[Modern capabilities in diagnosis and treatment of neurotrophic keratopathy]. / Sovremennye vozmozhnosti diagnostiki i lecheniya neirotroficheskoi keratopatii.

In recent years, the problem of diagnosing and treating neurotrophic keratopathy (NK) has become relevant in view of its prevalence reaching 1.6-11.0 per 10000 people. While previously it was associated only with neuroparalytic keratitis, at present the violation of sensitive and trophic innervation of the cornea with the development of characteristic keratopathy is observed in many diseases and injuries of the organ of vision. Diagnosis of NK is based on anamnestic information and assessment of clinical and functional parameters: determination of the stability of the tear film, tear production and assessment of staining of the ocular surface with vital dyes. The main role in the diagnosis of NK belongs to corneal sensitivity determined with the Cochet-Bonnet esthesiometer. Treatment of NK is designed to restore or increase corneal sensitivity and involves tear replacement therapy, instillations of preparations derived from patient's own blood, anti-inflammatory, metabolic and antibacterial therapy. However, instillations of human erve growth factor (NGF) - the drug Cenegermin (registered in Europe in 2017 at a dose of 20 µg/ml under the name Oxervate), a recombinant form of human rhNGF from Escherichia coli bacteria - exhibit the highest pathogenetic orientation. Its «target¼ is the affected nerve fibers (specific receptors for their growth factor), which makes it possible to eliminate the violation of reparative processes in neural and epithelial cells. A high and long-term clinical efficacy of a course of six (with an interval of 2 hours) instillations of the drug for 8 weeks in the treatment of children and adults with NK has been established. Among the pathogenetically justified methods of surgical treatment, there is the so-called surgical neurotization of the cornea involving the contralateral supraorbital, supratrochlear, great auricular and other nerves, which has a long-term clinical effect.

Concurrent Bell's Palsy and Facial Pain Improving with Multimodal Chiropractic Therapy: A Case Report and Literature Review.

BACKGROUND Bell's palsy, also called facial nerve palsy, occasionally co-occurs with trigeminal neuropathy, which presents as additional facial sensory symptoms and/or neck pain. Bell's palsy has a proposed viral etiology, in particular when occurring after dental manipulation. CASE REPORT A 52-year-old Asian woman presented to a chiropractor with a 3-year history of constant neck pain and left-sided maxillary, eyebrow, and temporomandibular facial pain, paresis, and paresthesia, which began after using a toothpick, causing possible gum trauma. She had previously been treated with antiviral medication and prednisone, Chinese herbal medicine, and acupuncture, but her recovery plateaued at 60% after 1 year. The chiropractor ordered cervical spine magnetic resonance imaging, which demonstrated cervical spondylosis, with no evidence of myelopathy or major pathology. Treatment involved cervical and thoracic spinal manipulation, cervical traction, soft-tissue therapy, and neck exercises. The patient responded positively. At 1-month follow-up, face and neck pain and facial paresis were resolved aside from residual eyelid synkinesis. A literature review identified 12 additional cases in which chiropractic spinal manipulation with multimodal therapies was reported to improve Bell's palsy. Including the current case, 85% of these patients also had pain in the face or neck. CONCLUSIONS This case illustrates improvement of Bell's palsy and concurrent trigeminal neuropathy with multimodal chiropractic care including spinal manipulation. Limited evidence from other similar cases suggests a role of the trigeminal pathway in these positive treatment responses of Bell's palsy with concurrent face/neck pain. These findings should be explored with research designs accounting for the natural history of Bell's palsy.

Uncommon cause of trigeminal neuritis and central nervous system involvement by herpes labialis: a case report.

BACKGROUND: Trigeminal neuropathy is characterized by numbness in the region innervated by the trigeminal nerves, with or without neuropathic weakness in the muscles of mastication. Trigeminal neuritis is a form of trigeminal neuropathy in which the lesion is caused by an inflammation. Herein, we report a patient with trigeminal neuritis due to central nervous system (CNS) involvement of herpes labialis (HL) infection, which was successfully treated with anti-viral and anti-inflammatory agents. CASE PRESENTATION: A young healthy female presented with numbness in the left hemiface for two weeks. She had a preceding typical HL infection on left facial lip one week before the sensory symptom onset. Brain magnetic resonance imaging revealed high signal intensities and asymmetrical thickening with enhancement along the cisternal segment of the left trigeminal nerve. Additionally, brain MR angiography showed multifocal stenoses in the M1 segment of the middle cerebral artery and the cavernous portion of the internal carotid artery. Cerebrospinal fluid (CSF) examination showed mild pleocytosis with normal protein level, glucose ratio, but CSF polymerase chain reaction assay for specific anti-viral antibodies including herpes simplex virus was negative, and CSF culture also did not identify a specific pathogen. The results of serologic testing including tumor markers and autoimmune markers were all unremarkable. A tentative diagnosis of trigeminal neuritis as a complication of HL involving the CNS was made considering the clinical, neuroradiological, and laboratory findings of the patient. Therefore, the patient was treated with intravenous methylprednisolone and acyclovir for 10 days. After the treatments, her sensory disturbance was markedly improved. Brain MRI at the 3-month follow-up also demonstrated improvement of previously identified high signal intensity lesions and multifocal intracerebral artery stenoses. CONCLUSION: HL is usually a self-limiting, benign disease without complications, but rarely presents as trigeminal neuritis due to CNS involvement. Therefore, meticulous evaluation may be necessary if trigeminal neuritis or CNS involving symptoms occur after HL.

Recombinant Human Nerve Growth Factor for Pediatric Neurotrophic Keratopathy.

ABSTRACT: A 4-year-old boy presented with right neurotrophic corneal ulcer, lagophthalmos, and facial palsy 8 months after neurosurgery for synchronous brain tumors. Initial treatment with topical antibiotics, topical corticosteroids, lubrication, and lateral tarsorrhaphy successfully treated the corneal epithelial defect; however, the cornea continued to demonstrate diffuse epitheliopathy and a dense stromal opacity and remained insensate on Cochet-Bonnet esthesiometry. After a course of topical cenegermin, central corneal sensation normalized, and the corneal epitheliopathy was markedly improved. Two years after the completion of cenegermin, corneal sensation was maintained; there were no recurrences of epithelial defects, and the stromal opacity had markedly improved. In vivo confocal microscopy (IVCM) demonstrated the presence of subbasal corneal innervation. This report highlights the safety and prolonged effects of cenegermin for the treatment of pediatric iatrogenic neurotrophic keratopathy, as evidenced by the clinical course and IVCM.

Cutting Edge: Topical Recombinant Nerve Growth Factor for the Treatment of Neurotrophic Keratopathy-Biologicals as a Novel Therapy for Neurotrophic Keratopathy.

ABSTRACT: Ophthalmologists find management of neurotrophic keratopathy (NK) challenging because conventional therapy lacks efficacy and may result in permanent loss of vision. Recombinant nerve growth factor (cenegermin) targets the underlying pathogenesis of NK by regenerating corneal nerves and healing the corneal epithelium through promotion of proliferation, maturing corneal epithelial cells. It has been approved as Food Drug Association-approved treatment of NK. In this article, the background, clinical trials, and impact of recombinant nerve growth factor as the first neurotrophic factor for the restoration of corneal integrity, homeostasis, and corneal nerve regeneration are discussed.

Topical Insulin-Utility and Results in Refractory Neurotrophic Keratopathy in Stages 2 and 3.

PURPOSE: The purpose of this study was to evaluate the clinical outcome of patients with refractory neurotrophic keratopathy (NK) in stages 2 and 3 treated with topical insulin. METHODS: Retrospective analysis of eyes with NK in stages 2 and 3 refractory to standard medical and/or surgical treatment which were treated with topical insulin (1 unit per mL). This treatment was applied 4 times per day and was continued until the persistent epithelial defect (PED) or ulcer resolved. The primary outcome of the study was the complete reepithelialization of the PED or persistent ulcer. "Best-corrected visual acuity" pretreatment and posttreatment, "days until complete reepithelialization" data, and anterior segment photographs were obtained. Outcome measures were compared before and after treatment in both groups using paired and independent samples t tests. RESULTS: Twenty-one eyes were included in this study, and 90% achieved complete reepithelialization of the PED and/or persistent ulcer within 7 to 45 days of follow-up. The mean number of days until complete reepithelialization was significantly lower in NK stage 2 (18 ± 9 days) when compared with NK stage 3 (29 ± 11 days) ( P = 0.025). The best-corrected visual acuity improved significantly in both NK stage 2 ( P < 0.001) and NK stage 3 ( P = 0.004). No side effects were reported during the follow-up. CONCLUSIONS: Our results suggest that topical insulin drops may be an effective therapeutic in refractory NK. This therapy may prove extremely useful because of its low cost and high accessibility.

Topical Nerve Growth Factor for the Treatment of Neurotrophic Keratopathy Caused by Wallenberg Syndrome.

PURPOSE: The aim of this study was to report a case of central neurotrophic keratopathy (NK) in Wallenberg syndrome (WS) and its successful management with topical recombinant nerve growth factor (rNGF). METHODS: A 47-year-old man with WS caused by a stroke in the territory of the left vertebrobasilar artery complained of progressive visual loss in his left eye (OS). Examination showed corneal anesthesia associated with a corneal epithelial ulceration consistent with a diagnosis of NK grade 3 of central origin. Topical treatment with rNGF, 1 drop 6 times daily, was started for 8 weeks, and the patient was followed up for 1 year. RESULTS: Topical treatment with rNGF was successful in promoting complete epithelial corneal healing. No recurrence was seen at 1-year follow-up. CONCLUSIONS: Clinicians should be aware that visual loss can also occur from NK of central origin. To the best of our knowledge, this is the first case report of NK caused by WS successfully treated with rNGF reported in the literature.

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

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

Successful Treatment of a Pediatric Neurotrophic Keratopathy With Cenegermin.

PURPOSE: We present a challenging case of a 9-year-old patient with refractory neurotrophic keratopathy (NK) who was successfully treated with cenegermin eye drops. METHODS: A 7-year-old boy developed an ocular infection after a visit to a public swimming pool. After having been unsuccessfully treated for 2 years with antibiotics, steroids, and artificial tears, the patient presented to our clinic with a therapy-refractory NK. We initiated treatment with autologous serum eye drops that showed only weak response. Therefore, treatment with cenegermin eye drops was started. RESULTS: After cenegermin therapy, a complete restoration of the corneal surface and an increase in visual acuity were achieved. CONCLUSIONS: The use of cenegermin is effective in treating pediatric NK.

Pediatric Use of Recombinant Human Nerve Growth Factor 20 µg/mL Eye Drops (Cenegermin) for Bilateral Neurotrophic Keratopathy in Congenital Corneal Anesthesia.

PURPOSE: This study aimed to present the efficacy and safety of cenegermin eye drop (Oxervate; Dompè Farmaceutici, Milan, Italy) treatment in a pediatric patient affected by neurotrophic keratopathy (NK) with Goldenhar syndrome. METHODS: This case reports an infant presenting ulceration and a small central opacity in the cornea of the right and left eyes, respectively. The NK bilaterally worsened despite the use of therapeutic contact lenses and temporary partial tarsorrhaphy. Magnetic resonance imaging showed absence and hypoplasia of the right and left trigeminal nerves, respectively. Cenegermin eye drops were administered 1 drop/each eye, 6 times daily for 8 weeks to promote corneal healing. RESULTS: Complete healing was achieved in both eyes after treatment. During the 16-month follow-up period, no epithelial defect, recurrence, or complications were noticed, whereas corneal opacities progressively became clearer, although insignificant improvements in corneal sensitivity or in the reflex tearing were observed. CONCLUSIONS: Cenegermin was effective in treating NK in an infant with Goldenhar syndrome.

Eslicarbazepine acetate interacts in a beneficial manner with standard and alternative analgesics to reduce trigeminal nociception.

RATIONALE: Acute pain states in the trigeminal region (headaches, dental pain) fall into the most prevalent painful conditions. Standard analgesics (paracetamol/NSAIDs) represent the cornerstone of their treatment, whereas triptans are primarily used in migraine attacks. Due to limited efficacy and/or side effects of current treatments, identifying favorable combinations of available drugs is justified. OBJECTIVES: Eslicarbazepine acetate (ESL) is a novel antiepileptic drug whose effectiveness against trigeminal pain was recently demonstrated. Here, we examined the interactions between ESL and several standard/alternative analgesics (paracetamol, propyphenazone, naproxen, zolmitriptan, and metoclopramide) in a model of trigeminal pain. METHODS: The antinociceptive effects of orally administered ESL, standard/alternative analgesics, and two-drug ESL-analgesic combinations were examined in the orofacial formalin test in mice. The type of interaction between drugs was determined by isobolographic analysis. RESULTS: ESL, analgesics, and two-drug ESL-analgesic combinations significantly and dose-dependently reduced nociceptive behaviour in the second, inflammatory phase of the test. Isobolographic analysis revealed that ESL interacted additively with paracetamol/propyphenazone/zolmitriptan and synergistically with naproxen/metoclopramide (with about a 4-fold and 3-fold reduction of doses in the ESL-naproxen and ESL-metoclopramide combination, respectively). CONCLUSIONS: ESL interacted in a beneficial manner with several analgesics that are used for trigeminal pain treatment, producing synergistic interactions with naproxen/metoclopramide and additive interactions with paracetamol/propyphenazone/zolmitriptan. Our results suggest that combining ESL with analgesics could theoretically enable the use of lower doses of individual drugs for achieving pain relief.

Topical Recombinant Human Nerve Growth Factor (Cenegermin) for Neurotrophic Keratopathy: A Multicenter Randomized Vehicle-Controlled Pivotal Trial.

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.

Neurotrophic Keratopathy: Therapeutic Approach Using a Novel Matrix Regenerating Agent.

PURPOSE: To evaluate the efficacy and tolerance of a new matrix-regenerating agent (RGTA), Cacicol®, a polymer that mimics heparan sulfates bound to extracellular matrix proteins, avoiding its proteolysis, to treat neurotrophic keratopathy (NK). METHODS: Uncontrolled prospective clinical study performed between January 2014 and May 2016. Twenty-five patients (25 eyes) with corneal neurotrophic ulcers, nonresponsive to at least 2 weeks of conservative therapy, were treated with Cacicol, instilled once/twice a week. During follow-up, slit-lamp examination, anterior segment photography, fluorescein-dye testing, and best-corrected visual acuity were analyzed. Ulcer evolution was evaluated using image analysis software (ImageJ®) and healing defined as decrease of the corneal ulcer area. An independent observer measured ulcer area. RESULTS: All patients had complete corneal healing within an average of 4.13 ± 2.32 weeks. Mean ulcer area decreased significantly (P = 0.001) from 16.51% ± 18.56% (1st day) to 8.68% ± 11.25% at the 7th day and to 4.73% ± 10.75% at the 14th day. Compared with day 1, mean ulcer area decreased 60.24% after 7 days (P = 0.001), 54.92% after 14 days (P = 0.059), and 83.00% after 21 days (P = 0.003). Two cases of recurrence (8.0%) were registered. No systemic or local side effects were noticed. CONCLUSIONS: The new regenerating agent, Cacicol, represents an effective and safe therapy to treat NK.

Use of Topical Insulin to Treat Refractory Neurotrophic Corneal Ulcers.

PURPOSE: To report the clinical course of 6 patients with refractory neurotrophic corneal ulcers that were treated with topical insulin drops. METHODS: Retrospective chart review of patients who had neurotrophic corneal ulcers or epithelial defects refractory to standard medical and surgical treatment. Insulin drops, prepared by mixing regular insulin in artificial tears with a polyethylene glycol and propylene glycol base at a concentration of 1 unit per milliliter, were prescribed 2 to 3 times daily. RESULTS: Six patients, aged 2 to 73 years, developed neurotrophic corneal ulcers refractory to a range of medical and surgical treatments, including bandage contact lens, amniotic membrane grafting, and permanent tarsorrhaphy. Each patient was administered topical insulin drops with complete corneal reepithelialization within 7 to 25 days. CONCLUSIONS: Topical insulin may be a simple and effective treatment for refractory neurotrophic corneal ulcers. Further study is required to determine the clinical efficacy and side effect profile of insulin drops.