| disease | Herpes Simplex Virus Keratitis |
Herpetic keratitis is currently the most severe common corneal disease, with a noticeable increase and worsening trend in recent years. Due to recurrent episodes and the rise in severe cases, it poses a significant threat to visual function. Therefore, strengthening research on this disease has become an urgent issue in ophthalmology.
bubble_chart Pathogenesis
HSV is highly contagious to humans. Among adults over 20 years old, the serum antibody positivity rate reaches 90%, while only 1-10% exhibit clinical symptoms. Primary infection occurs only in children with no immunity to the virus, mostly infants aged 6 months to 5 years. After primary infection, the virus remains latent in the body for life, waiting for an opportunity to reactivate. Secondary infections are more common in children over 5 years old and adults. Non-specific stimuli such as the common cold, fever, malaria, emotional stress, menstruation, sun exposure, corticosteroid use, nebula regression, and trauma can all serve as triggers for recurrence. According to Nesbarn and Green, the pathogenesis of this disease is roughly as follows:
1. Overt or latent infection: HSV spreads from tears to the cornea, conjunctiva, deep ocular tissues, and adnexa.
2. Neural latent infection: HSV travels from the trigeminal nerve endings along the nerve tract to the trigeminal ganglion cell nucleus, where it remains latent. The virus disappears from the surrounding tissues.
3. Reactivation of HSV in neurons: Under the influence of various provocative factors, the patient's systemic stability is disrupted, and the latent virus reactivates, traveling back along the nerve axons to the surrounding tissues.
4. Replication in surrounding tissues: The virus replicates in the surrounding tissues and spreads back into the tears.
5. Recurrence of keratitis.
6. Re-latency in neurons.
The exact mechanism of recurrence is not fully understood. In addition to factors related to HSV itself (type and strain) and latent infection, host-related factors also play a role, including the following:
1. Cellular immunity: Recent evidence suggests that humoral immunity does not play a significant role in the recurrence of stromal-type patients, as systemic antibody titers (IgM, IgG) show no significant changes. However, cellular immunity is lower than normal levels. Easty reported that lymphocyte transformation tests in stromal-type patients were significantly lower than in epithelial-type patients and healthy individuals. Centifan found that leukocyte migration inhibition tests in recurrent patients were also lower than in healthy populations. Kato Tomiko (1979) used five non-specific antigens for subcutaneous injection and observed delayed-type hypersensitivity reactions to assess cellular immune status. The results showed that over 98% of healthy individuals tested positive for three or more antigens, compared to only 71% of stromal-type patients, indicating a significant difference. Additionally, clinically, patients on long-term corticosteroids or immunosuppressants, or those with lymphocytic leukemia or multiple myeloma, are more prone to severe HSV keratitis, further supporting the idea that impaired cellular immunity is a major factor in recurrence.
2. Human leukocyte antigen (HLA): Recent studies suggest a certain association between this disease and HLA antigens. Zimmermann et al. found that the frequency of HLA-B4 was significantly higher in recurrent patients than in healthy individuals. The International Herpes Symposium noted that the frequency of DRW3 was 48% in stromal-type patients, compared to 24% in controls, showing a significant difference. Foster reported that HLA-A3 was significantly more common in frequently recurring patients, while HLA-B8 and B27 were also elevated (Grade I). In contrast, 80% of non-recurrent patients had HLA-A2. Thus, A3, B8, and B27 may be factors contributing to recurrence, while A2 may be protective against recurrence. However, research in this area is still in its early stages, with limited cases, and further validation is needed.3. Atopy Atopy is a type of hypersensitivity related to family lineage and reagin (mainly IgE). Statistics from Blndi, Michel, Denis, and others indicate that 37% of patients exhibit atopy, whereas only 10–15% of normal individuals do, showing a significant difference. Patients underwent desensitization therapy using extracts such as house dust mites and ticks. After 1–5 years of observation, clinical symptoms and recurrence rates were found to have decreased.
bubble_chart Clinical Manifestations
The clinical manifestations of this disease are complex. In addition to the typical dendritic, geographic, and disciform corneal lesion morphologies, there are also some atypical clinical changes, which make diagnosis and treatment very difficult. Each type not only has unique clinical features, but also differs in its pathogenesis and treatment principles. Moreover, the various types can transform into one another. The factors determining this transformation are highly complex, involving not only the type and strain of HSV and the host's immune function (primarily cellular immunity) but also the treatment methods (especially the use of corticosteroids).
1. Primary Infection Primary infection occurs only in individuals with negative serum antibodies, most commonly in children. Infants under 6 months can acquire antibodies against herpes simplex virus from their mothers via the placenta, so infections are rare. Later, as these antibodies gradually disappear, children aged 1–3 years are most susceptible. By age 5, 60% have been infected, and by age 15, over 90% have been infected.
⑴ Herpetic Eyelid Dermatitis Eyelid rashes form small blisters that dry up within a week, scab over, and fall off without leaving scars.
⑵ Acute Follicular Conjunctivitis The conjunctiva becomes congested and swollen, with follicular hyperplasia and even pseudomembrane formation.
⑶ Punctate or Dendritic Keratitis About two-thirds of patients with the above two symptoms may develop punctate or dendritic keratitis.
2. Recurrent Infection Individuals who have previously been infected with herpesvirus and have serum antibodies, whether experiencing their first episode or a recurrence under triggering factors, are considered cases of recurrent infection. The source of infection is mostly endogenous (i.e., the virus resides in the cornea, lacrimal gland, or trigeminal ganglion), though a minority may be exogenous.
⑴ Superficial Type This type involves the epithelium and superficial stromal layer and is the most basic, common, and easily diagnosed form of the disease. It includes dendritic keratitis and geographic corneal ulcer.
① Dendritic Keratitis This type results from direct HSV infection of epithelial cells. After the virus invades the epithelial cells, it causes cell proliferation, degeneration, and subsequent necrosis and sloughing, leading to epithelial defects. The epithelial cells at the edges of the lesion show active viral proliferation (i.e., intracytoplasmic inclusions), so the virus isolation rate can reach 90–100%.
The lesion appears dendritic, varying in size, with single or multiple branches. The ends or branch points show nodular swelling, with a width of about 1 mm, a slightly depressed center, and a grayish-white proliferative raised border. Under slit-lamp retroillumination, the raised border consists of fine gray-white granules. The lesion stains positive with fluorescein, which may diffuse into the surrounding subepithelial area. In the initial or atypical stages of dendritic keratitis, changes may include vesicular keratitis, punctate keratitis, stellate keratitis, or filamentary keratitis.
The course of the disease typically lasts weeks to months. Without other complications, 26–27% of cases may heal spontaneously, leaving no scars or only slight corneal nebulae. If the infection progresses deeper, it may evolve into a geographic corneal ulcer or disciform keratitis. Improper treatment or chronic persistence can lead to metaherpetic keratitis.
② Geographic Corneal Ulcer This develops from the expansion and deepening of dendritic keratitis. The epithelial cells at the ulcer edges show active viral proliferation, and the virus isolation rate is second only to dendritic keratitis.
The ulcer appears as an enlarged dendritic or irregular geographic shape with jagged edges and a distinct gray-white raised border. The ulcer base shows stromal edema and opacity, often accompanied by Descemet's membrane folds and anterior chamber flare.
What needs to be differentiated from geographic corneal ulcer are epidemic keratoconjunctivitis and other eye diseases that cause epithelial erosion. Slit-lamp retroillumination examination shows epithelial infiltration (+) at the marginal area in the former case and (-) in the latter.
After healing, most cases leave behind corneal nebula. If the condition progresses deeper, it may develop into a deep ulcer; epithelial healing with prolonged disease can lead to disciform keratitis; improper treatment may result in trophic ulcers.
(2) Deep Type: The lesion involves the deep stroma and endothelial layer, representing a complex form of the disease, including disciform keratitis, necrotizing stromal keratitis, deep ulcers, and keratouveitis.
① Disciform Keratitis: After the superficial lesion heals, chronic edema and infiltration persist in the stromal layer, leading to disciform keratitis. A few cases may develop directly. The exact pathogenesis remains unclear, with theories including direct viral infection, antigen-antibody reaction, and endothelial damage. Currently, the antigen-antibody reaction theory is more widely accepted. The stroma and endothelial cells, being mesodermal tissues, are less susceptible to herpes simplex virus than epithelial cells. Thus, the pathological changes are not due to cell proliferation or degeneration but rather a delayed hypersensitivity reaction to viral antigens. Disciform keratitis manifests as more stromal edema than infiltration, while necrotizing stromal keratitis results from continuous immune complex deposition in the stroma, complement activation, and massive neutrophil recruitment, causing more infiltration than edema, leading to tissue injury and dissolution. Viral isolation is rarely successful in these types, but electron microscopy may reveal viral particles in stromal cells.
Due to the characteristics of corneal circulation, a nearly disc-shaped gray-white opacity appears in the central or paracentral cornea, with blurred margins due to stromal edema, surrounded by an incomplete clear zone. The opacity has few new vessels, and the optical section shows significant thickening. Almost all cases exhibit Descemet's membrane folds. Fluorescein staining is negative. The active phase may be accompanied by epithelial edema and epithelial keratitis. Besides disciform opacity, other patterns include diffuse, localized, annular, and horseshoe-shaped opacities.
In disciform keratitis, 90% are caused by herpes simplex virus, while the remaining 10% may result from varicella-zoster, vaccinia, or mumps viruses. Differentiation requires history and viral isolation.
The prognosis for disciform keratitis is relatively good. In a few cases, after stromal edema subsides, annular or horseshoe-shaped opacities may remain. Chronic progression or long-term corticosteroid use can lead to herpetic degeneration.
② Necrotizing Stromal Keratitis: Clinically rare. Initially, dense gray-white patches and lumpy opacities appear in the edematous stroma, gradually expanding and merging, leading to tissue dissolution. The clinical and pathological changes closely resemble corneal graft rejection.
Necrotizing stromal keratitis is one of the most severe forms of the disease, with a very poor prognosis, often causing Descemet's membrane bulging, perforation, and iris prolapse.
③ Deep Ulcer: Evolves from improperly treated superficial lesions, worsened by corticosteroid abuse, further suppressing already low cellular immunity and inhibiting fibroblast, collagen, and mucopolysaccharide synthesis, leading to deep ulcer formation. Although the ulcer edge may show active lesions (intraepithelial infiltration), viral isolation is usually low. Immune function tests often reveal impaired cellular immunity.
The ulcer is located centrally or paracentrally, extending beyond half the stromal depth, with marked ciliary congestion. It loses the typical dendritic or geographic appearance, becoming round or oval, with radial folds around the ulcer. The base contains gray-white necrotic tissue, and severe cases may involve Descemet's membrane bulging, hypopyon, perforation, or mixed infection.
This type is easily confused with bacterial serpiginous corneal ulcers or fungal hypopyon corneal ulcers (especially in mixed infections). Differentiation requires history, smears, and culture tests.
The prognosis of this type is extremely poor. If left to its natural course, it often leads to extensive anterior synechiae, secondary glaucoma, endophthalmitis, and even the risk of losing the eyeball. Even if it barely heals with scarring, it will still result in blindness.
④ Keratitis and uveitis. These two types often coexist with iridocyclitis, hence termed keratouveitis. It may initially present with superficial damage before involving deeper tissues, or it may start in the deeper layers (iritis or endotheliitis) and then spread to the entire cornea. It has been confirmed that in some cases, viruses can be detected in the aqueous humor during episodes. Long-term topical use of corticosteroids may be one reason for the increased incidence of this type.
In addition to corresponding corneal changes, slit-lamp examination may reveal mutton-fat or large pigmented KP, hypopyon (occasionally hyphema), and elevated intraocular pressure. Nodules often form on the iris and pupillary margin, leaving gray-white depigmented spots after resolution.
Whether pure herpetic iritis exists remains controversial. This type is more commonly seen during influenza outbreaks.
Same as disciform keratitis or deep ulcer.
(3) Metaherpetic type. Although the lesion may involve the full thickness, it primarily affects the superficial layers, including chronic superficial keratitis and trophic ulcer.
Develops from superficial lesions or simple disciform keratitis, presenting a chronic course. It may be related to decreased corneal sensation, lacrimal gland abnormalities, injury to Bowman's membrane, or stromal inflammation. Recent studies emphasize a more direct association with unstable regeneration of epithelial basal cells, toxic reactions to antiviral drugs, and endothelial dysfunction. Therefore, long-term local misuse of corticosteroids and anti-herpetic drugs, as well as repeated use of cauterization and nebula-reducing therapies, are direct causes of this type. Viral isolation is rarely successful in this type. Immune function tests are mostly within the normal range.
① Chronic superficial keratitis. The morphology is variable, presenting as multiple epithelial erosions, filamentary keratitis, and microvesicular keratitis.
② Trophic corneal ulcer. Persistent epithelial erosions that repeatedly slough may progress to trophic corneal ulcers. These ulcers have sharply defined edges without raised margins of intraepithelial infiltration. They are round or oval with mild irritation symptoms, hence also called indolent ulcers.
This type was previously referred to as advanced-stage metaherpes, but it is not the final outcome of the disease. With accurate diagnosis and minimizing local irritants (including various medications) to promote epithelial repair, many cases can still achieve a favorable prognosis.
1. Clinical Diagnosis
(1) Basis for diagnosis of primary infection Mostly occurs in early childhood, rarely seen in adults. Ocular symptoms appear in only about 1% of cases. Main manifestations include herpetic vesicles, acute follicular conjunctivitis, and punctate keratitis. No scarring remains after healing, with occasional dendritic keratitis. Diagnosis mainly relies on serological tests.
(2) Basis for diagnosis of recurrent infection
① Typical corneal lesion morphology (dendritic, geographic, and disciform).
② History of multiple recurrences.
③ Slow disease progression, ineffective antibiotic treatment, corticosteroids worsen the condition.
④ Decreased or absent corneal sensation.
⑤ Presence of skin herpes at the corners of the mouth, eyelids, or alae nasi.
⑥ Specific recurrence triggers.
2. Laboratory Diagnosis
(1) Fluorescent antibody staining technique Collect infected cells from the lesion area or aqueous humor cells, and perform direct fluorescent antibody staining. Specific granular fluorescent staining can be found in the cytoplasm or nucleus of infected cells, enabling rapid diagnosis within 1–2 hours. Since labeled fluorescent antibodies are type-specific, type I or II viruses can also be distinguished under a fluorescence microscope.
(2) Virus isolation The most reliable method for etiological diagnosis. Methods include:
① Intracerebral inoculation in mice Most commonly used and most sensitive. Mice develop herpetic encephalitis and die within 2–3 days.
② Inoculation on chorioallantoic membrane of chicken embryos, or culture in various cell lines such as Hela, VERO, FL, and Hepz, all suitable for herpes virus propagation. Cytopathic effects occur within 24–48 hours, with obvious swollen round cell foci.
(3) Inoculation of scrapings onto rabbit cornea Has certain diagnostic value but is more costly.
(4) Cytological examination Scrapings from the cornea, conjunctiva, or eyelid vesicles are stained with HE to detect multinucleated giant cells, intranuclear inclusions, and ballooning epithelial cells. This method can only confirm viral infection but cannot distinguish HSV infection.
(5) Electron microscopy Viral particles can be detected in infected cells. This method is rapid and simple but cannot differentiate from varicella-zoster virus.
(6) Serological testing Measure neutralizing antibody titers in paired sera from the acute and convalescent stages. A fourfold or greater increase confirms the diagnosis. This method is only applicable to primary infections, as secondary infections already have high neutralizing antibody levels before onset, limiting its clinical utility.
(7) Immune function assessment Includes tests for humoral immunity (immunoglobulins) and cellular immunity, with increasing emphasis on the latter. Methods include the Rose flower test, lymphocyte transformation test, and leukocyte migration inhibition test. Some also use nonspecific antigens such as phytohemagglutinin (PHA), purified protein derivative (PPD), streptokinase-streptodornase (SK-SD), candidin, and parotin for intradermal injection to observe delayed cutaneous hypersensitivity. Although nonspecific, this method is simple and has some value.
(8) Other methods The fluorescein permeability coefficient is a new diagnostic method. Eighteen hours after iontophoresis of fluorescein into the eye, the aqueous humor content is measured with a fluorometer. This provides insight into corneal epithelial and endothelial function, particularly valuable for diagnosing herpetic keratitis.
bubble_chart Treatment Measures
1. Debridement of the Lesion: Primarily applicable to superficial cases. The principle involves removing infected cells and viruses through physical or chemical methods. Common methods include:
(1) Mechanical Debridement: After applying topical anesthesia, use a platinum spatula, blade, cotton swab, curette, or foreign body needle under a slit lamp to remove the ulcer along with 0.5 mm of surrounding healthy epithelium, followed by pressure patching for 48 hours. This method only removes infected cells and does not prevent viral replication, so it must be combined with antiviral eye drops for better therapeutic results.
(2) Chemical Debridement: After topical anesthesia, apply chemical disinfectants such as ether, ethanol, iodine, phenol, zinc sulfate, or silver nitrate with a cotton swab to the ulcer area, then rinse with saline. The goal is to detach infected epithelial cells through chemical action. However, this method may damage the corneal epithelial basement membrane and stromal layer, impairing healing and potentially worsening the lesion, so it must be used cautiously!
(3) Cryodebridement: Use a 2-mm cryoprobe with light pressure to freeze the ulcer edge first, then the center, typically at -60°C to -80°C. Freeze each spot for 6–8 seconds, then thaw with saline. Repeat if necessary. Although cryotherapy does not affect HSV activity, it destroys corneal epithelial cells more effectively than the above methods. Amoil suggests that ruptured epithelial cells release viral particles, which are then washed away by tears or neutralized by tear antibodies. Cryotherapy temporarily inhibits viral DNA activity and rapidly depletes ATP, the energy source required for viral replication.
(4) Photoinactivation Therapy: Instill 0.1% neutral red or 0.01% proflavine into the eye, then expose the affected eye to a fluorescent lamp at 15 cm for 15 minutes. The dye binds to viral DNA, causing breakage and inactivation.
2. Antiviral Drugs
(1) Idoxuridine (5-Iodo-2'-deoxyuridine, IDU; marketed as "Herplex" domestically): Like other antivirals, IDU is not viricidal but competes with enzymes to limit the incorporation of specific nucleotides into DNA. Its mechanism relies on its structural similarity to thymidine, partially inhibiting thymidine uptake and incorporating itself into viral DNA to create defective DNA, thereby suppressing viral replication.
Since Kautman (1962) first reported satisfactory results with IDU, numerous studies have evaluated its efficacy: ① IDU is 90% effective against epithelial dendritic keratitis, with 10% showing no response or recurrence. ② Average healing time is 6–8 days, leaving a thin, transient "ground-glass shadow" in the subepithelial layer for 1–2 weeks post-healing. ③ Alone, IDU is ineffective for simple disciform keratitis but works when combined with corticosteroids. However, corticosteroids should be avoided if there is epithelial injury. ④ IDU is ineffective against metaherpetic lesions, deep ulcers, necrotizing stromal keratitis, and keratouveitis, whether used alone or with corticosteroids.
The main disadvantages of idoxuridine are: ① It is prone to developing drug resistance (approximately 16–32% resistance). If clinical use exceeds 10 days without effect, other medications should be considered. ② Poor solubility and corneal permeability. Therefore, frequent application of a 0.1% solution is required to achieve effective tissue concentrations (50–100 μg/mL). The currently recommended regimen is hourly eye drops during the day, supplemented with a 0.1% ointment at bedtime or 0.1% ointment applied five times daily. ③ Topical application has certain toxic effects on ocular tissues, manifesting as eyelid allergic reactions, punctate epithelial keratitis, acute follicular conjunctivitis, drooping of the upper eyelid (blepharoptosis), and lacrimal punctum stenosis. ④ It is unstable in tissues, rapidly losing its halogenated groups and becoming ineffective. It also inhibits the activity of various corneal enzymes and protein synthesis, affecting corneal epithelial repair and delaying ulcer healing. ⑤ A 0.1% solution may cause teratogenic effects in pregnant rabbits. Although no such reports exist in humans, caution is warranted.
(2) Vidarabine (adenine arabinoside, abbreviated as Ara-A) Ara-A is an anticancer drug that was later found to have broad-spectrum antiviral activity against DNA viruses. It effectively counteracts HSV, chickenpox virus, cytomegalovirus, vaccinia virus, adenovirus, and others. Its metabolite, triphosphate, blocks 3–3.3%. Ara-A ointment applied five times daily is equally effective as 0.5% IDU ointment applied five times daily for treating superficial HSV keratitis. Abel reported that intravenous infusion (20 mg/kg/day) was effective in 505 cases of stromal keratitis combined with uveitis.
Based on foreign literature, its efficacy has been evaluated as follows: ① For cases resistant to idoxuridine (IDU) or those allergic to or intolerant of IDU due to toxicity, Ara-A may be effective. The reverse is also true. ② Local application has low toxicity and minimal immunosuppressive effects. ③ For cases worsened by corticosteroid use and unresponsive to IDU, switching to Ara-A may still be effective. ④ For deep stromal keratitis and keratouveitis cases, intravenous administration (20 mg/kg/day) is effective, with a treatment course of 1–3 months. The main drawbacks of Ara-A are its low solubility (maximum solubility of 0.5 mg/mL), limiting its local use to ointments or suspensions. Systemic injection requires a large fluid load, and intramuscular or subconjunctival injections of suspensions are highly irritating and prone to causing granulomas. Oral administration is ineffective. Therefore, its clinical application is significantly limited.
(3) Trifluorothymidine (abbreviated as F3T) is a new antiviral drug with a structure and mechanism of action similar to IDU. It is effective not only for superficial cases but also for deep stromal keratitis and keratouveitis. Wellings and Pavan-Langston reported that F3T is superior to IDU in treating superficial cases. Jones reported that it outperforms Ara-A in treating geographic corneal ulcers and is considered the best current treatment for this condition.
Current evaluations of this drug include: ① Its solution for superficial cases is faster-acting and has a higher cure rate compared to 0.1% IDU solution and 3% Ara-A ointment. ② Topical application causes no corneal toxicity or local allergic reactions. ③ It remains effective for cases resistant or unresponsive to IDU. ④ Its high solubility and excellent corneal penetration make it one of the most promising topical treatments for deep stromal keratitis and keratouveitis.
(4) Cyclocytidine (abbreviated as CC) is a cytosine-based antimetabolite. CC exerts its effects after being converted to cytarabine in the body. Our institute first discovered in 1972 its strong inhibitory effect on HSV in cell cultures. Subsequent clinical observations of 217 cases treated with 0.05% solution and ointment showed favorable results. Among them, 58 superficial cases showed no significant difference from the IDU treatment group, while 159 deep cases were significantly better than the IDU group. Compared to IDU, CC has advantages such as high solubility, low toxicity, good tissue penetration, resistance to deaminase degradation, and stable efficacy. It is one of the most widely used antiviral drugs domestically. Although clinically resistant cases have been encountered, some improved or were cured by increasing the frequency of eye drops or using subconjunctival injections (1–5 mg/0.1–0.5 mL daily). This aligns with our laboratory findings that CC-resistant strains still show significant antiviral effects at higher drug concentrations.
(5) Acycloguanosine (abbreviated as ACG) ACG is an antiviral drug containing purine nuclei, jointly developed by the latest research in the UK and the US. Tissue culture experiments have demonstrated its significant inhibitory effect on HSV (types I and II). Additionally, it also inhibits varicella-zoster virus, EB virus, and cytomegalovirus, but is ineffective against adenovirus and vaccinia virus. Its potency against HSV surpasses other antiviral agents, being approximately twice as effective as CC, 10 times as effective as IDU, 160 times as effective as Ara-A, and 15 times as effective as F3T. The exact mechanism of action is not entirely clear, but preliminary studies suggest the following: After ACG acts on HSV-infected cells, it is phosphorylated by the virus-specific thymidine kinase into monophosphate ACG, which is further converted into triphosphate ACG. This then deteriorates the viral DNA polymerase, inhibiting viral replication. ACG strongly inhibits viral DNA polymerase, with an effect approximately 10 to 30 times greater than on normal cellular DNA polymerase. Therefore, it is an antiviral drug that selectively inhibits viral DNA synthesis while exhibiting low toxicity.
Since Tones et al. first reported the significant efficacy of 3% ACG ointment in treating 24 cases of dendritic keratitis, Wilhelmus, Hikuma, and others (1981) have also reported similar findings. They used 3% ACG ointment to treat dendritic keratitis, achieving not only remarkable therapeutic effects with a shorter average cure time but also a lower recurrence rate after discontinuation compared to other antiviral drugs. Sun Bingji et al. (1983) treated 71 cases of various types with different concentrations and dosage forms of ACG, including 42 superficial cases. Even with low-concentration eye drops (0.1%), the efficacy was comparable to IDU and CC. They concluded that increasing the drug concentration has yielded encouraging results so far. ACG exhibits high selectivity for infected cells, minimal toxicity to the cornea, a low recurrence rate after discontinuation, and no cross-resistance with other antiviral drugs. This provides a new, highly effective, low-toxicity treatment option for clinical use, applicable both topically and systemically.
3. The Application of Corticosteroids
(1) The Harmful Effects of Corticosteroids on This Disease
① Impairment of the body's immune mechanisms: 1. Inhibition of B-lymphocyte release from regional lymph nodes to target organs, suppression or blockade of RNA and DNA or protein synthesis in small or medium lymphocytes, reducing antibody production. 2. Suppression of macrophage phagocytic function, weakening the ability of macrophages to process HSV antigens, allowing HSV to continue replicating. 3. Toxicity to immature T-lymphocytes and blockade of mature T-lymphocyte recirculation, significantly reducing mature T-lymphocytes in the blood. This causes greater damage to cell-mediated immunity, which is crucial for treating HSV keratitis, and diminishes the ability of various lymphokines (including macrophage inhibitory factor, lymphotoxins, interferon, etc.) to attack intracellular and extracellular viruses, enabling HSV to spread and worsen the condition. 4. Erosion of local immune mechanisms may lead to dual infections with fungi or bacteria.
② Damage to corneal tissue: 1. Topical application can increase corneal collagenase activity by 4–5 times, accelerating stromal dissolution and promoting ulcer expansion. 2. Inhibition of fibroblast regeneration in the corneal stroma and suppression of collagen fiber and mucopolysaccharide synthesis, hindering ulcer repair. 3. Long-term topical use may lead to dependency. After superficial corneal damage, the incidence of stromal keratitis and uveitis increases, potentially causing corneal softening and perforation.
(2) The Beneficial Effects of Corticosteroids on This Disease ① By inhibiting the release of histamine and toxic enzymes, they alleviate inflammatory reactions and tissue damage, reducing corneal scarring and neovascularization, thereby creating favorable conditions for corneal transparency recovery. ② By suppressing antigen-antibody reactions in the stromal layer, they reduce stromal edema and infiltration, significantly attenuating the inflammatory response in the stroma.
Thus, corticosteroids exhibit a clear duality in treating this disease, and their use must strictly adhere to the following principles.
1) Contraindicated in cases with epithelial damage or ulcers.
2) Temporarily avoid use in cases of unclear corneal diagnosis.
3) Must be combined with antiviral drugs.
4) Use the lowest concentration and minimal frequency of eye drops necessary to control inflammation.
5) Do not abruptly discontinue treatment; instead, gradually reduce the dosage after inflammation is controlled.
6) Remain vigilant for dual infections caused by compromised local immunity and consider adjunctive antibiotic or antifungal eye drops as needed.
4. The Application of Immunostimulants The use of immunostimulants to treat this disease is a relatively new therapeutic approach developed in recent years, still in the experimental stage. Reported agents in the literature include levamisole, polysaccharides from basidiomycetes, interferon, and its inducers.
⑴ Levamisole Levamisole is the levorotatory optical isomer of tetramisole, a broad-spectrum vermifugal medicinal. It has been proven to modulate cellular immunity, with the following characteristics: ① It can restore the functions of suppressed T lymphocytes and phagocytes to normal levels but does not elevate them beyond normal. ② It can elevate low cellular immune indicators. ③ It restores and enhances delayed-type cutaneous hypersensitivity reactions. ④ It promotes the migratory ability of polymorphonuclear leukocytes and monocytes. Levamisole has minimal or no effect on antibodies.
Both experimental and clinical studies have proven that it is ineffective for epithelial cases, but it has a good therapeutic effect on chronic stromal patients. Kato Tomiko et al. adopted an intermittent oral therapy (a course of treatment lasting 6 months, with continuous administration for 3 days per week in the first 3 months, 150 mg per day, divided into 3 doses; in the last 3 months, continuous administration for 3 days every other week, with the same dosage). Twenty-seven stromal cases were treated (before treatment, delayed-type skin tests confirmed that the cellular immune status was significantly lower than that of normal individuals). After one course of treatment, examinations showed not only a significant improvement in cellular immune status but also a 67% improvement in vision among patients clinically. Additionally, 92% of patients showed improvement in corneal edema, and the recurrence rate within one year dropped to 17% (generally around 30%). Since 1979, our institute has also adopted the above method to treat stromal patients but found the efficacy unsatisfactory, with some cases still worsening or recurring during treatment. The reasons may be related to the following factors: ①Case selection. ②Interference from other drugs, such as corticosteroids and CC eye drops, which may further reduce local cellular immune status. ③Irregular treatment, failure to adhere to timely medication, or further exploration of reasonable administration methods and doses, which are key to improving the therapy. Long-term use of this agent, apart from a few cases showing urticaria-like rashes, low-grade fever, or occasional leukopenia during the initial administration, has no other complications.
⑵ Basidiomycete polysaccharides: Polysaccharides extracted from basidiomycetes, like levamisole, have the ability to activate T cells and enhance immune function. Kato Tomiko et al. used polysaccharoid K (from Coriolus versicolor) to treat 13 stromal patients, with a method of 3 grams per day, divided into 3 oral doses, taken continuously for 3 to 14 months. After 3 months of treatment, not only was there a significant improvement in cellular immune function, but 83.3% of patients showed improved vision, and 87.5% showed improvement in corneal edema. The recurrence rate within one year dropped to 9%, with results similar to those of levamisole. Recently, the same researcher also used lentinan (from Lentinula edodes) to treat experimental HSV-induced stromal keratitis in rabbits, achieving good therapeutic effects.
⑶ Interferon and its inducers: Interferon is a protein produced by cells in response to stimulation by viruses, other microorganisms, or non-microbial agents. Overseas, the use of interferon to treat this disease has achieved good results. Fadeeva et al. used chicken embryo allantoic interferon and human leukocyte interferon as topical eye drops to treat 126 cases, achieving good results in 12 cases. Furer et al. used human leukocyte interferon as topical eye drops to treat 37 cases, achieving curative effects in 34 cases. Notably, patients who were unresponsive to IDU treatment still showed efficacy when switched to interferon. Recent studies on the combined use of interferon and antiviral drugs have achieved even higher efficacy. De Koning used human leukocyte interferon combined with F3T to treat dendritic keratitis, with an average cure time of 6.6 days, while the placebo group combined with F3T had an average cure time of 11.3 days, showing a significant difference. However, the effect of interferon is short-lived, and its high toxicity limits its potential for prevention and treatment of this disease. Nevertheless, some (such as Guevra et al.) have reported satisfactory therapeutic effects using 0.1% polyinosinic-polycytidylic acid (poly I:C) eye drops to treat this disease.
5. Surgical therapy: For severe cases (deep ulcers, necrotic stromal keratitis with perforation), relying solely on medication and conservative treatment is often ineffective. Surgical methods can not only shorten the treatment course and reduce suffering but also achieve better therapeutic outcomes. Surgical options include conjunctival flap covering, anterior chamber paracentesis, lamellar or penetrating keratoplasty.
⑴ Conjunctival flap covering technique. This method not only plays a preventive and therapeutic role in cases of impending perforation but also has certain positive therapeutic value for refractory deep ulcers. The covering conjunctival flap acts as a benign biological stimulus, which not only facilitates wound repair but also reduces friction between the wound and the eyelid as well as external irritation. The covering bulbar conjunctiva should be as thin as possible (without tearing) and firmly fixed. For cases where perforation has already occurred and the anterior chamber has disappeared, pressure bandaging should be applied postoperatively. Postoperative cases are unfavorable for subsequent corneal transplantation, so conjunctival flap covering should be avoided as much as possible for patients who are candidates for corneal transplantation.
⑵ Anterior Chamber Paracentesis This method is only suitable for patients with deep stromal type and keratouveitis. It can remove a large number of toxic substances and viral particles from the aqueous humor, facilitating the formation of new aqueous humor and providing greater defensive capabilities. Method: Use an Amsler needle to aspirate 0.2–0.5 ml of aqueous humor, then inject sterilized air. It is advisable to repeat the paracentesis at intervals of several days. Within a few days after the procedure, a reduction in corneal stromal edema, increased transparency, and shrinkage of endothelial and stromal necrotic foci can be observed.
⑶ Corneal Transplantation The use of corneal transplantation to treat this disease has been reported since the 1950s, with high evaluations of its therapeutic value. Some even consider it the best method for treating severe cases. For example, Hogan reported 27 eyes, with 25 achieving cure and only 4 experiencing recurrence. Ormsby reported success in all 25 eyes, with no recurrences. Fine reported 38 eyes, with inflammation controlled in 30 and recurrence in only 8. Domestically, Du Nianzu et al. reported 108 eyes, with an overall success rate of 76.8%, including 27 severe or perforated cases, of which 59.3% were successful. In recent years, we have also used corneal transplantation to save many eyes that were already blind or in extremely dangerous conditions.
For surgical indications and methods, refer to the section on therapeutic corneal transplantation.
6. Other Treatment Methods
⑴ Hydrophilic Soft Contact Lenses Primarily used for trophic corneal ulcers and cases at high risk of perforation. They protect the ulcer surface, reduce irritation, and promote epithelial regeneration. For early perforation cases, they also serve to seal the wound and act as a splint. If combined with antiviral eye drops, they provide a new drug delivery method by absorbing the medication.
⑵ Collagenase Inhibitors Topical collagenase inhibitors, though not directly effective against the virus, can reduce or prevent ulcer occurrence or progression by inhibiting collagenase activity. Commonly used drugs include 2% acetylcysteine and 2% sodium edetate.
⑶ Tissue Adhesives For cases of progressive melting or potential perforation, early local application of tissue adhesives can effectively halt ulcer progression and prevent perforation. The method involves cleaning the ulcer base under local anesthesia, removing necrotic tissue, applying a thin layer of adhesive, and allowing it to dry. Then, antibiotic ointment is applied, and the eye is bandaged or fitted with a hydrophilic soft contact lens. The adhesive is best retained for 6–8 weeks and removed after corneal healing.
