Impairment of Lacrimal Secretion in the Unaffected Fellow Eye of Patients with Recurrent Unilateral Herpetic Keratitis

doi:10.1016/j.ophtha.2013.02.037

Ophthalmology

Volume 120, Issue 10, October 2013, Pages 1959-1967

https://doi.org/10.1016/j.ophtha.2013.02.037 Get rights and content

Purpose

To assess the impact of recurrent unilateral herpetic keratitis (HK) on the tear secretion of the unaffected fellow eye.

Design

Prospective, noninterventional study.

Participants and Controls

Thirty-five patients with a history of recurrent unilateral HK (clinically quiescent for at least 3 months) (HK group) and 35 patients who were age- and sex-matched with no history of corneal disease (control group).

Methods

Tear osmolarity, tear instability (tear break-up time [TBUT]), tear reflex (Schirmer's I test), and central corneal sensitivity with the Cochet–Bonnet esthesiometer (Luneau, France) were measured in the HK and control groups.

Main Outcome Measures

Tear osmolarity, TBUT, Schirmer's I, and central corneal sensitivity were compared between the affected and unaffected eyes of the HK and control groups.

Results

Tear osmolarity and tear secretion reflex were similar between the affected and unaffected eyes of the HK group. Corneal sensitivity and TBUT were statistically lower in the affected eyes compared with the unaffected eyes in the HK group (P = 0.001 and P < 0.001, respectively). The central corneal sensitivity of unaffected eyes in the HK group was not significantly different from that in the control group (P > 0.05). The tear stability and tear secretion reflex were decreased and tear osmolarity was increased in the unaffected eyes of the HK group compared with the control group (P < 0.05, all cases). The difference between unaffected and control eyes varied according to the type of HK. All 4 tests were modified in patients with neurotrophic keratitis (KN). In the keratouveitis subgroup, only corneal sensitivity was normal, whereas Schirmer's I results were also normal in patients with archipelago keratitis. Tear osmolarity was consistently affected in both eyes of herpetic patients.

Conclusions

Tear function is impaired in the unaffected eyes of patients with unilateral recurrent HK, even when the disease is apparently quiescent. The higher severity of results in the unaffected fellow eye of patients with KN in comparison with other herpes subgroups suggests that recurrent HK induces a reduction in the afferent pathways of the tear secretion reflex from the affected eye, leading to tear dysfunction in the unaffected eye.

Financial Disclosure(s)

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Section snippets

Patients

Patients who presented to the Ophthalmology Department, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Paris, France, between February 2010 and January 2012 with recurrent unilateral keratitis presumably due to HSV were considered for inclusion in this prospective study.

The clinical diagnosis of keratitis was based on the notes from medical charts, including slit-lamp examination findings (epithelial or stromal abnormalities typical of HSV infection). A herpetic origin of the

Results

Thirty-five patients (21 male and 14 female) in the HK group and 35 patients (21 male and 14 female) in the control group were enrolled in this study. The mean age was 52.3±7.3 years in the HK group and 52.8±8.5 years in the control group. In the HK group, the mean time since the last inflammatory event and enrollment in the study was 11.05±4.8 months and the mean history of HSV was 8.4±3.7 years.

The demographic data and the results of tear assessment for both groups are summarized in Table 1.

Factors Related to Corneal Herpes That May Induce Tear Dysfunction

The integrity of the ocular surface is mandatory for maintaining visual quality and ocular health.⁸ Qualitative or quantitative tear abnormalities result in tear hyperosmolarity and eventually dry eye syndrome. Ocular dryness can result from various conditions such as Sjögren syndrome, which causes hyposecretion of tears, or from meibomian gland dysfunctions that cause excessive tear evaporation. The association between tear film quality and quantity disorders can result in factors causing

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Cited by (32)

Herpes simplex virus, varicella-zoster virus and cytomegalovirus keratitis: Facts for the clinician
2023, Ocular Surface
Citation Excerpt :
Another common characteristic is the overall loss of corneal sensitivity in the affected eye, due to the alteration of the corneal nociceptors [54] and the nerve fibers in the TG pathways [55]. The loss of corneal sensitivity ultimately induces bilateral signs of dry eye and neurotrophic keratitis [54,56], due to the decrease in the sensitive input from the affected eye to the brainstem areas involved in the regulation of the lacrimal functional unit. These clinical changes cause a significant decrease in the patient related quality of life [57].
Keratitis due to Herpes simplex virus (HSK), Varicella-Zoster virus (VZK) and Cytomegalovirus remains a frequent source of concern for many ophthalmologists. They are a frequent cause of emergency consultations at eye care centers and carry the risk of permanent loss of visual acuity or visual quality and/or chronic neurotrophic keratitis, resulting in a significant decrease in the quality of life. HSK and VZK can affect the corneal epithelium, stroma, or endothelium or a combination of layers. In contrast, most cases of CMV keratitis present as isolated endothelitis (CMVE), a clinical entity that has been described within the last 2 decades. These three types of viral keratitis are characterized by a high frequency of recurrences and each new episode increases the risk of sequelae. Hence, ophthalmologists must adapt the treatment to the clinical presentation of each recurrent episode in order to mitigate the immediate consequences of viral replication and the immune response on corneal transparency. In patients with frequent recurrences, preventive long-term antiviral treatment is strongly recommended. However, in some rare cases, continuous exposure to antivirals may promote the emergence of resistant viral strains, which can be difficult to manage. In the future, the introduction of new antiviral drugs, with differing modes of action compared to current medical therapy, could be an alternative until a truly effective preventive solution, such as a vaccine, is available.
Acyclovir-Resistant Herpes Simplex Virus 1 Keratitis: A Concerning and Emerging Clinical Challenge
2022, American Journal of Ophthalmology
Citation Excerpt :
Of the 18 patients, 11 had epithelial keratitis at the time at which the diagnosis of resistance was made. Although this clinical form has a good prognosis per se, and although these patients were efficiently managed with currently available antiviral treatments, those with this condition are at high risk for presenting with other, more severe forms of the disease on further recurrences,2 having a greatly affected quality of life,10 and developing dry eye and neurotrophic keratopathy.6 We observed a better visual outcome in immunocompromised patients, both at inclusion and at the end of follow-up.
To describe the clinical and virological profiles of patients with herpes simplex keratitis (HSK) caused by acyclovir-resistant (ACV^R) strains of herpes simplex virus 1 (HSV-1).
Multicenter retrospective case series.
HSV-1 resistance to ACV was confirmed using sequencing of genes encoding HSV-1 thymidine kinase (TK) and DNA polymerase (DNA pol). Data were collected on the number of HSK episodes before and after the diagnosis of resistance, ocular findings including the type of HSK, immune status of patients, antiviral treatments, and HSV-1 genotypic resistance profiles.
This study evaluated 18 HSK patients (13 male and 5 female, aged 66.8 ± 4.7 years) with ACV^R HSV-1−positive ocular samples. Genotypic resistance testing was performed because of frequent recurrences despite adequate antiviral prophylaxis (AVP) (n = 13, 72%), or poor response to suppressive antiviral therapy (n = 5, 28%). Resistance mutations were found in the TK (n = 15, 83%) or in the DNA pol gene (n = 3, 17%). Prior to the diagnosis of resistance, the duration of disease was 29.8 ± 20.4 years, with more than 10 HSK recurrences in 15 patients (83%). The number of recurrences between the first episode and the diagnosis of resistance was significantly lower in immunocompromised patients (n = 6, 33%) than in immunocompetent patients (n = 12; 67%) (11.5 ± 4.9 vs 16.4 ± 1.9, P = .05).
HSV-1 resistance to ACV must be suspected in HSK patients with recurrences despite AVP and/or in cases that respond poorly to a suppressive antiviral regimen. Immunocompromised patients and/or those with longstanding disease may be particularly at risk for developing resistance.
Corneal nerves in health and disease
2019, Progress in Retinal and Eye Research
The cornea is the most sensitive structure in the human body. Corneal nerves adapt to maintain transparency and contribute to corneal health by mediating tear secretion and protective reflexes and provide trophic support to epithelial and stromal cells. The nerves destined for the cornea travel from the trigeminal ganglion in a complex and coordinated manner to terminate between and within corneal epithelial cells with which they are intricately integrated in a relationship of mutual support involving neurotrophins and neuromediators. The nerve terminals/receptors carry sensory impulses generated by mechanical, pain, cold and chemical stimuli. Modern imaging modalities have revealed a range of structural abnormalities such as attrition of nerves in neurotrophic keratopathy and post-penetrating keratoplasty; hyper-regeneration in keratoconus; decrease of sub-basal plexus with increased stromal nerves in bullous keratopathy and changes such as thickening, tortuosity, coiling and looping in a host of conditions including post corneal surgery. Functionally, symptoms of hyperaesthesia, pain, hypoaesthesia and anaesthesia dominate. Morphology and function do not always correlate. Symptoms can dominate in the absence of any visible nerve pathology and vice-versa. Sensory and trophic functions too can be dissociated with pre-ganglionic lesions causing sensory loss despite preservation of the sub-basal nerve plexus and minimal neurotrophic keratopathy. Structural and/or functional nerve anomalies can be induced by corneal pathology and conversely, nerve pathology can drive inflammation and corneal pathology. Improvements in accuracy of assessing sensory function and imaging nerves in vivo will reveal more information on the cause and effect relationship between corneal nerves and corneal diseases.
Pathogenesis of herpes simplex keratitis: The host cell response and ocular surface sequelae to infection and inflammation
2019, Ocular Surface
Herpes simplex virus type 1 (HSV) keratitis is a leading cause of infectious blindness. Clinical disease occurs variably throughout the cornea from epithelium to endothelium and recurrent HSV stromal keratitis is associated with corneal scarring and neovascularization. HSV keratitis can be associated with ocular pain and subsequent neutrophic keratopathy. Host cell interactions with HSV trigger an inflammatory cascade responsible not only for clearance of virus but also for progressive corneal opacification due to inflammatory cell infiltrate, angiogenesis, and corneal nerve loss. Current antiviral therapies target viral replication to decrease disease duration, severity and recurrence, but there are limitations to these agents. Therapies directed towards viral entry into cells, protein synthesis, inflammatory cytokines and vascular endothelial growth factor pathways in animal models represent promising new approaches to the treatment of recurrent HSV keratitis.
Neurotrophic keratopathy
2018, Progress in Retinal and Eye Research
Citation Excerpt :
Recurrent HSK results in persistent epithelial defects in the cornea ipsilateral to the affected trigeminal pathway. This is associated with hyperosmolarity, reduced tear break up time, reduced tear secretion (Schirmer I test) and reduced sensations not only in the affected eye but also in the unaffected eye (Rousseau et al., 2015; M'Garrech et al., 2013; Jabbarvand et al., 2015). Unilateral herpes simplex and herpes zoster keratitis is associated with bilateral loss of corneal nerve receptors and dendritic cell infiltration (Hamrah et al., 2010, 2013; Cavalcanti et al., 2018).
Neurotrophic Keratopathy (NK) refers to a condition where corneal epitheliopathy leading to frank epithelial defect with or without stromal ulceration (melting) is associated with reduced or absent corneal sensations. Sensory nerves serve nociceptor and trophic functions, which can be affected independently or simultaneously. Loss of trophic function and consequent epithelial breakdown exposes the stroma making it susceptible to enzymatic degradation. Nerve pathology can range from attrition to aberrant re-generation with corresponding symptoms from anaesthesia to hyperaesthesia/allodynia. Many systemic and ocular conditions, including surgery and preserved medications can lead to NK. NK can be mild (epithelium and tear film changes), moderate (non-healing epithelial defect) or severe (stromal melting and perforation). Moderate and severe NK can profoundly affect vision and adversely impact on the quality of life. Medical management with lubricating agents from artificial tears to serum/plasma drops, anti-inflammatory agents, antibiotics and anti-proteases all provide non-specific relief, which may be temporary. Contact lenses, punctal plugs, lid closure with botulinum toxin and surgical interventions like tarsorrhaphy, conjunctival flaps and amniotic membrane provide greater success but often at the cost of obscuring sight. Corneal surgery in a dry ocular surface with reduced sensation is at high risk of failure. The recent advent of biologicals such as biopolymers mimicking heparan sulfate; coenzyme Q10 and antisense oligonucleotide that suppress connexin 43 expression, all offer promise. Recombinant nerve growth factor (cenegermin), recently approved for human use targets the nerve pathology and has the potential of addressing the underlying deficit and becoming a specific therapy for NK.
Persistent Impairment of Quality of Life in Patients with Herpes Simplex Keratitis
2017, Ophthalmology
Citation Excerpt :
Another explanation is the effect of recurrent HSK on ocular surface quality. Unilateral recurrent HSK induces bilateral DED over time,14 and, regardless of the initiating mechanism, DED induces a significant reduction in the QoL of patients.25 We observed that the results in all vision-related dimensions of the QoL questionnaires (daily activities, social behavior, sociability, and dependency) were significantly correlated to the VA in the affected eye.
To evaluate the quality of life (QoL) in patients with quiescent herpes simplex keratitis compared with control patients without ocular herpes.
Prospective, case-control study.
Thirty-three patients with a unilateral and relapsing herpes simplex keratitis (HSK group) that was quiescent during evaluation (no acute episode in the past 3 months) and 66 patients with no history of HSK (control group). Both groups were age and gender matched.
Three previously validated QoL questionnaires were used in this study: the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25), Glaucoma Quality of Life 17 (Glau-QoL17) questionnaire, and Ocular Surface Disease Quality of Life (OSD-QoL) questionnaire. Each questionnaire covered various aspects of the disease.
The outcomes of the 3 questionnaires were compared between groups. For the HSK group, the results were correlated to the clinical findings and the history of herpetic disease.
The mean total questionnaire scores of the 3 QoL questionnaires were significantly lower in the HSK group compared with controls (NEI VFQ-25: 70.5±3.8 vs. 91.1±0.8, P < 0.0001; Glau-QoL17: 68.2±3.1 vs. 87.9±1.0, P < 0.0001; and OSD-QoL: 65.4±2.9 vs. 93.1±0.6, P < 0.0001, respectively). In the HSK group, the level of visual acuity (VA) in the affected eye had the greatest impact on QoL, inducing lower QoL results related to “general vision,” “distance activities,” “dependency,” “peripheral vision,” “self-image,” “daily living,” and “driving” dimensions. Decreased VA in the unaffected eye also negatively affected “self-image” and “driving” results. Patients with frequent HSK relapses had lower QoL related to “ocular pain” and “acknowledgement.”
Even during a quiescent phase of the disease, unilateral and relapsing HSK significantly impairs the QoL of patients to a similar level as most sight-threatening diseases. The decrease of VA has the greatest overall effect, but other factors also significantly affect QoL, such as the frequency of relapses.

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: Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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Original articleImpairment of Lacrimal Secretion in the Unaffected Fellow Eye of Patients with Recurrent Unilateral Herpetic Keratitis

Purpose

Design

Participants and Controls

Methods

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Patients

Results

Factors Related to Corneal Herpes That May Induce Tear Dysfunction

Surv Ophthalmol

Exp Eye Res

Surv Ophthalmol

Ophthalmology

Ocul Surf

Prog Retin Eye Res

Ophthalmology

Ophthalmology

Ophthalmology

J Neurol Sci

Herpes simplex virus epidemiology and ocular importance

Cornea

Epidemiology of ocular herpes simplex. Natural history in Rochester, Minn, 1950 through 1982

Arch Ophthalmol

Tear film flow and stability in herpes simplex keratitis and chronic blepharitis

Acta Ophthalmol (Copenh)

Schirmer test values and lysozyme content of tears in acute dendritic keratitis

Invest Ophthalmol Vis Sci

Incidence of herpes simplex virus keratitis in France

Ophthalmology

Reflex and steady state tears in patients with latent stromal herpetic keratitis

Invest Ophthalmol Vis Sci

Tear osmolarity and ocular surface disease in keratoconjunctivitis sicca

Arch Ophthalmol

Using osmolarity to diagnose dry eye: a compartmental hypothesis and review of our assumptions

Adv Exp Med Biol

Tear osmolarity in the diagnosis and management of dry eye disease

Am J Ophthalmol

Role of the corneal nerves in destructive disease of the cornea

Trans Ophthalmol Soc U K

Tear film osmolarity measurements in dry eye disease using electrical impedance technology

Cornea

Original article
Impairment of Lacrimal Secretion in the Unaffected Fellow Eye of Patients with Recurrent Unilateral Herpetic Keratitis