal imaging, including nerve density measurements and retrograde labeling were performed to validate the model. In vivo assays of corneal maintenance and repair were used to examine whether treatment with corneal neurotization improved healing in rats with NK., Results: Corneal neurotization significantly increased corneal axon density in rats with NK (P < 0.01). Retrograde labeling of the cornea in rats with corneal neurotization labeled 206 ± 82 neurons in the contralateral trigeminal ganglion, confirming axons reinnervating the cornea derived from the contralateral infraorbital nerve. Corneal reinnervation after corneal neurotization improved corneal epithelial maintenance and corneal healing after injury (P < 0.01)., Conclusions: Donor nerve fibers reinnervate the insensate cornea after corneal neurotization and significantly improve corneal maintenance and repair. This model can be used to further investigate how corneal neurotization influences epithelial maintenance and repair in the context of NK.

Neurotrophic Keratopathy (NK) refers to a condition where corneal epitheliopathy leading to frank epithelial defect with or without stromal ulceration (melting) is associated with reduced or absent corneal sensations. Sensory nerves serve nociceptor and trophic functions, which can be affected independently or simultaneously. Loss of trophic function and consequent epithelial breakdown exposes the stroma making it susceptible to enzymatic degradation. Nerve pathology can range from attrition to aberrant re-generation with corresponding symptoms from anaesthesia to hyperaesthesia/allodynia. Many systemic and ocular conditions, including surgery and preserved medications can lead to NK. NK can be mild (epithelium and tear film changes), moderate (non-healing epithelial defect) or severe (stromal melting and perforation). Moderate and severe NK can profoundly affect vision and adversely impact on the quality of life. Medical management with lubricating agents from artificial tears to serum/plasma drops, anti-inflammatory agents, antibiotics and anti-proteases all provide non-specific relief, which may be temporary. Contact lenses, punctal plugs, lid closure with botulinum toxin and surgical interventions like tarsorrhaphy, conjunctival flaps and amniotic membrane provide greater success but often at the cost of obscuring sight. Corneal surgery in a dry ocular surface with reduced sensation is at high risk of failure. The recent advent of biologicals such as biopolymers mimicking heparan sulfate; coenzyme Q10 and antisense oligonucleotide that suppress connexin 43 expression, all offer promise. Recombinant nerve growth factor (cenegermin), recently approved for human use targets the nerve pathology and has the potential of addressing the underlying deficit and becoming a specific therapy for NK., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose: To assess corneal subbasal nerve density (SBND) and corneal sensitivity (CS) after pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD) without intraoperative 360-degree laser treatment using contact or noncontact panoramic viewing systems., Methods: This is a prospective study of 34 eyes affected by RRD, which underwent PPV using contact (18 eyes) and noncontact (16 eyes) panoramic viewing systems; 12 eyes which underwent scleral buckling, and 17 eyes which underwent cataract surgery. SBND and CS were assessed before surgery and 3 and 6 months postoperatively by in vivo confocal microscopy and Cochet-Bonnet esthesiometry., Results: Compared with baseline values, at 6 months, SBND and CS decreased in both contact PPV (SBND preoperative value: 19.1 ± 3.7 mm/mm; SBND postoperative value: 3.5 ± 1.3 mm/mm; CS preoperative value: 5.1 ± 0.5 cm; CS postoperative value: 1.5 ± 0.4 cm) and in noncontact PPV groups (SBND preoperative value: 19.5 ± 3.8 mm/mm; SBND postoperative value: 8.7 ± 2.3 mm/mm; CS preoperative value: 5.3 ± 0.5 cm; CS postoperative value: 2.5 ± 0.7 cm) (P < 0.001 for all comparisons). SBND reduction was greater in the contact PPV group than in the noncontact PPV group (P < 0.001). By contrast, the scleral buckling and cataract surgery group values were unchanged (P > 0.1 for all comparisons). In multivariate analysis, no significant effect was found for cataract surgery associated with PPV, pseudophakia, surgical time, intraocular pressure, or for laser in horizontal sectors for PPV groups. SBND was highly correlated with CS (r = 0.93)., Conclusions: A contact viewing system reduces SBND after PPV more than a noncontact system does.

Objective: This review aims to describe trigeminal neuralgia and the molecular basis contributing to the pathophysiology of this condition by focusing on the state of the art., Patients and Methods: An electronic search of PubMed was performed using the following keywords: "trigeminal neuralgia" AND "classification", "pathophysiology," "molecular basis" and "mitochondrial role.", Results: Mitochondrial abnormality, whether functional or morphological, can contribute to neurological disorders. Additionally, one recent finding showed that gain-of-function mutation in the voltage-gated sodium channel NaV1.6 contributes to the pathophysiology of trigeminal neuralgia by increasing the excitability of trigeminal nerve ganglion neurons. It also exacerbates the pathophysiology of vascular compression. Healing of the trigeminal nerve is controlled by many molecular signaling pathways, including extracellular-signal-regulated kinase, c-Jun, p38, Notch, and mitogen-activated protein kinases., Conclusions: More investigations regarding the gain-of-function mutation of NaV1.6 sodium channels are essential for the diagnosis and treatment of trigeminal nerve disorders, regardless of whether these are associated with vascular compression or not.

Purpose: The purpose of this study was to explore the effects of pigment epithelium derived factor (PEDF) and PEDF-derived peptides Mer44 and Mer34 on the severity of herpetic simplex keratitis (HSK) in mice., Methods: Adult C57BL/6 mice were infected ocularly with the herpes simplex virus type 1 (HSV-1, McKrae strain) and injected subconjunctivally with PEDF, Mer44, or Mer34. Corneal nerve degeneration, neovascularization, sensitivity, neutrophils, macrophages and CD4+ T-cell infiltration, virus contents, and expressions of VEGF, PEDF, and proinflammatory factors were evaluated during acute period. The direct inhibitory effect of PEDF on HSV-1 replication was further evaluated in cultured monkey Vero cells., Results: Following HSV-1 infection, corneal PEDF expression decreased at 3 and 7 days postinfection (dpi) but increased at 15 dpi, and returned to the similar level of normal mice at 45 dpi, which was accompanied with the progress of corneal nerve degeneration and neovascularization. Exogenous PEDF application attenuated corneal nerve degeneration and neovascularization and improved the impaired corneal sensitivity. Moreover, PEDF attenuated the neutrophils, but not macrophage or CD4+ T-cell infiltration, with the reduced expressions of IL-1β, IL-6, TNF-α, and VEGF. In addition, PEDF inhibited the replication of HSV-1 both in vitro and in mice. Mer44 attenuated corneal nerve degeneration more significantly than Mer34, whereas Mer34 inhibited corneal neovascularization., Conclusions: PEDF and its derived peptides reduce the severity of herpetic simplex keratitis in mice, representing the potential therapeutic approach to control HSK lesions.

Neuroma pain can be severe, persistent, and treatment-resistant. Forehead and scalp anesthesia is troublesome for patients. Following an iatrogenic ablative injury to the right supraorbital nerve, with subsequent painful neuroma formation, a human cadaveric nerve allograft (AxoGen, Alachua, FL) was used to restore sensation of the right forehead and treat pain. At 1-year follow-up, the patient was pain-free, and protective sensation to the right forehead was recovered with comparable static and dynamic 2-point discrimination between the injured (20 mm, 12 mm respectively) and the normal side (15 mm, 10 mm respectively). This is the first reported case of using a cadaver nerve allograft for successful direct neurotization of the skin and restoration of sensation in the upper part of the face, and for treating painful neuromas. Moreover, a brief review of the available techniques for treating neuromas of the supraorbital and supratrochlear nerves is provided.

Introduction: Here we are presenting a unique case of malignant triton tumor of the trigeminal nerve in a 4-year-old boy who presented with diplopia and ptosis., Intervention: Near total excision of the tumor was performed, and adjuvant chemotherapy and radiotherapy were administered., Results: The patient is in good health and has no evidence of clinical and radiological tumor recurrence for 22  months.

Competing Interests: Competing interests: None declared.

Purpose: To evaluate the long-term alterations of corneal nerves in patients with herpes simplex virus (HSV) keratitis using in vivo confocal microscopy (IVCM)., Design: Prospective, longitudinal, cross sectional., Methods: This study included 16 patients with a history of HSV keratitis and 15 age-matched normal controls. Slit-scanning IVCM was performed in all subjects at baseline and then after a mean follow-up of 37.3 ± 1.7 months in the patient group. Corneal subbasal nerve density and corneal sensation were compared between groups at baseline and follow-up., Results: At baseline, the mean subbasal nerve density was significantly lower in both affected eyes (1.4 ± 0.6 mm/mm 2 ) and contralateral unaffected eyes (6.4 ± 0.7 mm/mm 2 ) compared with the controls (14.1 ± 1.6 mm/mm 2 ; all P < .001). At the end of follow-up, the mean nerve density in affected eyes increased to 2.8 ± 0.7 mm/mm 2 (P = .006), with no significant change in contralateral unaffected eyes (6.5 ± 1.0 mm/mm 2 , P = .72). However, both eyes had lower nerve density than controls (all P < .001). Corneal sensation was significantly lower in affected eyes (2.6 ± 0.6 cm) than in the control group (6.0 ± 0.0, P < .001) and showed no significant change at the end of follow-up (2.5 ± 0.6 cm, P = .80). Corneal sensation in contralateral unaffected eyes was not different in comparison with controls at both baseline and follow up (all p > .05)., Conclusions: Our results demonstrate that although corneal nerve regeneration occurs in patients with HSV keratitis, this change is not clinically significant and does not results in changes of corneal sensation. Therefore, these patients need to be followed closely for complications of neurotrophic keratopathy and might benefit from neuro-regenerative therapies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Preclinical investigations have suggested that altered functioning of brainstem pain-modulation circuits may be crucial for the maintenance of some chronic pain conditions. While some human psychophysical studies show that patients with chronic pain display altered pain-modulation efficacy, it remains unknown whether brainstem pain-modulation circuits are altered in individuals with chronic pain. The aim of the present investigation was to determine whether, in humans, chronic pain following nerve injury is associated with altered ongoing functioning of the brainstem descending modulation systems. Using resting-state functional magnetic resonance imaging, we found that male and female patients with chronic neuropathic orofacial pain show increased functional connectivity between the rostral ventromedial medulla (RVM) and other brainstem pain-modulatory regions, including the ventrolateral periaqueductal gray (vlPAG) and locus ceruleus (LC). We also identified an increase in RVM functional connectivity with the region that receives orofacial nociceptor afferents, the spinal trigeminal nucleus. In addition, the vlPAG and LC displayed increased functional connectivity strengths with higher brain regions, including the hippocampus, nucleus accumbens, and anterior cingulate cortex, in individuals with chronic pain. These data reveal that chronic pain is associated with altered ongoing functioning within the endogenous pain-modulation network. These changes may underlie enhanced descending facilitation of processing at the primary synapse, resulting in increased nociceptive transmission to higher brain centers. Further, our findings show that higher brain regions interact with the brainstem modulation system differently in chronic pain, possibly reflecting top-down engagement of the circuitry alongside altered reward processing in pain conditions. SIGNIFICANCE STATEMENT Experimental animal models and human psychophysical studies suggest that altered functioning of brainstem pain-modulation systems contributes to the maintenance of chronic pain. However, the function of this circuitry has not yet been explored in humans with chronic pain. In this study, we report that individuals with orofacial neuropathic pain show altered functional connectivity between regions within the brainstem pain-modulation network. We suggest that these changes reflect largely central mechanisms that feed back onto the primary nociceptive synapse and enhance the transfer of noxious information to higher brain regions, thus contributing to the constant perception of pain. Identifying the mechanisms responsible for the maintenance of neuropathic pain is imperative for the development of more efficacious therapies., (Copyright © 2018 the authors 0270-6474/18/380465-09$15.00/0.)

Diabetes mellitus is a chronic disease that results from inadequate insulin production or ineffective insulin utilization. It is one of the most common systemic diseases worldwide with increasing prevalence. Diabetes mellitus is associated with premature mortality, macrovascular complications such as cardiovascular disease, and microvascular complications, including nephropathy leading to kidney failure, potentially blinding diabetic retinopathy, and diabetic neuropathy. While the retinal complications of diabetes are well recognized by eye care professionals, the effects on the ocular surface are poorly understood. Recent studies have reported on the association between peripheral neuropathy and corneal neuropathy, showing the latter to be of predictive value for the systemic disease. Corneal neuropathy can lead to loss of corneal sensation and can ultimately result in neurotrophic ulcers and significant visual morbidity. The epithelial fragility and poor wound healing that result from reduced epithelial adhesion to the underlying basement membrane in diabetes, together with corneal neuropathy, are thought to increase the susceptibility to persistent corneal erosions and infection, as well as to increase the risk of post-surgical complications. The aim of this article is to review the impact of diabetes on corneal nerve morphology and ocular surface integrity. Changes in the tear film and ocular surface microbiome are highlighted in discussion of the mechanisms that underpin ocular surface changes that increase the susceptibility to corneal erosion and infection., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The trigeminal nerve provides corneal sensitivity and trophic supply to corneal tissues. The impairment of corneal innervation leads to development of neurotrophic keratitis (NK). NK is a rare, degenerative corneal disease characterized by corneal hypo/anesthesia and development of nonhealing corneal epithelial defects and ulcers. NK is a challenging condition with high medical need due to the lack of approved treatments that can restore corneal integrity. Current treatment of NK aims at stimulating corneal healing and preventing disease progression. Cenegermin is a recombinant human nerve growth factor that was safe and well tolerated in preclinical and clinical studies. Cenegermin eye drops were safe and effective in restoring corneal integrity in two phase II clinical trials in patients with NK. The European Commission granted a full marketing authorization to cenegermin eye drops for the treatment of moderate to severe NK in July 2017., (Copyright 2017 Clarivate Analytics.)

Purpose: This study investigated the efficacy of monotherapy versus combination of menhaden oil, α-lipoic acid, and enalapril on corneal sensation and morphometry and other neuropathy-related endpoints in a rat model of type 2 diabetes., Methods: Male Sprague-Dawley rats (aged 12 weeks) were fed a high-fat diet for 8 weeks followed by 30 mg/kg streptozotocin. After 16 weeks of hyperglycemia, 12-week treatments consisting of menhaden oil, α-lipoic acid, enalapril, or their combination were initiated. Before and after treatments, we performed analyses of multiple neural and vascular endpoints including corneal sensitivity, corneal nerve density, vascular reactivity of epineurial arterioles, motor and sensory nerve conduction velocity, intraepidermal nerve fiber density, and thermal nociception., Results: Before treatment, all the neural and vascular endpoints in diabetic rats were impaired. Treating diabetic rats with monotherapy was effective in improving neural and vascular deficits with menhaden oil being most efficacious. However, the combination therapy provided the greatest benefit and improved/reversed all nerve and vascular deficits. The effect of combination therapy on corneal relative sensitivity and structure (in mm/mm), primary endpoints for this study, for control, diabetic, and diabetic treated rats was 4.2 ± 1.4 and 7.5 ± 0.5, 12.1 ± 1.3* and 3.8 ± 0.2*, and 6.6 ± 2.3 and 7.3 ± 0.5, respectively (*P < 0.05 compared with control rats; P < 0.05 compared with diabetic rats)., Conclusions: These studies suggest that a combination therapeutic approach may be most effective for treating vascular and neural complications of type 2 diabetes.

Migraine and tension type headache are the most common disabling primary headache disorders. Epidemiological studies have documented their high prevalence and high socioeconomic and personal impacts. According to recent data, migraine ranks as the third most prevalent disorder and seventh-highest specific cause of disability worldwide. Tension-type headache has lifetime prevalence in the general population ranging between 30% and 78% in different studies. According to the International Classification of Headache Disorders, 3rd edition, there also are many other headaches but their incidence in general population is lower than the previously mentioned headaches. Trigeminal nerve and upper cervical segments (C1-C3) are included in pain control of the head region and often evaluated in headache studies in order to improve differential diagnosis and headache treatment. In our study, we evaluated the potential role of electromyographic (EMG) blink reflex in establishing diagnosis of headache and evaluation of trigeminal nerve dysfunction as the possible underlying pathomorphological headache mechanism. Our study included 60 patients with different types of primary headaches and 30 control subjects. Statistical analysis was performed by use of χ2-test and statistical significance was set at p<0.001. Study results showed that patients with trigeminal dysfunction in EMG blink reflex had a 5.6-fold higher risk of developing headache in comparison to subjects with normal EMG blink reflex finding.

Purpose: To assess the repeatability of measuring the corneal nerve migration rate in individuals with and without neuropathy., Methods: Wide-field montages of the subbasal corneal nerve plexus were generated at baseline and after 3 weeks for 14 participants. Montages were manually examined side by side to identify a referent landmark in the inferior whorl region (origin) and throughout each montage. A software program was developed to measure nerve migration of all identified points relative to the origin. Repeatability was determined by measurement of nerve migration for within observer (one researcher on 2 occasions, 5 days apart) and between observers (2 observers) within 4 different zones based on the distance from the origin and in the vertical section of the wide-field montage. The impact of images being montaged with fully automated software on repeatability was also investigated., Results: The mean difference between observations 1 and 2 for observer 1 was 0.02 ± 1.3 μm/wk (P = 0.94), with an intraclass correlation coefficient (ICC) of 0.99 [95% confidence interval (CI) = 0.99-1.00], and the mean difference between observer 1 and 2 was 0.3 ± 1.2 μm/wk (P = 0.41), with an ICC of 0.99 (95% CI = 0.99-1.00). The mean difference between observations 1 (images montaged by semiautomated software) and 2 (images montaged by fully automated software) was 1.2 ± 4.9 μm/wk (P = 0.41), with an ICC of 0.96 (95% CI = 0.87-1.00)., Conclusions: Measuring corneal nerve migration rate is highly repeatable for within and between observers and when using different methods of image montaging.

Although diabetes mellitus is reaching epidemic proportions worldwide, ocular surface complications are still largely believed to be uncommon. Although these complications are not often sight threatening, the general well-being of patients and the cost of their health care can be respectively compromised and added by them. Over the last decade, an association of ocular surface complications (in particular reduced corneal sub-basal nerve density and corneal sensitivity) with peripheral neuropathy has emerged, which could help recognize the development of peripheral complications at an earlier stage and also provide research opportunities for examining new treatment modalities of diabetic neuropathies. The ocular surface complications of diabetes mellitus and their association with peripheral neuropathy are reviewed by this report., (© 2015 Royal Australian and New Zealand College of Ophthalmologists.)

Introduction: Hereditary gelsolin amyloidosis (GA) is a rare condition caused by the gelsolin gene mutation. The diagnostic triad includes corneal lattice dystrophy (type 2), progressive bilateral facial paralysis, and cutis laxa. Detailed information on facial paralysis in GA and the extent of cranial nerve injury is lacking., Methods: 29 GA patients undergoing facial corrective surgery were interviewed, examined, and studied electroneurophysiologically., Results: All showed dysfunction of facial (VII) and trigeminal (V) nerves, two-thirds of oculomotor (III) and hypoglossal (XII) nerves, and half of vestibulocochlear (acoustic) (VIII) nerve. Clinical involvement of frontal, zygomatic, and buccal facial nerve branches was seen in 97%, 83%, and 52% of patients, respectively. Electromyography showed marked motor unit potential loss in facial musculature., Conclusions: Cranial nerve involvement in GA is more widespread than previously described, and correlates with age, severity of facial paralysis, and electromyographic findings. We describe a grading method for bilateral facial paralysis in GA, which is essential for evaluation of disease progression and the need for treatment., (© 2016 Wiley Periodicals, Inc.)

Purpose: We have developed a novel technique to measure in vivo corneal nerve migration., Methods: Wide-field montages of the subbasal corneal nerve plexus were generated at baseline and after 3 weeks. The 2 montages were manually examined side by side to identify a referent landmark in the inferior whorl region and 20 additional nerve landmarks throughout each montage. A software program was developed to measure nerve migration by quantifying the movement of the nerve landmarks relative to the inferior whorl landmark over the 3-week period. To illustrate the utility of this technique, nerve migration was measured in 2 individuals with diabetes (one with and the other without neuropathy) and a healthy control participant., Results: The average nerve migration rate was calculated to be 18.4, 49.9, and 41.5 μm/wk for the diabetic individuals with and without neuropathy and the control participant, respectively. The number of landmarks for tracking nerve migration in the participants was 26, 21, and 20, and they were at an average distance of 1500, 1940, and 1461 μm, from the whorl, respectively. The rate of migration depended on the distance from the whorl; hence, linear equations were generated for each subject for comparison., Conclusions: This novel imaging technique allows rapid measurement of in vivo corneal nerve migration. The results indicate that diabetic neuropathy may be associated with reduced nerve migration; however, because of the high level of manual input required in this technique and the apparent complex characteristics of corneal nerve migration, repeatability and characterization studies are needed.

The etiology of trigeminal neuropathic pain is not clear, but there is evidence that demyelination, expression of cytokines, neuropeptides, and neurotrophic factors are crucial contributors. In order to elucidate mechanisms underlying trigeminal neuropathic pain, we evaluated the time course of morphological changes in myelinated and unmyelinated trigeminal nerve fibers, expression of cytokine IL-1β, neuropeptide substance P (SP), nerve growth factor (NGF), and glial derived neurotrophic factor (GDNF) in peripheral and ganglion tissues, using a rat model of trigeminal neuropathic pain. Chronic constriction injury (CCI) of the infraorbital nerve (IoN), or a sham surgery, was performed. Mechanical allodynia was evaluated from day 3 to day 15 post-surgery. Trigeminal nerves were divided into 2 sections - distal to CCI and ganglion - for morphological analyses, immunohistochemistry (IL-1β, SP), and protein quantification by ELISA (NGF, GDNF). At early postoperative time points, decreased mechanical responses were observed, which were associated with demyelination, glial cell proliferation, increased immunoexpression of IL-1 β and SP, and impaired GDNF production. In the late postoperative period, mechanical allodynia was present with partial recovery of myelination, glial cell proliferation, and increased immunoreactivity of IL-1β and SP. Our data show that demyelination/remyelination processes are related to the development of pain behavior. IL-1β may have effects both in ganglia and nerves, while SP may be an important mediator at the nerve endings. Additionally, low levels of GDNF may produce impaired signaling, which may be involved in generation of pain., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The cornea focuses external light onto the retina, a function for which it must be transparent and possess a smooth surface. Homeostasis of the corneal epithelium is regulated by various humoral factors present in the tear fluid and by neural factors derived from the trigeminal nerve. Neurotrophic keratopathy (NK) is characterized by corneal epithelial disorders that result from impairment of trigeminal nerve function and a consequent deficiency of neural factors. The ideal mode of treatment for this condition is the regeneration of damaged trigeminal nerve fibers, but such therapy is not currently available. In this review, we describe established and potential new treatments of NK. Our research demonstrated that a combination of the neurotransmitter substance P and insulin-like growth factor 1 (IGF-1) has a synergistic stimulatory effect on corneal epithelial migration in vitro and on corneal wound closure in vivo. Furthermore, we identified the minimal amino acid sequences of substance P and IGF-1 required for this synergistic action based on the assumption that the clinical application of peptides corresponding to these sequences would have fewer side effects compared with the full-length molecules. Combination of the substance P-derived peptide FGLM-amide and the IGF-1-derived peptide SSSR promoted corneal epithelial wound healing in patients with NK.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01756456.

Purpose: To assess the effects of 360-degree laser retinopexy on human corneal subbasal nerve plexus and to investigate correlations among corneal subbasal nerve plexus density, corneal epithelial thickness, and corneal sensitivity., Design: Prospective, observational, nonrandomized study., Participants: A total of 15 eyes of 15 patients who underwent pars plana vitrectomy (PPV) with 360-degree laser retinopexy for retinal detachment (RD) and 15 eyes of 15 patients who underwent PPV for macular hole (MH) without laser treatment., Methods: Corneal sensation, corneal epithelial thickness, and corneal subbasal nerve plexus density were assessed before surgery and 6 months after surgery via in vivo confocal microscopy, anterior segment optical coherence tomography (AS-OCT), and Cochet-Bonnet esthesiometry (Luneau Ophthalmologie, Paris, France)., Main Outcome Measures: Corneal subbasal nerve plexus density, corneal epithelium thickness, and central corneal sensitivity., Results: Compared with baselines values, the mean subbasal nerve density (P < 0.001), mean corneal epithelium thickness (P = 0.006), and mean corneal sensitivity (P < 0.001) in the RD group were significantly decreased 6 months after surgery by 74.3%, 4.7%, and 56.6%, respectively. Conversely, in the MH group there were no significant differences in the mean subbasal nerve density (P = 0.34), mean corneal epithelial thickness (P = 0.19), and mean corneal sensitivity (P = 0.42) between preoperative and 6-month postoperative values (0.7%, 0.4%, and 0.8%, respectively). The postoperative decrease in corneal subbasal nerve density after laser retinopexy was associated with a decrease in corneal epithelium thickness (r(2) = 0.42; P = 0.006) and a decrease in corneal sensitivity (r(2) = 0.48; P = 0.004). The postoperative decrease in corneal sensitivity poorly correlated with the decrease in corneal epithelial thickness (r(2) = 0.24; P = 0.045). Postoperative corneal nerve density decreased as total laser energy increased (r(2) = 0.51; P = 0.002)., Conclusions: Subbasal corneal nerve plexus density decreases after 360-degree laser retinopexy and is accompanied by epithelium thinning and decreased corneal sensation. Surgeons should eschew heavy confluent retinal laser treatment, and corneal sensitivity should be assessed postoperatively to determine whether significant anesthesia has occurred. In such instances, prophylactic measures may be warranted against the development of neurotrophic ulcers., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

: Post-LASIK (laser in situ keratomileusis) symptoms and signs of dry eye have multiple causes. For example, tear osmolarity and the concentration of inflammatory mediators can increase because of reduced aqueous production and increased evaporative loss as a result of lower blink rates and increased interblink intervals. The tear concentration of inflammatory mediators can also increase because of surgical trauma, wound healing, comorbid systemic and ocular diseases, and the use of punctal plugs. Studies that examine only mechanical sensitivity of the cornea cannot detect changes in chemical sensitivity, which can persist longer. Symptoms may be partly attributed to sensitization of the traumatized corneal or lid wiper sensory nerves by inflammatory mediators. Increased lid wiper sensitivity could increase awareness of blinks, especially if ocular surface lubricity is reduced. Incomplete blinks have been found to represent 10 to 22% of the total number of blinks. Loss of neural stimuli and lower blink rates increase the significance of incomplete blinks that approximately double related interblink intervals and tear evaporation. The most common location of post-LASIK epitheliopathy is the inferior area of the cornea, which is overexposed by incomplete blinks. The relevance of incomplete blinking to post-LASIK epitheliopathy is supported by the relative absence of this complication in the similarly neurotrophically disadvantaged upper corneal areas for which blink rates and other tear functions usually appear to be adequate to prevent epitheliopathy, which stains. Occupational or leisure-time activities such as computer use and reading, which have been found to reduce blink rates and blink completeness, appear to be significant risk factors for symptoms and signs of dry eye. Apart from reducing symptoms and signs of dry eye, prophylactic and post-LASIK blink exercises to reduce incomplete blink rates and associated overexposure of the ocular surface may also contribute to more accurate refractive outcomes through faster wound healing.

Purpose: To evaluate changes in ocular surface and central corneal sub-basal nerve fiber layer (SBNFL) after topical cyclosporin therapy in chronic glaucoma patients on long-term topical antiglaucoma therapy., Methods: A prospective comparative study of ocular surface evaluation of chronic glaucoma patients on long-term topical therapy treated concurrently with a topical cyclosporine 0.05% twice daily for 6 months and controls was done. The study parameters evaluated at recruitment and at the 6-month follow-up included details of topical antiglaucoma medications, visual acuity, intraocular pressure, ocular surface evaluation parameters (TBUT, Schirmers I, ocular surface staining scores and ocular surface disease (OSD) index score (OSDI)), central corneal sensation (Cochet Bonnett aesthesiometer), and central confocal microscopy to study the SBNFL density (SBNFLD)., Results: Thirty-two eyes of 16 patients with chronic glaucoma and 30 eyes of 15 normal subjects as controls were studied. Mean TBUT, pre/post CsA treatment was 8.67±3.01/12.24±1.83 s (P=0.007). Mean conjunctival/corneal staining scores pre/post CsA treatment were 3.38±1.93/1.50±0.718 (P=0.00) /5.19±1.82/1.81±0.78 (P=0.098), respectively. Mean OSDI pre/post CsA treatment scores were 30.63±14.61/14.76±6.06 (P=0.007). Mean corneal sensations scores pre/post CsA treatment were 4.64±0.46/4.94±0.39 (P=0.002). Central corneal SBNFLD pre and post CsA treatment was 8811.35±2985.29/10335.13±4092.064 μm/mm(2) (P=0.0001)., Conclusions: Schirmer's test, ocular surface staining scores, OSDI, corneal sensations, and corneal SBNFLD showed a statistically significant improvement following a 6-month concurrent topical CsA therapy.

Background: Levetiracetam is an antiepileptic drug with analgesic efficacy shown in pain models and small clinical trials. Sumatriptan is used in acute migraine treatment. Caffeine is widely consumed in some beverages/foods and is also an adjuvant in analgesic formulations. We examined the effects of systemic levetiracetam, sumatriptan, and caffeine and their interactions in 2-component combinations in the rat orofacial formalin test, a model of trigeminal pain., Methods: Rats received a subcutaneous injection of formalin solution into the perinasal area, and the total time spent in nociceptive behavior (face rubbing) was quantified. The antinociceptive effect of drugs/drug combinations was assessed 1 hour after per os administration. The type of interaction between levetiracetam/sumatriptan and caffeine was examined by comparing the effects of a fixed, effective dose of levetiracetam/sumatriptan alone with the effects of the same dose applied with increasing, subeffective doses of caffeine. The type of interaction between levetiracetam and sumatriptan was determined by isobolographic analysis., Results: Levetiracetam (1-50 mg/kg) and sumatriptan (0.5-5 mg/kg) produced significant and dose-dependent antinociceptive effects in both phases of the orofacial formalin test (P ≤ 0.001). Caffeine (7.5-100 mg/kg) produced significant antinociception in the second phase of the test (P = 0.04). Caffeine (1-7.5 mg/kg) significantly reduced the antinociceptive effects of levetiracetam (25 mg/kg) (first phase P = 0.002, second phase P < 0.001) and sumatriptan (2.5 mg/kg) (first phase P = 0.014, second phase P = 0.027); dose-dependent inhibition was observed in the second phase. Levetiracetam and sumatriptan exerted an additive interaction in the second phase of the orofacial formalin test., Conclusions: Results indicate that levetiracetam may be useful for treatment of pain in the trigeminal region. Dietary caffeine might decrease the effects of levetiracetam and sumatriptan; this needs to be considered in clinical settings. A levetiracetam-sumatriptan combination could also be useful in trigeminal pain treatment. Its efficacy and adverse effects should be examined clinically.

Introduction: This cases report confirms the hypothesis that embryonic and maxillofacial growth are influenced by the peripheral nervous system, including the trigeminal nerve (V). So, it's interesting to use the stigma of the trigeminal nerve as landmarks to analyze the maxillofacial volume and understand its growth. The aim of this study is to evaluate the validity of the three-dimensional cephalometric analysis of Treil based on trigeminal landmarks., Case Presentation: The first case is a caucasian female child with Goldenhar syndrome. The second case is a caucasian male adult affected by the same syndrome. In both cases, brain MRI showed an unilateral trigeminal nerve lesion, ipsilateral to the facial dysmorphia., Conclusion: The results of this radiological study tend to prove the primary role of the trigeminal nerve in craniofacial growth. These cases demonstrate the validity of the theory of Moss. They are one of anatomo-functional justifications of the three-dimensional cephalometric biometry of Treil based on trigeminal nerve landmarks., (© EDP Sciences, SFODF, 2015.)