Ophthalmic herpes

Herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) remain the most common viral pathogens causing various eye disorders. Ophthalmic herpes is traditionally thought to be caused by HSV-1.

Nevertheless, a number of researchers cite data on a significant percentage of cases of detection of HSV-2 in eye lesions, which more often causes genital herpes. The question of the possible roleof HSV type 6 in the pathogenesis of severe herpetic keratitis remains debatable.

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Epidemiology of ophthalmoherpes

Unfortunately, ophthalmic herpes is not subject to mandatory registration in Ukraine, so the spread of this eye infection can only be judged approximately, based on similar statistical data from foreign authors.

In the structure of ophthalmic herpes, the cornea of the eye (keratitis) is predominantly affected. Herpetic keratitis (HK) accounts for 20-57% of all inflammatory diseases of the cornea in adults and 70-80% of all inflammatory diseases of the cornea in children. Studies conducted in the period 1985-1987 in the Bristol Eye Clinic (England) showed that 120 cases of primary herpetic keratitis were registered annually for a population of 863,000, which corresponds to an incidence rate of primary herpetic keratitis of approximately 1:8000. These calculations are consistent with data previously reported by various authors.

Recurrent corneal herpes occurs in 25% of cases after the first eye attack and in 75% after repeated attacks. The factors for the development of the disease are reactivation of the persistent virus or reinfection with the exogenous herpes virus. Recurrent corneal herpes is a disease that has become one of the leading causes of disabling corneal opacities and corneal blindness in temperate countries.

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Pathogenesis of ophthalmoherpes

The pathogenesis of ophthalmic herpes is determined by the properties of the virus and specific immune reactions of the macroorganism that occur in response to the introduction of HSV. The virus affects the eye tissues when it overcomes local defense mechanisms, which include the production of secretory antibodies (S-IgA) by cells of the subepithelial lymphoid tissue, local production of interferon, and sensitized lymphocytes.

Getting into the eye tissue exogenously (through the epithelium), neurogenously or hematogenously, HSV begins to actively multiply in the cells of the corneal epithelium, which, due to cytopathic and dystrophic processes, undergo necrosis and sloughing. In superficial keratitis (the corneal epithelium is mainly affected), at this stage further reproduction of the virus in the cornea ceases, the corneal tissue defect is epithelialized, and the virus goes into a persistent state. In a persistent state, the virus can be found not only in the trigeminal ganglion, but also in the cornea itself.

The persistent virus can be activated under any unfavorable conditions. The most common causes are stress, pregnancy, trauma, insolation, infection, hypothermia. In isolated publications of foreign authors, the absence of a dependence of the frequency of HS relapses on age, gender, seasonality, skin manifestations of herpes infection was noted. In recent years, data on the occurrence of ophthalmic herpes relapses after laser exposure and against the background of treatment with prostaglandins (latanoprost) began to appear in the literature. Data are given on the recurrence of ophthalmic herpes during treatment with immunosuppressants - cyclophosphamide and dexamethasone. The role of latanoprost as a factor provoking the development of HS exacerbations is confirmed by experimental work on rabbits.

The pathogenesis of deep (with deep involvement of the corneal stroma) forms of GC is ambiguous. On the one hand, HSV has a direct damaging effect on cells, causing their death with subsequent development of inflammatory reactions. On the other hand, a number of authors point to the ability of HSV to antigen mimicry with the emergence of cross-reacting antigens responsible for triggering autoimmune reactions in the cornea.

Clinical forms and symptoms of ophthalmic herpes

The most complete classification, covering both pathogenetic and clinical variants of ophthalmic herpes, is the classification of Professor A.A. Kasparov (1989). It takes into account pathogenetic (primary and recurrent) and clinical-anatomical (lesions of the anterior and posterior parts of the eye) forms of ophthalmic herpes.

Primary ophthalmic herpes as an independent form is quite rare (according to various authors - no more than 10% of all cases of herpetic eye lesions). The majority (over 90%) is recurrent (secondary) ophthalmic herpes, with lesions of one eye most often observed.

Lesions of the anterior segment of the eye are divided into superficial forms - blepharoconjunctivitis, conjunctivitis, vesicular, dendritic, geographic and marginal keratitis, recurrent corneal erosion, episcleritis, and deep forms:

Posterior eye lesions include neonatal retinochoroiditis, chorioretinitis, uveitis, optic neuritis, perivasculitis, acute retinal necrosis syndrome, central serous retinopathy, and anterior ischemic retinopathy.

Among the superficial forms of damage to the anterior segment of the eye (superficial keratitis), dendritic keratitis is the most common. Groups of small vesicular defects are formed in the corneal epithelium, which tend to open and form an eroded area. As the disease progresses, they merge, forming a so-called dendritic defect with raised and edematous edges, which is clearly visible when examined with a slit lamp. In half of the cases, dendritic ulceration is localized in the optical center of the cornea. Clinically, dendritic keratitis is accompanied by lacrimation, blepharospasm, photophobia, pericorneal injection, and neuralgic pain. Decreased corneal sensitivity is often observed. Dendritic keratitis is generally considered a pathognomonic form of GI of the eye, and such a characteristic form of ulcer is caused by the spread of the virus along the dichotomously branching superficial nerves of the cornea.

Geographic keratitis usually develops from dendritic keratitis due to progression or improper treatment with corticosteroids. Marginal keratitis is characterized by perilimbal infiltrates that can merge.

The etiological role of HSV in the development of recurrent corneal erosion is ambiguous, since the reasons for its existence may be, along with a viral infection, previous eye trauma, corneal dystrophy, and endocrine disorders.

Deep (with deep involvement of the corneal stroma) forms in most cases are combined with inflammation of the anterior vascular tract, i.e., are essentially keratoiridocyclitis. Herpetic keratoiridocyclitis is usually divided into two variants depending on the nature of the corneal lesion - with ulceration (metaherpetic) and without it (varieties - focal, discoid, bullous, interstitial). Herpetic keratoiridocyclitis is characterized by common clinical characteristics: chronic course, the presence of iridocyclitis with serous or serous-fibrinous effusion and large precipitates on the posterior surface of the cornea, edema of the iris, ophthalmic hypertension.

The establishment of the herpesvirus etiology of the posterior eye lesion is quite ambiguous, since in some cases (anterior ischemic neuropathy, central serous retinopathy) the clinical picture differs little from the picture of this disease of another genesis. The doctor may be led to think about the herpes simplex virus as the cause of ophthalmopathology of the posterior eye by: the patient's young age, the presence of a previous acute respiratory viral infection in the anamnesis, recurrent herpes of the facial skin.

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Diagnosis of ophthalmic herpes

The characteristic clinical picture of ophthalmic herpes (in 70% of cases it manifests itself as keratitis), the recurrent nature of the course, herpes infection in the anamnesis, positive dynamics against the background of the use of specific antiviral agents - all this allows in most cases to establish the correct diagnosis. In doubtful cases, with atypical manifestation of ophthalmic herpes, especially with a severe course, it is necessary to verify the herpesvirus etiology in order to prescribe timely etiotropic treatment. Despite the many methods proposed over the past fifty years for detecting both the virus itself and specific antibodies, the fluorescent antibody method (FAM) modified by A.A. Kasparov has proven itself in wide clinical practice. The essence of the method is based on the detection of viral particles in the cells of the conjunctiva of the diseased eye using serum containing labeled antibodies. To exclude the usual virus carriage, the reaction is carried out in several serum dilutions at once (standard, 10-fold, 100-fold and 1000-fold). An increase in luminescence by 10-100 times compared to the luminescence in the standard dilution is associated with a true herpetic lesion of the eye. At the same time, like any laboratory diagnostic method, the result of the MFA depends on the form of keratitis, the period of the disease, previous treatment, etc.

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Treatment of ophthalmic herpes

Today, the main directions of treatment and prevention of ophthalmic herpes are chemotherapy, immunotherapy or a combination of these methods, as well as microsurgical treatment methods (microdiathermocoagulation, various types of keratoplasty, local auto-express cytokine therapy). The era of chemotherapy of viral eye diseases began in 1962 by N.E. Kaipapp, who scientifically substantiated and successfully used 5-iodine-2-deoxyuridine (IDU) in the clinic to treat patients with herpetic keratitis.

IDU - 5-iodo-2-deoxyuridine (kerecid, idukollal, stoksil, dendryl, gerplex, oftan-IDU) - is highly effective in the treatment of superficial GC, but it is ineffective in deep forms of herpetic keratitis and isolated iridocyclitis. Screening of compounds of this group that followed the discovery of IDU made it possible to create a number of now widely known drugs, such as acyclovir, TFT (triflurotimidine), vidarabine, ganciclovir, valacyclovir (valtrex), famciclovir, foscarnet, brivudine and sorivudine.

Trifluorothymidine (TFT, viroptic, trigerpin) is similar in structure and mechanism of action (analog of thymidine) to IDU, but unlike it is less toxic and more soluble. TFT is used as instillations of a 1% solution into the conjunctival sac every 2 hours (up to 8-10 times a day), and 2% ointment is applied (5-6 times a day). TFT is more effective than IDU in superficial forms, as well as in preventing complications caused by the use of corticosteroids.

Adenine-arabinoside-9-ß-D-arabinofuranosal-adenine (vidarabine, Ara-A) is used for herpetic keratitis in the form of 3% ointment 5 times a day, the therapeutic efficacy is equal to or slightly higher, and the toxicity is lower than that of IDU. Vidarabine is effective for IDU-resistant strains of HSV.

The drugs with antiviral activity, tebrofen, florenal, and riodoxol, synthesized in the early 1970s, are used primarily for superficial forms of GC in the form of ointments and drops.

The most significant progress in the treatment of ophthalmic herpes was outlined after the appearance in the arsenal of antiviral agents of acyclovir - a highly active drug with a unique mechanism of selective action on HSV. Over the past ten years, acyclovir has been considered a standard antiherpetic drug. There are three dosage forms of acyclovir: 3% paraffin-based ointment (Zovirax, Virolex); 200 mg tablets; lyophilized sodium salt of acyclovir for intravenous administration in vials of 250 mg. The ointment is usually prescribed 5 times a day at intervals of 4 hours. The usual dose for oral use is 5 tablets per day for 5-10 days. Second-generation acyclovirs - Valtrex and Famciclovir are distinguished by high bioavailability (70-80%) when taken orally, which allows reducing the frequency of administration from 5 to 1-2 times a day.

The drugs of the new direction of treatment are interferons (human leukocyte and recombinant) and their inducers. In ophthalmology, leukocyte interferon (a) with an activity of 200 U/ml and interlock, one ampoule of which contains 10,000 IU of interferon in 0.1 ml of phosphate buffer, are used. Both drugs are approved for use only in the form of instillations. Reaferon (recombinant a2-interferon) is used locally in the form of eye drops and periocular injections for superficial and deep keratitis.

Poludan (high-molecular inducer of interferonogenesis) is used in the form of instillations, periocular injections; it is also possible to introduce it by local electrophoresis and phonophoresis, as well as directly into the anterior chamber of the eye. Poludan stimulates the formation of a-IFN, to a lesser extent a- and y-interferons. The broad antiviral spectrum of action of Poludan (herpes viruses, adenoviruses, etc.) is also due to its immunomodulatory activity. In addition to interferon formation, the introduction of Poludan leads to a significant increase in the activity of natural killers, the level of which is initially reduced in patients with ophthalmic herpes. With frequent repeated administration of the drug, the level of interferon formation in the blood serum is up to 110 U/ml. There are reports of the creation of suppositories with Poludan for the treatment of patients with genital and ophthalmic herpes. The interferonogenic effect of Poludan is enhanced in suppositories by the addition of hyaluronic acid and antioxidants.

In the treatment of patients with dendritic keratitis, Poludan and Acyclovir (3% ointment) have equal potential. Early administration of the drug in the form of subconjunctival injections in combination with instillations (4 times a day) leads to the cure of 60% of patients with the most severe deep forms of herpetic corneal lesions. Among other interferonogens, the most widely used is the lipopolysaccharide of bacterial origin - pyrogenal. The literature presents data on the high efficiency of para-aminobenzoic acid (PABA) - actipol in patients with various forms of ophthalmic herpes with periocular administration and instillations.

Widely prescribed in the therapy of herpes infection in general, no less effective than Poludan, low-molecular inducer of interferonogenesis cycloferon is successfully used for ophthalmic herpes according to the following scheme: 250 mg once a day every other day for 7-10 days. Cycloferon normalizes the levels of serum interferon in the lacrimal fluid and blood serum. In another study, 18 patients with ophthalmic herpes were observed by an ophthalmologist, receiving complex therapy with cycloferon, 25 patients received traditional (BT) therapy. The results of treating patients with ophthalmic herpes with Poludan are presented for comparison. cycloferon was used according to the author's scheme: the drug was administered at 250 mg once a day, every other day, intravenously, for 7-10 days depending on the severity of the inflammatory process. The course dose was from 1250 to 2500 mg. Also, the introduction of CF was carried out by electrophoresis endonasally from the positive pole, every other day for 10 days.

Treatment of ocular herpes with CF had a positive effect in 94.4% of patients. Visual acuity increased in the group of patients receiving CF in 91.6% of cases, and in the control group of patients - in 3 people (12%). Thus, CF is quite effective in herpetic eye lesions (67.0-94.4% - superficial forms and stromal lesions of the cornea).

Thymalin, a complex polypeptide isolated from calf thymus, has proven itself well in the treatment of sluggish forms of ophthalmic herpes. It has interferonogenic properties, increases the interferon titer in the tear fluid to 20-40 U/ml, administered periocularly.

Today, the total number of immunocorrectors used in the complex therapy of ophthalmic herpes has exceeded two dozen. Levamisole was replaced by the powerful taktivin in injections, later by affinoleukin in injections and tablets of amixin and likopid. Amixin (a low-molecular inducer of interferonogenesis) reduces the treatment time, accelerates corneal healing, and has an antiviral effect. Amixin is prescribed according to the following scheme: the first two days, 250 mg (2 tablets), then 1 tablet every other day.

One of the very promising directions is the method of local auto-express cytokine therapy (LAECT), proposed by A.A. Kasparov.

The literature is still debating the importance of penetrating keratoplasty in the treatment of recurrent ophthalmic herpes. On the one hand, keratoplasty provides a certain anti-relapse effect due to the elimination of the active viral inflammation focus in the cornea, but does not completely protect the patient from subsequent relapses. On the other hand, in the postoperative period, long-term use of immunosuppressants cyclophosphamide and dexamethasone is necessary to prevent transplant rejection, which can provoke the development of a relapse of GC.

Prevention of ophthalmoherpes

An important aspect of the management of patients with ophthalmic herpes is the prevention of relapses. According to various authors, none of the currently existing methods of treating the acute period of ophthalmic herpes (medicinal and microsurgical) has a significant effect on the frequency of relapses. A.K. Shubladze, T.M. Mayevskaya in 1966 created an antiherpetic vaccine (PHV) based on the most common immunogenic strains of HSV isolated in our country. For the first time for the prevention of relapses of ophthalmic herpes, the antiherpetic vaccine was successfully used in 1972 by A.A. Kasparov, T.M. Mayevskaya in patients with frequently recurring ophthalmic herpes in the "cold period".

In order to increase the effectiveness of antiherpetic vaccination, it is possible to use PGV in combination with interferonogens (Poludan, Cycloferon, Pyrogenal, Actipol, Amiksin). Poludan and Actipol are used in instillations for 4-7 days, 2-3 times a day. It is recommended to start taking Amiksin simultaneously with PGV (1 tablet once a week) and continue after the end of the vaccination course as monotherapy.