Ocular Manifestations and Impression Cytology of Anorexia Nervosa

Ocular Manifestations and Impression Cytology of Anorexia Nervosa JASON M. GILBERT, MD,t JAYNE S. WEISS, MD,2 ANN L. SATTLER, MD,3 JORG M. KOCH, MD4

Abstract: A prospective age- and sex-controlled study of seven anorexia nervosa patients and seven normal control patients was conducted to determine the ocular manifestations of anorexia nervosa. Slit-lamp examination of the anorexic patients demonstrated a high incidence (4/7) of multiple episcleral capillary aneurysms and subconjunctival hemorrhages. Two of seven anorexia nervosa patients had bilateral superficial punctate keratopathy. Anesthetized Schirmer tear testing demonstrated a significantly (P < 0.005) reduced mean tear production in the anorexia nervosa group (11.3 mm) compared with the control group (22.4 mm). Masked interpretation of conjunctival impression cytology demonstrated moderate to severe conjunctival squamous metaplasia in the majority of the anorexia nervosa group (5/7) compared to normal conjunctival epithelium in the majority of the control group (5/7). Absence of nyctalopia, Bitot's spots, and xerosis, and lack of conjunctival goblet cell loss indicate that the anorexia nervosa group did not have vitamin A deficiency. Ophthalmology 1990; 97:1001-1007

Anorexia nervosa affects 1 to 3% of middle- and upperclass women. It is 20 times more prevalent in women than in men. I •2 Recent studies estimate that at least 5% of patients with anorexia nervosa die as a result of their disorder. I - 3 The Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) sets the following diagnostic criteria for anorexia nervosa: (1) weight loss leading to body weight 15% below normal, (2) intense fear of gaining weight and becoming fat, (3) distorted body selfimage, (4) amenorrhea equal to or greater than three expected menstrual cycles, and (5) absence of other physical disorders causing weight 10ss.4 Anorexia nervosa is often complicated by self-induced vomiting or abuse of diet pills, laxatives, or diuretics that Originally received: November 21, 1989. Revision accepted: April 2, 1990. Department of Ophthalmology, Tufts·New England Medical Center, Boston. 2 Division of Ophthalmology, University of Massachusetts Medical Center, Worcester. 3 Department of Pediatrics, University of Massachusetts Medical Center, Worcester. 4 Eye Clinic of the University of Essen, Essen, West Germany.

1

Reprint requests to Jayne S. Weiss, MD, University of Massachusetts Medical Center, 55 Lake Ave North, Worcester, MA 01655.

may lead to severe dehydration and electrolyte imbalances. 3,5 Self-imposed dietary restriction in anorexic patients typically affects fat and carbohydrate intake more severely than protein intake, and may increase their risk of fat-soluble vitamin deficiencies. 6 The disorder affects nearly every organ system and may result in dry skin, bradycardia, hypotension, pancytopenia, prolonged wound healing, gastrointestinal disease, and abnormalities in the hypothalamic-pituitary-ovarian hormonal axis. 7,8 Anorexia nervosa is a common disease with significant morbidity and mortality that is likely to be overlooked in the ophthalmologist's patient population. Because there is a dearth ofliterature investigating its ocular impact, we performed a prospective age- and sex-controlled study to determine the ocular manifestations of this disease.

PATIENTS AND METHODS Between September 1987 and June 1988, seven patients fulfilling DSM-III-R criteria for diagnosis of anorexia nervosa were referred by their physicians or psychologists for ocular evaluation at the University of Massachusetts Medical Center. Seven healthy, nonpregnant women who were 22 to 27 years of age volunteered to serve as normal 1001

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Table 1. Conjunctival Impression Cytology Grading System Points Assigned Cytologic Feature Nuclear:cytoplasmic ratio Cell sheet integrity Nuclear condensation Goblet cell and mucin imprintst

o ~1:4

Good Nonpyknotic >10

1:8 Reduced Moderate "snakes" * 1~T,S,orIP~10

3 ~ lor N ~ 10

2

3

1:12 No cell sheets Abundant "snakes" or pyknotic nuclei T, S, or IP = none lor N ~ 2

~1:16

NA Most nuclei lost NA

NA = not applicable; T = temporal quadrant; S = superior quadrant; I = inferior quadrant; N = nasal quadrant; IP = inferior palpebral. * "Snakes" are worm-like condensations of nuclear chromatin or organelles. t Per 4- to 6-mm diameter filter paper sample.

controls for this study. Informed consent and approval from the Human Investigation Review Committee were obtained for all controls. Patients and controls were evaluated in the same manner except where noted. Each participant was questioned about her systemic medical and dietary history, weight, and menstrual pattern. Patient history and weight were verified by review of the medical chart and weight measurement obtained within 2 weeks of her eye exam. Body mass index, weight(kg)/height(m)2, was calculated. Body mass index correlates well with triceps and subscapular skin-fold thickness as a measure of body fat.9-11 An ocular history was obtained, including inquiry about nocturnal visual symptoms. Snellen visual acuity, refractive error, pseudo-isochromatic color plate testing (American Optical Corp, 1965), external inspection of the face and eyelids, and slit-lamp inspection of the conjunctiva and anterior segment were done. The corneal tear film and the tear meniscus height were inspected. The tear breakup time was determined. A fine cotton wisp from a cotton-tip applicator was used to evaluate corneal sensitivity. After instillation of 1 drop of 0.5% proparacaine to each eye, the inferior cul-de-sac was dried with a cotton-tipped applicator. A Schirmer tear test strip (CooperVision, Lot JD 7301) then was applied to both eyes. The Schirmer tear strip wetting after 5 minutes was averaged for the two eyes. The unpaired, two-tailed t test was used for statistical analysis. 12 Applanation tonometry pressures were then taken. Dilated slit-lamp examination of the lens, and direct and indirect ophthalmoscopy of the fundus were done. Three normal controls declined dilated examinations. IMPRESSION CYTOLOGY

Conjunctival impression cytology then was done on the right eye. One drop of topical 0.5% proparacaine was applied. A 6-mm diameter disc of cellulose acetate filter paper with a pore size of 0.025 11m (VSWP 01300, Millipore Corp) was applied to each quadrant of the bulbar conjunctiva at a distance 2-mm from the limbus. A 4mm diameter disc of the same filter paper was applied to the lower palpebral conjunctiva. A plastic applicator with a 6-mm diameter circular tip was used to apply and com1002

press the dull side of the filter paper disc against the conjunctiva for 5 seconds. Blunt forceps were used to peel the discs with adherent cells from the conjunctiva and affix them to glass slides with double-sided tape. The unpreserved specimens were stained within 24 hours with periodic acid-Schiff and Gill's modified Papanicolaou's stain and mounted as previously described. 13 The impression cytology slides were evaluated by light microscopy and graded in a masked fashion by two independent observers using a ten-point grading scale. Progressively higher points were assigned for increasing conjunctival squamous abnormalities. Each slide was assigned points as follows: 0-3 points for nuclear to cytoplasmic ratio, 0-2 points for cell sheet integrity, 0-3 points for nuclear condensation, and 0-2 points for lack of goblet cells or their mucin imprints (Table 1).14,15 In category 4, if only one or two goblet cells or mucin imprints were present on a slide, this was considered a more severe abnormality if present in the inferior or nasal quadrants than if present in the temporal, superior, or inferior palpebral sites. In this instance, slides of the inferior or nasal quadrants were assigned higher grading points than the other slides because normal goblet cell density is known to be greatest in the inferior and nasal quadrants. 16 The mean score in each category of cytologic change from (1) to (4) was determined for the five slides from each eye. These mean category scores were then totaled to give a final impression cytology grade. A grade of 0 to 2 was considered normal, 3 to 4 indicated moderate conjunctival squamous metaplasia, and 5 to 10 indicated severe conjunctival squamous metaplasia. All eyes had at least three bulbar quadrants or inferior palpebral areas with interpretable impression cytology. Independent observers assigned the same overall impression cytology grade to each eye. The unpaired, one-tail t test was used for statistical analysis. 12 ,17 Previous conjunctival impression cytology studies have shown that a finding of absent goblet cells is a sensitive indicator of vitamin A deficiency.15,18-20 In this study, conjunctival impression cytology slides were evaluated for the presence, absence, or rarity (less than or equal to two per filter disc) of goblet cells or their mucin imprints as an indicator of vitamin A status. An eye was considered

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Table 2. Anorexic Group Characteristics and Findings Patient No.

Age (yrs)

Weight (Ibs)

BMI (Weight (kg)) height (mf

AN1 AN2 AN3 AN4 AN5 AN6 AN7

19 23 29 20 16 23 24

106 100 72 104 79 105 73

18.3 15.7 12.5 18.4 16.3 16.20 12.57

Drugs MVI TCA TCA TCA MVI MVI

Nighttime Photosensitivity

SPK

+

Episcleral Aneurysms and Hemorrhage

+ + +

+

+ + +

+

+

Schirmer (mm)

CIC Grade

17.5 10.0 17.0 3.5 6.0 15.0 10.0

10 5 3 7 1 1 4

BMI = body mass index; SPK = superficial punctate keratopathy; CIC = conjunctival impression cytology; MVI = multivitamins; TCA = tricyclic antidepressants.

to be rare or absent in goblet cells only if goblet cells and mucin imprints were rare or absent in all five impression cytology slides from an eye.

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RESULTS The seven anorexia nervosa patients and seven controls were all women. The mean age of the anorexic group was 22.0 years, and the mean age of the control group was 24.6 years. The anorexic group weights ranged from 72 to 105 lbs (mean, 93.3 lbs). The control group weights ranged from 115 to 150 lbs (mean, 134.8 lbs). The mean body mass index of the anorexic group was 15.72 kg/m 2 and was 28 .5% lower than the mean body mass index of the control group (21. 98 kg/m2; P < 0.00 1). In the anorexic group, six of seven patients were known to vomit after their meals on a periodic or daily basis. Severe dehydration, electrolyte imbalance, or acute absence of food intake had precipitated one or more hospital admissions for all anorexic patients. Their anorexic dietary habits had been present for at least 2 to 8 years in six of seven cases. Normal balanced dietary habits were present in all controls. Orug use for the anorexic group is listed in Table 2. Multivitamins were taken by one control subject. Tricyclic antidepressants were not taken by control subjects. The anorexic group denied symptoms of nyctalopia, but four of seven complained of significant nighttime sensitivity to lights and glare. These symptoms were absent in the control group. Four of the anorexic patients had findings that included dry skin, dry mouth, temporalis muscle wasting, thin brittle hair, parotid swelling, and perioral and periungual lesions. The latter three abnormalities are associated with chronic self-induced vomiting. 21 - 24 Corrected visual acuity was 20/20 in both eyes in both groups. Color vision was normal in both groups. Results of slit-lamp examination showed multiple episcleral capillary aneurysms and small subconjunctival hemorrhages in four of the seven patients with anorexia nervosa (Fig 2). A single tiny episcleral capillary aneurysm was present in two control subjects, but none of the controls had mul-

mm 20

10

o

.=.t •

·:·f o

O~----~r-------------~----~

Anorexic Group

Control Group

Fig 1. Schirmer tear strip wetting for anorexia nervosa group and normal control group.

tiple aneurysms or any subconjunctival hemorrhages. The remainder of the slit-lamp examination was normal in the control group. No Bitot's spots or xerosis were present in the anorexic group, but one patient had five tiny, raised, dull white, nonfluorescein staining nodules clustered in the temporal bulbar conjunctiva in one eye. Two anorexia nervosa patients had bilateral inferocentral superficial punctate keratopathy. One of these patients wore soft contact lenses, and the other blinked less frequently than once every 45 seconds and had underlying systemic motor retardation. The corneal sensation and tear breakup time was normal (> 12 seconds) in the anorexic group. The corneal tear film had moderate debris in two anorexia patients. Schirmer tear testing (Fig 1) demonstrated a significant decrease in mean tear production in the anorexic group (11 .3 mm; standard deviation [SO] = 5.4) compared with the control group (22.4 mm; SO = 5.4; P < 0.005). The two anorexia nervosa patients with the lowest Schirmer test values (3.5 and 6.0 mm) did not have corneal fluorescein staining. Mean applanation tonometry pressures 1003

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Fig 2. Top left, anorexia nervosa patient AN6, Episcleral capillary aneurysm (black arrow), temporal quadrant, right eye. Top right, anorexia nervosa patient AN6. Subconjunctival hemorrhages (black arrow), nasal quadrant, left eye. Fig 3. Center left, normal control patient NC6. Impression cytology of normal conjunctival epithelium with abundant pink goblet cells (white arrow). Cytologic features: nuclear/cytoplasmic ratio,;o,: I :4; cell sheet integrity, good; nuclear condensation, non pyknotic; goblet cells, > 10 (periodic acid-Schiff and Gill's modified Papanicolaou's stain; original magnification, X40). Fig 4. Center right, anorexia nervosa patient AN3. Conjunctival impression cytology with moderate SQuamous metaplasia and keratinization (pink cells). Cytologic features: nuclear/ cytologic ratio, 1:8 (notice that cells in the bottom left of this figure have a better ratio of;o,:I:4); cell sheet integrity, reduced; nuclear condensation, nonpyknotic; goblet cells, none; mucin imprints, 1 (white arrow) (periodic acid-Schiff and Gill's modified Papanicolaou's stain; original magnification, X 100). Fig 5. Bottom, anorexia nervosa patient AN4. Conjunctival impression cytology with severe squamous metaplasia and worm-like nuclear condensations called "snakes" (white arrow). Cytologic features: nuclear/cytoloplasmic ratio, 1:12; cell sheet integrity, very reduced; nuclear condensation, abundant "snakes"; goblet cell or mucin imprints, none (periodic acid-Schiff and Gill's modified Papanicolaou's stain; original magnification, X 100).

were 12.7 mmHg for the anorexic group and 15.4 mmHg for the control group. Dilated slit-lamp examination of the lens showed no significant opacities in the anorexic group. Funduscopic evaluation showed no hypopigmen ted lesions or other abnormalities in this group. Conjunctival impression cytology results are shown in Figure 6. Five of seven anorexia nervosa patients had moderate to severe conjunctival squamous metaplasia, whereas five of the seven controls had normal cytologic 1004

features (Figs 3-5). The difference between the impression cytology results of the anorexic and control groups was just below the threshold for statistical significance (P = 0.0516). Two of the anorexic patients and one of the controls had rare goblet cells. In the anorexic group, the conjunctival squamous metaplastic changes of reduced nuclear to cytoplasmic ratio, nuclear condensation, and loss of cell sheet integrity were out of proportion to the goblet cell loss. "Snakes," an abnormal cytologic finding

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10

8 Grading Scale

6 4

••• ••

2 00

0

Anorexic Group

o Normal

Control Group

0 Moderate

III Severe

Fig 6. Conjunctival impression cytology final grades for anorexia nervosa and normal control groups. Gray scale indicates normal epithelium and moderate or severe squamous metaplasia.

of worm-like condensations of nuclear organelles or chromatin,25.26 were found in the superior bulbar conjunctiva of one anorexia nervosa patient (Fig 5).

DISCUSSION Our study shows that patients with anorexia nervosa have a high incidence of episcleral capillary aneurysms and subconjunctival hemorrhages, an increased incidence of superficial punctate keratopathy, and reduced tear production as compared to normal controls. Nighttime glare sensitivity and moderate to severe conjunctival squamous metaplasia by conjunctival impression cytology were present in the majority of anorexia nervosa patients examined. The enrollment in our study of anorexia nervosa patients by referral from their physicians may have created a bias of selecting patients with the most severe dietary habits. Because of the small number of anorexia nervosa patients evaluated, the conclusions that may be drawn from this study are limited. The conjunctival impression cytology grading scale used in this study protocol was designed to obtain objective and repeatable interpretation of the impression cytology samples. Using this grading scale, two independent masked observers did assign the same impression cytology final grade to each eye. The criteria used in the grading scale were based on definable cellular changes, but the number of points assigned for each cellular change (Table I) could be considered arbitrary. We believe, however, that the final grades correlate well with the level of conjunctival squamous metaplasia. Episcleral capillary aneurysms and subconjunctival hemorrhages have not been reported previously in anorexia nervosa. In our anorexic group, six of seven patients, including all four with microvascular changes, had known periodic episodes of postprandial vomiting. The

Valsalva's maneuver and associated increased venous pressure during these episodes may be a causative factor in the production of these microvascular changes. To determine if vomiting was sufficient to cause these abnormalities, we performed slit-lamp examinations of four bulimia nervosa patients who had frequent episodes of binge eating, postprandial vomiting, and normal or elevated weight. 4 No episcleral microvascular abnormalities were found. The absence of episcleral microvascular changes in bulimia nervosa patients suggests that anorexia nervosa patients have an underlying microvascular fragility that makes them susceptible to aneurysm and hemorrhage. Anorexia nervosa patients have been shown to have a deficiency of essential fatty acids that are important components of vascular endothelium. 7,27 These patients also have been shown to have a diet deficient in vitamin E.7 Experimental vitamin E deficiency has been shown to cause abnormal vascular endothelial cell morphology and reduced vascular endothelial integrity,28-30 These nutritional deficits in anorexia nervosa may be causing capillary endothelial dysfunction resulting in increased susceptibility to aneurysm and hemorrhage. Schirmer tear testing demonstrated significantly reduced tear production in the anorexic group compared to the control group. The anorexic group's mean Schirmer tear test value of 11.3 mm was about one half that of the control group (22.4 mm); however, both of these values were above the commonly accepted threshold of 10.0 mm for an abnormal, anesthetized Schirmer tear test. Six of seven of our anorexia nervosa patients had well-documented systemic dehydration or were taking tricyclic antidepressants. Intravascular volume depletion previously has been shown by Schirmer tear testing to reduce tear production. 3l The anticholinergic effect of tricyclic antidepressants may also have reduced tear production in the anorexia nervosa patients. 32- 38 Schirmer tear testing has been shown to be of limited reliability and specificity in the diagnosis of dry eye syndromes in individuals39- 46 ; however, the results from the anorexic group indicate that persons with the disease have a relative decrease in tear production and may be poor candidates for contact lenses. Two case reports by Stigmar47 and Miller48 describe progressive bilateral subcapsular cataracts occurring in anorexia nervosa. The weights reported for their patients were 98 and 44 Ibs. We calculated the body mass index of these patients to be 16.7 and 8.9 kg/m 2 , respectively, compared to a mean body mass index of 15.72 kg/m 2 for our anorexic group. Photographs of their latter case demonstrate truly exceptional emaciation accompanied by orbital fat loss. In an Australian study by Abraham et al,49 dilated slit-lamp examinations were performed on nine patients with anorexia nervosa who met DSM-III-R criteria at the time of examination. Abraham's study found only a peripheral congenital cataract in one patient. Similarly, we found no cataracts in the anorexia nervosa patients. The symptom of nighttime glare sensitivity in the anorexic group was an unexpected and unsolicited finding that did not correlate with medication, keratopathy, other 1005

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ocular findings, or severity of weight loss. Its pathogenesis remains to be identified. Previous studies of vitamin A status in anorexia nervosa have found conflicting results. One study found serum retinol to be low,50 whereas other studies found carotene and retinol and its derivatives to be normal or elevated by nondietary means. 7,51,52 Plasma retinol levels are an insensitive means of detecting vitamin A deficiency. Liver biopsy is the gold standard for evaluating vitamin A status, but it is impractical in the anorexia nervosa patient population. 53-55 Our study used history, slit-lamp examination, and conjunctival impression cytology to evaluate vitamin A status. Prolonged vitamin A deficiency is required before the onset of symptoms of night blindness. 56 The dietary history of our anorexia nervosa patients indicated a reasonable long-term intake of vitamin A through dairy products and vegetables. Three patients had been taking multivitamins for prolonged periods. The anorexic group was without symptoms of nyctalopia, although dark adaptation testing would be more sensitive for detection of asymptomatic night blindness. None of the anorexia nervosa patients had any clinical evidence of ocular xerosis, Bitot's spots, or hypopigmented retinopathy typical of severe vitamin A deficiency. 56 This is consistent with Abraham's study in which he found no xerosis or Bitot's spots in his examination of nine DSM-III-R anorexia nervosa patients. 49 Abraham observed in one of his patients atypical conjunctival nodules similar to those we described in one of our anorexia nervosa patients. We measured the fasting serum vitamin A level in our anorexia nervosa patient with these nodules and found it to be high normal. Conjunctival impression cytology to determine if an eye lacks goblet cells has been shown to be a useful method for detection of subclinical vitamin A deficiency in undernourished populations. 15,18-20 Goblet cells were rare or absent in only two of seven anorexia nervosa patients, both of whom had severe conjunctival squamous metaplasia (grades 5 and 10). Goblet cell loss with or without additional conjunctival squamous abnormalities is not specific to vitamin A deficiency and can be seen in cytologic studies of dry eye and other ocular disorders. 57- 59 In the anorexic group, the conjunctival squamous metaplastic changes of reduction in nuclear to cytoplasmic ratio, nuclear condensation, and loss of cell sheet integrity were out of proportion to the goblet cell loss. This indicates that vitamin A deficiency is unlikely to have been a major factor in causing these conjunctival changes. Punctate keratopathy, which may be an early sign of vitamin A deficiency, was not present in the two anorexic patients with goblet cell IOSS.60,61 The dietary history, absence of nyctalopia, absence of conjunctival, corneal, and retinal findings typical of vitamin A deficiency, and lack of prominent goblet cell loss by conjunctival impression cytology support the conclusion that vitamin A status was adequate in the anorexia nervosa group. Although we cannot pinpoint the cause of the conjunctival squamous metaplasia in this group, we believe that the substantial evidence against vitamin A deficiency in these patients supports a conclusion that other factors (dry eye and other nutritional and metabolic 1006

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abnormalities) played a more substantial role in causing these abnormalities.

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