Establishment of mouse model of neurotrophic keratopathy through TRPV1 neuronal ablation.

Neurotrophic keratopathy (NK) is a challenging disease with the reduced innervation to the cornea. To establish a genetic and stable mouse model of NK, we utilized the TRPV1-DTR mice with intraperitoneal injection of diphtheria toxin (DT) to selectively eliminate TRPV1 neurons. After DT administration, the mice exhibited robust ablation of TRPV1 neurons in the trigeminal ganglion, accompanied with reduced corneal sensation and nerve density, as well as the decreased calcitonin-gene-related peptide (CGRP) and substance P levels. According to disease progression of TRPV1 neuronal ablation, tear secretion was reduced from day 3, which followed by corneal epithelial punctate lesions from day 7. From day 11 to day 16, the mice exhibited persistent corneal epithelial defects and stromal edema. By day 21, corneal ulceration and stromal melting were observed with the abundant inflammatory cell infiltration, corneal neovascularization, and enhanced cell apoptosis. Moreover, subconjunctival injection of CGRP delayed the NK progression with the characteristics of reduced severe corneal epithelial lesions and corneal inflammation. In addition, the impairments of conjunctival goblet cells, lacrimal gland, and meibomian gland were identified by the diminished expression of MUC5AC, AQP5, and PPARγ, respectively. Therefore, these results suggest that the TRPV1-DTR mice may serve as a reliable animal model for the research of NK pathogenesis.

Utility of MR Neurography for the Evaluation of Peripheral Trigeminal Neuropathies in the Postoperative Period.

Peripheral trigeminal neuropathies are assessed by MR neurography for presurgical mapping. In this clinical report, we aimed to understand the utility of MR neurography following nerve-repair procedures. We hypothesized that postoperative MR neurography assists in determining nerve integrity, and worsening MR neurography findings will corroborate poor patient outcomes. Ten patients with peripheral trigeminal neuropathy were retrospectively identified after nerve-repair procedures, with postsurgical MR neurography performed from July 2015 to September 2023. Postsurgical MR neurography findings were graded as per postintervention category and subcategories of the Neuropathy Score Reporting and Data System (NS-RADS). Descriptive statistics of demographics, inciting injury, injury severity, NS-RADS scoring, and clinical outcomes were obtained. There were 6 women and 4 men (age range, 25-73 years). Most injuries resulted from third molar removals (8/10), with an average time from the inciting event to nerve-repair surgery of 6.1 (SD, 4.6) months. In Neuropathy Score Reporting and Data System-Injury (NS-RADS I), NS-RADS I-4 injuries (neuroma in continuity) were found in 8/10 patients, and NS-RADS I-5 injuries were found in the remaining patients, all confirmed at surgery. Surgeries performed included microdissection with neurolysis, neuroma excision, and nerve allograft with Axoguard protection. Three patients with expected postsurgical MR neurography findings experienced either partial improvement or complete symptom resolution, while among 7 patient with persistent or recurrent neuropathy on postsurgical MR neurography, one demonstrated partial improvement of sensation, pain, and taste and one experienced only pain improvement; the remaining 5 patients demonstrated no improvement. Postsurgical MR neurography consistently coincided with clinical outcomes related to pain, sensation, and lip biting and speech challenges. Lip biting and speech challenges were most amenable to recovery, even with evidence of persistent nerve pathology on postsurgical MR neurography.

Perineural Treatment with High Mobility Group Box-1 Monoclonal Antibody Prevents Initiation of Pain-Like Behaviors in Female Mice with Trigeminal Neuropathy.

Post-traumatic trigeminal neuropathy (PTTN) is a type of chronic pain caused by damage to the trigeminal nerve. A previous study reported that pretreatment with anti-high mobility group box-1 (HMGB1) neutralizing antibodies (nAb) prevented the onset of PTTN following distal infraorbital nerve chronic constriction injury (dIoN-CCI) in male mice. Clinical evidence indicates a high incidence of PTTN in females. Although our previous study found that perineural HMGB1 is crucial in initiation of PTTN in male mice, it is currently unknown whether HMGB1 is also involved in the pathogenesis of PTTN in female mice. Therefore, in the current study, we examined the effect of anti-HMGB1 nAb on pain-like behavior in female mice following dIoN-CCI surgery. We found that dIoN-CCI surgery enhanced reactivity to mechanical and cold stimuli in female mice, which was suppressed by treatment with anti-HMGB1 nAb. Moreover, the increase in macrophages after dIoN-CCI was significantly attenuated by pretreatment with anti-HMGB1 nAb. Furthermore, anti-HMGB1 nAb treatment inhibited microglial activation in the trigeminal spinal tract nucleus. These data suggest that HMGB1 also plays a crucial role in the onset of PTTN after nerve injury in female mice. Thus, anti-HMGB1 nAb could be a novel therapeutic agent for inhibiting the onset of PTTN in female and male mice.

Unilateral non-healing ulcers in zosteriform pattern.

Trigeminal trophic syndrome (TTS) is a rare disease that occurs after injury to the trigeminal nerve. Though this condition has been reported in the early 20th century, it is still a rare entity, with only around 200 cases reported so far. It characteristically presents with persistent facial ulceration with loss of sensation and paraesthesia along the distribution of the trigeminal nerve. We here report a case of TTS developing as a complication of herpes zoster, which possibly occurred due to the nerve damage caused by varicella-zoster virus.

Long-Term Outcome of Unilateral Acoustic Neuromas With or Without Hearing Loss: Over 10 Years and Beyond After Gamma Knife Radiosurgery.

BACKGROUND: Since the long-term outcomes of 162 patients who underwent gamma knife radiosurgery (GKS) as an initial or adjuvant treatment for acoustic neuromas (ANs) with unilateral hearing loss were first reported in 1998, there has been no report of a comprehensive analysis of what has changed in GKS practice. METHODS: We performed a retrospective study of the long-term outcomes of 106 patients with unilateral sporadic ANs who underwent GKS as an initial treatment. The mean patient age was 50 years, and the mean initial tumor volume was 3.68 cm3 (range, 0.10-23.30 cm3). The median marginal tumor dose was 12.5 Gy (range, 8.0-15.0 Gy) and the median follow-up duration was 153 months (range, 120-216 months). RESULTS: The tumor volume increased in 11 patients (10.4%), remained stationary in 27 (25.5%), and decreased in 68 patients (64.2%). The actuarial 3, 5, 10, and 15-year tumor control rates were 95.3 ± 2.1%, 94.3 ± 2.2%, 87.7 ± 3.2%, and 86.6 ± 3.3%, respectively. The 10-year actuarial tumor control rate was significantly lower in the patients with tumor volumes of ≥ 8 cm3 (P = 0.010). The rate of maintaining the same Gardner-Robertson scale grade was 28.6%, and that of serviceable hearing was 46.4%. The rates of newly developed facial and trigeminal neuropathy were 2.8% and 4.7%, respectively. The patients who received marginal doses of less than 12 Gy revealed higher tumor control failure rates (P = 0.129) and newly occurred facial or trigeminal neuropathy rates (P = 0.040 and 0.313, respectively). CONCLUSION: GKS as an initial treatment for ANs could be helpful in terms of tumor control, the preservation of serviceable hearing, and the prevention of cranial neuropathy. It is recommended to perform GKS as soon as possible not only for tumor control in unilateral ANs with hearing loss but also for hearing preservation in those without hearing loss.

New-onset Immune-mediated Necrotizing Myopathy and Trigeminal Neuropathy after SARS-CoV-2 mRNA Vaccination in a Patient with Rheumatoid Arthritis and Sjögren's Syndrome.

We present the case of a 42-year-old woman with rheumatoid arthritis and Sjögren's syndrome treated with adalimumab who developed immune-mediated necrotizing myopathy (IMNM) and trigeminal neuropathy after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination. Trigeminal neuralgia and elevated serum creatine kinase levels emerged 12 days post-vaccination, followed by myalgia in the femoral muscles. IMNM was histologically diagnosed. The pathogenesis may involve molecular mimicry between the SARS-CoV-2 spike glycoprotein and autologous tissues triggered by vaccination. This case emphasizes the association between SARS-CoV-2 vaccination, tumor necrosis factor inhibitor, IMNM, and trigeminal neuropathy, as well as the importance of monitoring immune-mediated adverse events following SARS-CoV-2 vaccination in patients with autoimmune disease.

Neurotrophic keratopathy: An updated understanding.

PURPOSE: To propose an updated definition and staging system for neurotrophic keratopathy (NK) and provide consensus on diagnosis and treatment. METHODS: A study group was convened to review the data pertinent to NK using a modified nominal group process. They proposed an updated definition for NK and a new 6-step staging system (Neurotrophic Keratopathy Study Group [NKSG] Classification) that can be used in conjunction with the different treatment options available currently or in the future. RESULTS: NK is defined as the dysfunction of corneal innervation that results in dysregulation of corneal and/or cellular function. It is characterized by loss of corneal sensation and neuronal homeostasis, leading to eventual corneal epithelial breakdown and ultimately keratolysis if untreated. The NKSG classification emphasizes verifying corneal sensation early and distinguishes different epithelial and stromal aspects of NK with the following stages: stage 1 (altered sensation without keratopathy), stage 2 (epitheliopathy/punctate epithelial keratopathy [PEK] without stromal haze), stage 3 (persistent/recurrent epithelial defects without stromal haze), stage 4 (epitheliopathy/PEK or persistent/recurrent epithelial defects with stromal haze), stage 5 (persistent/recurrent epithelial defect with corneal ulceration), and stage 6 (corneal perforation). Treatment consists of a variety of modalities (both indirect and direct). CONCLUSIONS: This updated definition and staging system will provide clinicians with the necessary information to diagnose and treat NK at an early stage before it becomes a sight-threatening disorder. It also provides a framework for evaluating current and future treatment options at distinct stages of the disease.

Semiscleral Contact Lens Use After Direct Corneal Neurotization for Neurotrophic Keratopathy.

PURPOSE: To describe a case of a patient treated for neurotrophic keratopathy (NK) with direct corneal neurotization (CN), where a modification to the CN technique allowed for semiscleral contact lens use postoperatively. OBSERVATION: Our patient had successful CN with improved corneal sensation. During the procedure, a 1.0 mm gutter was created between the limbus and nerve graft to allow for semiscleral contact lens fitting. CONCLUSIONS: With the use of preoperative planning and a limbal gutter during CN, a semiscleral contact lens can serve as a well-tolerated postoperative management option to improve visual acuity and protect the corneal surface in patients with NK.

Trigeminal Nerve Involvement in Bulbar-Onset Anti-IgLON5 Disease.

OBJECTIVES: Anti-IgLON5 disease (IgLON5-D) may present with a bulbar-onset motor neuron disease-like phenotype, mimicking bulbar-onset amyotrophic lateral sclerosis. Recognition of their distinctive clinical and paraclinical features may help for differential diagnosis. We report 2 cases of atypical trigeminal neuropathy in bulbar-onset IgLON5-D. METHODS: Trigeminal nerve involvement was assessed using comprehensive clinical, laboratory, electrophysiologic, and MRI workup. RESULTS: Both patients were referred for progressive dysphagia, sialorrhea, and hoarseness. They were treated with bilevel positive airway pressure for nocturnal hypoventilation. Patient 1 complained of continuous facial burning pain with allodynia, exacerbated by mastication and prolonged speech. Patient 2 reported no facial pain. Anti-IgLON5 autoantibodies (IgLON5-Abs) were positive in serum for both patients and CSF for patient 1. Cerebral MRI revealed bilateral T2 fluid-attenuated inversion recovery (FLAIR) hyperintensity and enlargement of trigeminal nerves without gadolinium enhancement in both patients. Needle myography showed fasciculations in masseter muscles. Blink-reflex study confirmed bilateral trigeminal neuropathy only in patient 2. Cortical laser-evoked potentials showed a bilateral small-fiber dysfunction in the trigeminal nerve ophthalmic branch in patient 1. DISCUSSION: In case of progressive atypical bulbar symptoms, the presence of a trigeminal neuropathy or trigeminal nerve abnormalities on MRI should encourage the testing of IgLON5-Abs in serum and CSF.

Postoperative trigeminal neuropathy outcomes following surgery for tumors involving the trigeminal nerve.

OBJECTIVE: To observe the evolution and outcomes of postoperative trigeminal neuropathy following surgery of tumor involving the trigeminal nerve. METHODS: A prospective observational study was conducted between October 2018 and February 2019 involving 25 patients with tumors confirmed to involve the trigeminal nerve during surgery by senior author. Pre- and postoperative trigeminal nerve function status and clinical data were recorded. RESULTS: This study included 18 cases of meningioma and seven of trigeminal schwannoma. Among the meningioma cases, 55.6% of the patients reported facial sensory dysfunction before surgery, 33.3% presented ocular discomfort, and 5.6% had masticatory muscle atrophy. Postoperatively, all patients experienced facial paresthesia, 94.4% complained of eye dryness, and one (5.56%) exhibited keratitis. Additionally, one patient (5.56%) showed new-onset masticatory weakness. During follow-up, 50.0% of patients reported improvement in facial paresthesia, and one (5.56%) experienced deterioration. Eye dryness resolved in 35.3% of patients, and keratitis remission was observed in one patient. However, one patient (5.56%) developed neurotrophic keratitis. Overall, 55.6% of patients displayed mild masticatory weakness without muscle atrophy. In the cases of schwannoma, 28.6% of patients had facial paresthesia before surgery, 42.9% showed ocular discomfort, and one (14.3%) complained of masticatory dysfunction. Postoperatively, 85.7% of patients reported facial paresthesia and eye dryness, with one patient (16.7%) experiencing keratitis. During follow-up, 66.7% of patients demonstrated improvement in facial paresthesia, 28.6% showed eye dryness remission, and one patient (16.7%) recovered from keratitis. However, one patient (16.7%) developed new-onset neurotrophic keratitis. One patient (16.7%) experienced relief of masticatory dysfunction, but 42.9% reported mild deterioration. Another patient (14.3%) had facial anesthesia that had not improved. CONCLUSION: Postoperative trigeminal neuropathy is a common complication with a high incidence rate and poor recovery outcomes after surgery for tumors involving the trigeminal nerve. When trigeminal nerve damage is unavoidable, it is essential to provide a multidisciplinary and careful follow-up, along with active management strategy, to mitigate the more severe effects of postoperative trigeminal neuropathy.

Prevalence and clinical characteristics of neurotrophic keratopathy in hispanic population in northeastern Mexico.

PURPOSE: To evaluate the prevalence and clinical characteristics of neurotrophic keratopathy (NK) in northeastern Mexico. METHODS: Retrospective cross-sectional study in which NK patients admitted to our ophthalmology clinic between 2015 and 2021 were consecutively enrolled. Data regarding demographics, clinical characteristics, and comorbidities were collected at the time diagnosis of NK was made. RESULTS: In the period from 2015 to 2021, a total of 74,056 patients were treated and of these 42 had a diagnosis of neurotrophic keratitis. The prevalence found was 5.67 [CI95 3.95-7.38] in 10,000 cases. The mean age observed was 59 ± 17.21 years occurring more frequently in males in 59% and with corneal epithelial defects in 66.7%. The most frequent antecedents were the use of topical medications in 90%, the presence of diabetes mellitus 2 in 40.5% and systemic arterial hypertension in 26.2%. A higher proportion of male patients with corneal alterations and a higher proportion of female patients with corneal ulcerations and/or perforation were observed. CONCLUSION: Neurotrophic keratitis is an underdiagnosed disease with a broad clinical spectrum. The antecedents that were contracted corroborate what was reported in the literature as risk factors. The prevalence of the disease in this geographical area was not reported, so it is expected to increase over time when searching for it intentionally.

[Advancements in corneal sensory reconstruction for the treatment of neurotrophic keratopathy].

Neurotrophic corneal disease is a degenerative eye condition that occurs due to damage to the trigeminal nerve. This condition presents as a persistent corneal epithelial defect, corneal ulceration, or even perforation, and the main cause is a loss of corneal nerve function. While traditional treatments mainly focus on supportive measures to repair corneal damage, they cannot cure the condition completely. A new surgical treatment option called corneal sensory reconstruction surgery can rebuild the corneal nerve, slow down the progression of the corneal disease, promote corneal epithelial repair, and improve vision. This article reviews the surgical techniques used in corneal sensory reconstruction, including direct nerve repositioning and indirect nerve transplantation, and discusses their treatment outcomes and future prospects.

Is Surgical Repair With Nerve Allograft More Cost-Effective Than Non-Surgical Management for Persistent Trigeminal Neuropathy? Initial Assessment With Markov Model.

PURPOSE: Persistent trigeminal neuropathy (PTN) is associated with high rates of depression, loss of work, and decreased quality of life (QoL). Nerve allograft repair can achieve functional sensory recovery in a predictable manner; however, it bears significant upfront costs. In patients suffering from PTN, is surgical repair with allogeneic nerve graft, when compared to non-surgical therapy, a more cost-effective treatment option? MATERIALS AND METHODS: A Markov model was constructed with TreeAge Pro Healthcare 2022 (TreeAge Software, Massachusetts) to estimate the direct and indirect costs for PTN. The model ran for 40 years with 1-year-cycles on a 40-year-old model patient with persistent inferior alveolar or lingual nerve injury (S0 to S2+) at 3 months without signs of improvement, and without dysesthesia or neuropathic pain (NPP). The 2 treatment arms were surgery with nerve allograft versus non-surgical management. There were 3 disease states, functional sensory recovery (S3 to S4), hypoesthesia/anesthesia (S0 to S2+), and NPP. Direct surgical costs were calculated using the 2022 Medicare Physician Fee Schedule and verified with standard institutional billing practices. Non-surgical treatment direct costs (follow-up, specialist referral, medications, imaging) and indirect costs (QoL, loss of employment) were determined from historical data and the literature. Direct surgical costs for allograft repair were $13,291. State-specific direct costs for hypoesthesia/anesthesia were $2,127.84 per year, and $3,168.24 for NPP per year. State-specific indirect costs included decreased labor force participation, absenteeism, and decreased QoL. RESULTS: Surgical treatment with nerve allograft was more effective and had a lower long-term cost. The incremental cost-effectiveness ratio was -10,751.94, indicating surgical treatment should be utilized based on efficiency and cost. With a willingness-to-pay threshold of $50,000, the net monetary benefits of surgical treatment are $1,158,339 compared to $830,654 for non-surgical treatment. With a standard threshold incremental cost-effectiveness ratio of 50,000, the sensitivity analysis shows that surgical treatment would remain the preferred choice based on efficiency even if surgical costs were doubled. CONCLUSION: Despite high initial costs of surgical treatment with nerve allograft for PTN, surgical intervention with nerve allograft is a more cost-effective treatment option when compared to non-surgical therapy.

Concomitant Bandage Contact Lens, Oral Nicergoline, and Topical Autologous Serum for Severe Neurotrophic Keratitis.

BACKGROUND: To report the outcomes of using the combination of oral nicergoline, autologous serum, and contact lens to enhance corneal epithelization in neurotrophic keratitis and to discuss the clinical potential of this management. METHODS: This was a prospective consecutive case series study of eight patients treated for neurotrophic keratitis at the "Conde de Valenciana" Institute of Ophthalmology. Oral nicergoline, autologous serum, and bandage contact lens were initiated at the same time, immediately after stage 3 diagnosis keratitis was confirmed clinically, and until corneal epithelialization was achieved or eminent corneal perforation was seen. In patients where diabetes was a cause, glycosylate hemoglobin was measured to asses metabolic control. Corneal esthesiometry and corrected distance visual acuity were assessed before and after treatment. RESULTS: This study included eight eyes of eight patients (5 men [62.5%], average age 57±17.9 years). All patients completed at least 1 month of follow-up after nicergoline and contact lens suspension. Of the eight eyes, no one had positive culture growth and complete epithelial healing was achieved in all cases. Half of patients had diabetes and had a poor metabolic control. Corneal sensitivity improved in all eyes almost 2 centimeters in Cochet-Bonnet esthesiometry ( P= 0.01). In addition, final visual acuity gains were obtained ( P= 0.100). CONCLUSIONS: The combination of oral nicergoline, autologous serum, and bandage contact lens simultaneously could be an alternative in the management of stage 3 neurotrophic keratitis when conventional medical treatment has no improvement of corneal epithelization.

Umbilical Cord Graft for Refractory Neurotrophic Keratopathy.

PURPOSE: The purpose of this study was to evaluate whether an umbilical cord tissue graft (UCG) could promote reepithelialization in refractory cases of neurotrophic keratopathy, which failed traditional treatment modalities including amniotic membrane grafts. METHODS: This retrospective case series included 3 eyes of 3 patients who underwent UCG placement for refractory stage 3 neurotrophic keratopathy. Records were reviewed to evaluate the clinical course including previous treatments, time to UCG dissolution, time to corneal epithelialization, and recurrence of epithelial defects. RESULTS: The time of a nonhealing epithelial defect before UCG placement ranged from 7.7 to 30 weeks (mean 21.0). UCG dissolution time ranged from 1.7 to 8.1 weeks (mean 5.0) compared with the previous failed amniotic membrane dissolution time of 0.3 to 1.6 weeks (mean 0.95). The time to complete epithelialization after UCG placement was 7.7 and 8.1 weeks, respectively, for the first 2 cases, whereas the third case did not fully epithelialize. Only 1 eye did not have recurrence of an epithelial defect. The maximum time of maintained epithelialization without recurrence ranged from 5 to 86 weeks (mean 42.7). Follow-up time was 37 to 108.1 weeks (mean 62.2) after first UCG placement. CONCLUSIONS: UCG may allow for longer retention time of tissue grafts, provide a mechanical barrier for protection, and aid in regeneration of the ocular surface. UCG may be an option for re-epithelialization in recalcitrant cases of neurotrophic keratopathy, after conventional treatments such as amniotic membrane grafts have failed.

Nonpainful Trigeminal Neuropathy Associated with a Solitary Pontine Lesion: A Case Series.

A solitary pontine lesion (SPL) is a single brainstem lesion on the trigeminal nerve pathway without any other central nervous system lesion. This research aimed to investigate the demographic and clinical features of nonpainful TNO patients with SPL and identify the most frequently affected anatomical areas using lesion mapping techniques. Demographic and clinical features were retrospectively reviewed from the patients' charts. Brain lesions were mapped using MRIcroGL software. The study included 6 patients (three females and three males) with an SPL. The median age of the patients was 57 (range: 46-68) years. Cranial MRI displayed lesions in the dorsolateral pons and the cerebellar peduncle. The lesion mapping revealed that the lesions were on the trigeminal nerve pathway. SPL is an uncommon cause of TNO. Nonpainful SPL patients have demographic, clinical, and radiological features similar to those of painful SPL patients. The lesion mapping showed that the same brainstem areas are affected in painful and nonpainful SPL patients.

Concurrent facial and trigeminal nerve palsies in a child following COVID-19 vaccination with the Pfizer vaccine.

We present the case of a teenaged boy who attended our Ear, Nose and Throat Emergency clinic with a left-sided lower motor neuron (LMN) facial nerve paralysis associated with sensory loss in the distribution of the ophthalmic (V1) and maxillary (V2) divisions of the trigeminal nerve. This happened 3 days following a first dose of the Pfizer-BioNTech BNT162b2 vaccine. He had a House-Brackmann grade V facial palsy, with marked inability to close the left eye. He was treated with a 10-day course of oral steroids and referred to ophthalmology for eye care. He had an MRI scan of the head, which revealed no space occupying lesions or other abnormalities. Over the 6-week period of follow-up, the patient's V1 and V2 sensation gradually resolved, along with improvement of his LMN facial nerve palsy to House-Brackmann grade 3. Despite the potential temporal relationship, it is not possible to establish a causal relationship between the patient's symptoms and the Pfizer-BioNTech BNT162b2 vaccine, thus further research is required.

Bilateral Corneal Neurotization for Ramos-Arroyo Syndrome and Developmental Neurotrophic Keratopathy: Case Report and Literature Review.

PURPOSE: The purpose of this study was to report the use of bilateral corneal neurotization for neurotrophic keratitis in the setting of Ramos-Arroyo syndrome. METHODS: The case report and surgical technique are described in detail in this article, as well as a review of the literature on corneal neurotization for congenital corneal anesthesia. RESULTS: We report a 17-year-old patient who underwent bilateral corneal neurotization for neurotrophic keratitis secondary to corneal anesthesia in Ramos-Arroyo syndrome. Corneal neurotization was performed with great auricular nerve transfers extended by sural nerve autografts. CONCLUSIONS: We present the treatment of neurotrophic keratopathy with corneal neurotization in a patient with Ramos-Arroyo syndrome. We describe how bilateral corneal neurotization using the great auricular nerve technique is a safe and effective procedure for patients with congenital/developmental corneal anesthesia.