DRUG-INDUCED CILIARY BODY OEDEMA: A NEW THEORY

PETER H. KRIEG and ISAAC SCHIPPER Lucerne, Switzerland

SUMMARY The clinical picture is generally uniform. Symp­ Drug-induced oedema of the ciliary body is rare, and toms usually appear 1-2 days following ingestion of occurs predominantly following exposure to sulphona­ the drug and last for 2-8 days after the medication mides. In a 31-year-old patient in her 37th week of has been withdrawn. The degree of ranges 4 6 pregnancy, we observed reversible myopia of -4.75 from -0.75 to -8 dioptres. The patients are dioptres following the ingestion of chlorthalidone. In a predominantly young women, and the myopia occurs I 6 1 second case report we describe, in a 61-year-old patient particularly frequently during pregnancy. , .2 In suffering from aspirin-sensitive asthma, recurrent addition to myopia, the anterior chamber may ciliary body oedema with a marked spastic component become markedly shallower, a change which is which was triggered by the medications , associated with the risk of acute (angle-closure) 8 l5 dipivefrine and . We explain oedema of the ?, , ,2o,22 Furthermore, oedema of the ciliary body on the basis of the eicosanoids. We believe has often been observed, most commonly I 6 8 3 that the oedema is caused mainly by and with central, radial folds. • , .2o-2 Choroidal detach­ that leucotrienes are predominantly responsible for the ment has also been described? spastic component. We postulate a drug-induced Most authors have assumed that ciliary body elevation in eicosanoid concentrations, as well as oedema was responsible for such observations. Due certain interrelationships between ciliary body oedema to relaxation of the zonules, the oedema would lead and aspirin-sensitive asthma. to a thickening of the as well as to the 6 8 1 3 displacement of the -lens diaphragm. , . 0,2 In Drug-induced ciliary body oedema, with transient any case, convincing explanations for the aetiology of myopia as its cardinal symptom, occurs only rarely. oedema of the ciliary body are lacking. We present However, the phenomenon has been recognised for here a new theory to account for ciliary body many years, and numerous case reports describing it oedema, with and without a spastic component. exist in the literature. Our theory is based upon an imbalance in prosta­ In most of the reports, the disorder occurred glandin-thromboxane-Ieucotriene metabolism. following the ingestion of sulphonamides (mainly sulphonamides possessing long half-lives and with I 3 diuretic action): chlorthalidone; ,2 sulphanilamide; CASE REPORTS 4 5 7 indapamide; acetazolamide; - the chemotherapeu­ Case 1 8 tic, sulphonamide sulphamethoxazole; glibencla­ A 31-year-old patient who had suffered in her youth 9 mide, which is an anti-diabetic sulphonamide from asthma was prescribed a sulphonamide diuretic lo derived from sulphonylurea; ; the (chlorthalidone) for moderate oedema of the lower ll aldosterone antagonist spironolactone; the syn­ leg during her 37th week of pregnancy. The oedema l2 thetic hormone tetracasactrin (ACTH); isosorbide responded favourably to the first tablet, so that the 13 14 dinitrate; the prolactin antagonist ; patient did not take a second tablet until 5 days later, ls and a variety of other drugs such as tetracycline, by which time the oedema had worsened. Approxi­ 16 17 18 penicillamine, quinine, metronidazole, isotreti­ mately 6 hours later, after awakening from a mid-day 19 o noin and aspirin.2 nap, she experienced bilateral deterioration of her distance vision and consulted our emergency ward. From: Clinic, Cantonal Hospital, Lucerne. In this patient, whose ophthalmological anamnesis Switzerland. Correspondence to: P. Krieg, MD, Dorfstrasse 94, CH-8706 was uneventful and who did not wear spectacles, we Meilen, Switzerland. found an uncorrected visual acuity of counting

Eye (1996) 10, 121-126 © 1996 Royal College of Ophthalmologists 122 P. H. KRIEG AND I. SCHIPPER fingers at 2 m; corrected visual acuity with a acid) for incessant pain. The result was the develop­ refraction of -4.25 dioptres bilaterally was 20/20. ment of nocturnal dyspnoea and cough, becoming was 21 mmHg in the right , increasingly refractory to therapy. Ultimately, in and 18 mmHg in the left eye. The light reflex and the September 1991, the patient was referred to a high­ depth of the anterior chamber were normal. Central altitude clinic, where the diagnosis of non-atopic radial folds with fading of the foveal reflex could be bronchial asthma with suspected aspirin intolerance, observed on the . Diabetogenic metabolism along with chronic bilateral sinusitis maxillaris, was was excluded. Three days later, during her second made. The precipitating agent was declared to be the visit, we found a further worsening of the myopia, to non-steroidal anti-rheumatic medication, mafenamic -5 dioptres in the right eye and -4.75 dioptres in the acid. left; visual acuity was unchanged. Slit lamp examina­ The operation on the right eye was tion revealed irritation of the anterior chamber, with performed in our clinic on 5 December 1991 evidence of a moderate presence of cells. (phacoemulsification; posterior chamber lens implan­ Treatment with 2 drops of the cycloplegic agent tation, AMO SI 26 NB). As previously, an elevation cyclopentolate led to a significant improvement in in intraocular pressure in the right eye to 34 mmHg, the myopia within 1 day: to -1.25 dioptres and -1.0 unaccompanied by pain, occurred on the first post­ dioptres, right and left , respectively. During the operative day. Pressure normalised following a single final clinical examination 3 days later (7 days oral dose of acetazolamide 250 mg. Visual acuity following the onset of the symptoms) the patient improved from 20/80 to 20/20. had no complaints, with the exception of mild Three weeks post-operatively, the pressure in the soreness of the eyes which occurred while perform­ right eye had once again increased, this time to 38 ing close work. The right eye still presented a mmHg_ Therapy to reduce intraocular pressure (oral refraction of -0.5 dioptres, while the left eye had acetazolamide and locally applied 2% pilocarpine) become emmetropic. As determined echographi­ was administered as a temporary measure. cally, the anterior chambers had deepened by 0.57 We did not see the patient again until 11 May mm (right) and 0.52 mm (left) compared with the 1992, when he came with the complaint of blurring of first examination, that is, within 7 days. The vision in both eyes. Posterior capsular opacification diameters of the right and left lenses had decreased was diagnosed; the intraocular pressure measured 40 by 0.2 mm and 0.14 mm, respectively. mmHg OD and 22 mmHg OS. This, together with an increase in the cupldisc ratio and arcuate scotomata Case 2 in the visual field, made the diagnosis of glaucoma clear. There was no pressure reduction with betax- A 61-year-old patient was admitted to our clinic in 0101 eye drops but also no initiation of asthma. March 1991 for an operation on presenile cataract of One day after administration of dipivefrine 0.1 %, the left eye. His medical history included a myocar­ extremely sharp peri bulbar pain accompanied by dial infarction at the age of 29 years, and he suffered occurred. On slit lamp examination the from aspirin-sensitive asthma as well as (from the age right eye looked completely normal, and the of 45 years) from gout. Bilateral intraocular pressure measured 22 mmHg. with pressures up to 24 mmHg OD and 22 mmHg OS After reduction of the pain and of the intraocular had been diagnosed 1 year previously. The cataract operation in the left eye (phacoemulsification; pressure through acetazolamide administration, a intraocular implantation of a silicon lens, model second trial with dipivefrine was attempted, but AMO SII19 NB) was performed on 14 March 1991. sharp pain recurred. This time conjunctival injection, Due to a pronounced post-operative increase in flattening of the anterior chamber, mild flare with intraocular pressure to 50 mmHg, it was necessary to some cells in the anterior chamber, and could administer high oral and intravenous doses of be observed. acetazolamide during the first 36 hours following Dipivefrine was withdrawn, and therapy with the operation, to a total dose of 1.75 g. Although this pilocarpine was initiated. The pressure measured 15 treatment led to the normalisation of the intraocular mmHg OD, but an unbearable pain in the region of pressure, the patient subsequently complained of the right eye occurred. Massive cellular reaction of sharp, cramp-like pain in the region of the left eye. In the flattened anterior chamber, miosis, and marked consideration of his recognised aspirin intolerance, narrowing of the anterior chamber could be the patient was prescribed the analgesic acetamino­ observed. After cessation of pilocarpine therapy phen. Under this medication his complaints became and initiation of local therapy with prednisolone less severe but did not disappear entirely. Visual acetate, the irritation in the anterior chamber acuity improved from 20/80 to 20/20. lessened considerably. Pain was not relieved by Following discharge from the hospital, the patient cyclopentolate but was markedly reduced after mistakenly took an aspirin derivative (mefenamic administration of drops 2%_ DRUG-INDUCED CILIARY BODY OEDEMA 123

In August 1992, because of a rise in intraocular (especially that of prostacyclin, PGI2) are already pressure to 42 mmHg, thermal sclerostomy and local elevated during pregnancy.33 Further pharmacologi­ mitomycin application were performed. After an cal stimulation would suffice to precipitate oedema of initial reduction, pressure rose again and in Decem­ the ciliary body and also possibly of the macula. ber 1992 a double-plate Molteno device was A further unique characteristic of the prostaglan­ implanted. The pressure was normalised, but 1 dins relates to their capability (due to their vasodi­ month later a circular choroidal detachment with latory properties) of potentiating the oedema­ 4 35 severe pain occurred and responded well to systemic inducing effects of histamine and bradykinin? , corticosteroids. Since then the right eye has been Furthermore, in the anterior , a significant 6 quiet and the pressure normal, but the patient still increase in vascular permeability also occurS? This complains of slight pain. may explain why the ciliary body is the only tissue in which oedema is manifested following the intake of drugs of this type. Since drug-induced oedema of the DISCUSSION ciliary body occurs very rarely, there must be The transient myopia following the ingestion of numerous factors contributing to the local accumula­ chlorthalidone that is described in the first case tion of prostaglandins, such as an inborn error in report is similar to that in a number of previously eicosanoid metabolism or a clinical or sub-clinical reported cases which occurred following the inges­ infection which is associated with elevated prosta­ 1 2 5 21 tion of a sulphonamide preparation. , , , We also glandin concentrations. The precipitating drugs, believe that the aetiology in our patient is to be particularly sulphonamides, are commonly taken to traced to oedema of the ciliary body, resulting in treat infections. We also know that certain of these relaxation of the zonules and in turn leading to a substances have an additional effect, namely the thickening of the lens (proven echographically) and stimulation of histamine release. In particular this is an associated increase in the refractive index. true for the amide group of drugs, including Similarly, a displacement of the iris-lens diaphragm sulphonamides, the amidines, alkaloids and antibio­ occurred, with the anterior chamber becoming 7 tics? slightly shallower. Concerning these drug effects on the ciliary body, It has not as yet been possible to elucidate the which we explain on the basis of the ­ cause of oedema of the ciliary body. Some authors 8 histamine effect, we differentiate between ciliary suspect an underlying allergic basis. ,22 This theory body oedema alone, and ciliary body oedema with an must be rejected, however, since re-exposure to the l 10 associated spastic component. It is conceivable that same medication has proved uneventfu1. , We mild spasm of the ciliary body occurred in our first believe that ciliary body oedema is related to the patient, who did in fact report mild pain during close eicosanoids (a general term for prostaglandins, work and in whom discrete cells were present in the thromboxane and leucotrienes). Prostaglandins are anterior chamber. However, an unmistakable spastic recognised to be mediators of inflammation and 4 component, aetiologically much more complex, was cause vasodilation with increased permeability? In definitely present in our second patient. He suffered the eye, this can cause breakdown of the blood­ from aspirin-sensitive asthma caused by interference aqueous barrier, and oedema of the macula.25,26 7 with eicosanoid metabolism. Therefore, we suspect Furthermore, prostaglandins cause miosis2 and that the ciliary body spasm was caused by a similar exert a hypotensive effect following an initial rise in 8 intraocular pressure? Thus, oedema of the ciliary mechanism of action in the eye. body, like that of the macula, can be fully explained Despite the fact that not all the details underlying on the basis of the actions of prostaglandins. the aspirin-sensitive asthma syndrome have been Drugs belonging to the sulphonamide-diuretic elucidated, most authors agree that elevated leuco­ triene concentrations are spasmogenic and that the group stimulate the synthesis of prostaglandin E2. To date this has been established for frusemide,29 inhibition of cyclooxygenase, brought about by 30 l indapamide and bendrofluazide? There are indi­ aspirin or other non-steroidal anti-rheumatic drugs 32 ?8 cations that the same is true of acetazolamide, since plays a central role Cyclooxygenase metabolises following inhalation this substance, like frusemide, arachidonic acid to prostaglandins and to throm­ exerts a bronchodilatory effect, which can be boxane A2. The alternative metabolic pathway of explained on the basis of the synthesis of the arachidonic acid, via the enzyme 5-lipooxygenase, leads to the formation of the leucotrienes (LT). The bronchodilator, prostaglandin E2. As in our first case report, the literature reports initial product; LTA 4, is metabolised by a hydrolase numerous descriptions of oedema of the ciliary body to LTB4 or by glutathione-S-transferase to LTC4. during pregnancy (see above). This higher preva­ LTC4 is then converted by gamma-glutamyl-trans­ lence in pregnant women can be explained on the peptidase to LTD4, which is ultimately transformed 9 basis of the fact that levels of prostaglandins by a dipeptidase to L TE4? LTC4, LTD4 and LTE4, 124 P. H. KRIEG AND I. SCHIPPER previously known as the 'slow-reacting substance of extremely rarely in drug-induced oedema of the anaphylaxis', are sulphidopeptides; they are extre­ ciliary body. mely potent spasmogenic agents at the level of the The first clinical event in our patient with aspirin­ non-vascular, smooth musculature, including the sensitive asthma occurred in the immediate post­ bronchi.4o,41 Asthmatic bronchospasm can be largely operative phase, at a time when intraocular prosta­ explained on the basis of the spasmogenic properties glandin concentrations were almost certainly ele­ 36 of the leucotrienes. Leucotriene levels are elevated vated. Furthermore, the active transport system of following the ingestion of cyclooxygenase-inhibiting the ciliary body (responsible for the removal of 5 prostaglandins from the intraocular fluid 1) may have drugs; the underlying mechanism of action is 2 42 5 unknown. been a manifestation of a dysfunction due to the At the molecular level one can imagine that, as a trauma of the operation; this would then have result of the inhibition of prostaglandin synthesis, the contributed to a further elevation in prostaglandin interactions between the prostaglandins, throm­ levels. Following the administration of the sulphona­ 3 boxane A2 and the leucotrienes will be disturbed.4 mide acetazolamide (with the resulting possible These complex interrelationships are only now supplementary release of prostaglandins and perhaps beginning to be explored. It has been possible to of histamine), the equilibrium in eicosanoid metabo­ demonstrate in human neutrophils, on the one hand, lism was probably further upset. Compounding factors are the presumed pathological interactions that prostaglandin Fz-alpha inhibits the synthesis of 44 among the prostaglandins, thromboxanes and leuco­ LTB4. On the other hand, it has been shown in trienes, as well as the already elevated leucotriene animal studies that the inhibition of thromboxane A2 45 levels. leads to the suppression of the leucotrienes. We The operation on the opposite eye took place believe that these interrelationships between throm­ without development of ciliary body oedema, in spite boxane and the leucotrienes are disturbed in aspirin­ of the renewed administration of acetazolamide, sensitive asthma. Indeed, such patients have elevated albeit in lower doses, and not intravenously; this leucotriene values (urinary LTE4) even in the 2 further refutes an allergic basis for ciliary body absence of stimulation with aspirin;4 their throm­ 46 oedema. The pronounced manifestation of spasm of boxane A2 concentrations are likewise elevated. the ciliary body occurred shortly after topical Following the administration of cyclooxygenase application of a drop of 0.1% dipivefrine. Since inhibitors - which cancel out the leucotriene-inhibit­ agents stimulate the synthesis of prosta­ ing effect of prostaglandin Fz-alpha - a further 53 42 glandins and of other eicosanoids, the resulting increase in leucotriene levels takes place. oedema and the spasm may be explained on the basis Little is known about the intraocular effect of of the mechanisms described above. Shortly there­ leucotrienes in humans apart, for example, from the after, analogous symptomatology was observed fact that these substances could be detected in the 47 following topical treatment with pilocarpine. We of patients with . Most of explain this in the following manner: Pilocarpine our knowledge of the leucotrienes is taken from occupies cholinergic muscarinic receptors. When the animal studies. As suggested by their name, leuco­ M2 receptor subtype is occupied mainly with trienes (LTB ) in animals lead to the accumulation of 4 guanosine-5-triphosphate (GTH)-binding protein 8 leucocytes,4 and to marked miosis (especially 54 K, the enzyme phospholipase A2 is activated. This 49 LTC4). However, in contrast to the prostaglandins, leads to the accumulation of arachidonic acid and, they do not lead to breakdown of the blood-aqueous ultimately, of eicosanoids. For organs such as the barrier, nor do they lead to alterations in intraocular brain and the heart it has been possible to 48,50 pressure. demonstrate that stimulation of the muscarinic 55 On the basis of the aspirin-sensitive asthma in our receptors leads to the release of prostaglandin E2. second patient, as related to the metabolic abnorm­ What is unique in our patient is the chronic pain. alities described above, we postulate that oedema of Conceivably, the recurrent triggering of oedema of the ciliary body was triggered in a recurrent fashion the ciliary body, accompanied by spasm, might have with a spastic component. We speculate that the developed into a chronic inflammation, as is the case oedema was prostaglandin/histamine-dependent, in aspirin-sensitive asthma. while the spasm was additionally brought on by As mentioned in the Introduction, numerous leucotrienes. Clues supporting the hypothesis of descriptions can be found of ciliary body oedema leucotriene-induced spasm are to be found in the triggered by other drugs. Sulphonylurea antidiabetic subjective, cramp-like pain, in the marked miosos, drugs are related to the sulphonamides, both and in the presence of cells in the anterior chamber. chemically arid developmentally; therefore, a We reason in this manner since pain and irritation of mechanism of action similar to that of the sulphona­ the anterior chamber have been described only mides can be postulated. Likewise, an interrelation- DRUG-INDUCED CILIARY BODY OEDEMA 125 ship with prostaglandin metabolism is recognised for vaginal sulfanilamide suppositories. Am J Ophthalmol aldosterone antagonists, which act at the level of the 1984;98: 120-1. 56 4. Boissonnot L, Boissonnot M, Charles-Gervais C, renin-angiotensin-aldosterone system. Analogous Breux JP. Myopie aigue due a lindapamide. 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