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 Table of Contents  
CLINICAL PRACTICE GUIDELINES
Year : 2019  |  Volume : 57  |  Issue : 4  |  Page : 308-310

Nummular keratitis – A modern-day conundrum


1 Darshan Eye Care and Surgical Centre, Chennai, Tamil Nadu, India
2 Darshan Eye Care and Surgical Centre, Chaithanya Eye Hospital and Research Institute, Trivandrum, Kerala, India

Date of Submission08-Nov-2019
Date of Acceptance10-Nov-2019
Date of Web Publication26-Dec-2019

Correspondence Address:
Dr. Srinivas K Rao
T 80 (New No. 24), 5th Main Road, Anna Nagar, Chennai - 600 040, ,Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tjosr.tjosr_104_19

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How to cite this article:
Rao SK, Srinivas SP, Nair AK. Nummular keratitis – A modern-day conundrum. TNOA J Ophthalmic Sci Res 2019;57:308-10

How to cite this URL:
Rao SK, Srinivas SP, Nair AK. Nummular keratitis – A modern-day conundrum. TNOA J Ophthalmic Sci Res [serial online] 2019 [cited 2020 Jan 19];57:308-10. Available from: http://www.tnoajosr.com/text.asp?2019/57/4/308/273990



Normal corneal structure and function is essential for excellent vision and comfort. Sometimes, however, the presence of fine granular opacities in the shape of a coin can cause extreme patient discomfort and vision loss, and this condition is termed nummular keratitis. This is not a new entity, although it has acquired greater significance in recent times. With the recent endemic presence of severe adenovirus keratoconjunctivitis, this is probably the most important cause of nummular keratitis today. This article attempts to answer these questions and provide a rationale for the clinical approach to the management of adenoviral keratoconjunctivitis.

Normal corneal structure and function is essential for excellent vision and comfort. Sometimes, however, the presence of fine granular opacities in the shape of a coin can cause extreme patient discomfort and vision loss, and this condition is termed nummular keratitis. This is not a new entity, although it has acquired greater significance in recent times. It was first described by Dimmer[1] in 1905, and in an elaborate article in 1957, Pillat[2] tried to distinguish Dimmer's keratitis from the changes that occur after adenovirus keratoconjunctivitis, as he believed that the two were distinct entities. However, despite his elaborate discussion, no clear distinction could be found, and in 1983, von Bijsterveld and Obster[3] confirmed that Dimmer's keratitis falls under a heterogeneous group of diseases, characterized by distinct corneal changes, and it is difficult to distinguish the various entities causing these changes on corneal appearance alone. With the recent endemic presence of severe adenovirus keratoconjunctivitis, this is probably the most important cause of nummular keratitis today.

Adenovirus is a double-stranded DNA virus comprising of seven species (HAdV A–G), with fifty serotypes and seventy genotypes. It is responsible for respiratory, enteric, and ocular infections, and strains 8, 19, and 37 cause epidemic keratoconjunctivitis (EKC).[4] It is an unusually stable virus, resistant to a wide variety of physical, chemical, and pH changes, and this is responsible for its endemic presence over the centuries, and from clinical experience, it appears that its virulence has increased in recent times. Adenoviral infections, like all viral infections, are designed to be self-limited. The virus takes over the cellular machinery to multiply and propagate itself to other hosts. In immunocompromised hosts, it can destroy the tissue of residence as in Cytomegalovirus retinitis, but is usually eliminated by the host immune response, as in rhinovirus infections. In order to exist and multiply in the host, viral infections reduce host inflammatory responses and inhibit cellular apoptotic mechanisms to allow viral replication. However, a knockout of some genes in the adenovirus, which decreases the expression of the E1a and E3 proteins, reduces the ability of the virus to mute the host immune response, resulting in more severe clinical features.[5]

The usual course of adenovirus infections is to produce an infection of corneal epithelial cells, causing a fine superficial punctate keratitis in the 1st week, followed by the appearance of nummular subepithelial infiltrates (SEIs) at the level of the basement membrane and Bowman's layer by 2–3 weeks. It is believed that these changes represent a host immune response using polymorphonuclear leukocytes and lymphocytes. However, when managing adenovirus keratoconjunctivitis, several questions remain. Why do these subepithelial “nummular” lesions not occur in all adenovirus infections, what is the pathogenesis of these lesions, do they occur only in the more severe infections, is routine steroid use at the start of the infection deleterious to the cornea, is scarring inevitable in the natural history of SEI, and what is the best approach to managing and also preventing the occurrence of these lesions. This article attempts to answer these questions and provide a rationale for the clinical approach to the management of adenoviral keratoconjunctivitis.

It is known that ocular adenovirus infections can occur in three forms – simple follicular conjunctivitis, pharnygoconjunctival fever, and EKC. Keratitis is seen only in EKC. The Adenoplus rapid detection kit (Visufarma, Amsterdam, Netherlands) cannot distinguish between adenovirus strains; it can confirm the presence of adenovirus infection, but not the type. Hence, infections by strains 8, 19, and 37 are more likely to cause SEIs.[6] Jones[7] reported that SEIs represent the host immune response to the presence of viral antigens in the superficial stroma, thereby reaching diffusion during the epithelial infection stage. Recently, Chodosh et al.[6] have suggested that SEI may represent stromal infection by the virus, with a resultant host immune response. That these lesions are immunological in origin is further confirmed by the similarity in clinical appearance with Krachmer spots seen in corneal graft rejection, a host immune response against the graft antigens.[8] More severe infections occur when the viral pathogenicity is increased in some strains, resulting in increased antigenic load, or when host immune tolerance is abrogated, resulting in increased immune response. As SEIs represent an immune reaction, in both of these instances with more severe infections, the occurrence of SEIs increases.

Rabbit studies have shown that steroid use increases adenoviral replication,[9] and as increased epithelial infection promotes viral diffusion into the anterior stroma, steroids are best avoided in the routine initial management of EKC to decrease the occurrence of SEI. Untreated SEIs, with increased accumulation of immune cells and mediators in the anterior stroma, can result in the destruction of corneal collagen and stromal scarring. Hence, steroid use should be considered when appropriate to protect corneal clarity. These situations for steroid use include central SEI causing visual degradation; occupational requirements for clear vision, namely, ophthalmic surgeons; and when there is a confluence of SEI with overlap of adjacent spots as this can result in accelerated corneal damage and scarring. Thus, peripheral SEI or those causing only irritative symptomatology are best observed. Such lesions usually clear with time, as the immune defense removes the viral antigen – usually three episodes occur at 6–8 weeks, 3–4 months, and 9–12 months, with successive episodes being shorter in duration and lesser in severity.

Usually, surface-acting steroids such as loteprednol and fluorometholone suffice, although in the most severe cases, initiation of therapy with prednisolone or dexamethasone may be necessary. Once started, however, a very gradual taper of steroid therapy is required to reduce the chance of recurrence. The addition of 0.05%[10] or 1% topical cyclosporine A[11] and 0.03% tacrolimus ointment[12] has been reported to reduce the recurrence rate. A recent article describes the use of intracorneal injection of 0.2-ml betamethasone and 0.2-ml ganciclovir adjacent to the SEI, with good success.[13] Although the adenovirus does not respond to antivirals except cidofovir, there are reports that topical ganciclovir therapy[14] or treatment with 5% povidone-iodine,[15] or the combination of 1% povidone-iodine with 0.1% dexamethasone,[16] may limit the initial viral proliferation and antigenic load. Once SEIs are established, excimer surface ablation has been reported in the removal of these lesions, although the results are variable, with some articles reporting increased scarring after treatment.[17],[18] Once scars are formed, however, the treatment is either a rigid contact lens or superficial anterior lamellar keratectomy.

While adenovirus infections are currently the predominant cause of corneal SEIs, other conditions have been described. These include  Brucellosis More Details,[19] acanthameba,[20] lyme disease,[21] adult inclusion conjunctivitis,[22] Epstein–Barr virus,[23] herpes simplex virus and herpes zoster[24] corneal infections, and hyperimmunoglobulin D disease.[25] Recognizing these entities from adenovirus SEIs is usually based on the absence of a preceding attack of conjunctivitis, unusual persistence of lesions, a strictly unilateral occurrence, altered morphology and deeper location of the SEI, the presence of corneal findings such as peripheral vascularization and opacification, ocular findings such as keratic precipitates and anterior chamber reaction, and the occurrence of features of the accompanying systemic disease. However, adenovirus EKC still remains the most important cause of SEI, and it is important when such patients present in the acute stage to try and avoid steroid therapy unless imperative to reduce the occurrence of SEIs. If SEIs occur, however, appropriate initiation and taper of steroid therapy along with other immunomodulators can help protect corneal clarity and visual function, although this may be a protracted process requiring patience on the part of the surgeon and the patient. Hence, although common, nummular keratitis remains a corneal sign and not a specific disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Dimmer F. Nummular keratitis and its related corneal inflammation. Ztschr Augenh 1905;13:621-35.  Back to cited text no. 1
    
2.
Pillat A. The differential diagnosis of nummular keratitis (Dimmer) and epidemic keratoconjunctivitis. Am J Ophthalmol 1957;43:58-63.  Back to cited text no. 2
    
3.
van Bijsterveld OP, Obster R. Dimmer's keratitis nummularis, a doubtful disease. Klin Monbl Augenheilkd 1983;183:169-72.  Back to cited text no. 3
    
4.
Chigbu DI, Labib BA. Pathogenesis and management of adenoviral keratoconjunctivitis. Infect Drug Resist 2018;11:981-93.  Back to cited text no. 4
    
5.
Radke JR, Cook JL. Human adenovirus infections: Update and consideration of mechanisms of viral persistence. Curr Opin Infect Dis 2018;31:251-6.  Back to cited text no. 5
    
6.
Chodosh J, Astley RA, Butler MG, Kennedy RC. Adenovirus keratitis: A role for interleukin-8. Invest Ophthalmol Vis Sci 2000;41:783-9.  Back to cited text no. 6
    
7.
Jones BR. The clinical features of viral keratitis and a concept of their pathogenesis. Proc R Soc Med 1958;51:917-24.  Back to cited text no. 7
    
8.
Alldredge OC, Krachmer JH. Clinical types of corneal transplant rejection. Their manifestations, frequency, preoperative correlates, and treatment. Arch Ophthalmol 1981;99:599-604.  Back to cited text no. 8
    
9.
Romanowski EG, Yates KA, Gordon YJ. Topical corticosteroids of limited potency promote adenovirus replication in the Ad5/NZW rabbit ocular model. Cornea 2002;21:289-91.  Back to cited text no. 9
    
10.
Muftuoglu IK, Akova YA, Gungor SG. Effect of 0.05% topical cyclosporine for the treatment of symptomatic subepithelial infiltrates due to adenoviral keratoconjunctivitis. Int J Ophthalmol 2016;9:634-5.  Back to cited text no. 10
    
11.
Levinger E, Slomovic A, Sansanayudh W, Bahar I, Slomovic AR. Topical treatment with 1% cyclosporine for subepithelial infiltrates secondary to adenoviral keratoconjunctivitis. Cornea 2010;29:638-40.  Back to cited text no. 11
    
12.
Levinger E, Trivizki O, Shachar Y, Levinger S, Verssano D. Topical 0.03% tacrolimus for subepithelial infiltrates secondary to adenoviral keratoconjunctivitis. Graefes Arch Clin Exp Ophthalmol 2014;252:811-6.  Back to cited text no. 12
    
13.
Arenas E, Mieth A, Muñoz D. Combined intrastromal injection of ganciclovir and depot betamethasone for the management of nummular keratitis: Case series. Arch Soc Esp Oftalmol 2019;94:347-51.  Back to cited text no. 13
    
14.
Yabiku ST, Yabiku MM, Bottós KM, Araújo AL, Freitas DD, Belfort R Jr. Ganciclovir 0.15% ophthalmic gel in the treatment of adenovirus keratoconjunctivitis. Arq Bras Oftalmol 2011;74:417-21.  Back to cited text no. 14
    
15.
Yazar H, Yarbag A, Balci M, Teker B, Tanyeri P. The effects of povidone iodine (pH 4.2) on patients with adenoviral conjunctivitis. J Pak Med Assoc 2016;66:968-70.  Back to cited text no. 15
    
16.
Kovalyuk N, Kaiserman I, Mimouni M, Cohen O, Levartovsky S, Sherbany H, et al. Treatment of adenoviral keratoconjunctivitis with a combination of povidone-iodine 1.0% and dexamethasone 0.1% drops: A clinical prospective controlled randomized study. Acta Ophthalmol 2017;95:e686-92.  Back to cited text no. 16
    
17.
Alevi D, Barsam A, Kruh J, Prince J, Perry HD, Donnenfeld ED. Photorefractive keratectomy with mitomycin-C for the combined treatment of myopia and subepithelial infiltrates after epidemic keratoconjunctivitis. J Cataract Refract Surg 2012;38:1028-33.  Back to cited text no. 17
    
18.
Pineda R, Talamo JH. Late onset of haze associated with viral keratoconjunctivitis following photorefractive keratectomy. J Refract Surg 1998;14:147-51.  Back to cited text no. 18
    
19.
Woods AC. Nummular keratitis and ocular brucellosis. Arch Ophthal 1946;35:490-508.  Back to cited text no. 19
    
20.
Reinhard T, Schilgen G, Steinert M, Hacker J, Sundmacher R. Nummular infiltrates in Acanthamoeba keratitis. Acta Ophthalmol Scand 2003;81:541-3.  Back to cited text no. 20
    
21.
Lesser RL. Ocular manifestations of Lyme disease. Am J Med 1995;98:60S-2S.  Back to cited text no. 21
    
22.
Stenson S. Adult inclusion conjunctivitis. Clinical characteristics and corneal changes. Arch Ophthalmol 1981;99:605-8.  Back to cited text no. 22
    
23.
Pinnolis M, McCulley JP, Urman JD. Nummular keratitis associated with infectious mononucleosis. Am J Ophthalmol 1980;89:791-4.  Back to cited text no. 23
    
24.
Purtscher E. Clinical punctures of keratitis nummularis; occurrence of nummular corneal deposits in Dimmer's keratitis nummularis, keratitis herpetic, zoster keratitis and epidemic keratoconjunctivitis. Albrecht Von Graefes Arch Ophthalmol 1953;154:207-23.  Back to cited text no. 24
    
25.
Kraus CL, Culican SM. Nummular keratopathy in a patient with Hyper-IgD Syndrome. Pediatr Rheumatol Online J 2009;7:14.  Back to cited text no. 25
    




 

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