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Herpetic Simplex Immune Stromal Keratitis: Case Report, Review and Treatment By: Previous candidate. Actual case report submission ----------------------------- Abstract Purpose. To present a case study and discussion on the management of Herpes Simplex Virus Immune Stromal Keratitis. Case Report. A 57-year-old white female presented to the office complaining of a painful red eye. She was treated with topical Pred Forte (1% prednisolone acetate), which alleviated the acute symptoms, but after years of recurrences, found that oral Zovriax (acyclovir),was the most effective treatment to prevent outbreaks and decrease scarring. Conclusions. HSV Immune Stromal keratitis is an immune- mediated process, and is best treated with topical corticosteroids, with oral antiviral prophylaxis. The most important findings of HEDS were that use of topical corticosteroids shortened the course of HSV stromal keratitis, and prophylactic treatment with oral acyclovir decreased the risk of recurrent HSV ocular infection by 41%, which was evident in this case. Key Words: Immune Stromal Keratitis, Acyclovir, Herpes Keratitis Introduction The word herpes is derived from the Greek word meaning “to crawl,” because of the serpiginous nature of herpetic lesions.1 They are ubiquitous human pathogens capable of causing both asymptomatic infection and active disease in a wide variety of end organs. Herpes viruses affecting humans include herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella zoster virus (VZV), cytomegalovirus, and Epstein- Barr virus.1,2 These double- stranded DNA viruses have a viral derived capsid enclosed in a host cell–derived envelope with viral- derived glycoprotein projections. Although HSV-1 usually involves the oropharynx and HSV-2 usually involves the genital area, both types can infect either location. Typically, ocular disease is caused by type 1 rather than type 2, with the exception of herpetic keratitis in neonates, in which 75% is caused by HSV-2.3 Primary infection can be either asymptomatic or active and is followed by a latent state of nonreplication characteristic of herpesviruses.4 HSV is capable of causing severe primary disease in children and neonates and has been known to cause a variety of ocular diseases in addition to oral-facial infections, encephalitis, meningitis, myelitis, erythema multiforme, hepatitis, and disseminated infection resulting in death.4 More common infections include recurrent herpes labialis caused by HSV-1, which occurs in 20–45% of the world population, and herpes genitalis caused by HSV-2, which causes an estimated 100 000 new cases each year in the United States, with an increasing seroprevalence, estimated at 21.9% in the last NHANES (National Health and Nutrition Evaluation Survey).5 A longitudinal study by Liesegang et al. extrapolated data to an estimated 20 000 new cases of ocular HSV in the United States per year and between 40 000 – 60 000 episodes annually.1,6 HSV infection remains a serious public health problem associated with significant morbidity and mortality. Case Report Initial Visit 7/26/10 - Nancy H, a 57-year-old white female presented complaining of a painful left eye that was extremely sensitive to light. Her ocular history was remarkable for an “infection” about a year earlier in that same eye, that needed prescription eye drops to clear it up. Her medical history was significant for menopause. Her family history was remarkable for glaucoma (father and 8 of his siblings). Her medications include Premarin (conjugated estrogen), and she reported no known medical allergies. Best corrected visual acuity was 20/20 OD, OS. Pupils, extraocular muscles and confrontation fields were intact. The right anterior segment was clear. The left conjunctiva showed 1+ injection. The left cornea showed a focal area of stromal infiltration inferior to the visual axis surrounded by stromal cell and edema. There was no evidence of an epithelial break, and the cornea did not stain with fluorescein. There appeared to be some scarring on the cornea, perhaps from the previous event. There were no keratic precipitates on the endothelium. The anterior chamber had Trace-1+ cell. She was dilated with 1% tropicamide and the posterior segment showed no signs of inflammation OU, with cup to disc ratios at .3 /.3 OD, OS. Corneal sensitivity testing was reduced on the left eye using waxed dental floss. Tonometry by applanation was 16mmHg OU using Fluress. NH was diagnosed with HSV Immune Stromal Keratitis OS. Treatment prescribed consisted of topical Pred Forte (1% prednisolone acetate) every two hours, and oral Zovirax (acyclovir) 400mg BID to prevent epithelial breakthrough and to start preventative treatment. She was scheduled to return to the office in 2-3 days. 7/29/2010 – NH followed up stating things felt better and that she was not as sensitive to light, and overall feeling much much better. Best corrected visual acuity was 20/20 OD, OS. The right anterior segment was clear. The left conjunctiva showed trace injection. The left cornea showed reduced stromal infiltration inferior to the visual axis and much less stromal cell and edema. There was no evidence of an epithelial break, and the cornea did not stain with fluorescein. There was definite evidence of previous scarring on the cornea. There were no keratic precipitates on the endothelium. The anterior chamber had no cell. She was dilated with 1% tropicamide and the posterior segment showed no signs of inflammation OU, with cup to disc ratios at .3 /.3 OD, OS. Tonometry by applanation was 17mmHg OS using Fluress. NH was diagnosed with Resolving HSV Immune Stromal Keratitis OS. Treatment prescribed consisted of tapering topical Pred Forte (1% prednisolone acetate) every four hours for an additional 4 days (for 1 week total), then QID x 1 week, TID x 1 week, BID x 1 week, QD x 1 week and QOD x 1 week and stop. She was continued on oral Zovirax (acyclovir) 400mg BID as preventative. She was scheduled to return to the office in 3-4 weeks. When she returned all inflammation was resolved, and she was continued on oral Zovirax 400mg BID to prevent additional flare ups that could create more scarring and loss of vision. She was educated on the potential triggers and told to follow up immediately if she experienced any difficulties. 5/9/2011 - NH followed up for a routine exam stating things had been feeling fine and that it was almost a year, and would really like to get off the oral medication. Best corrected visual acuity was 20/20 OD, OS. The right anterior segment was clear. The left conjunctiva was clear. There was definite evidence of stromal scarring on the cornea inferior to the visual axis. There were no keratic precipitates on the endothelium. She was dilated with 1% tropicamide and the posterior segment was clear OU, with cup to disc ratios at .3 /.3 OD, OS. Tonometry by applanation was 18mmHg OU using Fluress. NH was diagnosed with a History of HSV Immune Stromal Keratitis OS (quiescent at this visit). Ongoing treatment was discussed at length, and NH made a strong case for discontinuing oral treatment (i.e., she was stopping regardless). She was educated on the potential triggers and told to follow up immediately if she experienced any difficulties and told to follow up for routine care. 6/24/2011 – Approximately two months of discontinuing the oral Zovirax, NH returned to the office complaining of a painful left eye that was extremely sensitive to light. Best corrected visual acuity was 20/20 OD, OS. Pupils, extraocular muscles and confrontation fields were intact. The right anterior segment was clear. The left conjunctiva showed 1+ injection. The left cornea showed a focal area of stromal infiltration inferior to the visual axis, but just superior to the previous bout, surrounded by stromal cell and edema. There was no evidence of an epithelial break, and the cornea did not stain with fluorescein. There was also evidence of neovascularization inferior to the scarring. There were no keratic precipitates on the endothelium. The anterior chamber had Trace cell. She was dilated with 1% tropicamide and the posterior segment showed no signs of inflammation OU, with cup to disc ratios at .3 /.3 OD, OS. Tonometry by applanation was 16mmHg OU using Fluress. NH was diagnosed with Recurrent HSV Immune Stromal Keratitis OS. Treatment prescribed consisted of topical Pred Forte (1% prednisolone acetate) every two hours, and she was restarted on oral Zovirax (acyclovir) 400mg BID to prevent epithelial breakthrough, and to restart preventative treatment. She was scheduled to return to the office in 2-3 days. When she returned, the HSV Immune Stromal Keratitis was responding nicely to treatment. The Pred Forte (1% prednisolone acetate) was then tapered to QID x 1 week, TID x 1 week, BID x 1 week, QD x 1 week and QOD x 1 week and stop. The oral Zovirax (acyclovir) 400mg BID was continued to prevent additional flare ups that could create more scarring and loss of vision. She was scheduled to return to the office in 3-4 weeks. 2/20/2012 - Approximately eight months later, NH returned to the office complaining of a painful left eye that was sensitive to light. She reported that she had not been terribly compliant with the oral Zovirax lately. She also reported that she had already started the Pred Forte that morning, and had been using it every two hours OS. Best corrected visual acuity was 20/20 OD, OS. Pupils, extraocular muscles and confrontation fields were intact. The right anterior segment was clear. The left conjunctiva showed 1+ injection. The left cornea showed a focal area of stromal infiltration inferior to the visual axis, but again superior to the previous bouts, surrounded by stromal cell and edema. There was no evidence of an epithelial break, and the cornea did not stain with fluorescein. There was also distinct evidence of previous scarring and neovascularization (see picture below). There were no keratic precipitates on the endothelium. The anterior chamber had Trace cell. She was dilated with 1% tropicamide and the posterior segment showed no signs of inflammation OU, with cup to disc ratios at .3 /.3 OD, OS. Tonometry by applanation was 17mmHg OU using Fluress. NH was diagnosed with Recurrent HSV Immune Stromal Keratitis OS. Treatment prescribed consisted of topical Pred Forte (1% prednisolone acetate) every two hours, and she was instructed to make sure she used the oral Zovirax (acyclovir) 400mg BID, not only to prevent epithelial breakthrough, but to prevent additional flare ups that could create more scarring and loss of vision. She was scheduled to return to the office in 2-3 days. When she returned, the HSV Immune Stromal Keratitis was responding nicely to treatment. The Pred Forte (1% prednisolone acetate) was then tapered to QID x 1 week, TID x 1 week, BID x 1 week, QD x 1 week and QOD x 1 week and stop. The oral Zovirax (acyclovir) 400mg BID was continued as a preventative therapy. She was scheduled to return to the office in 3-4 weeks. 1/28/2014 – NH followed up for a routine exam stating things had been feeling fine and that it was almost two years since she had a flare up. She had been very compliant with the oral Zovirax and was taking 400mg BID as prescribed. Best corrected visual acuity was 20/20 OD, OS. The right anterior segment was clear. The left conjunctiva was clear. There was definite evidence of stromal scarring and neovascularization on the cornea inferior to the visual axis. There were no keratic precipitates on the endothelium. She was dilated with 1% tropicamide and the posterior segment was clear OU, with cup to disc ratios at .3 /.3 OD, OS. Tonometry by applanation was 18mmHg OU using Fluress. NH was diagnosed with a History of HSV Immune Stromal Keratitis OS (quiescent at this visit). Ongoing treatment was discussed at length. The oral Zovirax (acyclovir) 400mg BID was continued to prevent additional flare ups that could create more scarring and loss of vision. She was educated on the potential triggers and told to follow up immediately if she experienced any difficulties and told to follow up for routine care. Summary of treatment: Visits 7/26/10 Treat ment Plan: HSV Immune Stromal Keratitis flare up HSV Immune Stromal Keratitis Resolving Pred Forte Q2H OS Pred Forte Taper QID OS x 1 week, reducing by drop a week Started Zovirax 400mg BID PO – Antiviral coverage during steroid tx and begin preventative 7/29/10 Cont Zovirax 400mg BID PO – long term preventative 5/9/11 6/24/11 H/O HSV Immune Stromal Keratitis Quiescent HSV Immune Stromal Keratitis flare up (2 mo off Zovirax) Zovirax. Almost year w no flares. Pt would like to D/C, so stopped Pred Forte Q2H OS Re-Started Zovirax 400mg BID PO – Antiviral coverage during steroid tx and restart preventative Visits 2/20/12 Treat ment Plan: HSV Immune Stromal Keratitis flare up (reports noncompliance with Zovirax) Pred Forte Q2H OS Edu on need for Continued Zovirax 400mg BID PO – Antiviral coverage during steroid tx and preventative 1/28/14 H/O HSV Immune Stromal Keratitis (Quiescent) Continue Zovirax. Almost two year w no flares. Pt reports good compliance with meds Discussion Life Cycle Humans are the only natural reservoir of HSV despite experimental models using other hosts. 2 Close personal contact is thought to be necessary for the spread of HSV because of the physical instability of the virus and the fact that the major portals of entry are the mucous membranes and external skin. Initial end-organ infection can be asymptomatic and unrecognized, and is followed by latency in sensory ganglia. In fact, primary infection manifests clinically in only 1– 6% of people infected with the virus.1,2 The oral route can provide access to the trigeminal ganglion and subsequently the eye.2 Because many patients with HSV infection do not have definitive contact with a source, it has been suggested that asymptomatic shedding of virus is an important source of transmission.2 In addition, clinical appearance of an infection may represent earlier primary infection at a different end organ. Therefore, what appears to be a primary ocular infection may indeed be an attack in a new end organ within a previously infected host. The time between contact and disease is typically between 3 and 9 days. After peripheral entry into the host and primary infection with viral replication within an end organ, HSV travels in a retrograde fashion to various ganglia including the trigeminal, cervical, and sympathetic gangliae, and possibly the brain stem.2 Here it resides during the lifespan of the host. This process usually begins within 1 to 2 days of the primary infection and may take several weeks to complete.2 Despite an early immune response by the host, ganglionic infection occurs rapidly and does not require virus replication. Once ganglionic presence has been established, active replication in neurons and surrounding cells leads to cell death. It has been suggested that virus replication within the trigeminal ganglion is of paramount importance for viral spread to sites other than the inoculation site. Regardless, latency can be established and is thought to represent the presence of the viral genome within the neuronal cells. 7 The cornea itself has also been found to host latent HSV virus, with potential for reactivation. Primary HSV Infection - Primary HSV ocular infection is frequently missed and rarely affects the cornea. The most common pattern of infection is blepharoconjunctivitis that heals without scarring. The associated follicular conjunctivitis is often mistaken for adenoviral conjunctivitis. However, unilateral, nonepidemic follicular conjunctivitis should always make one suspect HSV, as studies have shown at least 25% of such cases to be culture- positive for HSV.1 In rare instances, especially in patients with severe eczema or other immunocompromised states, this usually innocuous infection can become life threatening. Recurrent HSV Infection - Once the primary infection resolves, the virus becomes latent and remains in this state until certain triggers, such as fever, sunlight exposure, stress, and menses, cause it to reactivate, multiply, and travel back down the nerve to cause recurrent infection. It is uncertain whether ocular recurrences are caused by virus that initially infected ocular tissues or by “back-door spread,” via the trigeminal ganglion, from an initial oral infection.2 HSV utilizes cellular enzymes for replication and the cell dies when it is released from the cell. The loss of ganglion cells with recurrent infections leads to decreased corneal sensation, one of the hallmarks of HSK. Recurrent HSV infection most frequently involves the cornea, although all parts of the eye can be affected concurrently or independently. HSV can cause retinitis, trabeculitis, uveitis, and optic neuritis. Classification From a diagnostic and therapeutic perspective, HSV keratitis is one of the most challenging entities to diagnose. A variety of clinical manifestations of not only infectious keratitis, but also immunologic disease can affect all levels of the cornea. Corneal disease includes infectious epithelial keratitis, neurotrophic keratopathy, immune stromal (interstitial) keratitis, necrotizing stromal keratitis, and endotheliitis.2 Understanding the anatomic basis for this classification may give a clearer picture of the pathophysiology and treatment of the disease. HSV Epithelial Disease These forms of keratitis are usually caused by actively replicating virus. The most commonly recognized clinical manifestations of infectious epithelial keratitis are the dendritic and geographic ulcers. Corneal vesicles and marginal keratitis are less common and may go unrecognized as active infections. Most patients with infectious epithelial keratitis complain of photophobia, pain, and a thin, watery discharge; those with central lesions also may present with decreased vision. Corneal Vesicles are the earliest epithelial lesions of reactivated HSV. They are small vesicles in the epithelium, which have been described as punctate epithelial keratopathy (PEK). Careful examination of these lesions demonstrates minute, raised, clear vesicles that correspond to the vesicular eruptions seen in the skin or mucous membranes elsewhere in the body. These lesions are important to recognize. Typically, within 24 hours, the vesicles coalesce to form the typical dendritic and geographic ulcers, unless immunocompromised , then they could remain.1,2,4 Dendritic ulcer is the most common and classic herpetic corneal lesion that is caused by replicating virus. These lesions are linear and dichotomously branching, with each branch terminating with a bulb. The borders of the lesion are slightly raised and grayish and consist of HSV- infected cells that stain with rose bengal (RB) dye. These HSV- infected cells have undergone balloon degeneration. In contrast, the center of the lesion is devoid of cells and stains with fluorescein. This lesion represents a true ulcer in that it extends through the basement membrane. This clinical feature is important to recognize because it aids in differentiating a true dendritic ulcer from the many other branching lesions of the corneal epithelium.1,2,4 The underlying stroma has minimal inflammation. After dendritic epithelial keratitis resolves, a dendritic scar, called a ghost dendrite, may remain in the superficial stroma. Geographic ulcer is similar to a dendritic ulcer, and is also caused by replicating virus, but has a much larger epithelial defect. As it progresses, the ulcer loses its dendritic shape and takes on a form that often resembles the shape of a country—hence the term geographic. Like a dendritic ulcer, it is a true ulcer in that it is an epithelial lesion that extends through the basement membrane. This presentation usually occurs in persons with compromised immunity, especially patients taking topical corticosteroids. It can also occur in individuals who have untreated, long standing originally dendritic ulcers, in which case it can be hard to distinguish from a trophic ulcer. The dichotomous branching and terminal bulbs of the geographic ulcer, which are seen peripherally, however, often distinguish it from a trophic ulcer. Marginal keratitis lesions are located near the limbus and can resemble staphylococcal catarrhal ulcers. They tend to have more underlying stromal inflammation and tend to be more resistant to treatment. Also, they are more likely to become a trophic ulcer. These lesions result from active viral disease like that of the dendritic ulcer. However, the proximity of this lesion to the limbus, with its accompanying blood vessels, accounts for the unique clinical features. The epithelial lesion is quickly infiltrated with white blood cells from the nearby limbal blood vessels. The resultant lesion typically seen on presentation has an anterior stromal infiltrate underlying the ulcer and adjacent limbal injection. Careful inspection may show a dendritic ulcer overlying the stromal infiltrate. Marginal ulcers are typically more symptomatic than those with central dendritic ulcers, because of the intense inflammation associated with the marginal lesion.1,2,4 Neurotrophic or metaherpetic ulcers are the only form of epithelial ulceration that does not have any live virus. The ulcer is called trophic if it arises de novo and metaherpetic if it follows a dendritic or geographic ulcer, although the terms are frequently used interchangeably.1,2 Patients who have had infectious epithelial keratitis are at risk to develop neurotrophic keratopathy. This clinical entity is unique because it is neither immune nor infectious. Rather, it arises from impaired corneal innervation in combination with decreased tear secretion. The keratopathy may be exacerbated by chronic use of topical medications, especially antivirals. Although neurotrophic ulcers are difficult to differentiate from geographic ulcers, they can be distinguished by their smooth, gray, elevated borders that do not stain with RB. The RB dye stains the unhealthy epithelial cells attempting to migrate across the base of the ulcer, whereas fluorescein leaks through these poorly adherent cells into the stroma and stains the periphery so called reverse staining.1,2,4 HSV Stromal Disease This form of keratitis is usually an immune- mediated response to nonreplicating viral particles, but more severe forms may be caused by live virus. Although stromal disease accounts for approximately 2% of initial episodes of ocular HSV disease, it accounts for 20–48% of recurrent ocular HSV disease. The clinical course of immune stromal keratitis is chronic, recurrent inflammation that can persist for years. Patients may experience constant low-grade inflammation with mild fluctuations in severity. Other patients may have periods of complete resolution of inflammation with intermittent flare-ups of severe inflammation. Long-term topical corticosteroids may be required to suppress the inflammatory reaction of immune stromal keratitis. Some patients are exquisitely sensitive to mild reductions in topical corticosteroid. Untreated or undertreated inflammation can lead to stromal scarring, thinning, persistent neovascularization, lipid deposition, and severe loss of vision.1,2,4 The corneal stroma may be affected in HSV disease through a variety of mechanisms, either primarily or secondarily. Primary manifestations occur in two varieties, necrotizing and immune mediated. Necrotizing stromal keratitis occurs from direct viral invasion of the stroma, whereas immune stromal keratitis is the result of an immune reaction within the stroma. Secondary involvement may occur as a sequela to infectious epithelial keratitis, neurotrophic keratopathy, or endotheliitis.1,2,4,8 When stromal involvement occurs secondarily to infectious epithelial keratitis, neurotrophic keratopathy, or endotheliitis, the source of inflammation is in the epithelium or endothelium, and treatment must be focused toward the proper origin of inflammation if stromal injury is to be minimized. Necrotizing stromal keratitis is a rare manifestation of HSV that is thought to result from direct viral invasion of the corneal stroma. The clinical findings are necrosis, ulceration, and dense infiltration of the stroma with an overlying epithelial defect. The combination of replicating virus and severe host inflammatory response leads to destructive intrastromal inflammation that is often refractory to treatment with high-dose anti-inflammatory and antiviral medications. The severe inflammation may lead to thinning and perforation within a short period of time. The clinical findings of necrotizing stromal keratitis may resemble those of infectious keratitis secondary to microbial invasion.1,2,4 Therefore, bacterial and fungal pathogens must be considered when treating for necrotizing stromal keratitis. The use of topical corticosteroids without antiviral coverage has been implicated as a possible risk factor. Immune stromal keratitis on the other hand is a common chronic recurrent manifestation of HSV, occurring in 20% of patients with ocular HSV.1.2.4 Additional studies have reported the incidences of stromal disease of 21% within 2 years and 26% - 48% within 7 years of infectious epithelial keratitis.2,9,10 The inflammation is thought to be due to retained viral antigen within the stroma. This antigen triggers an antigen-antibody-complement (AAC) cascade that results in intrastromal inflammation.1.2.4 Molecular mimicry has been linked with activation of T-cellmediated autoimmune responses in murine models. Stromal infiltration is the most common finding in recurrent immune stromal keratitis and can present as punctate stromal opacities that most likely represent AAC immune complexes. The overlying epithelium is almost always intact except in the situation of combined infectious epithelial keratitis and immune stromal keratitis. In the acute phase, these opacities may be accompanied by haze that is indicative of inflammatory cellular infiltrate of the stroma. The haze and punctate lesions may become permanent opacities. The pattern of stromal inflammation may be focal, multifocal, or diffuse.1,2,4 Stromal infiltration is often accompanied by anterior chamber inflammation, ciliary flush, and significant discomfort. Stromal edema also can accompany this reaction. The edema most likely results from the consequences of stromal inflammation rather than endothelial dysfunction. Severe inflammation can lead to dense infiltration with subsequent scarring and profound visual loss. Vision loss from HSV immune stromal keratitis is the main reason that 3% of all penetrating keratoplasties have been performed in the United States in recent years. A specific form of stromal infiltration secondary to HSV is the immune ring. This ring is also thought to be an AAC precipitate similar to a Wessely ring. It can form an incomplete or complete ring and can be singular or multiple.2 It is most commonly found in the mid stroma of the central or paracentral cornea. Another finding of immune stromal keratitis is stromal neovascularization.1,2 Neovascularization may occur at any level of the cornea. In some cases of severe inflammation, there can be rapid neovascularization with multiple fronds of new vessels associated with intense infiltration. This rapid neovascularization can range from sectoral, with a single frond of vessels, to complete, involving all quadrants of the cornea. Neovascularization also can progress in a subacute or chronic fashion in response to persistent, low-grade stromal inflammation. The neovascularization in these less acute cases tends to be sectoral rather than circumferential. Aggressive treatment of inflammation can result in complete resolution of the blood vessels. Ghost vessels, which represent empty vessel channels within the stroma, can occur if the inflammation and neovascularization is long-standing before it is quieted. If ghost vessels are present, there is typically significant accompanying stromal scarring and thinning because of the chronicity of the inflammation. Lipid keratopathy can follow stromal neovascularization and can lead to further scarring and loss of vision. A more serious sequela of stromal neovascularization is permanent neovascularization of the cornea, which will decrease the success rate of penetrating keratoplasty because of increased risk of rejection Immune stromal keratitis may present days to years after an episode of infectious epithelial keratitis. In some cases, there may be no history of a dendritic ulcer; in other cases, the first documented ulcer may actually occur after an episode of immune stromal keratitis. In cases where there is no antecedent dendritic ulcer, the diagnosis of HSV immune stromal keratitis usually is made presumptively. HSV Endothelial Disease Disciform edema or a disciform keratitis reaction, is not a reaction of the stroma and should not be classified or treated as a stromal keratitis.2 Careful observation of the patient with disciform edema reveals that this process is an inflammatory reaction of the endothelium, with only secondary stromal and epithelial edema. This distinction between stromal and endothelial inflammation is important because the prognosis and clinical course are different, and visual outcome depends on proper recognition and treatment of the endothelium as the primary site of inflammation. HSV endotheliitis can be classified based on the distribution of the KP and the configuration of the overlying stromal and epithelial edema. The three forms of HSV endotheliitis are disciform, diffuse, and linear.2,8 Disciform endotheliitis is most common presentation of endotheliitis. Patients present with photophobia and mild to moderate ocular discomfort. Limbal injection is usually seen, as these patients have an accompanying iritis. Visual acuity may range from normal to severely reduced, depending on the location and severity of the stromal edema. The most striking finding of disciform endotheliitis on slit lamp examination is a round or disc-shaped area of stromal edema.2,8 This edema may be in the central or paracentral cornea. The edema usually spans the entire stromal thickness, resulting in the usual ground-glass appearance seen with corneal edema from other entities of endothelial decompensation. Typically, in disciform endotheliitis, the edema is within a strikingly focal pattern with a definite demarcation between involved and uninvolved cornea. In the acute setting, the stroma is void of infiltrate and neovascularization. In all cases of disciform endotheliitis, KP are present.2,8 The KP underlie the distribution of stromal edema and are not found in the nonedematous areas. It is sometimes difficult to see the KP because of the severity of the stromal edema. In these cases, it is useful to view the endothelium obliquely to detect the KP. Often, as the stromal edema resolves, the hidden KP become visible because the KP tend to resolve at a slower rate than the edema. An iritis may accompany disciform endotheliitis, but can be difficult to detect through the edematous cornea. In addition, elevated intraocular pressure, which may be severe, is often present. The increased pressure may be due either to inflammatory cells blocking aqueous outflow or to a primary trabeculitis. An episode of disciform endotheliitis may occur months to years after a documented episode of infectious epithelial keratitis. Often, there will not be a documented history of HSV disease, and a careful examination looking for footprints of HSV is helpful in making the proper diagnosis. Diffuse endotheliitis is a rare presentation of HSV keratitis. These patients experience pain, photophobia, injection, and decreased vision. They typically have scattered KP over the entire cornea with overlying diffuse stromal edema. A mild to moderate iritis is usually present, although it may be difficult to detect because of the corneal edema. Epithelial edema is present in cases of significant stromal edema. In severe cases, a dense, retrocorneal plaque of inflammatory cells accompanied by hypopyon may be seen. Diffuse endotheliitis represents an immune reaction targeted against the corneal endothelium. Failure to control the inflammation leads to scarring, neovascularization, persistent edema, and loss of vision.2,8 Linear endotheliitis is the rarest form and appears clinically as a line of KP on the corneal endothelium that progresses centrally from the limbus. It is accompanied by peripheral stromal and epithelial edema between the KP and the limbus. The line of KP can be sectoral or, in some cases, circumferential. It may have a distinct linear pattern as it moves centrally, but in some cases it may have a more serpiginous appearance. There is usually a well-demarcated line between the area of edematous and nonedematous cornea, with the KP located at the leading edge of the edema. The major complaints are pain, photophobia, and injection. Linear endotheliitis is quite difficult to treat. Failure to recognize and properly treat this condition leads to corneal decompensation.2,8 Diagnosis Although the diagnosis of primary and recurrent ocular HSV infection relies on a thorough ophthalmic examination, viral culture can help make a definitive diagnosis. This requires early culturing (usually within several days of the onset) and may require up to 1 week of incubation. Laboratory tests are of no use in stromal keratitis. The following tests can be useful in challenging cases of epithelial keratitis:2,11 Corneal Sensitivity – using either an esthesiometer or waxed dental floss Herpes Culture - The virus, once grown, can be typed to HSV-1 or HSV-2. Fluorescent Antibody (FAB) Testing - The corneal swab can be smeared on a slide, or impression cytology using a nitrocellulose membrane can be performed. DNA Amplification - This test does not require a high number of viral particles, but it is more expensive. Tzanck Smear - Papanicolaou or Giemsa stains of corneal smears are examined for the presence of multinucleated giant cells and intranuclear eosinophilic inclusion bodies. Serum Antibody Testing - The presence of anti-HSV IgM in a child may indicate active infection. However, false negatives are common and positive titers in adults merely indicate past infection, which is nearly universal. Management Herpetic Eye Disease Study12 The Herpetic Eye Disease Study (HEDS) was originally organized to evaluate oral acyclovir for herpetic stromal keratitis. Eight eye centers throughout the United States joined together to prospectively test whether acyclovir was effective in the management of stromal HSV. Five randomized double-masked placebo-controlled multicenter clinical trials have studied specific treatment protocols for the management of ocular HSV disease. Trial design in each of the HEDS has included well-defined inclusion criteria, standardized treatment protocols, careful monitoring of patient compliance during the study, and precise outcome measures. Herpetic Eye Disease Study: a controlled trial of oral acyclovir for herpes simplex This study was designed to evaluate the efficacy of oral acyclovir in treating stromal keratitis caused by HSV in patients receiving concomitant topical corticosteroids and trifluridine. The stromal keratitis included disciform disease, which is non-necrotizing keratitis and necrotizing stromal keratitis. The authors reported on 104 patients randomized to receive a 10-week course of either oral acyclovir (400 mg 5 times daily, n = 51) or placebo (n= 53). All patients also received a standard regimen of topical prednisone phosphate and trifluridine. Ophthalmologic examinations were performed for 6 months after entry into the trial. The results showed that the median time to treatment failure (defined as worsening or no improvement of stromal keratitis or an adverse event) was 84 days for the acyclovir group and 62 days for the placebo group. By 16 weeks, 75% in the acyclovir group and 74% in the placebo group had failed treatment. By that time, the keratitis had resolved with trial medications, and there was no subsequent worsening in 18% in the acyclovir group and 19% in the placebo group. None of these results were statistically significant. Visual acuity improved over 6 months in significantly more patients in the acyclovir group than in the placebo group. The study concluded that there was no clinically significant beneficial effect of oral acyclovir in treating HSV stromal keratitis in patients receiving concomitant topical corticosteroids and trifluridine in regard to time to treatment failure, proportion of patients who failed treatment, proportion of patients whose keratitis resolved, time to resolution, or 6-month best-corrected visual acuity. Herpetic Eye Disease Study: a controlled trial of topical corticosteroids for herpes simplex stromal keratitis The efficacy of topical corticosteroids in treating herpes simplex stromal keratitis was evaluated in this study. One hundred six patients with active herpes simplex stromal keratitis who had not received any corticosteroids for at least 10 days before the study were enrolled. Patients were assigned to the placebo group (n = 49) or the steroid group (topical prednisolone phosphate; n =57). Both regimens were tapered over 10 weeks, and both groups received topical trifluridine. Ophthalmic examinations were performed for 6 months after entry into the trial. Compared with placebo, corticosteroid therapy reduced the risk of persistent or progressive stromal keratouveitis by 68%. The steroid-treated group had a significantly shorter time to resolution of stromal keratitis. Postponing steroid treatment during careful observation for a few weeks delayed resolution of stromal keratitis but had no adverse effect on the visual outcome at 6 months. The incidence of recurrent herpes was not affected by topical steroid use. It was concluded that topical steroid treatment was significantly better than placebo in reducing persistence or progression of stromal inflammation and in shortening the duration of HSV stromal keratitis. Herpetic Eye Disease Study: a controlled trial of oral acyclovir for iridocyclitis caused by herpes simplex virus This study was designed to evaluate the benefit of adding oral acyclovir to a regimen of topical prednisolone phosphate and trifluridine for the treatment of iridocyclitis caused by HSV. Patients were randomly assigned to receive a 10-week course of either acyclovir 400 mg, 5 times daily, or oral placebo in conjunction with topical trifluridine and a topical corticosteroid. Follow-up examinations were done for 26 weeks after enrollment. The trial was stopped because of slow recruitment after only 50 of the originally planned 104 patients were enrolled in more than 4 years. Treatment failure was defined as persistence or worsening of ocular inflammation, withdrawal of medication because of toxicity, or request by the patient to withdraw from the trial for any reason. Treatment failure occurred in 50% of the 22 patients in the acyclovir-treated group and in 68% of the 28 patients in the placebo group. The treatment effect noted seemed slightly greater when only the patients with a persistence or worsening of ocular HSV were considered as treatment failures. The possible benefit of acyclovir became apparent after 3 weeks of follow-up. While the number of patients studied was too small to achieve statistically conclusive results, the results suggested a benefit of oral acyclovir in the treatment of HSV iridocyclitis. Herpetic Eye Disease Study: a controlled trial of oral acyclovir for the prevention of stromal keratitis or iritis in patients with herpes simplex virus epithelial keratitis The efficacy of oral acyclovir in preventing stromal keratitis or iritis in patients with epithelial keratitis caused by HSV was tested in 287 patients. These patients were randomly assigned to receive a 3-week course of oral acyclovir, 400 mg 5 times a day (n = 153), or placebo (n = 134) in addition to topical trifluridine for their epithelial disease. Patients were assessed for a 12month follow-up period. Stromal keratitis or iritis developed in 11% of the acyclovir group and in 10% of the placebo group. The development of stromal keratitis or iritis was more frequent in patients with a history of HSV stromal keratitis or iritis than in those without such a history (23% vs 9%). The study concluded that for patients with HSV epithelial keratitis treated with topical trifluridine, no apparent benefit of a 3-week course of oral acyclovir in preventing HSV stromal keratitis or iritis was seen during the subsequent year. Herpetic Eye Disease Study: acyclovir for the prevention of recurrent herpes simplex virus eye disease This study was designed to evaluate the efficacy of oral acyclovir as a prophylaxis for the prevention of recurrent ocular HSV disease. Seven hundred three patients with a history of ocular HSV disease within the preceding year were randomly assigned to receive 400 mg of acyclovir (n = 357) or placebo (n = 346) orally twice daily. The study outcomes were the rates of development of ocular or nonocular HSV disease during a 12-month treatment period and a 6month observation period. The cumulative probability of a recurrence of any type of ocular HSV disease during the 12-month treatment period was 19% in the acyclovir group and 32% in the placebo group. In the subset of patients with a history of stromal keratitis, the cumulative probability of recurrent stromal keratitis was 14% in the acyclovir group and 28% in the placebo group. The cumulative probability of a recurrence of nonocular (primarily orofacial) HSV disease was also lower in the acyclovir group than in the placebo group (19% vs 36%). There was no rebound in the rate of HSV disease in the 6 months after acyclovir treatment was stopped. The study concluded that long-term oral prophylaxis is effective in reducing the rate of recurrent ocular HSV disease and orofacial HSV disease, and is most important for the subset of patients with a previous history of HSV stromal keratitis. Medical Management Treatment of HSV epithelial keratitis differs dramatically from that of HSV immune mediated stromal keratitis. HSV Epithelial Keratitis Epithelial keratitis often resolves spontaneously; however, the aim of treatment is to minimize scarring and stromal inflammation. The infected cells are poorly adherent, and a gentle wiping debridement with a cotton tipped applicator removes nearly all infected cells without damaging normal epithelium. Debridement results in much faster resolution and consequently less scarring. Debridement should be performed prior to initiating drug therapy.2,11 Topical antivirals are the drugs of choice for acute epithelial disease. Topical Viroptic (1% trifluridine) can be used every 2 hours until the ulcer heals, followed by every 4 hours for an additional week. Trifluridine is effective in the treatment of epithelial keratitis, but can cause significant epithelial toxicity. It also contains thimerosal as a preservative and has a highly acidic pH that adds to its toxicity. Another option is topical Zirgan gel (0.15% ganciclovir), used 5 times a day until the ulcer heals, then 3 times a day for an additional week.13 Both are effective at eliminating the ulcer and should result in complete resolution. Oral acyclovir may be another option for both pediatric and allergic patients. A good rule of thumb is that epithelial disease that is adequately treated but persists beyond 2 or 3 weeks is either metaherpetic (noninfectious), caused by virus that is resistant to the antiviral agent, or due to drug toxicity. HSV Stromal and Endothelial Keratitis The mainstay of treatment is topical corticosteroids. Corticosteroids suppress inflammation by interfering with the normal immunologic response to various stimuli. Interference with lymphocyte function, migration, and the release of cellular digestive enzymes are all part of the mechanism of action seen clinically.2,11 The use of these agents in the setting of HSV ocular disease presents a challenge requiring both knowledge and experience. The use of antivirals is essential in the elimination of virions in the setting of active infection. However, the benefit of these agents when the disease has an immunologic component is controversial. Although HEDS did not show any statistically significant difference in visual outcome with the use of corticosteroids, they do accelerate resolution of HSV ocular infection. Simultaneous oral antiviral prophylaxis decreases the risk of HSV reactivation at the ganglion level. Topical corticosteroids used for the treatment of HSV stromal keratitis and uveitis are always given under antiviral cover. Typically, 1% prednisolone acetate or 0.1% dexamethasone is used. The dosing frequency should be based on the severity of the inflammation. On resolution of the inflammation, the steroids need to be tapered gradually to prevent rebound inflammation. Another option for treating immune mediated stromal disease is topical cyclosporine. 14 Cyclosporine is an immunomodulator that inhibits activation of T cells. Understanding that the pathological mechanism of immune mediated stromal HSV is not active viral infection, but viral antigens initiating a T-lymphocytic destruction of the stroma, helps predict the potential success of cyclosporine. Clinical studies have documented that cyclosporine after topical application accumulates at the ocular surface and cornea reaching concentrations that are sufficient for immunomodulation.15 It has also been used as an alternative treatment to topical steroids in the treatment of the inflammatory response in progressive corneal melting. Although no long term studies have been performed, several case reports showing the efficacy of topical cyclosporine A in prevention of immune mediated herpes stromal disease have been published.14 The typical regimen is two times daily of topical 0.05% cyclosporine A (Restasis, Allergan, Irvine, CA) for as long as needed to prevent reactivation. Neurotrophic Keratitis The basic principle of therapy for this disease is to rapidly heal the epithelial defect. Methods to accomplish this include stopping use of toxic medications, performing punctal occlusion, instilling tear film supplements, fitting a bandage contact lens, amniotic membrane, tarsorrhaphy, and, if there is significant underlying inflammation, cautiously using topical corticosteroids while watching carefully for corneal melts.2,11 Prophylaxis and Medications Oral antivirals are typically used as systemic prophylaxis against reactivation of HSV at the ganglion level. Topical medications are toxic with prolonged usage and are usually reserved for acute epithelial disease. Prophylaxis is useful in patients who have multiple recurrences (two or more in one year); those who have scarring close to the visual axis; those who are using topical corticosteroids for stromal disease; and those who are systemically immunocompromised. For prophylaxis of HSV infection, acyclovir is most commonly used at a dosage of 400 mg twice daily.9,11 All the current antivirals used in the treatment of ocular HSV, are nucleoside analogues that inhibit viral replication by competitively inhibiting viral DNA polymerase. Systemic antivirals are used primarily for prophylaxis of recurrent disease or as an antiviral cover during corticosteroid therapy for stromal keratitis. The three main systemic antivirals for the treatment of HSK are acyclovir, valacyclovir, and famciclovir. They have a high therapeutic index but resistance is an issue, especially in immunocompromised patients. Unfortunately there is cross- resistance among these three agents.9,11,16 Long-Term Complications Unfortunately, resolution of HSK does not protect the eye from future complications. Recurrent disease is the major cause of the morbidity associated with HSK. Each recurrent episode causes increased inflammation and scarring and further decreased corneal sensation. In addition, the risk of stromal disease increases with multiple recurrences of HSV epithelial keratitis. Even when HSK is treated promptly, scarring is common and can cause significant morbidity. A recurrent episode usually occurs adjacent to the site of a previous episode—thus the visual axis is invariably involved eventually. Corneal hypesthesia is a sensitive sign of previous HSK. The lack of innervation causes poor tear production and decreased release of growth factors in response to injury, leading to persistent epithelial defects and neurotrophic ulcers that may melt and perforate.2 Conclusion Dendritic and geographic epithelial ulcers are caused by live virus and are best treated with topical antiviral medications. Stromal keratitis is an immune- mediated process and is best treated with topical corticosteroids, with oral antiviral prophylaxis. Neurotrophic ulcers are neither infectious nor immune- mediated and are treated with measures to promote epithelial healing. The most important findings of HEDS were that use of topical corticosteroids shortened the course of HSV stromal keratitis, and prophylactic treatment with oral acyclovir decreased the risk of recurrent HSV ocular infection by 41%, which was evident in this case. References: 1. Tulia SS. Herpetic Corneal Infections. Focal Points 2008;26(8)1-16. 2. Holland EJ, Schwartz GS, Neff KD. Herpes Simplex Keratitis. Cornea Fundamentals, Diagnosis and Management 2011;79(1):953-984. 3. Waggoner-Fountain LA, Grossman LB: Herpes simplex virus. Pediatr Rev 2004;25:86-93. 4. Goodman JL: Infections caused by herpes simplex viruses. Hoeprich PD Jordan C Ronald AR Infectious diseases. 5th ed 1994 JB Lippincott Philadelphia 5. Fleming DT, et al.: Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med. 337 (16):1105-1111 1997 6. Liesegang TJ, Melton J III, Daly PJ, Ilstrup DM: Epidemiology of ocular herpes simplex. Arch Ophthalmol 1989;107:1155-1159. 7. Chang TW: Recurrent viral infection. N Engl J Med 1971;284:765-771. 8. Inoue Y. Review of Clinical and Basic Approaches to Corneal Endotheliitis. Cornea 2014;0:1–6. 9. Young RC., Hodge DO, Liesegang TJ. Incidence, Recurrence, and Outcomes of Herpes Simplex Virus Eye Disease in Olmsted County, Minnesota, 1976-2007 The Effect of Oral Antiviral Prophylaxis. Arch Ophthalmol. 2010;128(9):1178-1183. 10. Wilhelmus KR, Dawson CR, Barron BA. Risk factors for herpes simplex virus epithelial keratitis recurring during treatment of stromal keratitis or iridocyclitis. Br J Ophthalmol 1996;80:969-972. 11. Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis (Review). Cochrane Database of Systematic Reviews. 2011; Issue 8. 12. Sudesh S, Laibson PR. The impact of the Herpetic Eye Disease Studies on the management of herpes simplex virus ocular infections. Current Opinion in Ophthalmology 1999, 10:230–233. 13. Aggarwal S, Cavalcanti BM, Pavan-Langston D. Treatment of Pseudodendrites in Herpes Zoster Ophthalmicus With Topical Ganciclovir 0.15% Gel. Cornea 2014;33:109–113. 14. Sheppard JD, Wertheimer ML, Scoper SV. Modalities to Decrease Stromal Herpes Simplex Keratitis Reactivation Rates. Arch Ophthalmol. 2009;127(7):852-856 15. Tang-Kiu, Diane DS, Acheampong A. Ocular pharmacokinetics and safety of Cyclosporine-A. A novel topical treatment for dry-eye. Clin Pharmacokinet 2005; 44: 247-261 16. Ludema C, Cole SR, Poole C. Association Between Unprotected Ultraviolet Radiation Exposure and Recurrence of Ocular Herpes Simplex Virus. Am J Epidemiol. 2014;179(2):208–215.