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Dermatopathology: Practical & Conceptual July - September 2008
7. Hypothesis: The pathogenesis of rosacea keratitis
Almut Böer, M.D.
Review of the literature
Review of the literature
Fewer than 30 articles were identified that investigated and/or discussed pathogenetic mechanisms that might contribute to the clinical manifestation of so-called ocular rosacea. [
] While it is long known that rosacea may at times involve the eye, considerable confusion about the pathogenesis existed already in the beginning of the last century. A comprehensive work by Walker published in 1948 included a review of previous studies by various colleagues who had suggested that "digestive upsets" (Ryle and Berber 1920, Brown 1925, Eastwood 1928 and 34), "deficiency diseases" (Johnson and Eckard 1940, Sydenstricker, Sebrell, Cleckley and Kruse 1940, Johnson 1941, Fish 1943), and "hormonal disorders" (Zondek, Landau and Bromberg 1947) contributed to the development of rosacea keratitis. All these authors agreed that rosacea keratitis was a manifestation of a systemic metabolic disease and not a local process. [
] Walker herself, however, studied 76 patients with ophthalmic rosacea, 50 of whom had signs of keratitis while 26 showed only blepharitis and conjunctivitis. Walker investigated the association of rosacea with allergies and found that 52 of her patients had signs of allergies. Therefore she concluded that rosacea keratitis is an allergic condition. [
Borrie, in 1953, noted blepharitis involving the meibomian glands in nearly 100% of patients having rosacea, [
] while Jenkins et al., in 1979, found foreign body sensation, burning, superficial punctate erosions, chalazia, and blepharitis to be the most common signs of ocular rosacea. [
] The latter authors later studied systematically 75 patients with recurrent chalazia and noted 65% of them to have rosacea of the face clinically. [
] McCully and Sciallis, in two articles that appeared in 1977 and 1983, [
] confirmed that patients with chronic blepharitis involving meibomian glands often had rosacea of the face and they suggested that "
a generalized sebaceous gland dysfunction that included the meibomian glands"
might be the explanation for the association of skin and eye symptoms in those patients. The authors concluded that
"stagnation of the meibomian glands presumably caused a defect in the tear lipid layer, this resulted in an unstable tear film that produced superficial punctate keratopathy."
In 1981, Jester, Nicolaides, and Smith undertook a major study about histology of the meibomian glands independently from the situation in rosacea; they pointed out the similarities and differences between meibomian glands of the eyelids and sebaceous glands in the folliculosebaceous unit of the skin. [
] The authors postulated that
"abnormalities of keratinization"
may be responsible for what they called "
meibomian gland dysfunction
." These findings were confirmed by Gutgesell, Stern, and Hood, in 1982, who noted obstruction and dilatation of ducts, what they interpreted as squamous metaplasia, foreign body reaction, and granuloma formation in sections of tissue of patients who had what they called
"severe meibomian dysfunction"
and were undergoing ectropium repair. [
In 1984, Lemp and coworkers studied 60 patients with ocular rosacea with Schirmer's test and compared the results with those in healthy control subjects. The prevalence of dry eyes was significantly greater in the patients with rosacea. The authors hypothesized that
"The coexistence of keratoconjunctivitis sicca and ocular rosacea probably causes a high level of symptoms that lead patients to examination."
] Robin et al., however, in 1985, supported the hypothesis that "
dysfunction of meibomian glands
" might be an important factor in the pathogenesis of rosacea by in vivo transillumination biomicroscopy and they found marked distortion and loss of normal gland anatomy in patients with rosacea. [
Hoang-Xuang and coworkers investigated sections of tissue of epibulbar conjunctiva by immunofluorescence and immunohistochemistry; their results showed an increase of nearly all cell types in the conjunctiva of patients with rosacea, but especially of T-helper cells.[
] They concluded that
"rosacea is primarily a skin disease and . . . that all the ocular lesions are secondary to the eyelid involvement,"
but then they supposed that
"a type IV hypersensitivity reaction [is] . . . the predominant immunologic mechanism accounting for the conjunctival inflammation in ocular rosacea."
Gudmundsen et al., in 1992, suggested a connection between what he called "
and the finding of dry eyes in patients with rosacea, averring that "
If the outer lipid layer of the tear film, which is derived from meibomian gland secretions, is abnormal in rosacea, then the tear film may become unstable with greater tendency to break up and to evaporate, thereby resulting in dryness of the ocular surface."
] Occasionally extensive squamous hyperplasia of the meibomian duct has been reported in rosacea. [
Zengin et al., in 1995, confirmed again that patients with what they diagnosed as
"meibomian gland dysfunction"
and rosacea had a pathologic Schirmer test, that indicating that their tear film break-up time was significantly reduced; they suggested that
"meibomian gland dysfunction is an important feature in ocular rosacea
] Driver and Lemp, in 1996, in their review about meibomian gland dysfunction summarized that "
meibomian gland dysfunction is . . . an important form of blepharitis. . . . and frequently associated with dermatologic conditions such as acne rosacea."
And they continued to say that
"Histopathologic studies suggest that hyperkeratinization is important in the pathogenesis of meibomian gland dysfunction. Narrowing of the ductule lumen and desquamation of epithelial cells leads to glandular obstruction."
Akpek et al., also in 1996, examined more than 100 patients with rosacea involving the eye and found meibomian gland dysfunction, telangiectasia, and irregularity of the lid margins to be the features encountered most often, whereas conjunctival hyperemia and keratoconjunctivitis sicca were by far less common. [
] Nevertheless the authors concluded that
"none of the findings of ocular rosacea are specific."
Quarterman et al., in 1997, described erythema, telangiectasia, and meibomian gland dysfunction, defined as inspissation, distortion, and plugging of meibomian glands, as the most common sign of ocular rosacea. [
] Even though the authors stated that
"Rosacea is a vascular disorder,"
they added later that
"it is interesting to speculate that meibomian glands, a modified sebaceous gland of the eyelid, may play an important role in the disease."
Barton et al., in 1997, studied the concentrations of IL-1a, and TNFa in the tears of patients with rosacea, they observed an elevation of IL-1a, but the relevance of these findings was not explained compellingly by the authors. In their comment they say that
"it may form an important positive feedback mechanism that encourages tear stagnation and the perpetuation of ocular surface inflammation."
] Pisella, Brignole et al., in 2000, investigated the conjunctival epithelium by flow cytomeric analysis, they demonstrated an increase of HLA-DR and ICAM-1 and confirmed previous findings that Schirmer test was significantly decreased in patients with rosacea. [
] The authors claimed that
"the cause of ocular irritation in patients with rosacea has not yet been established"
and they propose that their results confirm that
"rosacea is most likely a consequence of chronic ocular surface disease."
In 2001,Yaylali and Ozyurt published a major study on ophthalmic rosacea that was undertaken to evaluate the significance of tear function tests in the disease. [
] The authors confirmed that patients with rosacea often complain about dry eyes that can be measured objectively by Schirmer test. Additionally they recognized that the most frequent clinical finding in ophthalmic rosacea was what they considered to be Meibomitis; it was noted in more than 90 % of the patients. All other findings like telangiectasis, blepharitis, and keratopathy were noted less often. The authors realized that
"most ocular symptoms [in rosacea] are related to dry eye"
"meibomian dysfunction . . . may aggravate the clinical findings of the ocular disease in rosacea"
but they did not interpret their findings in a pathogenetic point of view.
In 2004, Bron and Tiffany reviewed the current conceptions and hypotheses about the pathogenesis of tear film alterations and their consequences. They emphasized that a
"lipid layer is the major barrier to evaporation from the ocular surface."
In their opinion, a decrease in its thickness was likely to cause evaporative dry eye. They considered
"obstructive meibomian gland dysfunction"
to be the most common cause of the evaporative dry eye and mentioned that this condition occurs as a primary disorder or secondary to rosacea, seborrheic or atopic dermatitis, and with cicatrizing conjunctival disorders, such as trachoma, erythema multiforme, and cicatricial pemphigoid. [
As recently as 2007, Baudouin attempted to clarify the pathogenesis of diseases associated with a dry eye and stated that many different diseases could cause tear film impairment and ocular surface damage, by tear instability and evaporation, tear hyposecretion, or both. In his opinion,
"tear film instability/imbalance can be considered as the key point of dry eye disease."
He also mentioned that what he called meibomian gland dysfunction as well as lipidic changes influenced tear film stability directly facilitating tear evaporation. [
Articles about rosacea in the literature of dermatology, however, usually make no mention of pathophysiologic considerations in regard to ocular rosacea as they were published in the literature of ophthalmology. Wilkin, in 1994, stated that
"Ocular rosacea is principally vascular and correlates with the severity of flushing."
] Tanzi and Weinberg, in 2001, also stated that "
the ocular manifestations of rosacea are commonly nonspecific and variable. The etiology of the inflammation is unknown and there is no diagnostic test for the disease."
Michel and colleagues, in 2003, found only 6% of patients with cutaneous rosacea to have involvement of the eye; [
] the severity of the ocular damage did not correlate with the stage of cutaneous involvement. Ghanem et al., however, emphasized in their investigation on the prevalence of ocular signs in acne rosacea that dermatologists were not as skilled at recognizing involvement of the eye compared with ophthalmologists and that this doubtlessly affected the assessment of incidence of ocular rosacea if only charts of dermatology patients were reviewed. [
In a review article undertaken in 2004 by Stone and Chodos, the authors remarked that comparatively few papers on ocular rosacea have been published recently and that those on the pathogenesis of ocular rosacea focused on the role of bacterial lipases, and interleukin-1alpha and matrix metalloproteinases in the blepharitis and corneal epitheliopathy, respectively. [
] In a review article on Ocular rosacea that appeared in 2005, Alvarenga and Mannis suggested that
"an altered inflammatory response plays an important role in both cutaneous and ocular rosacea."
Recently, special attention has been given to involvement of the eye in children with rosacea. A study by Nazir et al., in 2004, on ocular rosacea in childhood revealed that eyelid telangiectases and what he called "meibomian gland disease" were the most common findings in these patients. [
] Cetinkaya and Akova, in 2006, studied four patients with ocular rosacea in pediatric patients and found Meibomitis, blepharitis, conjunctival hyperemia, and punctuate epitheliopathy to be present commonly. [
] In 2008, Chamaillard et al. studied cutaneous and ocular signs of childhood rosacea and found that among the ophthalmologic manifestations, chalazions and blepharoconjunctivitis were the main presenting symptoms. [
In sum, blepharitis, Meibomitis, so-called meibomian dysfunction and keratoconjunctivitis sicca are the changes mentioned most often in patients with ocular rosacea who are described in the literature of ophthalmology. Sicca syndrome can be demonstrated by Schirmer test. Meibomitis is diagnosed clinically by the presence of papules and pustules at the ostia of meibomian glands at the lid margin. meibomian gland dysfunction is a hypothesis rather than a clinical diagnosis. No method is available yet to demonstrate objectively that the gland itself plays a role pathogenetically. The only features demonstrated repeatedly by way of clinical and microscopic examination of the eyelid is alterations of the duct of meibomian glands which was said to be distorted, plugged, and exhibiting squamous differentiation. Histopathologic studies of rosacea of the eyelid do not exist, but it is interesting that just as in many biopsies taken from patients with rosacea, granuloma formation has been observed in patients with so-called meibomian dysfunction.
Special investigations applying methods of immunology and immunohistochemistry have not contributed much to the understanding of clinical symptoms in patients with this condition.
Similarities of rosacea of the skin and the eye are addressed rarely, and the pathogenetic considerations in regard to rosacea of the eye made by ophthalmologists mostly did not find entry into the literature of dermatology. Only few authors took into consideration that rosacea of the eye is primarily rosacea of the eyelid and that changes of the disease in both places might be essentially the same. On the eyelids of patients with rosacea, the openings of meibomian glands were often found to show inflammation and plugging. Some authors suggested that inflammation of meibomian glands followed by meibomian gland dysfunction could be responsible for conjunctivitis sicca in patients with ocular rosacea, because the secretion of meibomian glands is considered to contribute to the outer lipid layer of the tear film, thereby protecting in from evaporation.
Even in the most recent publications about ocular rosacea, considerations about pathophysiological connections between all signs and symptoms of patients with rosacea are sparse and there is no uniformly accepted explanation of the association of symptoms of the skin and the eye.
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