A C T A O P H T H A L M O L O G I C A V O L . 5 8 1 9 8 0

THE EFFECT OF CARBONIC ANHYDRASE INHIBITION ON CENTRAL CORNEAL THICKNESS AFTER CATARACT EXTRACTION

BY

CARSTEN BO NIELSEN

T h e influence o f acetazolamide (a carbonic anhydrase inhibitor) on central thickness of the human cornea in vivo was studied. Corneal thickness as measured after cataract surgery was significantly increased by acetarolamide, if the specular microscopy revealed central corneal guttae, pre-operatively When no guttae were seen by specular microscopy, no effect could be demonstrated.

Kr? niords: corneal thickness ~ endothelium - carbonic anhydrase - acetazo- laniide.

Normal function of the limiting layers of the cornea is crucial for maintaining stromal hydration. The endothelium is believed to function on basis of a pump-leak theory (Mishima & Kudo 1967; Trenberth & Mishima 1968; Maurice 1972). The active component in rabbit endothelium has been characterized by dependence on bicarbonate (Hodson 1971, 1974; Dikstein & Maurice 1972) and carbonic an- hydrase (Fischbarg & Lim 1974; Hodson & Miller 1976; Hull et al. 1977) for conversion of exogenous COn to HCO?. Silverman (1973) found carbonic anhydrase in the endothelium in the same order of magnitude as in most secretory tissues.

The previous studies were performed on rabbit corneas in vitro. The purpose of the present study was to reveal the possible significance of carbonic anhydrase activity in the human cornea in vivo.

As no effect on normal corneal thickness was found when a carbonic anhydrase

Received June 5, 1980.

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Cnrptpn Ro Nielwn

inhibitor was administered (unpublished data), patients to be cataract extracted

were chosen. The post-operative condition, comprising a hyperhydrated state

would seem to favour the possibility of showing a decrease in the deswelling

capacity of the endothelium.

Patients with cornea guttata were considered a separate group. These patients are

seen t o have a different CCT-response to cataract surgery (Olsen 1980) and a

higher incidence of postoperative corneal oedema gaffe 1976), probably as a sign

of endothelial malfunction.

Material and Method

MatPrzrcl. The material comprised 55 consecutive patients with senile cataract. Patients with other past or present eye disease or intraocular pressure > 21 mmHg were omitted. The first 25 patients received acetazokdmide, and the next 30 served as control. In the drug-group 5 of the 25 were excluded (2 with surgical complications, 2 with striate oedema leading to uncertain CCT-measurements and 1 due to drug intolerance). In the control-group 3 were excluded ( I with surgical complications, 1 with striate oedema and 1 with post-operative hyphaema).

All operations were performed with the same technique (corneal incision, cryoextraction, running 10-0 nylon suture) by 6 surgeons. No significant difference in corneal first-post- operative-day thickness of the patients, operated by the different surgeons, could be demonstrated.

M ~ t h o d . The endothelium of all eves to be operated on were examined by non-contact specular microscopy as described by Olsen (1979). 3-4 exposures were taken of each cornea, paying attention to the possible presence of central corneal guttae. Guttae were defined as round dark areas, comprising defects in the endothelial reflex larger than two endothelial cells and changing in size with the focusing. If more than one defect, defined as above, were present on either exposure, the cornea was classified as guttata.

Further the central corneal thickness (CCT) and intraocular pressure (IOP) were measured. The CCT-measurements (mean of 3 readings to the nearest 5 prn) were performed with a modified Haag-Streit pachorneter (Ehlers & Sperling 1977) using the technique (alignment A) described by Olsen et al. (1980) with a coefficient of variation - 0.01. IOP was measured with applanation tonometry.

ExpPrirnPnts. The drug-group included a total of 20 patients. Rased on the pre-operative specular microscopy 8 patients were classified as normal (age 67.1 2 3.8. mean t SEM) and 12 as guttata (75.1 k 2.6). The 27 patients, to serve as control, comprised 14 normal (age 69.1 f 3.6) and 13 guttata (73.0 t 1.62).

The patients to be medicated were given acetazolamide (Diamox@ Duplex, Lederle) 500 mg X 2 for 3 days, starting on the first post-operative day in the evening, ending on the fourth day in the morning.

The CCT was measured at the same time of the day, pre-operatively and daily from the first to the sixth post-operative day. IOP was measured pre-operatively and daily from the second to the sixth post-operative day.

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Arrtuzolamadr and Corneal Thzcknrcc

20

lo

30

--

--

20

10

A C C T 0

- lo t l m

-20

-30 - 1 2 3 4 5 6

30 t

Fig. 1. CCT (mean zk SEM) relative to the first-post-operative-day value for the operated eye.

Left: guttata. Right: normal. Closed circles: after acetazolamide. Open circles: control.

Results

The aim was to test the ability of the cornea to deswell from a given thickness, during simultaneous acetazolamide medication. It was decided to let the individual CCT as recorded on the first post-operative day be the zero value. Doing this a ‘contamination’ based on interpersonal variation in CCT, as measured in absolute numbers, was avoided. The mean increase in CCT on the 1. post-operative day relative to the pre-operative value was not significantly different from group to group (normalidrug 63.8 5 11.1 pm, mean k SEM, norrnalicontrol 70 f 6.1 pm, guttataidrug 66.6 4 9.3 pm and guttataicontrol74.6 f 12.5 km).

The corneal deswelling in the 4 groups are shown in Fig. 1. Acetazolamide did not affect the deswelling rate of the normal corneas, whereas guttata corneas actually swelled. On all days were the CCT-values recorded in this group greater than the value on day 1. Considering the group controliguttata a secondary rise in CCT is found on day 4 and 5. The mean CCT in the guttataidrug group are different from control by approximately 30 pm (day 1 and 2: P < 0.01, day 3 and 4: P < 0.05, t-test).

The IOP on each day was not found to be significantly different between any two groups (Fig. 2 ) .

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Carrterz Bo NiuLyen

k- w- P 2 3 4 5 6 P 2 3 4 5 6

Fz,g 2. IOP (mean t_ SEM) relative to the pre-operative (P) value for the operated eye. Left: guttata.

Right: normal. Closed circles: after acetazolarnide. Open circles: control.

A CCT 7ok 0

I

A lOP mm Hg

t+- P 2 3 4 5 6

- 5 t

Fzg 3. CCT (mean f SEM) relative to the first post-operative-day value and IOP (mean f \ P M )

relative to the pre-operative (p) value, Both recordings are for the guttata fellow non- operated eye. Closed circles: after acetazolamide. Open circles. control.

Fig. 3 shows CCT and IOP for the non-operated fellow-eye in the guttata groups. CCT in the druggroup is greater than control on day 4 (I' < 0.02, t-test). Between the normal groups no such significant difference was found, neither considering CCT nor IOP (not shown).

Discussion

The aqueous concentration of the lipidsoluble acetazolarnide in steady state is assumed to be equal to the free active fraction in plasma (Davson 1950), and so the effective concentration would be the same. The dose was 7-10 rngikg giving an

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aqueous concentration of 0.5 - 1.0 X M, both in the middle of the range for sole effect on carbonic anhydrase, as stated by Mar& (19’77). No effect of acetazolamide other than carbonic anhydrase inhibition is known for concentra- tions below M (Maren 1977).

It was found that after systemically administered acetazolamide, cornea guttatae did not retain the deswelling capacity, as seen in the control group. Considering the fellow non-operated guttata eye a small swelling tendency was also noted. A tendency towards an IOP-drop, however, was seen in this case. Normal corneas were not affected by acetazolamide. The reason for this could be several. Differen- ces in IOP may be ruled out (Fig. 2 ) . Becker (1957) and Mar& (1976) found only small changes in the aqueousiplasma ratio (already nearly one) of pH, C1, HCOj and Na+ after acetazolamide medication, changes so small that they could not explain the loss of capacity for corneal deswelling (Hodson 1971; Dikstein & Maurice 1972).

Differences in aqueous concentration of acetazolamide between normal and guttata eyes cannot be completely ruled out. The relative permeability of the ciliary epithelium of cornea guttata eyes to acetazolamide is not known, neither in the normal state nor when modified as after cataract surgery. Further, in the actual region of drug-concentration ( 1 0 - 5 M), the physiological response exhibits a step course, so that small changes in concentration would yield greater physiological response.

It seems tempting to speculate that corneae guttatae are in a state close to

decompensation, considering dehydration. The uncatalyzed hydration of CO2 in aqueous is so fast (tW = 5 sec, Silverman 1973) that only when corneal dehydration is almost decompensated could an effect of carbonic anhydrase inhibition be ex- pected. Fuchs’ endothelial dystrophy, exhibiting corneal guttae, is a condition with frank oedema. The carbonic anhydrase dependence of the pump was found to be 33-607T (Fischbarg & Lim 1974: Hodson & Miller 1976: Hull et al. 1977), so partly inhibiting an active, maybe nearly decompensated, fluid-pump may be ‘the straw that broke the camel’s back‘.

T h e post-operative CCT-course of the group guttataicontrol is seen to follow the two normal groups for the first 3 days. Then a secondary rise in thickness is noted, also found by Olsen (1980). After penetrating keratoplasty Bramsen & Ehlers (1979) found that not until 3 days after operation was CCT at maximum value, if corneal host disease was Fuchs’ endothelial dystrophy, suggesting some aqueous factor to be involved in the regulation of CCT.

This study would seem to contradict the use of acetazolamide in the treatment of Fuchs’ endothelial dystrophy (Warring et al. 1978).

So the results in this clinical study on the human cornea would be consistent with earlier studies on rabbit corneas in vitro, that fluid transport across corneal endothelium. at least partly, is based on carbonic anhydrase supplying bicarbonate to a transport system.

Cnrstpn Bo Nirl,\en

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A irthor'r mldrev Carsten Bo Yielsen, Department of Ophthalmology, h-huS Kommunehospital, DK-8000 Arhus C, Denmark