Corneal neurotization in the management of neurotrophic keratopathy: A review of the literature.

Neurotrophic keratopathy (NK) is a rare degenerative disease in which damage to the corneal nerves leads to corneal hypoesthesia or anesthesia. Neurotrophic corneal ulcers are notoriously difficult to treat and can lead to blindness. Corneal neurotization (CN) is a recent surgical technique aimed at restoring corneal sensation and may offer a definitive treatment in the wake of NK. Herein, we review the surgical techniques utilized in direct and indirect CN. Technical considerations, outcomes, current limitations and future perspectives are also discussed. This article highlights the key points of this promising procedure and biological aspects that will help provide the best treatment options for patients with severe NK.

[Treatment of neurotrophic keratopathy in combined lesions of the trigeminal and facial nerves]. / Lechenie neirotroficheskoi keratopatii pri sochetannom porazhenii troinichnogo i litsevogo nervov.

Ocular symptomatology in lesions of the facial nerve is associated with disturbed innervation of the circular muscle of the eye that leads to disruption of the protective function of the eyelids and the development of exposure symptoms, and is accompanied by a breach in corneal tear film integrity. The main clinical manifestation of the trigeminal nerve damage is the loss of sensory innervation of the cornea and disruption of the supply of neurotransmitters to its cells, manifesting as corneal hypo- or anesthesia. This triggers a cascade of pathological processes that lead to the development of neurotrophic keratopathy. In combined pathology of the facial and trigeminal nerves, a number of interrelated and mutually aggravating problems arise that require correction of lagophthalmos and functional restoration of the trigeminal nerve, since there is an interaction between the corneal epithelium and trigeminal neurons through trophic neuromodulators, which normally contribute to the proliferation of epithelial cells, their differentiation, migration and adhesion, and are essential for vital functions, metabolism and healing of surface lesions of the eye. Classical methods of treating neurotrophic keratopathy aim to protect the ocular surface, and are palliative or auxiliary, do not provide radical relief of the symptoms of neurotrophic keratopathy. Modern surgical technique of neurotization of the cornea allows restoring the structural growth of the nerve, which provides nerve trophism and corneal sensitivity, and is the only pathogenetically substantiated method of effective treatment of neurotrophic keratopathy. At the same time, direct neurotization has undeniable advantages over methods involving intercalary donor nerves, since neuropeptides from nerve fibers are immediately released into the recipient tissue and start reparative processes. Taking into account the accumulated positive experience of neurotization surgeries, scientific and clinical research should be continued in order to improve the most effective methods of corneal neurotization and promote their wider implementation into clinical practice.

Blink Reflex in Neurotrophic Keratopathy: An Electrophysiological Evaluation.

PURPOSE: Neurotrophic keratitis (NK) is a rare condition which may result in visual loss. This case review investigates if there may be an association between NK and the blink reflex in the absence of facial nerve palsy and lagophthalmos. METHODS: This is a retrospective case review of 5 patients with trigeminal nerve damage referred to the oculoplastic department with suspected anesthetic corneae. Information on etiology, symptoms, duration, associated medical conditions, medications, examination findings including Mackie stage of keratopathy, management of keratopathy, and blink electrophysiology results was obtained. RESULTS: All 5 patients demonstrated absence of corneal sensation. All patients had preserved facial nerve function with no evidence of lagophthalmos. Keratopathy ranged from Mackie stage 0-2. Management ranged from ocular lubricants to Botulinum-toxin-induced ptosis. Blink studies demonstrated reduction in amplitude as well as increased latency in 2 patients, conferring reduced blink strength. Two patients demonstrated an absent blink reflex on the affected side. One patient had blink latency within the normative range; this patient recovered corneal sensation and was discharged. CONCLUSIONS: Our finding of reduced amplitude in blink studies offers both a factor in pathogenesis of NK and a potential therapeutic target. Additionally, blink studies may provide prognostic information for recovery and therefore guide management. We suggest performing blink electrophysiology in patients with trigeminal nerve damage to assess nerve function.

Clinical Outcomes of Minimally Invasive Corneal Neurotization After Cerebellopontine Angle Neurosurgical Procedures.

PURPOSE: To report 12 patients with neurotrophic keratopathy due to the trigeminal nerve injury after intracranial tumor surgeries underwent minimally invasive corneal neurotization and evaluate the outcomes of corneal reinnervation. METHODS: Twelve patients (12 eyes) with neurotrophic keratopathy caused by the trigeminal nerve injury after intracranial surgeries received minimally invasive corneal neurotization. All the preoperative central corneal sensation was under 5 mm, and minimally invasive corneal neurotization was performed over 6 months after the intracranial surgery. Follow-up was conducted 1 week and 1 month after the surgery and then every 3 months. Twelve healthy age-matched participants were enrolled as controls. The indicators included corneal sensation, best-corrected visual acuity, corneal nerve fiber length and branch density, diameter of nerve trunk, corneal ulcer lesion ratio, and sensation of the contralateral forehead. RESULTS: Mean follow-up was 24.7 ± 7.1 months. Mean central corneal sensation rose from 0.4 ± 1.4 to 31.7 ± 21.8 mm. Corneal nerve fiber length improved from 9.56 ± 5.00 to 14.96 ± 4.65 mm/mm2 and corneal nerve branch density and diameter of nerve trunk both increased (p < .01 and p < .05, respectively). Corneal lesion ratio decreased from 0.17 ± 0.12 to 0.10 ± 0.10 (p < .01). CONCLUSIONS: Minimally invasive corneal neurotization promotes corneal reinnervation for patients with neurotrophic keratopathy induced by the trigeminal nerve injury after intracranial surgeries. The process of corneal reinnervation after minimally invasive corneal neurotization often lasts over 12 months, and it takes about 18 months to return to a higher level. Corneal sensation and corneal nerve fiber length are related to clinical outcomes such as corneal ulcer lesion and best-corrected visual acuity. The effect on the sensation of the contralateral side forehead is temporary, and most patients can restore normal forehead sensation of the contralateral side.

Bilateral corneal perforation caused by neurotrophic keratopathy associated with leprosy: a case report.

BACKGROUND: Neurotrophic keratopathy (NK) is a rare degenerative corneal disease caused by damage to the trigeminal nerve. We hereby describe a severe case with bilateral corneal perforation due to leprosy (Hansen's disease)-associated NK. CASE PRESENTATION: An 89-year-old man with a history of leprosy treated 40 years previously in our sanatorium developed bilateral corneal perforation due to NK. He had a history of bilateral persistent epithelial defects and bacterial keratitis. Although epithelialization was obtained with the use of autologous serum eye drops, progressive corneal thinning concomitant with stromalysis led to bilateral perforation. Over one month treatment with topical antibiotics, anti-inflammatory and lubricants resulted in healing of the epithelial defects and corneal perforations. A Cochet-Bonnet esthesiometer demonstrated a total absence of corneal sensation in both eyes. CONCLUSIONS: The present case indicated the irreversible nerve damage due to leprosy that had been cured 23 years ago, which can progress over the years and cause bilateral corneal perforations.

[Recognition, classification and treatment of trigeminal neuropathy].

Trigeminal neuropathy (TNO) manifests with unilateral or bilateral facio-oral sensory disturbances accompanied by pain and trigeminal nerve dysfunction. Although TNO may be posttraumatic or idiopathic, a thorough history and examination including magnetic resonance imaging is needed to exclude the multitude of secondary TNO causes. TNO-related pain necessitates multimodal treatment which in severe cases may encompass neurosurgical neuromodulation.

Neurotrophic Keratitis in a Pediatric Patient With Goldenhar Syndrome and Trigeminal Aplasia Successfully Treated by Corneal Neurotization.

Herein, the authors report an unusual case of a 6-year-old boy with right-sided Goldenhar syndrome and trigeminal nerve aplasia who developed neurotrophic keratopathy (NK). Despite the use of therapeutic contact lenses and multiple temporary tarsorrhaphy, NK worsened showing a central corneal scar, neovascularization, and significant stromal thinning, with risk of corneal perforation. Cochet-Bonnet esthesiometry revealed complete corneal anesthesia. To minimize additional corneal complications, the patient underwent indirect corneal neurotization by a sural nerve autograft anastomosed to the contralateral supratrochlear nerve. At 24-month follow up, no epithelial defects, complications, or recurrence were observed. Significant improvements in corneal sensitivity with esthesiometry score of 20 mm and reflex blinking were achieved. This case highlights corneal anesthesia should be suspected among Goldenhar syndrome ophthalmologic abnormalities and monitored before corneal changes become irreversible. Since corneal neurotization can successfully improve corneal sensation, it could be considered as an early therapeutic option to avoid refractory NK.

Expert consensus on the identification, diagnosis, and treatment of neurotrophic keratopathy.

BACKGROUND: Neurotrophic keratopathy (NK) is a relatively uncommon, underdiagnosed degenerative corneal disease that is caused by damage to the ophthalmic branch of the trigeminal nerve by conditions such as herpes simplex or zoster keratitis, intracranial space-occupying lesions, diabetes, or neurosurgical procedures. Over time, epithelial breakdown, corneal ulceration, corneal melting (thinning), perforation, and loss of vision may occur. The best opportunity to reverse ocular surface damage is in the earliest stage of NK. However, patients typically experience few symptoms and diagnosis is often delayed. Increased awareness of the causes of NK, consensus on when and how to screen for NK, and recommendations for how to treat NK are needed. METHODS: An 11-member expert panel used a validated methodology (a RAND/UCLA modified Delphi panel) to develop consensus on when to screen for and how best to diagnose and treat NK. Clinicians reviewed literature on the diagnosis and management of NK then rated a detailed set of 735 scenarios. In 646 scenarios, panelists rated whether a test of corneal sensitivity was warranted; in 20 scenarios, they considered the adequacy of specific tests and examinations to diagnose and stage NK; and in 69 scenarios, they rated the appropriateness of treatments for NK. Panelist ratings were used to develop clinical recommendations. RESULTS: There was agreement on 94% of scenarios. Based on this consensus, we present distinct circumstances when we strongly recommend or may consider a test for corneal sensitivity. We also present recommendations on the diagnostic tests to be performed in patients in whom NK is suspected and treatment options for NK. CONCLUSIONS: These expert recommendations should be validated with clinical data. The recommendations represent the consensus of experts, are informed by published literature and experience, and may improve outcomes by helping improve diagnosis and treatment of patients with NK.

Associated Neurotrophic Keratopathy in Complex Regional Pain Syndrome.

PURPOSE: To report a case of neurotrophic keratopathy (NK) in a patient with complex regional pain syndrome (CRPS) with ipsilateral facial involvement. METHODS: Case report. RESULTS: An 18-year old woman with a 5-year history of CRPS type I, a systemic disorder with a neuropathic component with associated limb and right facial involvement, presented with an insidious onset of blurred vision and pain in the right eye. Ocular examination revealed decreased corneal sensation, as measured by Cochet-Bonnet testing, associated with recurrent epithelial defects and whorl-like superficial corneal epitheliopathy. NK was suspected and confirmed by in vivo confocal microscopy (IVCM), which revealed rarefaction of the subbasal nerve plexus in the affected eye. To enhance corneal nerve health, plasma rich in growth factors drops were used. Persistence of NK prompted a superficial keratectomy with placement of an amniotic membrane graft and a course of cenegermin 0.002% (Oxervate; Dompé Farmaceutici SpA, Italy) in the postoperative period. This combination therapy resulted in successful epithelial closure and vision improvement after 8 weeks of therapy with no recurrence of disease for 11 months. Importantly, at that final visit, IVCM demonstrated growth of corneal nerves for the first time in this patient. CONCLUSIONS: This is the first case report of NK occurring in the context of CRPS, a neuropathy with ipsilateral facial pain involvement. IVCM was important in the diagnosis of NK, which responded successfully to ocular surface treatments focused on nerve health stimulation that ultimately resulted in corneal nerve growth.

Combining In Vivo Corneal Confocal Microscopy With Deep Learning-Based Analysis Reveals Sensory Nerve Fiber Loss in Acute Simian Immunodeficiency Virus Infection.

PURPOSE: To characterize corneal subbasal nerve plexus features of normal and simian immunodeficiency virus (SIV)-infected macaques by combining in vivo corneal confocal microscopy (IVCM) with automated assessments using deep learning-based methods customized for macaques. METHODS: IVCM images were collected from both male and female age-matched rhesus and pigtailed macaques housed at the Johns Hopkins University breeding colony using the Heidelberg HRTIII with Rostock Corneal Module. We also obtained repeat IVCM images of 12 SIV-infected animals including preinfection and 10-day post-SIV infection time points. All IVCM images were analyzed using a deep convolutional neural network architecture developed specifically for macaque studies. RESULTS: Deep learning-based segmentation of subbasal nerves in IVCM images from macaques demonstrated that corneal nerve fiber length and fractal dimension measurements did not differ between species, but pigtailed macaques had significantly higher baseline corneal nerve fiber tortuosity than rhesus macaques (P = 0.005). Neither sex nor age of macaques was associated with differences in any of the assessed corneal subbasal nerve parameters. In the SIV/macaque model of human immunodeficiency virus, acute SIV infection induced significant decreases in both corneal nerve fiber length and fractal dimension (P = 0.01 and P = 0.008, respectively). CONCLUSIONS: The combination of IVCM and robust objective deep learning analysis is a powerful tool to track sensory nerve damage, enabling early detection of neuropathy. Adapting deep learning analyses to clinical corneal nerve assessments will improve monitoring of small sensory nerve fiber damage in numerous clinical settings including human immunodeficiency virus.

Acute Unilateral Masseter Muscle Paralysis Caused by Pontine Infarction.

In the present report, we discussed the case of a 57-year-old man with unilateral masticatory muscle weakness, nystagmus, skew deviation and facial hypesthesia due to pontine tegmental infarction. Trigeminal motor neuropathy attributed to brain infarction is very rare. Brain magnetic resonance imaging revealed a small dot-like infarction lesion in the pontine tegmentum. Masticatory muscle weakness was confirmed by an electrophysiological study performed on the day after admission in which there was an incomplete interference pattern without spontaneous denervation activity, suggesting that the patient's masseter muscle weakness was caused by an infarction of the trigeminal motor nucleus proper or trigeminal motor nerve fascicles rather than Wallerian degeneration of the trigeminal nerve or the progression of masseter muscle degeneration.

Case Report: Ocular Tilt Reaction with Internuclear Ophthalmoplegia and Multiple Cranial Nerve Palsies.

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.

Trigeminal trophic syndrome: an important simulator of discoid cutaneous lupus erythematosus - a case series.

Trigeminal trophic syndrome occurs secondary to trigeminal nerve injury, leading to anaesthesia and paraesthesia, with consequent vigorous facial skin manipulation and lesion production, simulating other facial diseases such as ulcerative discoid lupus erythematosus, tumours and other artificially produced lesions. Ulceration and destruction of the ala nasi is a typical feature besides scratching end excoriations in the cutaneous segment affected. In this series, we present the features of five patients with trigeminal trophic syndrome, highlighting possible confusion with cutaneous lupus. Differential diagnoses, including discoid lupus erythematosus, are discussed, as well as possible treatment modalities.

A Comparative Study on the Diagnostic Utility of Corneal Confocal Microscopy and Tear Neuromediator Levels in Diabetic Peripheral Neuropathy.

AIMS: To determine the utility of corneal confocal microscopy and tear neuromediator analysis in the diagnosis of diabetic peripheral neuropathy (DPN) as a result of type 1 and type 2 diabetes. METHODS: Seventy individuals with either type 1 diabetes or type 2 diabetes (T1D/T2D) underwent corneal confocal microscopy to assess the corneal nerve morphology. The concentration of substance P and calcitonin gene-related peptide (CGRP) in tears was measured by enzyme-linked immunosorbent assay. Motor excitability studies were conducted on the median nerve to assess axonal ion channel function. Based on total neuropathy score (TNS), participants were stratified into DPN (DPN+ve; TNS ≥ 2; T1D, n = 19; T2D, n = 16) and without DPN (DPN-ve; TNS ≤ 1; T1D, n = 19; T2D, n = 16). Areas under the receiver operating characteristic curves (AUCs) were calculated to obtain specificity and sensitivity of the measures to diagnose DPN. RESULTS: In T1D, the concentration of substance P and confocal microscopy measures were significantly reduced (P < .010) in DPN+ve. Also, for the nerve excitability measures, mean peak response, percentage of threshold electrotonus at peak and after 90-100 ms, superexcitability and subexcitability were significantly reduced (P < .050) in DPN+ve. In T2D, except for inferior whorl length (P = .190), all other corneal confocal microscopy measures were significantly reduced (P < .010) in DPN+ve, but there was no difference in substance P concentration. For the diagnosis of DPN in T1D, the AUC for inferior whorl length (0.910), mean peak response (0.800) and concentration of substance P (0.770) were high and in T2D, the AUC for corneal nerve fiber length (0.809) and nerve fractal dimension (0.777) were high. CONCLUSION: Corneal confocal microscopy parameters provide a better diagnostic ability to detect DPN in T1D and T2D than nerve excitability measures or concentrations of tear neuromediators. The concentration of substance P could also be useful in diagnosing DPN but for T1D only.

A Trigeminal Schwannoma Masked by Solely Vestibulocochlear Symptoms.

BACKGROUND: Intracranial schwannomas are most commonly associated with the vestibulocochlear nerve, often leading to hearing loss, tinnitus, and vestibular dysfunction. Much less often, a schwannoma can arise from the trigeminal nerve which can lead to facial pain, numbness, and weakness. PURPOSE: We explored a case of a patient with an magnetic resonance imaging (MRI)-confirmed trigeminal schwannoma that was mistaken for a vestibulocochlear schwannoma because of a myriad of ipsilateral vestibulocochlear symptoms. RESEARCH DESIGN: This is a retrospective chart review and case study, with no statistics applied. RESULTS: This diagnostic error led to clinical confusion and inaccurate medical record-keeping. Radiologists and radiation oncologists deemed the patient's symptoms to be unrelated to the asymptomatic trigeminal schwannoma, and she was referred to an otolaryngologist following complaints of ear fullness, ear pain, and hearing loss. The patient's audiogram showed ipsilateral, asymmetric sensorineural hearing loss, and she was diagnosed with concurrent Meniere's disease. Alternative explanations, such as an additional schwannoma or external compression of the vestibulocochlear nerve, were considered, but not apparent on MRI. CONCLUSIONS: From this case, we see that symptoms do not always concur with imaging results and that multiple etiologies, especially when one is rare, can confuse a clinical picture.

REVERSIBLE NEUROTROPHIC KERATOPATHY ASSOCIATED WITH ROSUVASTATIN THERAPY: A CASE REPORT.

BACKGROUND: Rosuvastatin is a 3-hydroxy-3-methyl-glutaryl-CoA reductase enzyme inhibitor that is in wide use with few reported ocular adverse events. OBJECTIVES: To report a case of bilateral neurotrophic keratopathy associated with rosuvastatin therapy that dramatically improved following drug discontinuation. CASE PRESENTATION: A 65-year-old female presented with painless diminution of vision in both eyes of gradual onset and progressive course for 1 month. She had recently started rosuvastatin therapy for hyperlipidemia. Examination revealed bilateral stage 2 neurotrophic keratopathy with impaired corneal sensation which was previously resistant to conservative ulcer treatment. Following discontinuation of rosuvastatin therapy, there was dramatic bilateral improvement in corneal sensation, size of the corneal ulcers, and visual acuity. CONCLUSION: Rosuvastatin may result in reversible trigeminal nerve impairment and neurotrophic keratopathy.