Herpes Simplex Virus (HSV) keratitis is the most common frequent infectious cause of corneal blindness in industrialized countries, and it is considered a major public health concern [1]. It has an annual incidence of 12–31.5 cases/100,000 inhabitants, of which 42% are new cases and 58% are due to recurrences [1,2]. PCR studies on cadavers have shown a HSV-1 prevalence of 100% in the trigeminal ganglion of people older than 60 years old [3]. After the primary infection, the virus travels to the trigeminal ganglion, where it remains latent [4]. After the initial primary infection, the risk of recurrence in the subsequent 10–20 years is approximately 60–70% [5]. Recurrences are considered a main problem in patients with HSV keratitis, because they increase the risk of corneal scarring and corneal nerve damage [5,6].

During recurrence, HSV keratitis can affect various corneal layers, including the epithelium, stroma and endothelium [7,8]. Recurrent herpetic stromal keratitis (HSK) and endothelitis occur mainly due to the host immune response, whereas dendritic or geographic epithelial keratitis are typically caused by direct viral replication [9]. Persistent chronic inflammation during HSK and direct nerve damage induced by the HSV can both lead to corneal nerve loss and eventually to neurotrophic keratopathy (NK) [6]. Reduced corneal sensitivity is considered the main sign of NK, and can lead to severe ocular surface disease, epithelial defects, ulceration, melting, and potentially to corneal perforation [10]. Thus, the long-term clinical course of the disease, in part, depends on the level of nerve loss and regeneration of corneal nerves to maintain a healthy ocular surface [11].

Corneal nerves can directly be visualized by in vivo confocal microscopy (IVCM), which is a non-invasive, high-resolution, real-time device that allows visualization of the cellular structures of the anterior segment with a high-resolution magnification of 800-times [12]. It is a rapid and non-invasive technology that is widely used to evaluate corneal nerves in different ocular and systemic conditions, such as ocular surface diseases [13], NK [14], viral, bacterial, Acanthamoeba, and fungal keratitis [6,15,16], as well as in post-surgical corneal complications [17,18], diabetes and neurodegenerative diseases [19,20], among others. Our previous studies have shown significant decrease in the subbasal nerve plexus in both the affected and contralateral eyes of patients with unilateral corneal infections [[21], [22], [23]]. Similarly, others have reported that patients suffering from unilateral ocular conditions, such as HSV keratitis and NK, can clinically develop bilateral ocular surface disease [24].

More recently, in a cross-sectional study, we have demonstrated that patients with HSV-induced central corneal scars show a more severe decrease in subbasal nerves and corneal sensation, compared to patients with peripheral HSV-induced corneal scars [15]. Although it has been shown that corneal nerve recovery may occur after HSV keratitis [6], to our knowledge no prior studies have assessed the effect of scar location on corneal nerve regeneration in both affected and contralateral eyes. Thus, the purpose of the current study was to assess the effect of the HSV-induced corneal scar location on nerve regeneration in different corneal quadrants of patients with unilateral corneal scar over a 1-year period and to correlate the corneal nerve density measured by IVCM with corneal sensation. We hypothesize that patients with central scars demonstrate less corneal nerve regeneration as compared to patients with peripheral scars and that our results could aid clinicians in predicting patients with HSV keratitis that have a higher risk of developing or progressing towards NK.