Herpes simplex virus keratitis is currently the most serious common keratoconus, and there has been a significant increase and intensification in recent years. Due to the recurrent attacks, the number of severe cases has increased, and the visual function is seriously threatened, so strengthening the research on this disease has become an urgent issue in ophthalmology.
Diagnosis
1.Clinical diagnosis
(1) Diagnostic basis of primary infection Most often occurs in early childhood, and is less common in adults. Only about 1% of the cases have ocular symptoms. The main manifestations are herpetic blisters, acute follicular conjunctivitis and punctate keratitis. There is no scarring after healing, and dendritic keratitis is occasionally seen. The diagnosis mainly relies on serological examination.
(2) Diagnosis of recurrent infection based on
(1) Typical morphology of corneal lesions (dendritic, map and disk).
②History of multiple recurrences.
(3) Slow disease course, ineffective antibiotic treatment, and worsening of the disease by corticosteroids.
④Sluggish or absent corneal sensation.
⑤ Skin herpes on the corners of the mouth, eyelids, and nose.
⑥Specific triggers for recurrence.
2.Laboratory diagnosis
(1) Fluorescent antibody staining technique, take the infected cells or atrial fluid cells in the lesion area and examine them directly with fluorescent antibody staining, specific granular fluorescent staining can be found in the infected cell pulp or cell nucleus, which can make a rapid diagnosis in 1 to 2 hours. Since the labeled fluorescent antibody has type specificity, it can also distinguish type I or type II virus under fluorescence microscopy.
(2) Virus isolation, which is the most reliable etiological diagnosis of the disease, was performed using the following methods.
(1) Intracerebral inoculation in mice, the most commonly used: the most sensitive. Mice died of herpes encephalitis within 2 to 3 days.
(2) Chicken embryo chorionic villus allantoic membrane inoculation, Hela, VERO, FL, Hepz and various other passaged cell cultures, all suitable for herpes virus propagation, cytopathic lesions occur in 24 to 48 hours, and obvious swollen round cell foci appear.
(3) Scrapings inoculated with rabbit corneas have some diagnostic value, but are economically costly.
(4) Cytological examination, scrapings from the cornea, conjunctiva or eyelid blisters for HE staining can reveal multinucleated giant cells, intranuclear inclusion bodies and wind-like epithelial cells. This method only confirms viral infection, but does not distinguish between HSV infection.
(5) Electron microscopy can detect virus particles in the infected cells. This method is quick and easy, but cannot be distinguished from herpes zoster virus.
(6) Serologic examination, take two copies of serum for neutralizing antibody potency in the acute and recovery periods, and confirm the diagnosis if there is a 4-fold increase or more. This method is only applicable to primary infections, secondary infections have high neutralizing antibodies in the blood before the onset of the disease, so the clinical application is not very valuable.
(7) The examination of immune function status, including the examination of humoral immune serum (immunoglobulin) and cellular immunity, especially the latter is getting more and more attention. The following methods are used: rose node test, lymphocyte transformation test and leukocyte movement inhibition test. Non-specific antigens such as phytohaemagglutinin (PHA), purified protein derivative (PPD), streptokinase-streptokinase (SK-SD), nematocystin, and parotoxin have also been used for intradermal injection to observe delayed cutaneous allergic reactions. This method is non-specific, but the method is simple and has some value.
(8) Other methods, fluorescein permeability system number is a new diagnostic method, fluorescein ion introduction into the eye 18 hours after the measurement of atrial fluid content with a fluorometer, to understand the function of corneal epithelium and endothelium has some value, especially for degenerative herpes more diagnostic significance.
【Treatment measures
1, lesion debridement: mainly applicable to superficial type cases. The principle is to remove the infected cells and virus by physical or chemical methods. Commonly used methods are.
(1) Mechanical debridement: After local point surface anesthetic, use a white multi-shovel, blade, cotton swab, restorer or foreign body needle to remove the ulcer together with its surrounding 0.5 mm healthy epithelium under slit lamp, after pressure including 48 hours. This method can only remove the infected cells, but cannot stop the virus from continuing to multiply, so it must also be treated with drops of antiviral drugs to achieve better treatment results.
(2) Chemical debridement: After point surface anesthesia, a cotton swab is dipped into ether, ethanol, iodine, carbolic acid, zinc sulfate, silver nitrate and other chemical inactivators, then applied to the ulcerated area and rinsed with saline. The purpose is to make the infected epithelial cells fall off by chemical cold. This method must be used with caution because of the possibility of damaging the basement membrane and stroma of the corneal epithelium, affecting the repair and prompting the lesion to develop deeper!
(3) Cryo-clearing: use a 2 mm diameter freezing head, with very light pressure to freeze the edge of the ulcer first, followed by freezing the center of the ulcer, the temperature is generally -60 ℃ to 80 ℃. Each point is frozen for 6-8 seconds, then thawed with saline and repeated several times if necessary. Amoil believes that the virus particles released by the rupture of corneal epithelial cells can be washed away by tears or neutralized by tear-listening antibodies. Cryopreservation of corneal lesions can temporarily inhibit the activity of viral DNA, but also rapidly reduce the supply of energy adenosine triphosphate needed for viral replication.
(4) light inactivation therapy, to 0.1% neutral red or 0.01% Prue yellow drops into the eye, and then 15 cm distance from the affected eye to receive ordinary fluorescent light for 15 minutes, the dye rice that binds to the virus DNA and break it, so as to achieve the effect of inactivation of the virus.
2.Anti-viral drugs
(1) iodoside (5-lodo-2′-deoxyuridine, IDU for short. domestic trade name “herpes net”) iodoside and other antiviral drugs are not virucidal, they can only be in the process of restriction and composition of special nucleotides into DNA until the competitive role with the enzyme. The mechanism of action of iodoside is to take advantage of its structural similarity to thymidine nucleosylation, and by partially inhibiting the uptake of thymidine nucleoside, to adulterate itself into viral DNA to produce pseudo-DNA in order to inhibit viral multiplication.
Since Kautman (1962) first used iodoside to treat this disease with satisfactory efficacy, there have been more reports at home and abroad, and the evaluation of its efficacy can be summarized as follows: ①Iodoside is effective in 90% of epithelial dendritic keratitis, and 10% have no response or recurrence. ②The average healing time is 6-8 days, and a thin and temporary “hairy glass-like phantom” remains under the epithelium at the original lesion 1 to 2 weeks after healing. (③) alone is not effective for simple discoid keratitis, combined with corticosteroids is effective. However, if there is skin damage, corticosteroids should not be used. ④It is ineffective for degenerative herpes, deep ulcers, stromal necrotizing keratitis and keratoconjunctivitis, either alone or in combination with corticosteroids.
The main drawbacks of iodoside are: ①resistance is easily developed (about 16-32% resistance), so if clinical use is ineffective for more than 10 days, you should consider switching to other drugs. ② Poor solubility and corneal permeability. Therefore, it is necessary to use 0.1% solution to frequently dab the eyes in order to make the tissues reach the effective concentration (50-100 micrograms/ml); the current recommended method is to dab the eyes once every hour during the day, and add 0.1% eye ointment once before bedtime or 0.1 eye ointment five times a day. ③Topical drops are toxic to ocular tissues, manifesting as eyelid allergic reactions, epithelial punctate keratitis, acute follicular conjunctivitis, ptosis, and lacrimal stenosis. ④It is unstable in tissues, quickly dehalogenated and becomes ineffective, and can inhibit the activity of various corneal enzymes and protein synthesis, affecting corneal epithelial repair and delaying ulcer healing. ⑤ 0.1% solution of eye spotting can cause malformations in pregnant rabbits, although humans have not been reported, it is worth warning.
(2) Adenine arabinoside (Ara-A) Ara-A is an anticancer drug, which was later found to have a broad-spectrum anti-DNA virus effect. It can effectively antagonize HSV, varicella virus, cytomegalovirus, cowpox virus, adenovirus, etc. Its metabolite triphosphate blocking 3 to 3.3% Ara-A ophthalmic ointment is comparable to 0.5% IDU ophthalmic ointment 5 times daily for the treatment of superficial HSV keratitis. Abel reported that intravenous drops (20 mg/kg/day) were effective in stromal cases 505 with combined uveitis.
The efficacy of Ara-A has been evaluated in the foreign literature as follows: (1) in ineffective cases resistant to iodoside, allergic to iodoside or intolerant due to moldiness, the application of Ara-A may be effective. The opposite is also true. ②Low toxicity and immunosuppressive effect of local application. ③In cases aggravated by the use of corticosteroids, iodoside treatment is ineffective, and Ara-A is still effective when used instead. ④In cases of deep stromal type and keratoconjunctivitis, static ocean (20 mg/kg/day) is effective for 1 to 3 months. the disadvantage of Ara-A is mainly its low solubility (maximum solubility 0.5 mg/ml). It can be applied topically only as an eye ointment or suspension. Systemic injection with a large liquid load, suspension for intramuscular injection or subconjunctival injection, irritation, easy to produce granulomas, and oral administration is ineffective. Therefore, the clinical application is greatly restricted.
(3) Trifluorothymidine (F3T) is a new antiviral drug, whose structure and mechanism of action are similar to those of iodoside. Wellings and Pavan-Langston reported that F3T was more effective than iodoside in treating superficial cases, and Jones reported that it was more effective than Ara-A in treating mapped corneal ulcers, which is considered to be the best drug for this disease.
The current evaluation of the drug is that: (i) the solution has the advantage of fast efficacy and high cure rate compared with 0.1% iodoside solution and 3% Ara-A ophthalmic ointment in treating superficial cases. ②There are no adverse reactions such as corneal toxicity and local allergy in topical eye spotting. ③It is still effective in cases that are resistant or ineffective to iodoside. ④Large solubility and good corneal permeability, it is one of the most promising topical drugs for the treatment of deep and corneal uveitis.
(4) Cyclocytidine (CC) is a cytosine antimetabolite. Cyclocytidine is converted into cytarabine in the body before it takes effect. In 1972, our institute first found that cyclocytidine had good HSV inhibition effect in cell culture tubes. Subsequently, 217 cases of each type were treated with 0.05% solution and eye ointment by clinical observation, and good results were achieved. Among them, 58 cases of superficial type were not significantly different from iodoside treatment group, and 159 cases of deep type were significantly better than iodoside treatment group. Compared with iodoside, this agent has the advantages of high solubility, low toxicity, good permeability, low anti-deaminase isolation in tissues and stable efficacy, which is one of the most widely used antiviral drugs in China. Although clinically ineffective drug resistance is also encountered, some of these cases increased the number of eye dots or the use of subconjunctival injection (1-5 mg/0.1-0.5 ml/day) and tended to improve the cure, which is consistent with the results of the CC-resistant strains seen in my laboratory in increasing the concentration of drugs can still produce a significant exchange of toxic effects.
(5) acycloguanosine (ACG) ACG is an antiviral drug containing purine nuclei, which is the latest joint research of Britain and the United States. In addition, it has inhibitory effect on herpes zoster, EBV and cytomegalovirus, but not on adenovirus and cowpox virus. Its effect on HSV is stronger than that of other antiviral agents, about 2 times that of CC, 10 times that of IDU, 160 times that of Ara-A and 15 times that of F3T. The mechanism of action is not yet clear, but according to preliminary research, it can be summarized as follows: ACG is phosphorylated by virus-specific thymidine nucleoside kinase after the action of HSV-infected cells, turning into ACG monophosphate, and further into ACG triphosphate, thus being bad for viral DNA polymorphase and inhibiting viral replication, which has a strong inhibitory effect on viral DNA polymorphase, about 10-30 times stronger than that on normal cell DNA polymorphase. It is a kind of antiviral drug that can selectively inhibit the synthesis of viral DNA with low toxicity.
Since Tones et al. first reported the remarkable efficacy of 3% ACG ophthalmic ointment in treating 24 cases of dendritic keratitis, Wilhelmus and Nikuma (1981) have also reported that they used 3% ACG ophthalmic ointment in treating dendritic keratitis, which not only had excellent efficacy and short average cure days, but also had a lower recurrence rate than other antiviral drugs after discontinuation of the drug. Sun Bingji et al. (1983) used different concentrations and dosage forms of ACG to treat 71 cases of various types, including 42 cases of superficial type, even with low concentrations of ophthalmic solution (0.1%) whose efficacy was similar to that of IDU and CC, and concluded that by increasing the concentration of the drug or so far, the results of ACG treatment of this disease are encouraging, which has a high degree of selectivity for infected cells, no toxicity to the cornea The recurrence rate is low after discontinuation of the drug, and there is no cross-resistance with other antiviral drugs, which provides a new drug with high efficiency and low toxicity for clinical treatment of this disease, which can be used both locally and systemically.
3.The application of corticosteroids
(1) The harmful effects of corticosteroids on the disease
(1) Damage the immune mechanism of the body: inhibit the release of B lymphocytes from regional lymph nodes to target organs, inhibit or block the synthesis of RNA and NDA or protein in small or medium lymphocytes, so that antibody formation is reduced; inhibit the phagocytic function of macrophages, so that the processing ability of macrophages for HSV antigens is weakened and HSV can continue to reproduce; poison immature T lymph and close the recirculation of mature T lymph, so that the blood This causes greater damage to cellular immunity, which is decisive for the treatment of HSV keratitis, and removes the ability of various lymphatic factors (including macrophage inhibitory factor, lymphotoxin, interferon, etc.) to b combat viruses inside and outside the cells, allowing HSV to spread and multiply, aggravating the disease; because local immune mechanisms can cause dual infection with fungi or bacteria due to the pinning down of local immune mechanisms.
② Damage to corneal tissue: local eye spotting can enhance the activity of corneal collagenase 4 to 5 times, so accelerate the dissolution of the stroma, prompting the ulcer to expand in depth; inhibit the regeneration of fibroblasts in the corneal stroma, inhibit the synthesis of collagen fibers and mucopolysaccharides, thus hindering the repair of the ulcer; long-term local application will also become addicted. After superficial corneal damage, stromal keratitis and uveitis will occur more often, even causing corneal softening and perforation.
(2) The beneficial effects of corticosteroids on this disease ① Because the release of histamine and toxic solution enzymes is inhibited, thus reducing a series of inflammatory reactions and tissue damage, also reducing corneal scar formation and angiogenesis, creating favorable conditions for the recovery of corneal transparency. ② The stromal inflammatory response process was significantly atrophied due to the inhibition of the antigenic response in the stroma and the reduction of stromal edema and infiltration.
The application of corticosteroids must strictly adhere to the following principles: it is prohibited in cases with epithelial damage or ulceration; it is not used temporarily in cases of corneal disease with unclear diagnosis; it must be applied together with antiviral drugs; the lowest concentration and the minimum number of drops that can control inflammation is the principle; the drug should not be stopped abruptly in treatment but gradually reduced after the inflammation is controlled; we should always be alert to the local Immune mechanism pinching caused by fungal or bacterial dual infection, with appropriate antibiotics and anti-mycotic drugs as appropriate.
4, the application of immune boosters, the application of immune boosters for the treatment of this disease, is a new treatment method gradually developed in recent years, is still in the trial stage. The literature reports the application of drugs levamisole, stretcher-like polysaccharide, interferon and its inducers, etc.
(1) levamisole, levamisole is the levo-optical isomer of tetramisole, a broad-spectrum anthelmintic, has been proved to have a regulatory effect on cellular immunity, and its characteristics are: (1) it can restore the function of suppressed T lymphocytes and phagocytes to normal level, but will not make it higher than normal. (2) It can raise the low cellular immunity index. (iii) Restores and enhances the delayed skin hypersensitivity response. ④Promotes the ability of polymorphonuclear leukocytes, monocytes to wander. Levamisole has little or no effect on antibodies.
It has been shown both experimentally and clinically to be ineffective in epithelial cases, while it does have better efficacy in patients with chronic stromal type. Tomiko Kato et al. used intermittent oral therapy (a course of 6 months, 150 mg per day in 3 divided doses 3 days a week for the first 3 months and 3 days every other week for the second 3 months). 27 stromal cases were treated (cellular immune status was demonstrated to be significantly lower than normal by a delayed skin test prior to treatment). When examined after one course of medication, not only did the cellular immune status improve significantly, but also 67% of the patients had clinically improved visual acuity. 92% of the patients had improved corneal edema, and the recurrence rate dropped to 17% within one year (generally about 30%). Our institute has also been treating stromal patients with the above method since 1979 and found that the efficacy was not satisfactory, and some cases were still aggravated or recurred during the treatment process. The reasons for this may be related to the following factors: ① case selection. ②Interference of other drugs, such as corticosteroids and CC dot eyes have the possibility of further decreasing the local cellular immune status. ③ Irregular treatment, failure to adhere to regular dosing, or further search for a reasonable dosing method and dosage is the key to improve therapy. Long-term use of this agent, except for a few cases of urticaria-like rash, hypothermia or occasional leukopenia during the initial administration, no other combined flat.
(2) Polysaccharides from tamariums, which are extracted from tamariums, have the same efficacy as levamisole in activating T cells and activating immune function. Tomoko Kato et al. treated 13 cases of stromal type patients with polysaccharoidk by taking 3 grams per day in 3 oral doses for 3 to 14 months. After 3 months of treatment, not only did the cellular immune function improve significantly, but also 83.3% of the patients’ visual acuity improved, 87.5% of the patients’ corneal edema improved, and the recurrence rate decreased to 9% within 1 year. The results were similar to those of levamisole. Recently, the mushroom polysaccharide (lentinan) has been used to treat experimental HSV keratoconjunctivitis in rabbits, and good therapeutic results have been received.
(3) interferon and its inducing agent, interferon is a protein that is produced when cells are stimulated by viruses or other microorganisms or non-microorganisms. Fadeeva et al. treated 126 cases with chicken embryo allantoic interferon and human leukocyte interferon topical spot eye treatment, combined with good results in 12 cases cured. 37 cases were treated with human leukocyte interferon topical spot eye treatment, Furer et al. also achieved 34 cases cured. It is particularly noteworthy that patients whose IDU treatment was ineffective were still effectively treated with interferon instead. Recent studies have achieved higher efficacy with the combination of interferon and antiviral drugs. de Koning used human leukocyte interferon in combination with F3T for dendritic keratitis, and the mean number of days of treatment cure was 6.6 days, compared to a mean of 11.3 days in the placebo combined with F3T treatment group, a significant difference between the two. For interferon and transient, coupled with high toxicity, there is little hope for prevention and treatment of this disease, but there are reports (Guevra et al.) of satisfactory results with 0.1% polymyxin dotted eye treatment for this disease.
5, surgical treatment: severe patients (deep ulcers, stromal necrotizing keratitis combined with perforation) rely on drugs and conservative treatment alone is difficult to achieve, the use of surgical methods can not only shorten the course of treatment to reduce pain, but also to achieve a better therapeutic effect. Surgery includes conjunctival flap masking, anterior chamber puncture, and lamellar or penetrating corneal transplantation.
(1) Conjunctival flap masking, this method is not only for cases of imminent perforation until the preventive and therapeutic effects, but also for stubborn deep ulcers have some extremely positive treatment value. The masked conjunctival flap acts as a benign biogenic stimulus that not only facilitates the repair of the trauma, but also reduces friction between the trauma and the eyelid and external irritation. The thinner the masked bulbar conjunctiva, the better (no rupture), and the fixation should be secure. For those who have perforated anterior chamber disappearance, postoperative pressure should still be added to include. Post-operative cases are unfavorable to the posterior corneal transplantation, so for those who are eligible for corneal transplantation should try not to make conjunctival flap cover.
(2) anterior chamber puncture, this method is only applicable to patients with deep stromal type and keratoconjunctivitis, can remove a large amount of toxic substances and viral particles in the atrial water, facilitate the formation of new atrial water, endowed with greater defensive capabilities. Method: Aspirate 0.2 to 0.5 ml of atrial fluid with an Amsler needle, then inject sterile air. Repeated punctures at intervals of several days are desirable. Corneal stromal edema is reduced, transparency is increased, and corneal endothelial and stromal necrotic foci are reduced several days after surgery.
(3) corneal transplantation, the use of corneal transplantation for the treatment of this disease, from the 1950s onwards, has been reported, its therapeutic value is highly evaluated, and even considered to be the best way to treat severe cases. For example, Hogan reported that 25 out of 27 eyes were cured and only 4 eyes recurred, Ormsby reported that 25 eyes were successful and none of them recurred, Fine reported that 30 out of 38 eyes were able to control the inflammation and only 8 eyes recurred. In China, Du Nianzu et al. reported 108 eyes with a total success rate of 76.8%, including 27 eyes with severe disease or perforation, which also had 59.3% success. In recent years, we have used corneal transplantation to save many eyes that had fallen into blindness or were in a very dangerous situation.
For more information about the indications and surgical methods, please refer to the section on therapeutic corneal transplantation.
6.Other treatment methods
Hydrophilic soft contact lenses, mainly used for dystrophic corneal ulcers and cases that are prone to perforation. It protects the ulcer wound, reduces irritation, and facilitates epithelial regeneration. In cases of early perforation, it also has the effect of occluding the wound with a splint. If an antiviral drug is administered at the same time, it provides a new method of drug delivery because of its ability to absorb drugs.