Dorzolamide-induced immune thrombocytopenia: a case report and literature review.

PURPOSE: To report a severe case of dorzolamide-induced immune thrombocytopenia, to review the literature on this topic, and to draw attention to the serious potential side effects of this topical sulfonamide. CASE REPORT: An 83-year-old man with primary open-angle glaucoma in both eyes who was taking topical dorzolamide therapy for 3.5 years developed a severe thrombocytopenia (10,000 platelets/microL). The amount of platelets was not influenced by prednisone therapy but increased rapidly to 100,000/microL after the withdrawal of dorzolamide. LITERATURE REVIEW: Although the potential capacity of sulfonamides to induce thrombocytopenia is well known, no case of dorzolamide-induced immune thrombocytopenia was published in the medical literature until July 2000. CONCLUSION: Considering the possible severe side effects that can be induced by topical dorzolamide 2%, ophthalmologists should carefully evaluate during the medical history of their patients the risk of sensitivity to sulfonamides.

Type a syndrome of insulin resistance: anterior chamber anomalies of the eye and effects of insulin-like growth factor-I on the retina.

BACKGROUND: The purpose of this work was to describe the anterior chamber and iris anomalies as well as to evaluate the effects of recombinant human insulin-like growth factor-I (rhIGF-I) on the retinal vessels in 2 diabetic patients with type A syndrome of insulin resistance, a rare condition associated with acanthosis nigricans. METHODS: Ophthalmologic examinations, including photographs and fluorescein angiograms, were performed before, and 2 and 4 weeks after starting subcutaneous rhIGF-I treatment, and 3 months after withdrawal of rhIGF-I treatment. RESULTS: Both patients had goniodysgenesis with mild elevation of the intraocular pressure. Before and after 2 weeks of treatment with rhIGF-I, the fundus and the fluorescein angiograms were mainly normal. After 4 weeks of rhIGF-I treatment both patients' retinas revealed leakage of fluorescein. Three (case 1) and 4 months (case 2) after withdrawal of rhIGF-I, the fundus of all four eyes were again without leakage. CONCLUSIONS: The anterior chamber anomalies found in these patients may be part of the type A syndrome of insulin resistance and could alert clinicians that these patients might not have the usual type of diabetes. Moreover, the data show that exogenous rhIGF-I administration in patients with type A syndrome of insulin resistance alters the permeability of the superficial layer of retinal capillaries which is comparable to the earliest angiographic changes in childhood diabetic retinopathy. Whether this is a direct effect of rhIGF-I, as suggested by experiments in an animal model, or an indirect effect due to the near-normalization of the glucose levels by rhIGF-I warrants further investigations. Finally, this work points to an important caveat regarding the therapeutic use of rhIGF-I in this patient population.

Xanthurenic acid derivative formation in the lens is responsible for senile cataract in humans.

BACKGROUND: The tryptophan degradation pathway leads to NAD production via 3-hydroxykynurenine. Kynurenine aminotransferase (KAT) transforms 3-hydroxykynurenine into xanthurenic acid. In this study, we measured the activity of KAT in human lenses and studied the consequences of xanthurenic acid formation METHODS: KAT activity was determined by the method of Tobes. Fluorescence spectroscopy and SDS-PAGE were used for the protein studies. Thin-layer chromatography and infrared and fast atom bombardment spectrometry were used for substance characterization. RESULTS: The KAT activity was detected in senile cataratous lenses, but was absent in the young lenses. Xanthurenic acid at physiological pH exists in equilibrium with its tautomeric form reported by us as oxo-xanthurenic acid (OXA), which is oxidized to di-oxoxanthurenic acid (DOXA), a naphthoquinone-like substance. The incubation of DOXA with crystallins in a solution of physiological pH led to crystallin crosslinking and formation of conjugates with glutathione. CONCLUSIONS: Xanthurenic acid is formed in human lenses. Its tautomerization and oxidation leads to a naphthoquinone-like substance, DOXA. DOXA provoked formation of conjugates with glutathione and crosslinking of crystallins. Thus, KAT activity seems to be the initial event in senile cataract formation in humans.

Indoleamine 2,3-dioxygenase: antioxidant enzyme in the human eye.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is the first enzyme of the tryptophan degradation pathway. IDO is an antioxidant enzyme because it is a direct scavenger of superoxide radicals. In this study, we measured the activity of IDO in the human eye. METHODS: IDO was detected in the protein extract of human retina, iris/ciliary body, and lens. The products formed were measured using HPLC with electrochemical detection. Enzyme activity was expressed as the quantity of kynurenine and 3-hydroxykynurenine formed. RESULTS: IDO activity in the retina extract was 51.5 (+/-10) nmol/g tissue/h, and kynurenine formation was detected. In the iris/ ciliary body, IDO activity was 191.8 (+/49) nmol/g tissue/h, and both kynurenine and 3-hydroxy-kynurenine were formed from tryptophan. In the extract of lens cortex only 3-hydroxykynurenine was formed from tryptophan. IDO activity was 351 (+/-67.3) nmol/g tissue/h. CONCLUSION: Free tryptophan is degradated in the human eye by IDO, an antioxidative enzyme. IDO may be an antioxidant mechanism in the eye.

3-hydroxykynurenine transamination leads to the formation of the fluorescent substances in human lenses.

The levels of alanine, aspartate and glutamine transaminase increase considerably in some diseases. We measured the activity of these enzymes and of the transaminase of 3-hydroxykynurenine, an aminoacid, which acts as a UV lens filter. Alanine and glutamine transaminases (carboxypeptidase) were not detected in normal and cataractous human lenses, and aspartate transaminase was found only in the cortex of normal lenses. 3-hydroxykynurenine transaminase was not found in lenses from persons below thirty years of age, but was found in lenses at about fifty years of age, and in cataractous lenses. Transamination of 3-hydroxykynurenine leads to the formation of xanthurenic acid and its derivatives. These substances appear to be responsible for the increase of lens fluorescence during cataract development.

Deamination of 3-hydroxykynurenine in bovine lenses: a possible mechanism of cataract formation in general.

BACKGROUND: 3-Hydroxykynurenine, a metabolite of tryptophan, acts as UV filter in the human lens. In this study, we looked for this substance and its metabolites in young and old bovine lenses, because of their possible role in the formation of cataract. METHODS: The substances were detected by HPLC analysis. The fluorescent substance formed from 3-hydroxykynurenine was characterized by thin-layer chromatography followed by reaction with ninhydrin, UV and fluorescence spectrum analysis, and atom bombardment for molecular mass determination. The kynurenine aminotransferase activity was determined by the method of Tobes. RESULTS: 3-Hydroxykynurenine was detected at concentrations of 0.07, 0.19, and 1.14 micrograms/g of tissue in the bovine iris/ciliary body, retina, and transparent bovine lenses respectively. 3-Hydroxykynurenine was deaminated in old bovine eyes but not in calf eyes. In old eyes, kynurenine aminotransferase activity was 2.7, 3.5, and 9.6 mumol/g of tissue per h in retina, iris/ciliary body, and lens respectively. CONCLUSION: The deamination of 3-hydroxykynurenine resulted in the formation of a fluorescent substance which was identified as oxidized xanthurenic acid. This substance, accumulating in the bovine lens and interacting with lens proteins, could induce cataract formation.

Serotonin in human tears.

It has been postulated that serotonergic receptors are present in the corneal epithelium and that their activation by serotonin released from subepithelial corneal nerves raises the level of cyclic AMP, which in turn stimulates active CI-secretion by the corneal epithelium. We looked for serotonin in tears because these bathe the corneal epithelium. Twenty-two normal subjects, 14 women and 8 men between 25 and 60 years of age (average 36.5 +/- 9 years), participated in this study. Twenty microliters of tears were collected in capillary tubes after trigeminal stimulation (pepper in the nose) and were immediately analysed using high-performance liquid chromatography with electrochemical detection. Serotonin was identified and measured in every subject. Its mean concentration was 2.74 +/- 1.99 ng/ml. No difference was found between women and men. Emotionally evoked tears were obtained from two subjects. The amount of serotonin in these samples was much higher than in the samples obtained by trigeminal stimulation. These results demonstrate for the first time that serotonin is present in human tears. The possible role of this serotonin in chloride transport in the corneal epithelium and the probable difference between "emotional" and stimulated tears warrants further investigation.

[Genetics of glaucoma]. / La génétique du glaucome.

The glaucomas are the second cause of blindness in the industrialized world. As well as all other pathologies, they take advantage of recent developments in the field of the molecular biology. The run for the pathological genes has just begun. Indeed, in Mai 1993, the first pathological gene was localized on the long arm of chromosome 1q21-q31 in every involved members of a family with juvenile glaucoma. Sequencing of the gene is in progress and should be soon successful. The multitude of clinical glaucoma forms lets foresee several pathological genes. Nosological associations known since long time as glaucoma and diabetes mellitus (certain forms) seem assumed to common chromosomic anomalies. The different types of glaucomas and the most frequent ocular anomalies with glaucoma were examined under the genetic point of view. Whereas the juvenile glaucomas are transmitted according a autosomal dominant pattern with a almost full penetrance, the primary open angle glaucomas are transmitted according a multifactorial mode. This fundamental difference between the diverse forms of glaucomas could have large outcomes on the evolution of the knowledges of the disease and its treatment. The discovery of the genetical anomalies responsible for glaucomas should, in the next three decades, transform radically the treatment of glaucoma. Of symptomatic by lowering of the intraocular pressure, the treatment will become ethiological, either pharmacological through correction of production of the pathological gene, either genic through direct correction of the gene.

Indoleamine 2,3-dioxygenase activity in the aqueous humor, iris/ciliary body, and retina of the bovine eye.

The enzyme indoleamine 2,3-dioxygenase (IDO), which uses free oxygen radicals to cleave the pyrrole ring of indoleamines and give kynurenamines, has previously been found in most tissues, but not in the eye. In this study, IDO activity was measured in post-mortem bovine eyes using Yamazaki's method with L-tryptophan as substrate. Because of the physiological importance of IDO in the protection against free oxygen radical damage, a search was conducted to find this enzyme in the eye. Products of tryptophan degradation by IDO, the kynurenine and 3-hydroxyanthranilic acid were detected and measured in the aqueous humor, iris/ciliary body, and the retina by high-performance liquid chromatography (HPLC) coupled with electrochemical detection. IDO activity was 3.2, 9.0 and 10 nmol/mg protein per h for the aqueous humor, iris/ciliary body, and retina, respectively. These findings suggest that, because of its scavenger properties, IDO is involved in the protection of the eye where, because of its transparency, free radicals are formed not only in the normal oxidation process, but also photochemically.

Dopamine and its metabolites in human tears.

Dopamine is known to stimulate ion transport in the corneal epithelium. Since epithelium is in contact with tears, we searched for dopamine and its metabolites in tears. Twenty normal subjects participated in this study. Twenty microliters of tears were collected in capillary tubes after trigeminal stimulation and immediately analyzed using high-performance liquid chromatography with electrochemical detection. Dopamine and two of its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were identified and measured. The mean concentration of dopamine was 8.9 +/- 5.1 ng/ml; DOPAC, 2.2 +/- 1.6 ng/ml; and HVA, 0.55 +/- 0.4 ng/ml. These results permit us to suggest that dopamine is deaminated by monoamine oxidase, then methylated by catechol-O-methyltransferase and that catabolism occurs in the lacrimal gland and perhaps in corneal epithelium. Finally, part of the dopamine involved in ion transport may come from tears.

Effects of timolol on visual-field mean retinal sensitivity in normal subjects.

This single-blind, randomized study investigated the effects of unilateral instillation of 0.5% maleate timolol twice a day for 7 days on visual-field parameters of both eyes. Twelve normal, young subjects (30.6 +/- 4.2 years) participated in this study. Using program G1 of the Octopus 500 automated perimeter, the visual fields were measured one week and one day before therapy and a third time one week after beginning therapy. The paired T-test was used for statistical analysis, where a P-value < or = 0.05 indicated significance. Whereas nothing statistically significant was found in the treated eyes, the contralateral, untreated eyes showed a statistically significant decrease of mean sensitivity between the first visual fields and the third ones (P < 0.01) This diminution of mean sensitivity in the untreated contralateral eyes may be due to statistically significant lowering of blood pressure (P < 0.01) and slowing of cardiac frequency, which were not compensated by a local decrease of intraocular pressure. If confirmed, these findings could be of clinical importance in the management of glaucoma patients, since some authors have, in some cases, recommended a unilateral therapy.

[Pathogenesis and treatment of primary closed-angle glaucoma]. / Pathogénie et traitement du glaucome primaire par fermeture de l'angle.

With an incidence of about 1/1000, primary angle-closure glaucoma is 4 to 5 times less frequent than primary open-angle glaucoma. It occurs most frequently due to pupillary block, itself both due to anatomical configuration and to either physiological or pathological changes in the anterior chamber. Pupillary block causes an increase of pressure in the posterior chamber, which leads to anterior displacement of the iris and, finally, to angle closure. The treatment of choice - dictated by the pathogenesis - consists of diminishing the posterior chamber pressure by means of hyperosmotic agents such as glycerin per os or mannitol iv. After reduction of the posterior-chamber pressure has been attained, a mild miotic, i.e. one which causes neither a strong miosis nor a flattening of the anterior chamber, is administered. If it is an acute attack, the application of these principles will permit normalization of pressure within about one hour. Several therapeutic guidelines are proposed, adapted to certain classical situations as well as to some less classical.

The ciliary body--the third organ found to synthesize indoleamines in humans.

Indoleamines are associated with circadian rhythms in pineal gland and retina. Because the ciliary epithelium has an embryonic origin similar to that of pineal gland and retina, and intraocular pressure shows circadian variations, indoleamines were searched for in aqueous humor and ciliary body in humans. In aqueous humor, serotonin, 6-hydroxymelatonin, and melatonin were simultaneously detected and measured using high-performance liquid chromatography with electrochemical detection. The concentration was 48.7 +/- 10.9 ng/ml for serotonin, 0.47 +/- 0.8 ng/ml for melatonin, and 13.9 +/- 7.7 ng/ml for 6 hydroxymelatonin. In ciliary bodies from freshly enucleated human eyes, tryptophan, 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid were detected using high-performance liquid chromatography with simultaneous fluorescence- and electrochemical detection. Finally, the enzymatic activities of arylalkylamine N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT), enzymes indispensable in the synthesis of melatonin, were measured. The NAT activity was 273 +/- 25 pmol/mg protein/hour and that of HIOMT, 13520 +/- 50 pmol/mg protein/hour in ciliary body. Comparison of these activities (NAT versus HIOMT) permits the suggestion that NAT is a limiting enzyme in serotonin metabolism in this tissue. These findings indicate that a circadian rhythm of indoleamines exists in human aqueous humor and that the human ciliary body is the third organ, after the pineal gland and the retina, found to synthesize indoleamines in humans.

Normal intraocular pressure in man.

Whereas the values of 120/70 mm Hg are universally recognized as being normal for the parameter of systemic blood pressure, the value for 'normal intraocular pressure' remains very vague. Indeed, values between 7 and 21 mm Hg are often considered normal. However, a careful review of the literature and original data reported here suggest that the intraocular pressure in normal subjects, although dynamic, is a more accurate parameter than is generally expected. The normal value during the day in healthy, young adults is about 12 +/- 2 mm Hg, and it increases by 1 mm Hg per decade after 40 years of age.

[Dysgenesis of the neural crest, ectoderm, mesoderm and fetal alcohol syndrome]. / Dysgénésie de la crête neurale, de l'ectoderme, du mésoderme et syndrome alcoolique foetal.

A case is described having malformation of the anterior chamber with bilateral high IOP combined with multiple ocular anomalies in a 13-year-old girl. Here, embryotoxon posterius, synechiae out to Schwalbe's line, and hypoplasia of the iris stroma in the form of Rieger's anomaly are associated with: myelinated corneal nerves concurrent with appearance of vessels without scleralization, unilateral orbital hypoplasia without microphthalmia and without enophthalmos within the scope of a unilateral facial hypoplasia, bilateral epicanthus with asymmetry of the lid-openings without hypertelorism, bilateral delayed development of the tear ducts, horizontal myopic astigmatism and bilateral relative amblyopia, dental deformation, urogenital malformation, deformation of the joints, slightly delayed mental development, ataxia, normal karyotype. In a chronically alcoholic mother, the association between these systemic and ocular anomalies constitutes a fetal alcohol syndrome. Although the anomalies of other derivatives of the neural crest have already been described in this context, certain of these anomalies, such as malformations of the ectoderm or mesoderm, have not been reported.

[At-risk keratoplasty, HLA antigens and cyclosporin A]. / Kératoplasties à risque, antigènes HLA et cyclosporin-A.

Keratoplasty in a calm and avascular cornea usually involves no histocompatibility problem. This is not the case if the recipient cornea is inflamed or vascularized. In such cases, and in those where the donor button has been rejected, HLA matching and particularly the search of HLA DR is important. More than 80 potential kidney donors (160 eyes) are tested each year at Zurich University Hospital. The availability of matched corneas, a certain degree of homogeneity of DR group in our population, and an "anti-DR" action of cyclosporin-A gave us the incentive to perform this study and to place these corneas at the disposal of every Swiss clinic. For this purpose, the HLA groups of high-risk patients must be established and sent to Zurich Eye Bank where these data are regularly compared with matched corneas. Every time an HLA A, B, and especially an HLA DR compatible donor-recipient pair occurs, the clinic involved will be quickly informed. In cases where HLA DR antigens are not compatible, cyclosporin-A should be part of the treatment and in cases where they are compatible, advice would be given to do without it. Since optimal preservation, with the medium used lasts 5 days, there is sufficient time for most corneas with a known HLA group to be grafted on the most compatible recipient.