Diagnostic Role of Anterior Segment Optical Coherence Tomography in an Atypical Presentation of Varicella Zoster Virus Interstitial Keratitis: A Case Report

Introduction

Keratitis is a corneal inflammation that can be infectious or non-infectious, resulting in corneal edema and infiltration of inflammatory cells [1]. The incidence varies among countries; in an epidemiological study in California, the incidence of ulcerative keratitis was 27/100 000 person-year [1]. The diagnosis starts by careful evaluation of the ulcer, followed by corneal scraping to isolate the organism if present [1]. The treatment options vary based on the identified organisms [1]. Varicella zoster virus (VZV) is a member of the herpes virus family that affects various organs [2]. The virus can affect nearly all ocular structures including the sclera, conjunctiva, cornea, uvea, and retina, with keratitis being the most common [2–4]. Patients can present with symptoms such as redness, pain, photophobia, and vision impairment [2]. Diagnosing VZV interstitial keratitis can be challenging, with different etiologies leading to similar clinical presentations [2]. Corneal intraepithelial neoplasia (CIN), a rare corneal condition, is a form of ocular surface squamous neoplasia (OSSN) characterized by the presence of neoplastic cells confined to the corneal epithelium [5]. Herein, we report a case of VZV interstitial keratitis presenting with a clinical picture mimicking corneal intraepithelial neoplasia. To the best of our knowledge, this is the first case of an atypical presentation of VZV interstitial keratitis mimicking corneal intraepithelial neoplasia. Our case report shows the unusual presentation of VZV interstitial keratitis and the importance of utilizing appropriate diagnostic investigations to rule out other mimickers.

Case Report

A 26-year-old woman was referred to our tertiary eye center with suspected isolated CIN in the right eye. She had a history of unilateral headache with alopecia and loss of eyelashes, along with photophobia and redness on the right side over the past 5 years. She had no history of vesicular rashes or other skin lesions. A provisional diagnosis of herpes zoster virus infection was established by a neurologist and the patient reported receiving a course of antiviral medication, after which the symptoms improved. She had no medical issues or previous ocular interventions. Examination revealed a best-corrected visual acuity of 20/20 and normal bilateral intraocular pressure. Corneal sensation remained intact. Slit-lamp examination of the right eye showed clear lids, mild sectoral superior-nasal conjunctival injection with prominent vascularity, and a single large-bore episcleral vessel approaching but not crossing the limbus. The cornea showed ghost vessels and a diffuse greyish superficial (subepithelial) corneal opacity with an amoeboid pattern extending from 3 to 9 o’clock, sparing the central visual axis (Figure 1). There was no corneal edema or keratic precipitation and the anterior chamber was quiet. A complete fundus examination was performed, with unremarkable results. Examination of the left eye was unremarkable as well. Varicella zoster interstitial keratitis was suspected and anterior segment optical coherence tomography (AS-OCT) with epithelial mapping was performed to confirm the diagnosis (Figure 2A, 2B). A baseline renal function test was performed. Treatment was initiated with oral valacyclovir (1 g 3 times daily for 10 days) and topical prednisolone acetate 1% (4 times daily, tapered over 8 weeks). At the 1-month follow-up, the patient reported improvement in photophobia and redness. Biomicroscopy showed decreased corneal opacity with scarring, and no evidence of active keratitis (Figure 3A, 3B). She was maintained on a prophylactic dose of valacyclovir and monitored for 1 year after completion of therapy, with no recurrence or reactivation observed. The corneal findings remained stable, showing only residual scarring.

Discussion

This case report highlights the importance of a thorough assessment of atypical presentation of interstitial keratitis through the integration of both clinical and imaging ocular findings, enabling appropriate management, and avoiding unnecessary investigations and interventions. Herpes zoster virus can affect all corneal layers and presents various clinical presentations, with a risk of evolution towards neurotrophic keratopathy [2]. Similar to Herpes simplex virus, it can latently infect and reactivate from the trigeminal ganglion. Keratitis can occur secondary to active viral infection and replication, similar to epithelial keratitis, secondary to an immune-mediated mechanism, or as in interstitial keratitis [2]. Relapses of primary HZV ocular disease are common, with recurrently triggered inflammation requiring a prolonged course of oral antiviral and topical steroids [2,3,6]. Herpes Zoster Ophthalmicus (HZO)-related corneal involvement was studied by Liesegang et al in 94 patients, with 61 patients presenting with corneal involvement ranging from punctate epithelial keratitis to neuropathy [2]. Anterior stromal keratitis was described in 25 cases, with 6 patients manifesting a patchy granular infiltrate in the anterior stroma just under the Bowman’s layer, similar to our case [2]. However, the exact pathophysiology remains unknown. Theories suggest that an immune response involving antigen–antibody interactions from the overlying epithelium can result in prolonged or recurrent attacks [2]. Cases with VZV infection can present with various clinical presentations [7]. Our patient presented with headache, alopecia, and madarosis, which have been linked to VZV infection [7]. Although patients with HZO usually present with skin rash or vesicles, several reports have described an absence of skin rash and vesicles in cases of corneal involvement secondary to HZO, particularly among immune-compromised patients [2,8,9,10]. Clinically, HZO without rash requires a high index of suspicion, as delayed diagnosis and initiation of antiviral therapy can lead to worse scarring or vision loss. In the present case, although a viral PCR was not performed due to the chronic inactive nature of the lesion at presentation, the combination of unilateral systemic and ocular manifestations, along with the patient’s favorable response to antiviral therapy, supported a diagnosis of VZV infection.

Multiple case reports highlight the importance of differentiating various corneal lesions from malignant conditions such as OSSN because early diagnosis and treatment are crucial in such cases. These studies reported OSSN cases mimicking peripheral ulcerative keratitis (PUK), superior limbic keratoconjunctivitis (SLK), nodular scleritis, and viral epithelial keratitis with corneal pannus [11–14]. In contrast, other studies report conditions of limbal pseudoepitheliomatous hyperplasia, inflammatory myofibroblastic tumor of the conjunctiva, and corneal epithelial hyperplasia misdiagnosed as OSSN [15–18].

Therefore, it is important to utilize different diagnostic tools to detect serious conditions in the initial phases. AS-OCT is a noninvasive tool that plays an important role in the diagnosis of various ocular surface conditions [5,19,20]. In particular, it plays a key role in the assessment of ocular surface pathologies when the clinical diagnosis is unclear, and can help in decision-making and surgical planning. Indeed, the lack of epithelial thickening, absence of abrupt transition from normal to abnormal epithelium, and presence of subepithelial rather than epithelial hyperreflectivity on AS-OCT ruled out the diagnosis of OSSN and deferred the need to obtain a biopsy [5,19,20].

Despite the great advantages of AS-OCT, it also has several limitations. In cases with poor image quality, mainly secondary to dense corneal opacity, the diagnostic accuracy can be affected. Furthermore, AS-OCT cannot provide histopathological confirmation of cellular atypia. Therefore, it should be integrated with other diagnostic modalities such as impression cytology, confocal microscopy, and histopathological examination when indicated [20,21].

When differentiating between keratitis and corneal intraepithelial neoplasia, a multimodal diagnostic approach is often most effective. AS-OCT provides detailed structural information about epithelial and subepithelial layers, while confocal microscopy allows visualization of cellular morphology and inflammatory infiltrates at a microscopic level. Previous studies have shown that IVCM findings closely correlate with histopathological features. In OSSN, key characteristics of the basal epithelium include pleomorphism, anisocytosis, and an increased nucleus-to-cytoplasm ratio, with ill-defined cell borders [22]. Impression cytology offers cytological confirmation of atypical epithelial changes, although histopathology assessment remains the standard method for definitive diagnosis. Compared with these techniques, AS-OCT is rapid, noninvasive, and repeatable, but lacks cellular resolution. Combining these modalities provides a more comprehensive understanding of corneal pathology and increases diagnostic accuracy, particularly in challenging or overlapping cases [20,21]. This multimodal approach also guides therapeutic decisions by helping to distinguish inflammatory from neoplastic processes.

Nanji et al reported the characteristic features of corneal and conjunctival pathologies using high-resolution OCT [21]. The distinct feature of AS-OCT of the OSSN is the severely thickened and strongly hyper-reflective corneal epithelium, usually with an abrupt transition from normal to abnormal epithelium [21]. Unlike OSSN, the pterygium and pingueculum usually present with a subepithelial mass and a normal to slightly thickened epithelium with mild hyperreflectivity [21]. In the same study, all cases of OSSN showed a strongly hyper-reflective epithelium and epithelial thickening. At the thickest measurement point, the epithelium measured 390±247 mm (range: 124–1000 mm). The epithelial thickness of OSSN was greater than that observed in all normal controls and other benign lesions like pterygiae or pingueculae, which preserve a normal to slightly elevated epithelial corneal thickness (~50–100 μm) with a dense subepithelial mass beneath it [20]. These distinct OCT patterns (epithelial vs subepithelial lesion) enable noninvasive differential diagnosis.

Similarly, Kieval et al found on ultra-high-resolution OCT that OSSN eyes had an average epithelial thickness of 346 μm vs 101 μm in pterygiae, with the OSSN scans showing an abrupt transition from normal to abnormal epithelium [23]. Moreover, Başkan et al found a mean epithelium thickness of 295.3±111.3 μm in OSSN vs 80.7±43.4 μm in pterygium, and proposed a 97 μm cutoff, which gave 100% sensitivity and ~95% specificity for OSSN diagnosis [24]. Corneal carcinoma in situ showed no characteristic pattern, unlike other corneal pathologies. However, in most cases, the epithelial thickness was more than 60 μm, unlike our case [24].

Conclusions

This case report emphasizes the need to consider infectious causes, including varicella zoster virus, when evaluating atypical corneal lesions and highlights the diagnostic utility of anterior segment optical coherence tomography in differentiating corneal intraepithelial neoplasia. The use of AS-OCT and corneal epithelial thickness mapping can provide important diagnostic clues to distinguish ocular surface squamous neoplasia from other non-neoplastic conditions. Early recognition of viral keratitis presenting with neoplasia-like features can help avoid unnecessary surgical procedures and allow timely initiation of appropriate antiviral treatment.