Herpes simplex virus keratitis mimicking Acanthamoeba keratitis: a clinicopathological correlation

Abstract

A 36-year-old male, soft contact lens wearer was referred by his primary ophthalmologist for corneal ulcer of the right eye (OD), which was persistent despite topical fluoroquinolone therapy for 1 month. A ring-shaped infiltrate typically seen in Acanthamoeba infection was noted, and topical therapy with chlorhexidine and polyhexamethylene biguanide was initiated. However, the patient’s condition deteriorated over the next several weeks; thus, diagnostic and therapeutic penetrating keratoplasty was performed. The postoperative immunohistochemical analysis suggested a diagnosis of herpes simplex virus (HSV) keratitis. The patient ultimately improved after initiation of oral valacyclovir following penetrating keratoplasty. We report a case of a commonly encountered clinical entity, HSV keratitis, with an atypical clinical presentation, masquerading as Acanthamoeba keratitis.

Background

Infective keratitis often presents with protean clinical manifestations depending on the organism responsible for the disease. Often, infectious keratitis due to organisms such as bacteria, fungi, protozoa and viruses may have overlapping clinical features leading to difficulty in the diagnosis.¹ Therefore, a high index of clinical suspicion and accurate microbiological evaluation is necessary for an accurate diagnosis.

Among the contact lens users, corneal infection due to Acanthamoeba is often reported; especially among individuals cleaning or storing lenses with a home-made saline solution or tap water.² During the early stages of infection, Acanthamoeba keratitis usually presents with dendriform ulcers mimicking herpes simplex virus (HSV) keratitis.³ In this case report, we discuss a rare case of HSV-related corneal infection in a young contact lens user presenting with ring infiltrate mimicking Acanthamoeba keratitis. A similar case of infectious keratitis due to HSV presenting with a clinical image typically attributed to Acanthamoeba has not been reported in the literature. The diagnosis was confirmed after penetrating keratoplasty, by thorough histological and cytopathological analysis.

Case presentation

A 36-year-old man was referred to our clinic by his ophthalmologist, with a history of severe pain, photosensitivity in the right eye and similar but milder symptoms in the left eye. The patient reported the presenting symptoms in his left eye, about a week before his right eye. The patient had was being treated for presumed bacterial keratitis, with topical moxifloxacin 0.5% four times a day, tobramycin 0.3% four times a day and bacitracin 0.3% at bedtime for 1 month. However, the patient did not show any improvement. The patient was a soft contact lens wearer and reported good contact lens hygiene. He had no ocular or medical history, no history of trauma and no known allergies.

Investigations

On slit-lamp biomicroscopy, the patient had a corneal ulcer with ring shaped infiltrate in the right eye, and a round corneal scar in the left eye (figure 1A,B). His best-corrected visual acuity (BCVA) at presentation was 20/640 in the right eye and 20/80 in the left eye. The intraocular pressure was measured to be 12 mm Hg in both eyes, using non-contact tonometer. The right eye was moderately injected, and trace cells were present in the anterior chamber. A sizeable epithelial defect could be seen with corneal fluorescein staining under cobalt blue light. The left eye showed minimal injection, no epithelial defect and minimal anterior chamber reaction.

Figure 1.

Slit-lamp photos of the patient’s corneas on initial presentation, with ring infiltrate and ulceration in the right cornea (A) and a well-circumscribed stromal scar in the left cornea (B).

The corneal scrapings from the patient’s right eye were obtained and sent to the Ocular Pathology laboratory for culture sensitivity tests and histological evaluation. The confocal microscopy of the right cornea was inconclusive. After the corneal scrapings were obtained, the patient was immidiately started on topical chlorhexidine 0.02% every 2 hours and polyhexamethylene biguanide three times a day, for presumed Acanthamoeba keratitis on the basis of presenting symptoms, lesion morphology, history of contact lens use and non-response to topical anti-bacterial therapy.

The histological evaluation of the corneal scrapings showed no double-walled cyst structures consistent with Acanthamoeba. The corneal scrapings cultured in potato dextrose tube, Tryptan soy broth tube and 1.5% non-nutrient agar plate did not show any growth, thus ruling out fungal, bacterial and Acanthamoebic aetiology, respectively. The patient did not show any improvement in his symptoms, instead his clinical course deteriorated over the next 2 weeks, with worsening pain, persistent photophobia and corneal ulceration in the right eye.

Differential diagnosis

The patients with Acanathamoeba keratitis typically present with pain, photophobia and epiphora. With the delay in diagnosis and management, the organisms breach the epithelium and infest the corneal stroma, thus making the management extremely difficult. Acanthamoeba keratitis is usually unilateral, progresses slowly and may present with pseudodendrites, perineural or ring-shaped infiltrates.⁴

The fungal corneal ulcers have a dry, raised, necrotic slough surface, feathery margins and satellite lesions, usually yellowish white or greyish white in color. An endothelial ring is a differentiating presentation in fungal ulcers as compared to viral or bacterial keratitis. The slit-lamp examination may show a creamy white exudate at the base of the lesion, eyelid oedema, conjunctival injection, chemosis, corneal epithelial defect and endothelial plaque. Some patient may form a hypopyon in the anterior chamber that could result in ocular hypertension.

Infectious keratitis due to viral aetiologies like herpes zoster and adenovirus may have a clinical presentation similar to HSV. Adenoviral infections present with severe conjunctivitis, tarsal and epibulbar follicles and petechial haemorrhages in some cases.⁵ At a later stage, multifocal, centrally located, nummular corneal infiltrates are seen in 95% of the patients.

The patients infected with herpes zoster present with either extraocular or ocular symptoms as well as both symptoms, simultaneously. In the prodromal phase of infection, the patients typically present with complaints of excessive fatigue, malaise and low-grade fever. These symptoms may last up to 1 week before the eruption of a vesicular rash on the eyelids, which may cause scarring and ptosis. The patients present with conjunctivitis, severe injection, petechial haemorrhages, and typical punctate epithelial keratitis, with swollen corneal epithelial cells. In chronic, untreated infection, there may be scarring, ulcers and loss of corneal sensation.⁶

The patients with a history of chemical burns, physical injuries or corneal surgery, may present with neurotrophic keratopathy as a consequence of trigeminal neuropathy. It may also occur due to compression of the trigeminal nerve or ganglion, by intracranial space-occupying lesions such as neuroma, meningioma and aneurysms, or subsequent to systemic diseases such as diabetes, multiple sclerosis and leprosy which decrease the sensory function of trigeminal nerve leading to corneal anaesthesia.⁷ Persistent exposure to thiomersal, an organomercury compound in soft contact lens storage solutions may cause non-specific conjunctival changes, limbal follicles, superficial punctate keratopathy and superior corneal epithelial opacity.⁸

Treatment

To manage the non-healing ulcer, a diagnostic and therapeutic penetrating keratoplasty was performed in the right eye. The patient was started on 1% prednisolone acetate four times a day, which was subsequently tapered down on a monthly basis. The histological appearance of the H&E staining at low magnification power showed loss of Bowman’s layer, replaced by scar tissue and re-epithelisation, as well as extensive inflammatory infiltrate in the stromal layer of the cornea. The repeated bacterial, fungal and Acanthamoeba cultures inoculated with tissue from the excised cornea were negative. The immunohistochemical staining of the excised tissue also ruled out the presence of the aforementioned infectious etiologies. However, the corneal tissue stained strongly positive for HSV-1 antigen in numerous keratocytes in the stroma (figure 2).

Figure 2.

(A) H&E stain of corneal tissue at low power showing a large area of epithelial denudation on the right, and underlying loss of the Bowman’s layer, with some preserved Bowman’s layer on the left. (B) H&E stain of corneal tissue. Keratocytes appear elongated due to the apparent presence of intranuclear inclusion bodies, suggestive of viral pathology. (C) Herpes simplex virus stain was showing keratocytes strongly positive for viral antigen.

Outcome and follow-up

The patient’s anti-Acanthamoeba treatment was discontinued 5 days after the surgery, and antiviral therapy was initiated. The patient reported improvement in clinical symptoms with oral valacyclovir 1 g three times a day, for 10 days. At the most recent follow-up 6 weeks after the surgery, the right eye corneal transplant remains clear and the left eye has a visually significant stromal scar. The patient’s BCVA improved to 20/40 in his right eye and was stable at 20/80 in the left eye.

Discussion

Clinical diagnosis of atypical HSV keratitis can often be challenging. The index case was diagnosed initially as Acanthamoeba keratitis considering the clinical presentation: ring-shaped infiltrate, severe pain and photophobia and a history of contact lens wear. However, cultures were negative for Acanthamoeba, and no Acanthamoeba cysts were detected in the excised cornea button. HSV antigen staining revealed the presence of keratocytes in the corneal tissue obtained during the diagnostic keratoplasty. Such antigens may be seen in infections caused by HSV-1, HSV-2 and varicella zoster virus. Ring infiltrates documented in HSV keratitis are caused due to a type III hypersensitivity mechanism involving immune complex deposition in the corneal stroma, known as the Wessely stromal immune ring.^{9 10} The case presented here is unusual given the bilateral keratitis, the epithelial involvement and severe pain, all of which are more suggestive of active Acanthamoeba infection, than an immunological response to HSV. The factors that might lead to an atypical presentation of HSV keratitis as seen in this case are attributed to a history of wearing poor fitting contact lenses, inadequate lens hygiene and microtrauma, leading to the reactivation of infection.

Learning points.

• Clinical presentation alone is not reliable for diagnosis of infectious keratitis, and the underlying aetiology.

• High clinical suspicion can aid in early diagnosis, which would help in prompt treatment with prophylactic antivirals, especially following penetrating keratoplasty to prevent complications.

• While it is known that Acanthamoeba may masquerade as herpes simplex virus (HSV) keratitis, an Acanthamoeba-like presentation of HSV keratitis may present, although less frequently.