*3.2.2 Stromal keratitis*

Stromal involvement in case of herpetic keratitis develops on an immune related basis. Inflammatory response to the HSV is connected with the activation and infiltration of myeloid-derived cells, CD4+ T-cell and NK cells. Stromal inflammation may lead to the reduced corneal transparency, persistent scar formation, may also cause an irreversible tissue pathology including vascularization and stromal necrosis. The inflammation process is often accompanied by stromal localized or extensive corneal edema and a mild anterior chamber reaction. Several recurrences may lead to the lack of the corneal innervation. Moreover, the severity of disease may increase with each subsequent episode, as inflammatory reaction becomes stronger despite no detectable viral activity.

Throughout the years multiple clinical forms in terms of stromal keratitis were described, being the source of confusion in diagnostic terminology, including: immune stromal, interstitial, necrotizing, nonnecrotizing, disciform, focal, multifocal, diffuse. This could contributed to misdiagnosis, especially in early phases of the disease and misapplications of therapy in clinical practice. For example, in Japan, "disciform" keratitis is considered a type of stromal keratitis. "Immune stromal" term also is misleading, suggesting, that other forms of HSV stromal keratitis do not involve immune reaction. That is why a simplified classification of the stromal keratitis was

#### **Figure 1.**

*Representative images of the slit-lamp photograph of the epithelial HSV keratitis. (A, B) Central, single dendritic ulcer before and after fluorescein installation. Branches with terminal bulbs visible. (C, D) Single dendritic ulcer with branches are raised above the corneal surface. Stromal haze accompanying the ulcer is noticeable. (E) Multiple, small dendritic ulcers visible under blue light after fluorescein installation. (F) Geographic, paracentral ulcer visible under blue light after fluorescein installation.*

proposed, dividing the keratitis into two distinct forms: stromal with and without an overlying epithelial ulceration. Stromal keratitis without ulceration, is the more common form, historically described as "nonnecrotizing," "immune-stromal," and "interstitial." Stromal keratitis with ulceration is the effect of severe inflammation and relates to historical description of "necrotizing" keratitis. The form with the ulcer is more probably the result of stromal HSV reactivation, although the neurotrophic pathogenesis of the ulcer also cannot be ruled out. This terminology could be easily implemented in clinical practice and allows ophthalmologists to properly counsel patients regarding diagnosis, treatment and prognosis [12]. **Figure 2** contains clinical presentations of the range stromal keratitis. **Figure 3** present a clinical case of a patient diagnosed with stromal keratitis with ulceration throughout the treatment process.

Marginal keratitis is a special, rarely occurring form of stromal and epithelial keratitis. Clinically it is difficult to differentiate from other forms of marginal keratitis, thus laboratory testing may be helpful in establishing the final diagnosis. The lack of corneal sensitivity could also be used as a clinical clue in differential diagnosis.

#### *3.2.3 Endothelitis*

This form is believed to be a result of endothelial cells viral infection coexisting with immune reaction. Usually, the endothelitis is localized with a distinct area of

*Recent Advances in the Diagnosis and Management of Herpetic Keratitis DOI: http://dx.doi.org/10.5772/intechopen.96898*

#### **Figure 2.**

*Representative images of the slit-lamp photograph of eyes with the different involvement of the stromal keratitis or with corneal scars following HSV keratitis. (A) Paracentral stromal infiltration with profound, active limbal vascularization. (B) Epithelial, dendritic ulcer accompanied by active stromal keratitis with vascularization. (C) Central stromal scarring with deep, peripheral vascularization. (D) Stromal haze in the course of recurrent stromal HSV keratitis. (E) Excessive corneal scarring with significant, deep, peripheral vascularization. (F) Significant area of corneal scar accompanied by lipid keratopathy and deep vascularization.*

the corneal edema. Therefore, it was historically described as disciform endothelial keratitis. Focal keratic precipitates, as well as Descemet membrane folds may be spotted in the affected area. Rarely, diffuse stromal edema, accompanied by trabeculitis with elevated intraocular pressure occurs. Various range of endothelitis is presented in **Figure 4**.

#### *3.2.4 Neurotrophic ulcer/metaherpetic ulcer*

This should be considered as a different entity, because there is no virus activation in case of neurotrophic ulcer. Also, the inflammation level compared to active HSV keratitis is lower. The most characteristic feature is the absence of corneal innervation and a non-healing corneal ulcer with smooth margins. As HSV keratitis alters the corneal nerves, the disease is one of the leading causes of neurotrophic keratopathy,

#### **Figure 3.**

*Slit-lamp photographs presenting the follow up of a 65-year old patient with HSV stromal keratitis with ulcer. (A, B) Baseline, at diagnosis. Recurrent stromal keratitis with significant ulcer, stromal infiltration, vascularization and corneal thinning. Patient treated with the combination of antiviral medication (Oral acyclovir 800 mg, 5 times daily at baseline; topical 3% acyclovir ointment 4 times daily) combined with 0,1% dexamethasone (3 times daily) and preservative free lubricant eye drops (hourly). (C, D) At 1 month in the course of treatment. Significant decrease of the area of the ulcer. Remaining significant corneal infiltration with vascularization. Oral acyclovir dosage tapered gradually to 400 mg 4 times daily. Topical acyclovir discontinued. (E, F) At 3 months in the course of treatment. Ulcer healed completely. Punctate keratopathy visible under blue light. Decreased stromal infiltration, but stromal haze, thinning and vascularization visible. Oral acyclovir and 0,1% dexamethasone doses tapered very carefully within months to prevent active keratitis recurrence. Patient was recommended a frequent use of the preservative free eye lubricant drops.*

among others, such severe dry eye disease, ocular burns or denervation post neurosurgical procedures. The pathogenesis is complex and include toxicity from antiviral medications, lack of nerve growth factors, the nerve damage as a result of recurrent keratitis. The neurotrophic keratitis is characterized by three stages of the severity: stage 1, punctate epithelial keratitis (PEK); stage 2, a nonhealing corneal persistent epithelial defect (PED); and stage 3 involving stromal involvement in the form of the neurotrophic ulceration. Possible accompanying signs are neovascularization, stromal haze and scarring. Consequently corneal poor ability to heal may result in corneal melting, prolonged ulceration, corneal perforation and endophthalmitis. A corneal sensitivity test is essential to confirm a diagnosis of neurotrophic keratitis. The test should be performed in regards to corneal location (central, peripheral), using a cotton-tipped swab or an esthesiometer. **Figure 5** presents forms of the neurotrophic keratitis.

*Recent Advances in the Diagnosis and Management of Herpetic Keratitis DOI: http://dx.doi.org/10.5772/intechopen.96898*

#### **Figure 4.**

*Representative images of the slit-lamp photograph of the different forms of HSV endothelitis. (A, B, C, D) The slit lamp photographs of the eye of a 34-year old patient with recurrent, excessive endothelitis with significant corneal edema and Descemet folds. (A, B) At baseline. Diffuse corneal edema with Descemet folds and punctate keratopathy. Patient treated with the combination of antiviral medication (oral acyclovir 800 mg, 5 times daily at baseline combined with 0,1% dexamethasone (7 times daily) and preservative free lubricant eye drops (5 times daily). (C, D) At 2 months in the course of treatment. Significant decrease in stromal edema, with only subtle stromal haze. Improvement of the punctate epitheliopathy. (E) Distinct area of the corneal edema - disciform endothelial keratitis. (F) Distinct area of the corneal edema - disciform endothelial keratitis at retroillumination. Ghost, profound vessels visible.*

#### **3.3 Confocal microscopy**

Confocal microscopy (IVCM - in vivo confocal microscopy) is the imaging technique developed to analyze corneal layers with the resolution of 1 μm. Imaging with confocal microscopy is used in clinical practice in differential diagnosis of microbial keratitis, corneal dystrophies and degenerations. The technique allows microscopic analysis of the cornea layer by layer and detailed assessment of keratocytes and inflammation cells. Features characteristic for HSV-1 keratitis depending on the stage and form include: microerosions, distortion of the superficial and basal epithelium, changes in superficial epithelial cell density, increase in epithelial cell size, squamous metaplasia, subepithelial infiltration of highly reflective dendritic

#### **Figure 5.**

*Representative images of the slit-lamp photograph of the different forms of neurotrophic keratitis. (A) Neurotrophic keratitis stage 2. A nonhealing corneal persistent epithelial defect (PED) after fluorescein installation. (B) A single, central corneal ulcer with stromal infiltration and peripheral corneal vascularization. (C) Central corneal perforation in the course of the corneal thinning and scarring and vascularization. (D) Neurotrophic keratitis stage 3. Neurotrophic ulceration with elevated borders and significant stromal haze.*

structures (correspondind to Langerhans cells), keratocytes activation, sub-basal nerve plexus alteration or absence, stromal fibrosis and endothelial precipitates. **Figure 6** presents the example of confocal microscopy results in case of patients with HSV keratitis. Confocal microscopy could guide in the disease diagnosis and monitoring the treatment results. In patients with stromal involvement the mean subbasal nerve density was proved to be significantly lower compared to healthy eyes. Also, in patients qualifying for surgical interventions, the technique has a potential role in assessing the sub-basal nerve plexus anatomy, helping the surgeons to procced with intervention decisions. The prognosis of patients with significantly altered corneal nerve plexus is poor after traditional transplant surgery [13–16].
