SURVEY OF OPHTHALMOLOGY VOLUME 31 NUMBER 3 NOVEMBER-DECEMBER 1986 REVIEW Ocular Rosacea DAVID J. BROWNING, M.D., PH.D.,’ AND ALAN D. PROIA, M.D., PH.D.* ‘Charlotte Eye, Ear, Nose and Throat Associates, Charlotte, North Carolina, and “Departments of Ophthnlmol- og,p and Pathology. Duke University Medical Center, Durham. North Carolina Abstract. The demographic, clinical, and histopathologic characteristics of ocular rosacea are reviewed, with emphasis on examination of the skin in patients with external ocular disease. Since no single clinical or pathological hallmark of rosacea exists, a proposed point system for diagnosis is presented. Studies of pathogenesis reveal that no single unifying hypothesis accounts for all the expressions of ocular rosacea. Reports of treatment with tetracycline and other antibiotics demonstrate efficacy, although the mechanisms of action of these drugs are not known. More recently, other classes of drugs, including isotretinoin and hexachlorocyclohexane, have proven to be effective in dermatologic manifestations of rosacea, but effects on ocular manifestations are unknown. (Surv Ophthalmol 31:145-158, 1986) Key words. dermatologic disease l ocular rosacea l rhinophyma l tetracycline Rosacea is a syndrome of unknown etiology in- volving the skin and eye. Recognition of the disease has been traced by Rolleston6’j at least as far back as Chaucer ( 1387)) whose description of the summon- er’s face in The Canterbury Tales evokes rosacea.” The painting “An Old Man and His Grandson,” by Ghirlandaio (1480), almost certainly depicts the characteristic rhinophyma of rosacea (Fig. 1). Shakespeare’s character, Bardolph, has a face that “is all bubukles and whelks, and knobs, and flames o’fire: and his lips blows at his nose, and it is like a coal of fire, sometimes blue and sometimes red . . .“76, which evokes advanced rosaceous facies well. Falstaff suggests an alcoholic etiology for Bar- dolph’s visage,” an hypothesis which has persisted among many students of the disease to the present.5 The ophthalmologic manifestations of the rosacea were not recognized as early as the dermatologic ones. According to Wise, g2ArlP first noted conjunc- tivitis and keratitis in patients with rosacea in 1864. A large literature on ocular rosacea has accumulat- ed since those early descriptions, with the most re- cent twentieth century reviews by Doggart,*’ Wise,g4 Fig. 1. “The Old Man and His Grandson,” by Ghirlan- diao (c. 1480), is thought to depict rhinophyma character- istic of rosacea.“6 45
Transcript
SURVEY OF OPHTHALMOLOGY VOLUME 31 NUMBER 3 NOVEMBER-DECEMBER 1986
REVIEW
Ocular Rosacea
DAVID J. BROWNING, M.D., PH.D.,’ AND ALAN D. PROIA, M.D., PH.D.*
‘Charlotte Eye, Ear, Nose and Throat Associates, Charlotte, North Carolina, and “Departments of Ophthnlmol- og,p and Pathology. Duke University Medical Center, Durham. North Carolina
Abstract. The demographic, clinical, and histopathologic characteristics of ocular rosacea are reviewed, with emphasis on examination of the skin in patients with external ocular disease. Since no single clinical or pathological hallmark of rosacea exists, a proposed point system for diagnosis is presented. Studies of pathogenesis reveal that no single unifying hypothesis accounts for all the expressions of ocular rosacea. Reports of treatment with tetracycline and other antibiotics demonstrate efficacy, although the mechanisms of action of these drugs are not known. More recently, other classes of drugs, including isotretinoin and hexachlorocyclohexane, have proven to be effective in dermatologic manifestations of rosacea, but effects on ocular manifestations are unknown. (Surv Ophthalmol 31:145-158, 1986)
Key words. dermatologic disease l ocular rosacea l rhinophyma l tetracycline
Rosacea is a syndrome of unknown etiology in-
volving the skin and eye. Recognition of the disease
has been traced by Rolleston6’j at least as far back as
Chaucer ( 1387)) whose description of the summon- er’s face in The Canterbury Tales evokes rosacea.” The painting “An Old Man and His Grandson,” by
Ghirlandaio (1480), almost certainly depicts the
characteristic rhinophyma of rosacea (Fig. 1).
Shakespeare’s character, Bardolph, has a face that
“is all bubukles and whelks, and knobs, and flames o’fire: and his lips blows at his nose, and it is like a
coal of fire, sometimes blue and sometimes red . . .“76, which evokes advanced rosaceous facies well.
Falstaff suggests an alcoholic etiology for Bar-
dolph’s visage,” an hypothesis which has persisted among many students of the disease to the present.5
The ophthalmologic manifestations of the rosacea were not recognized as early as the dermatologic ones. According to Wise, g2 ArlP first noted conjunc- tivitis and keratitis in patients with rosacea in 1864. A large literature on ocular rosacea has accumulat- ed since those early descriptions, with the most re- cent twentieth century reviews by Doggart,*’ Wise,g4
Fig. 1. “The Old Man and His Grandson,” by Ghirlan- diao (c. 1480), is thought to depict rhinophyma character- istic of rosacea.“6
Fig. 2. Rosacea in a black patient. Extreme oiliness of the skin and rhinophyma are illustrated. Severely affected right eye has been enucleated and replaced with a pros- thesis. (Reprinted from Browning DJ, Rosenwasser G, Lugo M: Am J Ophthalmol 101:441-444, 1986, with per- mission of Ophthalmic Publishing Company.)
Goldsmith 27 and Stenson.82 This review emphasizes
progress in the study of this disease since Gold-
smith’s 1953 review.
I. Demographic Characteristics
Ocular rosacea most commonly affects adults but may occasionally occur in patients in their late
teens.g,40191 The age range most common for patients with rosacea, as reported in the dermatologic litera- ture, is 40 to 50 years. ‘s40 In a series of 47 patients with ocular rosacea, the decade of peak prevalence was 5 l-60 years. 32 The youngest rep orted patient in modern studies was 14 and Triebenstein in 1922
reported no cases in children under age 10 among 274 patients with rosacea.85 Rosacea without ocular involvement involves women twice as often as men g,7’,g4 but cases with ocular manifestations are about evenly divided between the sexes or show only a small female preponderance. The distribution of cases by age in the two sexes is similar.9%“0
Fig. 3. Patient affected primarily with erythema and flushing.
There are no data on the variation in prevalence
of rosacea among races. Wise reported that only one
case of rosacea in a black had appeared in the world literature prior to 1943 and that none of his 60 pa-
tients were black, leading him to conclude that “ro- sacea probably does not occur in the Negro race.‘19’
Dermatologists, however, accept the existence of ro-
sacea in blacks, although the condition is rare.‘Q3 Recently, Browning et alI5 documented ocular rosa- tea in blacks. Increased pigmentation masking the early lesions of rosacea may account for previous failure to recognize the disease in blacks. As far as we know, there are no data in the English literature on prevalence of rosacea in oriental races.
There is a widespread clinical impression that rosacea mainly affects fair-skinned people of north- ern European descent, but we are unaware of hard data to substantiate this. Most reports, however, do originate from institutions serving such patient pop- ulations 1.7.9-11,13.14,20.21,27,31.4~,64,79
OCULAR ROSACEA
Fig. 4. Patient with telangiectasia as most promine component, but with erythema and papules as well. chalazion of the left lower lid is present.
nt
A Fig. 5. Photograph of a patient with severe facial and
ocular rosacea who developed cornea1 neovascularization and scarring of both eyes and required cornea1 transplan-
tation for the left eye. (See Fig. 6.)
IX. Skin Manifestations
Skin involvement in rosacea is characterized by
erythema, telangiectasis, papules, pustules, and se-
baceous gland hypertrophy. Various presentations
of rosacea are shown in Figs. 2-5. The lesions are reported to be distributed only in ilush areas, in- cluding cheeks, forehead, nose, chin, and the “V” of
the neck. Certain persons flush in other areas, such
as the epigastrium, and rosaceous lesions can occur there in such casesgo Rosacea is distinguished from
acne vulgaris by the absence of comedones and by
its confinement to flush areas. Acne vulgaris com- monly involves the back and chest as well as the
face. In addition, the flushing and phymatous changes seen in rosacea are not features of acne vulgaris. Rosacea generally affects patients older than those affected by acne vulgaris. Since both ro- sacea and acne vulgaris are common diseases, it is not uncommon for a single patient to have both diseases.
and burning, recurrent chalazia, cornea1 vasculari-
zation and scarring, cornea1 and scleral perforation, episcleritis and iritis have all been reported to occur in rosacea.g~2’*3’,64,67~81.g4 The minor ocular manifesta-
tions are more prevalent than the major ones (Table
1). As would be expected, reports from ophthalmol- ogy clinics indicate higher prevalences of ocular
manifestations than reports from dermatology chn-
its. It is reported that ocular rosacea is usually bi- lateral,2” but data documenting this point are lack- ing. Except for interstitial keratitis, all of the eye lesions in rosacea are nonspecific. Regarding inter- stitial keratitis, Duke-Elderz3 and Goldsmithz7 de-
scribed a “pathognomonic” picture of superficial cornea1 vessels in a zone of cornea1 opacity at the limbus, especially inferiorly. Roper-HalP’ described specific vascularized triangular cornea1 stromal
*Present paper. Not all reports summarized in this table denote ocular signs in the same way. Wise’s g4 conjunctivitis and
keratitis categories correspond to our conjunctival hyperemia and cornea1 vascularization and scarring categories, respectively. Jenkins et al’s3’ stromal thinning and vascularization category corresponds to our cornea1 vascularization and thinning category and their thinning, vascularization, and infiltrates category corresponds to our cornea1 vascularization and infiltrate. The eighteen patients in the report by Brown and Shahinian~3 were subsumed in the 49 patients in the report by Jenkins et al; 31 thus only the larger series is included here.
Other data on prevalence exists (e.g., Ref. 9), but these were broken down according to sex without giving numbers ofpatients in each category and therefore are not readily comparable to the series summarized here.
opacities with bases toward the limbus and a clear
zone separating the base of the opacity and the lim-
bus. Not all agree that the keratitis is specific, how- ever,94 and our clinical experience suggests that it is
not. A masked study in which photographs of inter- stitial keratitis of rosacea and of other etiologies are
examined to determine if a clinical distinction can be made would be useful. Vitritis has not previously been associated with active ocular rbsacea; howev- er, in our series of41 patients, two patients have had vitritis not explained by other etiologies. We do not propose that rosacea caused the vitritis in these
cases, but the association seems frequent enough to merit inclusion with other rarely documented mani- festations of rosacea.
The clinical appearances of the eye lesions of ro- sacea have been well described elsewhere.2’~23*27 Sev- eral of these lesions (chalazion, conjunctival hypere- mia, episcleritis, cornea1 scarring and vessels) are
illustrated in Figs. 2-6. Excellent photographs of other ocular lesions are found in Stenson’s chapter,82
and photographs with accompanying clinical histo-
ries are found in Donaldson’s.22
A number of associated clinical observations have been reported. ~oldsmithz7 described a scant wa-
tery discharge seen in patients with conjunctival hyperemia. Lemp et a137 reported that 36.6% of 60 rosacea patients had subnormal tear production compared to only 4.1% of 120 controls using Schirmer’s test without anesthesia. <Jenkins et a13’
noted that patients with ocular rosacea frequently had complaints of burning out of proportion to the clinical signs of disease, and we have been struck by this also. Lempert et aP found that 57% of all pa- tients over age 19 scheduled for chaiazion excision had rosacea. Several observers have commented on the frequent superimposition of staphylo~oc~al blepharoconjunctivitis on the basic lid margin and
OCULAR ROSACEA
Fig. 6. Photographs of eyes of patient in Fig. 5 prior to penetrating keratoplasty. Left: The cornea1 surface has been distorted by scarring as seen by the irregular light reflex. Right: Engorged cornea1 new vessels.
conjunctival abnormalities of rosacea.2’.25.g4
IV. Relationship of Skin and Ocular Mamfestations
To diagnose rosacea with certainty, skin manifes-
tations must be present. The ocular manifestations
alone are too nonspecific to enable a reliable diagno- sis to be made.‘.” It is, therefore, important that the
ophthalmologist be able to recognize the variable
presentation of facial rosacea in order to make the
diagnosis. The prevalence of ocular involvement in
a genrral population of patients with rosacea is un-
known but has been reported to be as low as 3%” and high as 58%.Kl Because the ocular manifesta- tions are so varied, it would be useful in future stud-
ies to analyze prevalence of ocular manifestations
according to specific entities (e.g., episcleritis, su-
perficial punctate keratopathy, etc.), as Jenkins et al” and Brown and Shahinian’j have done.
In patients who have both skin and ocular mani-
festations, 20% develop their ocular manifestations
first, 53% develop their skin lesions first, and 27%
develop both manifestations simultaneously.g Since
the proper diagnosis cannot be made until skin le-
sions develop, it is apparent that proper therapy
(tetracycline) for a large subset of patients will often be delayed.
There have been few reports comparing the natu- ral history of the ocular and skin manifestations of rosacea. Some authors feel that the courses taken by skin and eye changes are independent of each oth- er,g.1’.6i but others affirm a correlation.“’ More spe-
cifically, Starr and MacDonald”’ found a statistical-
ly significant association between a strong tendency to flush and the presence of ocular manifestations of rosacea. Our experience with these patients sup-
ports the view that a flare of ocular manifestations
often occurs without skin involvement, but a formal
natural history study to specifically address the
point would be useful in resolving the controversy.
V. The Problem of Underdiagnosis
Duke-Elder” stated that ocular rosaea is a com-
mon disease that is frequently undiagnosed, and
more recent authors have echoed this impression.”
Lempert et al:jH emphasized that 57% of patients
presenting for excision of chalazia were found to
have rosacea. At least three factors contribute to the
problem of underdiagnosis.
First, the ophthalmolgist often fails to inspect the
entire face when performing the external ocular ex-
amination. It should be emphasized that the skin
lesions required to confirm a suspicion of ocular
rosacea need not be severe. Minor erythema, telan-
giectasia, or the presence of a few papules or pus-
tules may help to establish a questionable diagnosis.
Second, 20% of patients present with the nonspe-
cific ocular problems of rosacea. but ha\re not yet
developed the skin lesions.’ In these cases, there is no test that can distinguish rosacea from other dis-
eases causing the same nonspecific signs and symp-
toms. Abelson et al’ reported that tear pH was ele-
vated in seven patients with active ocular rosacea
but normal in twenty patients with a variety of other ocular diseases; tear pH returned to normal in pa- tients treated with tetracycline. The authors sug- gested that tear pH be used to confirm the diagnosis of active ocular rosacea, but acknowledged that fur- ther studies of tear pH values in patients with other ocular disorders needed to be done before the test’s specificity could be established. In contrast. Jaros and COW” found tear pH to br si,qnificantly acidic
in patients with ocular rosacea compared to control
patients. BrowningI found that patients with ocular
rosacea had tear pH identical to that of control pa-
tients. Further attempts to find a test separating
ocular rosacea in patients without skin lesions are
warranted, as the disease is common and the treat-
ment specific and effective.
A third factor responsible for underdiagnosis is
the lack of criteria for the ophthalmologist in mak-
ing a definitive diagnosis. As the pathogenesis of the
disease is unknown and no undisputed histopatho-
logic or laboratory hallmark ofthe disease exists, the
diagnosis rests largely on a constellation of clinical
signs. In other diseases in which diagnosis is based
strictly on clinical examination, such as Behqet’s
disease and rheumatoid arthritis, point systems for
expressing degree of confidence in diagnosis have
been developed. We believe a similar approach is
warranted in studying rosacea? and we suggest the
scheme shown in Table 2. This scheme acknowl-
edges the primacy of dermatologic findings in that
one or more of these characteristics must be present to yield the 20 or more points required to make a probable diagnosis. A certain diagnosis would also require a concurring dermatologic consultation, since a variety of acneiform eruptions, drug reac- tions, polymorphous light eruptions, and other con- ditions can confuse the ophthalmologist unfamiliar with dermatologic differential diagnosis. A tentative diagnosis based on a point total of 11-19 would be possible solely from ophthalmologic findings, thus accommodating Borrie’s observation that these pre- cede dermatologic manifestations in 20% of pa- tients.” A clinical suspicion is raised by a point total from 6 to 10. It is our bias that treatment with tetracycline need not be withheld because the diag- nosis is less than certain. In fact, response to a clini- cal trial of this drug may be helpful in confirming a tentative diagnosis. Consultation from a dermatolo- gist in diagnosing rosacea and managing the skin disease is invaluable.
VI. Hypotheses of Etiology
The etiology of rosacea is unknown, as the prolif- eration ofhypotheses attest. Many studies have pro- vided negative data, however, tending to rule out certain hypotheses. Some newer studies have pro- vided clues to etiologies not previously considered.
A. BACTERIAL INFECTION
Marks+’ examined the hypothesis that rosacea re- flects a bacterial infection by culturing skin swabs and skin biopsies of patients with rosacea. Cultures of swabs grew micrococcus and Staphylococous aureus,
with no predominent strain. The skin biopsies were
sterile in 44% of cases and in the biopsies from
TABLE 2
Signs and Symptoms of Rosacea With Suggested Assignment of Points
Clinical Sign or Symptom Points
Rhinophyma 20 Pustules 9 Papules 9 Telangiectasia 8 Erythema 8 Cornea1 new vessels 3 Cornea1 scarring or thinning 3 Recurrent chalazia 2 Recurrent hordeola 2 Blepharitis 1 Conjunctival hyperemia 1 Meibomian gland plugging 1 Short tear break up time 1 Superficial punctate keratopathy 1 Iritis 1 Burning or tearing of eyes 1 Flushing 1
Suggested interpretation: Clinical suspicion = G-10 points Tentative diagnosis = 1 l-19 points Probable diagnosis = 20 or more points Certain diagnosis = 20 more points with concurring
opinion of consulting dermatologist.
Skin lesions must be confined to flush areas for the diagno-
sis of rosacea to be considered. The weight for each manifes-
tation was chosen to insure that a certain diagnosis requires
one or more of the characteristic facial dermatological fea-
tures. More weight is given for signs that are more easily
verified by independent examiners (such as papules and pus-
tules), and less weight for less easily verifiable signs or symp-
toms (such as erythema and flusding).
which organisms were cultured, the isolates were normal flora. The presence of mycobacteria was ruled out by culturing skin biopsies on Lowenstein- Jensen slants and by staining histologic sections with the Ziehl Nielsen acid fast technique. No con-
trol patients were studied. Wise performed a similar study in patients with rosacea blepharoconjunctivi- tis.g” Cultures from lid margins and conjunctiva were taken in 200 control patients, 38 patients with ocular and facial rosacea, and 22 patients with facial rosacea alone. Results of cultures were categorized only as pathogen or nonpathogen. “Pathogens” (noted to be staphylococci in all but one case) were isolated in 60.5% of patients with ocular and facial rosacea, 22.7% of cases with facial rosacea, and 4.5% of controls. The ocular rosacea patients with positive cultures had signs and symptoms common in staphylococcal infections, and Wise interpreted the infection to be secondary to the underlying rosacea.
These data taken together suggest that whereas patients with rosacea may often have secondary in-
OCULAR ROSACEA 151
fection, the etiology cannot he bacterial as it is not
uncommon to see clinically typical lesions of rosacea that are sterile. Better controlled studies with efforts to isolate organisms that fail to grow on convention- al media (e.g., anaerobic organisms and mycoplas- mas) seem justified, however, in view of the fact that most of the effective therapies of the disease are antibiotics.
B. CLIMATIC EXPOSURE
Sobye,“’ surveying 128 consecutive patients pre- senting to a dermatology clinic with rosacea, found that 66.4% presented during the months of March, 4pril. and May, and suggested a relationship of disease exacerbation to Springtime increase in sun exposure. Aggravation by heat was reported in 18/128 patients and by cold in 19/128 patients.” Goldsmith analyzed 117 attacks of rosacea keratitis observed in patients of Middlesex Hospital, Eng- land and found a marked preponderance of attacks in spring, peaking in May.?’
Marks used three approaches to assess the hypothesis that exposure to sun, wind, or cold is important in the pathogenesis of rosacea.t” First, he examined the occupational and avocational histo- ries of74 patients with rosacea and 74 controls using a scoring system for the amount ofexposure patients had to the elements. He found no apparent diffcr- ence in climatic exposure between the two groups. The second part of his study involved exposing 18 patients with rosacea to light of wavelength 300nm to find the minimal dose producing erythema. This dose was within the normal range for the laboratory in all 18 cases. This work does not rule out a possible role of‘sun exposure in rosacea, as other dermatoses, such as polymorphous light eruption, follow sun exposure yet mav be difficult to elicit in the labora- tory using artificial radiation.“’ The third part of
Marks’ study was a pathologic search for actinically damaged elastic fibers in 45 skin biopsies. Elastotic change was found in 42 of the 45, but control pa- tients were not studied. In a later study, Marks and Harcourt-Webster” found more extensive elastotic changes in 39 patients with rosacea than in 39 con- trol patients despite the fact that the control patients had more sun exposure. However, there were pa- tients with rosacea who had less elastotic change in their skin than the control patients.
Nunzi et al” suspected that sun exposure in rosa- tea patients might lead to UV-induced pyrimidine dimers which could generate antinuclear antibodies found on circulating lymphocytes in some rosacea patients. They looked for dimers in two patients with rosacea and in two control patients and found them in no patients, suggesting that if sun exposure in some way contributes to rosacea, it is not via
pyrimidine dimer formation.“’ In summary, the hypothesis that rosacea arises
from exposure to the elements is not convincing. The study by Marks and Harcourt-Webster sug- gests that skin ofpatients with rosacea is more sensi- tive to actinic damage since these patients have no greater solar exposure, but do have more elastotic degeneration. In addition, some but not all patients report that exposure to sun, wind, heat, and cold exacerbate their lesions.*‘,“’
C. PSYCHOSOMATIC DISORDER
The possibility that patients with rosacea have distinguishing psychological characteristics that
may have etiologic significance was investigated by Whitlock using interviews and questionnaires from 50 patients with rosacea and 50 controls with other dermatologic disorders. ‘I5 No pattern of psychologic traits peculiar to patients with rosacea was found. Sixteen percent of patients considered that an emo- tional disturbance precipitated their illness, but these were only impressions. Marks studied 70 pa- tients with rosacea and 70 controls using interviews and psychiatric questionnaires.‘” Anxiety, depres- sion, obsession and neurosis were scored and the results showed more depression and neurosis in the patients with rosacea. However. as noted by the author, one cannot know whether the psychiatric
problems are causal or rather are secondary to the considerable cosmetic disfigurement suffered by these patients. although the data do not substanti- ate the psychosomatic hypothesis, individual case reports clearly show that in some patients psycho- logic input can change disease severity.‘“,‘”
D. GASTROINTESTINAL DISORDER
Etiologic associations of rosacea with a variety of gastrointestinal disorders have been proposed since Ryle and Barber”’ reported that patients with rosa- tea were more likely to have alkaline gastric secre- tions and achlorhydria than a control set of patients. Wise measured the pH of gastric contents of 17 patients with rosacea, finding it high in four, normal in ten, and low in three.“” None had achlorhydria. Wise’s review of the literature also supported the conclusion that lowered gastric acidity was not spe- cific for rosacea.“’ Nonetheless, the hypothesis that hypochlorhydria and rosacea are associated contin- ues to circulate.’
Jejeunal mucosal atrophy has also been associat- ed with rosacea. Watson” reported in 1965 that of 60 patients having rosacea, 20 had areas ofjejeunal mucosal atrophy by biopsy and four had celiac sprue. Marks et a14’ failed to confirm this association in their study ofjejeunal biopsies from 34 patients with rosacea and 34 control patients having other
skin disorders. When the biopsies were reviewed by nicotinic acid ingestion, in use of phentolamine me-
pathologists unaware of the clinical diagnoses, there sylate, or in the carcinoid syndrome in that cloni-
were no differences in prevalence of mucosal atro- dine given in low doses fails to block rosaceous
phy between the groups. In addition, there were no flushing, but does block the other flushing reac-
differences in gastric biopsies from the two groups. tions.g2
Several authors have linked rosacea to consump-
tion of alcohol, excessive carbohydrates, caffeine
containing drinks, and spicy foods.2’.24 A dietary sur-
vey by Marks showed no differences in consumption of these foods between patients with rosacea and
controls,40 but this work fails to show that these
agents exacerbate rosacea since rosacea patients
may avoid foods that they have learned make their
lesions worse.
Thus, for none of the gastrointestinal hypotheses
are substantiating data to be found.
E. DISORDER OF VASODILATION
The pronounced telangiectasia and erythema in
rosacea have prompted many studies on possible
arterial and venous vasomotor abnormalities. Such
abnormalities, if they exist, must be functional rath-
er than structural. Marks and Harcourt-Webster””
found markedly dilated vessels in the upper dermis of rosacea patients, but there was no evidence of
primary vascular damage. The authors felt the vas-
cular dilatation was most likely secondary to an
altered connective tissue framework in the dermis.43
There are other physiologic and pharmacologic
vasoactive substances which may have relevance to
rosacea and need further investigation. Notably, pa-
tients with carcinoid syndrome have red eyes simi- lar to those in rosacea and may develop rhinophyma
indistinguishable from that seen in rosacea.s’
Rowe11 and Summerscales’j8 measured 5HIAA lev-
els in 24-hour urine collections from 22 patients with
rosacea and found them to be normal. We have
recently confirmed this finding in two patients with
rosacea using a different assay and have also found urine free serotonin to be normal in one patient.
Both substances are usually, but not always, elevat-
ed in patients with carcinoid syndrome. Bradykinin
levels are often high in carcinoid syndrome, but they
have never been measured in rosacea. Perhaps pa-
tients with rosacea have elevated bradykinin levels or increased vasoresponsiveness to normal levels of
this substance.
Borrie’O has shown that the problem in rosacea is
not increased blood flow secondary to arteriolar di-
lation. Borrie measured skin temperature in 26 pa-
tients with rosacea and in 26 control subjects and found no statistically significant differences.” Wil-
kin and Josephsg’ took infrared photographs of pa-
tients with rosacea and found no high temperature vascular patterns leading them to conclude that the
disorder in rosacea involves proximal blood vessels
and not the superficial collecting veins.
Endorphin levels and receptors are yet another
aspect of vasoregulation needing further investiga-
tion. Bernstein and Soltan? administered beer con-
taining 6% ethanol to live patients with rosacea who
were pretreated with either naloxone or saline under
double-blind cross-over conditions. All patients ex-
hibited a flush reaction to the ethanol that was in-
hibited by naloxone. It is possible that patients with
rosacea have higher levels of endorphins in involved tissues or an increased sensitivity to normal levels of
endogenous endorphins.
Another line of investigation has arisen from the specificity of rosaceous involvement for flush areas
of skin. These areas are unique in that the small vessels have a relatively pure vasodilator innerva-
tion. They lack compensatory vasoconstrictor in- nervation thus explaining their failure to blanch on cooling. ” Looking for abnormal responses to vaso- active substances, Borrie applied epinephrine, nor- epinephrine, acetycholine, and histamine to the fa- cial skin of 17 patients with a rosacea and 17 control subjects. ” He measured concentration of a drug re- quired to produce pallor and size of zones of flare in reaction to standard exposure to a drug. There were no differences between patients with rosacea and controls in their responses to any of the tested phys- iological substances which normally play a role in the maintenance of vascular tone. The flushing in rosacea is distinct from that seen in menopausr, in
In summary, there is no evidence demonstrating
rosacea to be a primary disorder of blood vessels,
although several issues in this regard are open for
further study. It is unlikely that the marked inflam-
mation seen in the disease can be explained on the
basis of a vasoregulatory disturbance.
F. ABNORMALITIES OF SEBACEOUS GLANDS
Biopsies of rosaceous skin may show hypertrophy
and plugging of sebaceous glands.43 It is natural, therefore, to postulate an abnormality in these glands as the original lesion leading to the other manifestations of the disease. As the analogous glands lubricating the ocular surface, the meibo-
mian glands have been implicated in the ocular le- sions of the rosacea.46.47 Although pathologic docu- mentation is lacking, it is clinically common to see inspissation of secretions at meibomian gland ori- fices in patients with ocular rosacea.47 This stagna- tion of secretions has been cited as a possible cause of the decreased tear break-up times and conse-
OCULAR ROSACEA 153
quent superficial punctate keratopathy seen in
many patients with ocular rosacea.46.47 Tear break-
up times return to normal in these patients with expression of fresh meibomian secretions into the
tear film. Pye et alb’ found no significant difference in skin
lipid composition in 3 1 patients with rosacea and in
31 age matched controls. In addition, there was no
difference in lipid composition after tetracycline
therapy. Gory et al”’ performed an analogous study for meibomian gland secretions and likewise found
no differences in any meibomian secretion lipid frac-
tion between patients with ocular rosacea and con-
trols. The sebum excretion rate in rosacea is not
elevated.” Tetracvcline treatment does not affect
the composition of meibomian lipid secretions.”
This area is fertile for further investigation. It is
reported that certain free fatty acids are more irri- tant than others - for example, those with twelve
carbon backbones.“” The distribution of fatty acid
chain lengths in meibomian secretions does not nor-
mally contain a peak at twelve carbons,” but per- haps patients with rosacea have greater amounts of
these irritant free fatty acids despite having normal overall quantities of free fatty acids. Preliminary
data by McCulley et al”’ support the possibility of abnormal fatty acid profiles in patients with hleph-
aritis. It is known that branched chain fatty acids
are present in meibomian gland secretions in twice
the concentration reported for sebaceous secretion.’
Branched chain fatty acids have lower melting points than their unbranched analogues and are
therefore thought to be important in the spreading of tears. Patients with rosacea may have smaller
fractions of this type fatty acid and consequently
shortened tear breakup times. Likewise, unusual high molecular weight fatty acids have been found
in human meibomian gland secretions which may
help spread other lipids over the tear film.” Patients
with rosacea may have abnormalities in this frac-
tion, but this possibility has not been assessed.
G. DEMODEX FOLLICULORUM AND ROSACEA
Infestation of skin by Demodex folliculorum has
been linked to the pathogenesis of rosacea since the report of Kaufmann-Wolf. “’ Subsequently Ayres
and Anderson’ examined 14 women and three men
with rosacea and found many demodex in pustules of involved skin. Pus from 13 patients with acne vulgaris had no demodex. With applications of anti- parasitic sulfur ointment, there was concomitant improvement in the skin lesions and a decrease in
the density of organisms. In 1961, Ayres and Ayres’ summarized 30 years experience with 196 patients having what they termed ‘&acne rosacea (Dcmo- dtx).” 7’hcy ditTcvntiatc~tl “acne rosacea of internal
origin,” which they attributed to “gastrointestinal
disturbances, impaired liver function, or excessive
alcohol intake,” from acne rosacea (Demodex) which stems from infestation by the demodex. The main clinical distinction, however, was that the skin
in acne rosacea of internal origin was oilier and the
papules and pustules larger.” In a later report on an
unknown number of patients with rosacea, Russell”
reported that 25% of normal controls had demodex
whereas 88% patients with rosacea had them. In
simple acne vulgaris only 11% patients were infest-
ed. Hoyjo and Dominguez’” examined ten patients
with rosacea and ten with acne vulgaris. Nine of ten
patients with rosacea had more than four mites per
skin follicle, whereas none of the patients with acne
vulgaris had any mites. ” Morgan and Coston stud-
ied 18 patients with rosacea and found demodex
infesting the lash follicles in all of the patients.‘” In a
series of 54 patients with seborrhea, blepharitis, and
dandruff; but not rosacea, demodex were not found.
Rufli et al”” found demodex in the potassium hy-
droxide-treated skin scrapings of 16 out of 18 pa-
tients with rosacea.“’ The organisms feed on sebum and their distribution in the skin matches the distri-
bution of skin lesions in rosacea. Although demodex
have been associated with the eyelid lesions of rosa-
tea,” they have never been linked in a pathoaenetic way to lesions of the globe.
The general consensus in the more recent litera-
ture is that demodex has no etiologic role in most
cases of rosacea. The basis for this viewpoint rests
mainly on studies by Robinson”’ and Marks and Harcourt-Webster.t” Robinsonh” compared demo-
dex counts in skin from 23 patients with active rosa- tea to counts in skin after therapy with sulfur oint-
ment (regardless of whether the skin lesions
improved or not). He found no significant diff‘erence
in the number of mites in skin before and after ther-
apy. This study design is flawed in that treatment failures were lumped with successes. If one consid-
ers only those patients in which there was clinical
improvement in skin lesions after treatment, one finds that nine of their twelve cases did show re- duced numbers of demodex. The other negative
study by Marks and Harcourt-Webstert’ reported histopathology of 74 skin biopsies in patients with
rosacea. Only 19% of the follicles showed infesta- tion with demodex. Moreover, the tbllicles infested with demodex were not preferential centers of in- flammatory infiltrates and this suggested to the au- thors that the mite does not play a significant role in the causation of rosacea. Further support against a role for demodex was given in a study by Ramelet and Delacretay.“” Thirty-eight hiopsies from 36 pa- tients with perioral dermatitis (thought by many to he a form ol‘rosacca) were csamined histopathologi-
Fig. 7. The corneai button from the patient shown in Fig. 5 exhibits scar- ring of the superficial stroma and vas- cularization (two blood vessels are identified with arrows). The centrat stroma (to the left) is markedly thinned.
Fig. 8. Histopathologic field from cor- neal button of patient shown in Fig- ure 5. The scarred cornea contains an occasional mononuclear inflamma- tory cell. A break in Descemet’s mem-
brane and a retrocorneal membrane
are also present.
tally and only two sections revealed demodex. Despite a considerable literature on the subject, it
remains an open question whether demodex is re- sponsible for one or more aspects of the clinical picture of rosacea or instead is simply a fellow trav- eler. In future studies, examining different param- eters of demodex infestation - e.g., density (per follicle) as suggested by Spickettso and the role of the immune response to demodex antigens - may be more helpful than noting simple presence or ab-
sence and total number of organisms.
VII. Pathology
Excellent pathologic studies of skin in patients with rosacea are available and will not be reviewed in detail here.43 Briefly, marked vascular dilation
with a perivascular infiltrate of histiocytes, lympho-
cytes, and occasional plasma cells are observed in the upper dermis. Pustules containing neutrophils
may be noted and when the stage of rhinophyma is reached, the pathologic substrate is found to be se- baceous gland hypertrophy. In papular rosacea, there may be granulomatous inllammation contain-
ing multin~cleated giant cells. Lymphocyte subtyp- ing using monoclonal antibodies has shown that most lymphocytes in rosacea lesions are helper-in- ducer T ceIls.70
Few studies exist examining the pathologic changes in the eye and ocular adnexa.23,a” Fig. 5 shows the appearance of a patient suffering severe rosacea for 12 years uncontrolled by oral tetracy- cline, topical sulfur, topical corticosteroids, and
OCULAR ROSACEA 15.5
Fig. 9. Histopathologic field from cornea1 button of pa- tient shown in Fig. 2. Moderate chronic inflammator)
infiltrate and neovascularization are present within scar tissue.
topical astringents. Severe ocular rosacea with iritis
and keratitis resulted in cornea1 vascularization and
scarring and led to reduction of vision to 20130 in
the right eye and 20/400 in the left. The patient underwent penetrating keratoplasty of the left eye.
Fig. 6 shows the eyes before surgery. Figs. 7 and 8 show photomicrographs of the cornea1 button
stained with hematoxylin and eosin. The changes
are nonspecific, consisting of scarring of the superfi- cial stroma, vascularization, and a scant infiltrate of
mononuclear inflammatory cells. The central corne-
al stroma was markedly thinned. A break in Desce-
met’s membrane was associated with a retrocornral membrane.
The patient shown in Fig. 2 had severe facial and
ocular rosacea resulting in cornea1 perforations of both eyes. The right eye developed dense cornea1 scarring, became hypotonous, lost light perception and was enucleated because of discomfort. Histo- pathologic examination revealed a central cornea1 perforation with acute and chronic inflammation. Away from the perforation, the superficial one-half of the cornea was scarred. A moderate chronic in- flammatory infiltrate and neovascularization were
present within the scar tissue (Fig. 9). Other find-
ings in the eye included an hypopyon and acute
iritis.
The nodular conjunctivitis of rosacea is charac- terized by accumulations of epithelioid histiocytes,
lymphocvtes, plasma cells, and occasional multinu- cleated giant cells. X6 The lesions resemble those that may occur in the skin lesions of papular rosacea.
Similar granulomatous inflammation has been seen
in the superficial cornea in the early stages of kerati-
tis.‘)‘,“’ Brown and Shahinian” have performed di-
rect immunofluorescent studies of hyperemic con-
junctiva of 13 patients with ocular rosacea and from uninvolved conjunctiva of three other patients with rosacea. Six biopsies showed “tissue-fixed” immun-
oglobulins (live in the epithelium and one in the
basement membrane) and five stained for C3. In
five patients with the most severe conjunctival in- volvement, repeat biopsy after clinical impro\.ement
showed no change. The pattern of immunoglobulin
deposition was not described and the significance of
these findings is unclear. Starr and hlacDonald ha\.e v+ritten that “histo-
pathological descriptions of the skin disease are . . unhelpful in suggesting the causation.““’ Too little tissue from the various involved ocular and periocu-
lar structures has been studied to extend this state-
ment to the ocular manifestations of the disease.
VIII. Treatment
A. ANTIBIOTICS
Of the many treatments for rosacea proposed
over the years, the only ones which have stood the
test of time are antibiotics. For treatment of the skin
lesions of rosacea, tetracycline, ampicillin, erythro- mycin and metronidazole have all been reported to
be eflicacious,“-t’ ‘H.i4.i’.if.7H although erythema and
telangiectasia are improved little. In ocular rosacea, only tetracycline has been critically studied and it has been reported to be effective in all ocular lesions
of rosacea.” The mechanism of action of tetra- cycline is unknown although several hypotheses
have been studied, as reviewed by Salamon.” Not
all of the proposed mechanisms of action involve
antibacterial effects of these drugs. reflecting the
fact that sometimes small chronic doses of tetracy- cline can keep rosacea lesions under control. Tetra- cycline may influence the interaction of sebaceous substances and bacteria without actually killing
bacteria. ,Jenkins et al” treated 37 patients ha\ing ocular
rosacea with tetracycline (250 mg four times per day) for three weeks followed by one week of no
therapy. This cycle was repeated until maximal im-
provement was reached and then the dose of tetra- cycline was tapered and discontinued. Of the 37
patients, 36 improved markedly. The response time varied from four days to three weeks. Over a follow-
up period of live to 28 months, fifteen of the 37
patients had no recurrence after stopping the drug.
Twenty of 37 patients had recurrence and three of
these were not controlled on restarting tetracycline. Five of the 20 patients with recurrence were signifi-
cantly but incompletely relieved by restarting tetra- cycline. Twelve of these 20 patients responded com-
pletely. All patients with severe keratitis were
healed within 28 days of starting therapy. No chala- zion recurred while patients were taking tetracy-
cline. The improvement in ocular lesions was tem-
porally dissociated from improvement in the skin
lesions. Side effects of tetracycline therapy were gen-
erally minor and included dyspepsia, diarrhea, and
drowsiness. Some patients must be kept on a low
dose of tetracycline indefinitely to prevent recur-
rence of active disease.
Bartholomew et al7 performed a double blind,
cross-over trial of oxytetracycline (250 mg orally
twice a day for six weeks) versus placebo in 35 pa- tients with ocular rosacea. Eleven of 17 patients
randomized to oxytetracycline therapy showed re-
missions in their signs and symptoms as compared
to 5 of 18 patients taking placebo. All signs of rosa-
tea responded to treatment except cornea1 neovas-
cularization and healed cornea1 scars. Responses
generally developed only after two weeks of therapy.
Nine of 35 patients were not improved or worsened
after having been exposed to the oxytetracycline
part of the trial. Overall, the results support the conclusions of the study by Jenkins et al,“’ but the efficacy of oxytetracycline was less universal than
that of tetracycline. We are aware of ophthalmol-
ogists who use minocycline 100 mg orally twice per day instead of tetracycline, but no study exists
showing equal efficacy of this regimen. Since many patients with rosacea have blephari-
tis, a continuing regimen of eyelid margin hygiene
using dilute baby shampoo scrubs seems to be a
good idea. The conventional management of chala- zia and styes, including warm compresses and inci- sion with curettage, may help speed resolution of these lesions while tetracycline is taking effect. There is no data documenting better results when these adjunctive modalities are added to tetracy- cline.
B. HEXACHLOROCYCLOHEXANE
Rufli et a16’ reported that topical hexachlorocy- clohexane .25% and benzyliumbenzoilum 2.5% cured 18 patients (all on whom it was tested) with rosacea. Twelve had facial rosacea and four had
facial and ocular rosacea. Sixteen of 18 had demo-
dex present before therapy whereas only one of 18
had demodex present afterwards and this excep- tional patient had marked reduction in density of infestation. Hexachlorocyclohexane is an organic
volatile solvent similar to ether, a substance that Coston’g and Norn55 found very toxic to demodex. It
is interesting to speculate that an acaricidal effect of
this treatment may be related to its efficacy in treat-
ing rosacea.
C. ISOTRETINOIN
Recently, isotretinoin has been found effective for
treating rosacea patients with skin lesions refractory
to standard therapies. Plewig et a16’ reported large reductions in numbers of inflammatory facial le-
sions in patients taking 0.5 to 1.0 mg/kg per day. The effect was noted within four weeks of onset of
therapy. Fulton et al 26 administered 0.5 mg/kg per day isotretinoin to eight patients with rosacea and
found a progressive fall in number of palpable le- sions in all patients, an improvement by masked
examination of pre- and post-treatment photo-
graphs in six patients, and reduced sebum excretion
rate.26 The erythema component of the disease was unaffected. Isotretinoin markedly reduces sebum
production and causes shrinkage of sebaceous folli-
cles. Although it is the first nonantibiotic drug re-
ported to improve rosacea, it does reduce density of
propionibacteria on skin, probably secondary to
changes in bacterial habitat. Since sebum is the sub-
strate for demodex infestation as well, the effect of
the drug on this parameter would be of interest. The effect of the drug on the ocular lesions in rosacea is
unknown but there have been reports of the drug’s
causing blepharoconjunctivitis in 043% ofpatients in a dose-dependent manner.4g A remarkable effect
of the drug is the induction of prolonged remissions
from lesions in patients with acne vulgaris after a
course of therapy. 6o Patients with rosacea may re-
spond differently; Marsden et al’” noted relapse in skin lesions by eight weeks after stopping isotretin-
oin. The drug cannot be used in women at risk for
pregnancy because of its potential teratogenic side effects.
D. STEROIDS
Topical corticosteriods can be useful in managing
the iritis, keratitis, and episcleritis of ocular rosacea until tetracycline takes effect. Close follow-up and the lowest concentration of steroid that is effective are recommended, as it is said that patients with rosacea are prone to rapid cornea1 melting with higher corticosteroid concentrations.” We are un- aware of any studies to document this clinical max- im, which, nevertheless, seems prudent.
OCULAR ROSACEA
E. PENETRATING AND LAMELLAR
KERATOPLASTY
Rosacea patients with cornea1 disease who re- quire penetrating keratoplasty are more prone to
graft rejection than other patients because their cor- neas are usually well vascularized. The patient in
Fig. .5 has not been weaned from topical corticoste-
roids in the three years since his cornea1 grafting.
Leigh has stated that lamellar keratoplasty can re-
duce the frequency and severity of attacks of rosacea
keratitis, but no data are presented.36
IX. Summary
Rosacea is a disease of skin and eyes of unknown
etiology and protean manifestations. The clinical
and pathological features of the eye disease are non-
specific and the disease is widely underdiagnosed by
ophthalmologists. Underdiagnosis is particularly
lamentable because treatment with tetracycline is
reported to be specific, effective, and relatively free
of side effects. Twenty percent of cases of ocular
rosacea present before skin lesions develop. No test
available at present reliably indicates the diagnosis
in these cases. Empiric trials of oral tetracycline
may be warranted in cases with the nonspecific
signs and symptoms of ocular rosacea without skin lesions if they are not responding to the trial of
artificial tears, lid hygiene, and topical antibiotics
and corticosteroids commonly used.
Acknowledgment
We thank Renate Wend for translating German articles.
I.
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I.
II.
III.
IV. V.
VI.
VII. VIII.
IX.
Outline
Demographic characteristics Skin manifestations Ocular manifestations Relationship of skin and ocular manifestations The problem of underdiagnosis Hypotheses of etiology A. Bacterial infection B. Climatic exposure C. Psychosomatic disorder D. Gastroinestinal disorder E. Disorder of vasodilation F. Abnormalities of sebaceous glands G. Demodex folliculorum and rosacea Pathology Treatment A. Antibiotics B. Hexachlorocyclohexane C. Isotretinoin D. Steroids E. Penetrating and lamellar keratoplasty Summary
A portion of this work was performed while Dr. Browning was a Heed Foundation Fellow and Dr. Proia was a Research to Prevent Blindness-Dolly Green Scholar.
Reprint requests should be addressed to David J. Browning, M.D., Ph.D., Charlotte Eye, Ear, Nose, and Throat Associates, 1600 East Third Street, Charlotte, North Carolina 28204.
