RU2840756C1 - Method of conservative treatment of neurotrophic keratitis - Google Patents

Abstract

FIELD: medical science.

SUBSTANCE: invention refers to medicine, namely to ophthalmology. Method includes administering into conjunctival sac: 0.1% fluorometholone 4 times a day in dose of 0.05 ml, 0.05% cyclosporine 2 times day by 0.05 ml, sodium hyaluronate 0.15-0.5% and dexpanthenol 1.0-2.0% 3-6 times a day in dose of 0.05 ml daily. Drug-induced therapy is conducted for 2 to 6 months.

EFFECT: method allows to reduce the inflammatory process severity and to strengthen the reparation in the corneal tissues, makes it possible to avoid surgical intervention and increases the patient's standard of living, allows to obtain better result for preservation of visual function in comparison with other combinations of medicines used for treatment of neurotrophic keratitis.

1 cl, 2 dwg, 1 tbl, 3 ex

Description

The proposed invention relates to ophthalmology and is intended for the treatment of neurotrophic keratitis.

Neurotrophic keratitis is a degenerative disease of the cornea that causes decreased corneal sensitivity, spontaneous damage to its epithelium, and impaired healing. This condition can be caused by various reasons, such as trauma, surgery, herpes virus infection, and other diseases. Early clinical manifestations include unevenness of the corneal surface and lack of normal corneal luster. Then, punctate epithelial erosions may develop, which may merge with each other and progress to chronic erosion of large sizes. Chronic erosion in neurotrophic keratitis is often oval in shape with clear boundaries and is localized in the central parts of the cornea. Persistence of erosion in neurotrophic keratopathy ultimately leads to ulceration of the stroma. A neurotrophic ulcer retains the same shape with clear boundaries, has thickened edges formed by swollen epithelium. Complications of neurotrophic keratitis include stromal scarring up to the formation of a leukoma, neovascularization, perforation and secondary bacterial infection. Due to changes in the corneal epithelium, neurotrophic keratitis is always accompanied by the development of dry eye syndrome (DES), since the homeostasis of the tear film is disrupted. Xerosis is an integral part of the pathogenesis of the neurotrophic process, provokes increased inflammation and prevents the restoration of the integrity of the cornea, the severity of neurotrophic keratitis directly correlates with the severity of DES.

Treatment of neurotrophic keratitis should be comprehensive and may include both drug therapy and surgical intervention.

Surgical interventions may include keratoplasty, corneal conjunctival grafting, tarsorrhaphy, and other techniques aimed at restoring corneal sensitivity.

Drug treatment of neurotrophic keratitis is aimed at improving corneal trophism, stimulating its regeneration, as well as preventing and treating secondary infections. The main groups of drugs used to treat neurotrophic keratitis are:

- keratoprotectors - drugs that protect the cornea from external influences and promote its healing. These include artificial tear preparations: gels and drops with dexpanthenol and sodium hyaluronate.

- Antibacterial drugs are used to prevent and treat secondary corneal infections. These include antibiotics in the form of drops and ointments, as well as systemic antibiotics for severe infections.

- anti-inflammatory drugs are used to reduce inflammation of the cornea. These include glucocorticosteroids in the form of drops or ointments.

- drugs that improve corneal trophism, stimulate blood supply and nutrition of the cornea. These include vasodilators, drugs that improve microcirculation, and antioxidants.

Autologous blood serums in the form of eye drops containing growth factors, cytokines, and stem cells are also used in therapy.

The most promising drug therapy for neurotrophic keratitis is currently considered to be local application of a recombinant form of nerve growth factor. There are eye drops containing rhNGF called Cenegermin. However, this drug is not registered in the Russian Federation and is expensive, making it inaccessible to most patients.

Currently, there is no single standard for the treatment of neurotrophic keratitis. We offer an effective drug therapy regimen that includes the use of eye drops Fluorometholone 0.1%, Cyclosporine 0.05% and sodium hyaluronate 0.1-0.5% and dexpanthenol 1.0-2.0%.

Fluorometholone 0.1% (1 mg/ml) is a corticosteroid (glucocorticoid), a derivative of deoxyprednisolone. It belongs to a group of well-known steroids used in the treatment of inflammation of the organs of vision. Glucocorticosteroids bind to cytoplasmic receptors and control the synthesis of infection mediators, thereby suppressing inflammatory reactions (tissue edema, fibrin deposition, capillary dilation, phagocytic migration), as well as capillary proliferation, collagen deposition and scarring.

Ciclosporin 0.05% (0.5 mg/ml) contains the immunosuppressant calcineurin inhibitor for topical use, which has anti-inflammatory action. Ophthalmic emulsion is indicated to increase lacrimation in patients in whom lacrimation is suspected to be suppressed due to ocular inflammation associated with dry eye syndrome.

An ophthalmic sterile solution containing dexpanthenol and hyaluronic acid in the form of sodium hyaluronate, which is a natural moisturizing substance with a high ability to bind with water. Sodium hyaluronate 0.1-0.5% (1-5 mg / ml) has a smaller molecular size compared to hyaluronic acid, which allows the substance to penetrate tissues more easily and ensure the formation of a uniform, stable and durable protective layer on the cornea of the eye. Due to these properties of hyaluronic acid, when instilling the product into the eyes, a thin film is formed on the front surface of the cornea of the eye, protecting the eye from drying out, relieving the feeling of discomfort, dryness, fatigue, burning and irritation of the eyes. Dexpanthenol 1.0-2.0% (10-20 mg/ml) additionally moisturizes, promotes healing and restoration of the corneal epithelium, enhances the water-retaining properties of sodium hyaluronate. The acceptable ratio of dexpanthenol and sodium hyaluronate in the solution is from 2:1 to 20:1.

A possible disadvantage of the method may be the occurrence of side effects after using eye drops in the form of a burning sensation in the eye, eye irritation, hyperemia of the conjunctiva of the eye, a sensation of a foreign body in the eye, pain and itching in the eye, discharge from the eye, blurred vision, photophobia, headache.

The objective of this invention is to increase the effectiveness of drug treatment by stopping the inflammatory process in the corneal tissues, stimulating reparative processes, and accelerating the epithelialization of erosion.

The technical result of the claimed solution is the suppression of the inflammatory process in the corneal tissues, the formation of stable epithelium in the area of chronic erosion, and a reduction in the likelihood of surgical intervention.

The specified technical result is achieved by the fact that a method for conservative treatment of neurotrophic keratitis is proposed, which includes the introduction into the conjunctival sac of: 0.1% fluorometholone 4 times a day at 0.05 ml, 0.05% cyclosporine 2 times a day at 0.05 ml, sodium hyaluronate 0.1-0.5% and 1.0-2.0% dexpanthenol 3-6 times a day at 0.05 ml daily, while drug therapy is carried out for 2-6 months.

The developed tactics of using eye drops: cyclosporine 0.05% in combination with the use of fluorometholone 0.1% and sodium hyaluronate 0.1-0.5% and dexpanthenol 1.0-2.0% leads to inhibition of the inflammatory process and increased reparation in corneal tissues, faster restoration of epithelial regeneration, the formation of less pronounced corneal opacity, which ultimately leads to better visual functions and allows avoiding surgical intervention.

The method is carried out as follows - the drugs must be used daily for 2 or more months according to the instructions for the drugs: fluorometholone 0.1% 4 times a day, 0.05 ml (1 drop) in the conjunctival sac, cyclosporine 0.05% 2 times a day, 0.05 ml (1 drop) in the conjunctival sac and sodium hyaluronate 0.1-0.5% and dexpanthenol 1.0-2.0% 3-6 times a day, 0.05 ml (1 drop) in the conjunctival sac.

The frequency of instillations is selected based on the instructions for the drugs and the maximum dosage regimen to avoid the development of side effects and to obtain the best effect by stimulating the reparation of corneal tissue.

Two groups of patients were formed, each group consisting of 10 people. The groups were composed of patients who had previously undergone treatment in a 24-hour ophthalmological hospital with a diagnosis of keratitis of unknown etiology (ICD H16.8), in whom the expected positive dynamics were not achieved during conservative therapy. After discharge from the hospital, patients were taken under control for further observation and outpatient treatment. To confirm the diagnosis of neurotrophic keratitis and select patients for inclusion in the observation groups, the following were performed: biomicroscopy (corneal changes characteristic of neurotrophic keratitis stages 1 and 2), determination of tactile sensitivity of the cornea at 13 points (significant decrease or absence of sensitivity). In addition, all patients underwent the following studies: tear film breakup time (TBUT), Schirmer test, visometry. For the purposes of differential diagnostics and exclusion of bacterial and other etiologies of keratitis, laboratory tests were performed: conjunctival smear, conjunctival culture on nutrient media, scraping with a platinum loop from the cornea with subsequent microscopy of the scraping material. Initially, all patients were observed to have corneal erosion biomicroscopically, which has an oval shape with smooth borders and thickened edges, in most cases the erosion was located in the optical zone. To assess the condition of the cornea and clarify the configuration of the erosion, all patients underwent a fluorescein test. All patients were found to have absent or decreased corneal sensitivity in the affected eye, decreased Schirmer test values, VRSP. The average values for both groups of patients: the Schirmer test and VRSP values were, respectively, 4±2.0 mm and 2±1.5 sec, tactile sensitivity of the cornea was reduced or absent, visual acuity was 0.1±0.05.

Fig. 1 shows an example of neutrophic keratitis - a photograph before conservative treatment using the claimed methods.

Fig. 2 shows an example of neutrophic keratitis - a photograph 5 months after treatment with the claimed method.

Patients of the 1st group, who received complex therapy by the described method, attended control examinations 1 month after the start of therapy, 2, 3, 6 months. After 1 month from the start of treatment by the proposed method, patients demonstrated slightly positive dynamics: tactile sensitivity of the cornea is reduced or absent, Schirmer test results are 6±1.5 mm and VRSP 3±2.0 sec, visual acuity is 0.12±0.03. After 2 months, the assessed parameters were: tactile sensitivity of the cornea is reduced or absent, some patients showed partial restoration of corneal sensitivity, Schirmer test results are 7±1.8 mm and VRSP 4±1.5 sec, visual acuity is 0.14±0.05. At the follow-up appointment after 3 months: tactile sensitivity of the cornea is reduced or absent, most patients showed partial restoration of corneal sensitivity, Schirmer test results were 8±2.1 mm and VRSP 5±1.8 sec, visual acuity was 0.15±0.05. At the follow-up examination after 6 months from the start of treatment, patients in group 1 showed positive dynamics: tactile sensitivity of the cornea was partially restored in most patients, Schirmer test results were 10±2.3 mm and VRSP 6±1.5 sec, visual acuity was 0.2±0.1.

Patients of the 2nd group received reparants, artificial tears, antibiotics or antiseptics as drug therapy according to current clinical guidelines. The frequency of instillations was prescribed in accordance with the instructions for the drugs. Patients of the 2nd group also attended control examinations 1 month after the start of therapy, 2, 3, and 6 months later. At the control examination 1 month after standard drug therapy, the average indicators are: tactile sensitivity of the cornea is reduced or absent, Schirmer test results are 3±1.5 mm and VRSP 2±1.0 sec, visual acuity is 0.09±0.03. After 2 months: tactile sensitivity of the cornea is reduced or absent, Schirmer test results are 3±1.2 mm and VRSP 2±1.0 sec, visual acuity is 0.08±0.05. At the follow-up appointment after 3 months, the average indicators were: tactile sensitivity of the cornea was reduced or absent, Schirmer test was 2±1.0 mm and TBUT was 1±1.0 sec, visual acuity was 0.05±0.03. At the follow-up examination after 6 months from the start of treatment, the patients of group 2 still showed no positive dynamics: tactile sensitivity of the cornea was reduced or absent, Schirmer test indicators were 2±0.5 mm and TBUT was 1±1.0 sec, visual acuity was 0.03±0.02. In some patients (n=4), surgery was performed during 6 months of observation for corneal ulcer with the risk of perforation and/or corneal perforation. Thus, based on the objective examination data over 6 months, a statistically significant difference was revealed between the 1st and 2nd groups of patients (p≤0.05), the data are presented in Table 1.

Table 1

Group Period (day) Visual acuity Sensitivity Schirmer test (mm) VRSP (sec) 1 Before treatment 0.1±0.05 Tactile sensitivity of the cornea is reduced or absent 4±2.0 mm 2±1.5 sec 30 0.12±0.03 Tactile sensitivity of the cornea is reduced or absent 6±1.5 mm 3±2.0 sec 60 0.14±0.05 Tactile sensitivity of the cornea is reduced or absent; some patients experienced partial restoration of corneal sensitivity 7±1.8 mm 4±1.5 sec 90 0.15±0.05 Tactile sensitivity of the cornea is reduced or absent; most patients showed partial restoration of corneal sensitivity 8±2.1 mm 5±1.8 sec 180 0.2±0.1 Corneal tactile sensitivity was partially restored in most patients 10±2.3 mm 6±1.5 sec 2 Before treatment 0.1±0.05 Tactile sensitivity of the cornea is reduced or absent 4±2.0 mm 2±1.5 sec 30 0.09±0.03 Tactile sensitivity of the cornea is reduced or absent 3±1.5 mm 2±1.0sec 60 0.08±0.05 Tactile sensitivity of the cornea is reduced or absent 3±1.2 mm 2±1.0 sec 90 0.05±0.03 Tactile sensitivity of the cornea is reduced or absent 2±1.0 mm 1±1.0 sec 180 0.03±0.02 Tactile sensitivity of the cornea is reduced or absent 2±0.5 mm 1±1.0 sec

Clinical example #1

Patient G., 62 years old. In 2023, she suffered from herpes zoster involving the left eye (dendritic keratitis), was treated in hospital, received antiviral therapy, and locally used antibacterial, antiviral, and antiseptic drops. Three months after discharge from the hospital, a follow-up examination diagnosed neurotrophic keratitis. Diagnosis upon visit on November 18, 2023: OS - neurotrophic keratitis, complicated cataract, moderate dry eye syndrome. Visual acuity before treatment: OD - 0.6sph+ 1.0= 0.8, OS 0.05 does not correct. Biomicroscopy: the right eye is calm, weak conjunctival injection, the cornea is unremarkable. OS: conjunctiva of the eyelids and eyeball weak mixed injection, cornea - oval erosion measuring 6 by 4 mm with clear boundaries and raised, undermined edges formed by edematous epithelium, epitheliopathy on the periphery, xerosis phenomena. When touching at 13 points of the cornea, sensitivity is reduced - recorded at 3 points out of 13. Schirmer test OD = 8 mm; OS = 6 mm, Norn test OD = 5 sec, OS = 2 sec; Recommended therapy for the left eye: Fluorometholone 0.1% 4 times a day, 0.05 ml into the conjunctival sac, Cyclosporine 0.05% 2 times a day, 0.05 ml into the conjunctival sac, sodium hyaluronate 0.1% and dexpanthenol 2.0% 3 times a day, 1 drop into the conjunctival sac in both eyes. A check-up after 2 months showed that the left eye is calm, there is a slight cloud-like opacity on the cornea, the erosion is completely epithelialized, the epithelial cover is stable, when checking sensitivity to touch at 13 points, sensitivity is recorded at 13 points. Visual acuity after treatment: OD - 0.6sph+ 1.0= 0.8, OS 0.4 does not correct. Functional tests: Schirmer test OD = 13 mm; OS = 14 mm, Norn test OD = 10 sec, OS =10 sec.

Clinical example #2

Patient U., 85 years old. In 2022, she suffered an acute cerebrovascular accident (ACVA), which resulted in right-sided hemiparesis and dysarthria as a complication. A few months after the ACVA, a thick fog appeared in front of the right eye and redness of the eye. She was treated on an outpatient basis for 3 months using antibacterial, anti-inflammatory and reparative drugs. Diagnosis upon visit on 04/05/2023: OD - neurotrophic corneal ulcer, complicated cataract, severe dry eye syndrome. Visual acuity before treatment: OD - 0.02 does not correct, OS 0.6 does not correct. Biomicroscopy: the left eye is calm, the cornea is unremarkable. OD: moderate pericorneal injection of the conjunctiva of the eyelids and the eyeball, a teardrop-shaped erosion on the cornea measuring 5 by 3 mm with clear boundaries and raised edges, ulceration of the stroma in the central zone, perifocal edema of the corneal tissue and descemetitis. There is no sensitivity when touching 13 points of the cornea. Schirmer's test OD = 2 mm; OS = 10 mm, Norn's test OD = 0-1 sec, OS = 9 sec; Recommended therapy in the right eye: Fluorometholone 0.1% 4 times a day, 0.05 ml into the conjunctival sac, Cyclosporine 0.05% 2 times a day, 0.05 ml into the conjunctival sac, and sodium hyaluronate 0.5% and dexpanthenol 1.0% 5 times a day, 1 drop into the conjunctival sac. The control carried out after 6 months showed that the right eye is calm, opacity has formed on the cornea within the ulceration: stroma, stable epithelium in the area where the erosion was previously located, when checking sensitivity to touch at 13 points, sensitivity is recorded at 6 points. Visual acuity after treatment: OD - 0.1 does not correct, OS 0.6 does not correct. Functional tests: Schirmer test OD = 11 mm; OS = 11 mm, Norn test OD = 7 sec, OS = 9 sec.

Clinical example #3

Patient R., 29 years old. In 2022, a neurosurgery was performed for an acoustic neuroma on the right. A few months after the operation, a fog in front of the eye and redness of the eye appeared. The patient was treated with antibacterial, anti-inflammatory and reparative drugs for 5 months. Diagnosis upon visit on 08/22/2023: OD - neurotrophic corneal ulcer, lagophthalmos, severe dry eye syndrome. Visual acuity before treatment: OD - 0.01 n / a, OS - 1.0. On general examination: asymmetry of the right half of the face, incomplete closure of the right palpebral fissure is observed. On biomicroscopy: the left eye is calm, the cornea is normal. OD: conjunctiva of the eyelids and eyeball with pronounced pericorneal injection, on the cornea there is a subtotal oval erosion measuring 5 by 4 mm with clear boundaries and ridge-like edges, in the central zone there is ulceration of the stroma, perifocal edema and descemetitis, newly formed vessels in the cornea extend to the ulcer. There is no sensitivity when touching 13 points of the cornea. Schirmer's test OD = 4 mm; OS = 15 mm, Norn's test OD = 1 sec, OS = 15 sec; Recommended therapy - in the right eye: Fluorometholone 0.1% 4 times a day, 0.05 ml into the conjunctival sac, Cyclosporine 0.05% 2 times a day, 0.05 ml into the conjunctival sac and sodium hyaluronate 0.15% and dexpanthenol 2.0% 6 times a day, 1 drop into the conjunctival sac. The control carried out after 3 months showed: the right eye is calm, vascularized opacity has formed on the cornea in the ulcer area, stable epithelial cover along the entire cornea. Visual acuity after treatment: OD - 0.1 eccentric n / a, OS - 1.0, Schirmer test OD = 10 mm; OS = 16 mm, Norn test OD = 5 sec, OS = 13 sec.

Thus, the objective of the claimed solution is achieved: stopping the inflammatory process in the corneal tissues, stimulating reparative processes, accelerating the epithelialization of erosion, which leads to an improvement in visual function and increases the quality of life of patients.

Claims (1)

A method of conservative treatment of neurotrophic keratitis, including the introduction into the conjunctival sac of: 0.1% fluorometholone 4 times a day at 0.05 ml, 0.05% cyclosporine 2 times a day at 0.05 ml, sodium hyaluronate 0.15-0.5% and 1.0-2.0% dexpanthenol 3-6 times a day at 0.05 ml daily, while drug therapy is carried out for 2 months or more.