A local challenger of ocular calciphylaxis in patients with chronic renal failure: a hypothesis.

BACKGROUND: It is generally accepted that the elevated calcium phosphate product in dialysis patients is associated with the development of extraskeletal calcification. There is, however, no clear association between the raised levels of calcium and phosphate ions and the degree of limboconjunctival calcification. This article focuses on the role of tissue devitalisation in the development of ocular calcification. METHODS: Local injury of the outer eye can be visualised by the Lissamine green staining test. We measured the pre- and postdialysis staining score in 38 dialysis patients. The differences between pre- and postdialysis tear fluid secretion and tearfilm stability were also assessed, as was the degree of limboconjunctival calcification. Serum calcium and phosphate levels were measured in all patients. RESULTS: In 14 of the 38 patients, demonstrable tissue injury was present as a result of a recurrent decrease of tear secretion after each dialysis session. There was a statistically significant association between the degree of limboconjunctival calcification and both the difference between the pre- and postdialysis Lissamine green staining score and the total number of haemodialysis sessions. CONCLUSION: Local factors, such as minor tissue injury of the limboconjunctival epithelium, referred to as "local challenger", are more likely to determine the degree of ocular calcification in dialysis patients than are systemic factors. Tissue injury of the outer eye in these patients is the result of a chronic decrease of tear fluid that occurs after each hemodialysis session.

The role of serum calcium in the development of the acute red eye in chronic renal failure.

In patients with chronic renal failure treated by long-term dialysis, inflammatory reactions occasionally develop in the bulbar conjunctiva; the episcleral tissue is only rarely involved. Diffuse congestion of both the conjunctiva and episclera was present in 5.3% of our patients and was associated with a sudden, marked rise in serum calcium. Histopathological examination suggests that this form of hyperemia, clinically preceded by a marked shedding of calcific precipitates, is the result of a neurogenic-driven inflammatory reaction in which mast cell degranulation is mediated by the axon reflex. Focal hyperemia associated with elastosis ("pingueculitis") was present in 6.7% of the patients. This type of hyperemia was observed after an extended period of increasing levels of BUN and seemed independent of both serum calcium and phosphorus. Diffuse hyperemia of the conjunctiva, being clinically distinctly different from the combined diffuse conjunctival and episcleral hyperemia, was also observed in 6.7%. Diffuse conjunctival hyperemia seemed to be associated with low BUN. Here, again, there was no association with serum calcium and phosphorus levels.

Can hydroxyapatite deposition in the eye cause a neutrophil-related inflammatory reaction?

Patients with chronic renal failure on intermittent dialysis sometimes develop an acute diffuse conjunctival and episcleral hyperaemia. In this study the hypothesis was tested whether the precipitation of hydroxyapatite crystals could result in an inflammatory reaction mediated by enzymes liberated from polymorphonuclear leucocytes (PMN). Ingestion of the crystals by PMN's can result in cell death and membranolysis and subsequent release of intracellular enzymes into the surrounding tissues. This 'suicide sac' hypothesis for the inflammatory reactions of the conjunctiva and episclera was rejected after histopathological examination of conjunctival biopsies failed to show complement activation or crystal ingestion by PMN's despite the presence of small subepithelial hydroxyapatite crystals.

Rapid progression of band-shaped keratopathy with early central localisation in a patient on chronic dialytic treatment.

This clinical study reports on an unusual start of a band-shaped keratopathy in a patient with diabetic nephropathy on dialytic treatment. The earliest corneal manifestations were centrally located small greyish-white disc-shaped lesions evenly distributed in the interpalpebral area in the left eye. Later a typical peripheral band-shaped keratopathy developed. In the course of the observation period the peripheral keratopathy rapidly spread towards the centre, finally resulting in a complete band-shaped keratopathy in which only the most central original disc-shaped lesions could be identified. Serum calcium and phosphorus concentrations were markedly elevated at the time of the progression of the band-shaped keratopathy but no tertiary hyperparathyroidism was present.

Diffuse and focal hyperaemia of the outer eye in patients with chronic renal failure.

In 8 of 57 patients with chronic renal failure that all had deposition of calcium salts in the limboconjunctival area, a focal hyperaemia of the conjunctiva was observed. This focal hyperaemia developed gradually around one or more greyish, slightly elevated, areas situated in the bulbar conjunctiva in the interpalpebral fissure. Clinically these lesions are very much alike inflamed pingueculae. Three patients showed a diffuse inflammatory reaction of the eye that was characterized by a waxy red episcleral and conjunctival hyperaemia extending beyond the palpebral fissure. The average value of the serum calcium concentration in these patients was particularly high and statistically significantly higher than in patients with calcification but without inflammatory signs and also higher than in patients that showed focal hyperaemia. In addition to the focal hyperaemia and the diffuse hyperaemia, we observed another diffuse hyperaemia located principally in the conjunctival tissue. This conjunctival redness often followed the focal hyperaemia associated with pingueculae or preceded the more acute fiery red episcleral hyperaemia, but it could also be present in isolation.

Limbal and corneal calcification in patients with chronic renal failure.

In patients with chronic renal failure on regular dialysis treatment, limboconjunctival degenerations and calcifications are commonly observed. In this study three groups of patients were followed over a period of 6 years. The first group consisted of 47 patients with renal failure, the second group of 17 patients with renal failure and hyperparathyroidism not controlled by drugs, and the third group seven patients with primary hyperparathyroidism without renal failure. The aim of this study was to determine the progression of the limboconjunctival changes over time. The hypothesis that an increase in serum calcium and phosphorus concentrations, as a result of tertiary hyperparathyroidism, could possibly add a corneal component to the limbal calcification was also tested. All patients with renal failure (in as much as the degenerative limbal features were not obscured by deposits of lime salts), had a type II white limbus girdle of Vogt. This limbal degeneration was observed in only 45% of controls. In all 47 patients with renal failure conjunctival calcification was observed; 26 of them also had limbal calcification. After 6 years 41 patients had developed limbal calcification. This progression was statistically significant. In 15 out of 17 patients with tertiary hyperparathyroidism a band-shaped keratopathy developed in addition to the limboconjunctival calcification.

Therapy for ocular toxoplasmosis.

We conducted a prospective multicenter study of the efficacy of current therapeutic strategies for ocular toxoplasmosis in 149 patients. Treatment consisted of the following three triple-drug combinations: group 1, pyrimethamine, sulfadiazine, and corticosteroids; group 2, clindamycin, sulfadiazine, and corticosteroids; and group 3, trimethoprim, sulfamethoxazole and corticosteroids. Patients with peripheral retinal lesions were not treated systemically. No difference in the duration of inflammatory activity was observed between treated and untreated patients (P = .5). The most important factor predicting the duration of inflammatory activity was the size of the retinal lesion itself, independent of the treatment (P < .001). We found a reduction in size of the retinal inflammatory lesion for 49% of the pyrimethamine-treated patients (17 of 35) compared to 20% of the untreated patients (eight of 41) (P < .01). However, the most frequent occurrence of side effects was also associated with pyrimethamine medication (26%, nine of 35). The mean recurrence rate after three years of follow-up was 49% for all patients (60 of 122 patients), with no differences between treated and untreated patients (P = .6).

The red eye of renal failure: a crystal induced inflammation?

Of 57 patients with chronic renal failure and calcification of the anterior membranes of the eye eight developed inflammatory reactions, clinically indistinguishable from pingueculitis. In three patients an acute inflammatory reaction of the episcleral tissue and the conjunctiva over it developed which we considered to represent the red eye of renal failure. In these patients massive shedding of calcium phosphate salts was clinically evident. Histopathologically in all these patients calcific deposits were observed. Although sporadically polymorphonuclear leucocytes were present in the inflamed tissues we could not demonstrate crystal phagocytosis. We believe that in the red eyes in renal failure and, more specifically, in the red eyes of renal failure a crystal induced inflammatory mechanism is not operative.

Metastatic or dystrophic conjunctival calcification in renal failure?

In renal failure the incidence of pingueculae is significantly higher than in a comparable control group but there is no evidence that the calcific precipitation in renal failure is of a dystrophic nature. The lime salts are not located within the area of elastotic degeneration, a prerequisite for dystrophic degeneration. Moreover there is no association between the magnitude of the conjunctival degeneration and the degree of calcification. This makes it likely that the calcium precipitates represent metastatic calcification even though admittedly support for this assumption is tenuous.

Red eyes in renal failure.

Of 57 patients with chronic renal failure who all had deposition of calcium salts in the conjunctival and corneal tissue two developed a brief episode of painful irritation and redness of the conjunctiva and subconjunctiva. This hyperaemia was adjacent to erosions of the corneal epithelium of the eye as a consequence of exfoliation of calcium concretions from the superficial corneal epithelium. Eight patients showed inflammatory reactions of the conjunctivae that were clinically identical to inflamed pingueculae. Three patients showed an inflammatory reaction of the eye that was characterised by a waxy red, more or less diffuse, episcleral and conjunctival hyperaemia extending beyond the palpebral fissure. The average value of the serum calcium concentration in these patients was particularly high and statistically significantly higher than in patients with calcification but without inflammatory signs and also higher than in patients who showed pingueculitis. We propose to reserve the term 'red eye of renal failure' for the latter group of patients.

The diagnostic power of the tests for tear gland related keratoconjunctivitis sicca.

Laboratory tear function tests, such as the lactoferrin and the lysozyme test, reflect the level of tear gland deficiency and are, therefore, very useful for the clinician in the diagnosis of keratoconjunctivitis sicca (KCS). Although these tests do have an excellent discriminatory ability, they should be used in addition to clinical tests, such as the Schirmer-1 test, the tear film break-up time (BUT) and the Rose bengal (Rb) staining test. Schirmer's test, the most commonly used clinical test, measures tear fluid production. The tear film BUT, on the other hand, is the only test which establishes tear film instability. The Rose bengal score is strongly related to secondary damage of the superficial epithelium of the cornea and conjunctiva in patients with KCS. Thus, combining the results of these various tests facilitates the diagnosis of KCS and also the differentiation between Sjögren's KCS and non-Sjögren's KCS.

Changes in the diagnostic parameters during keratoconjunctivitis sicca therapy.

In 35 patients with mild, moderate and severe keratoconjunctivitis sicca, an association was found between treatment effect, break-up time value and Rose bengal score. Neither of these tests, used separately, was successful as a clinically valuable predictor of treatment effect as the scatter, in score points, was too large. Analysed together, however, as in a partial regression analysis, an adequate prediction is possible, which is clinically of some value.

Decrease in adverse reactions after repeated ivermectin treatment in onchocerciasis.

We assessed the side-effects after multiple single-dose treatment with ivermectin (150 micrograms/kg) in onchocerciasis patients form a hyperendemic area in Sierra Leone, in order to investigate whether medical surveillance was always necessary. After initial treatment 87 onchocerciasis patients were examined for adverse reactions. Fourty-four of these 87 patients (51%) received a second dose of ivermectin 5 months later and thirty-five (40%) received a third dose one year later. The side-effects after the second and third doses were significantly diminished, when compared with the initial dose of ivermectin in the treatment of onchocerciasis (chi2 test p less than 0.005, resp. p less than 0.008). Side-effects requiring therapy were observed in 32% of patients after the first dose, in 18% after the second dose and in 11% after the third dose of ivermectin. Severe side-effects (9%) were only seen after the initial ivermectin dose. All the severe adverse reactions appeared within 48 hours. In view of our findings, it seems necessary that the first treatment with ivermectin should take place under strict medical supervision during at least two days. Five months after treatment with a single dose of ivermectin 29 out of 44 patients (66%) still had a positive skin-snip test. Seven months after the second dose 15 of 35 patients (43%) had a positive skin-snip count. Since almost half of the patients had a positive skin-snip test despite two treatments with ivermectin, it could be argued that in hyperendemic areas treatment should consist of at least two doses in the first year.

Ocular involvement in patients with onchocerciasis after repeated treatment with ivermectin.

We assessed ocular changes after therapy at six and 12 months with ivermectin (150 micrograms/kg of body weight) in a 12-month prospective study of 29 patients with ocular onchocerciasis and 15 patients with onchocerciasis without ocular involvement. The patients lived in a hyperendemic area in Sierra Leone, West Africa, where no vector control was instituted. Five months after initial treatment, the microfilarial load in skin and eyes had decreased significantly (P less than .0000), but 28 of 44 (63%) patients had positive skin-snip test results and nine of 29 (31%) patients with ocular involvement had active ocular disease. Twelve months after initial treatment, 15 of 41 (37%) patients had positive skin-snip test results and eight of 26 (31%) showed active ocular involvement. All patients with persistent ocular disease after therapy showed evidence of active onchocerciasis at that time, which suggests that a dose of ivermectin at six-month intervals is not sufficient for intensely infested patients with severe ocular disease. We developed an ocular involvement score to evaluate the patient's total ocular status and observed a significant relation between the pretreatment severity of ocular involvement and the persistence of active ocular disease after treatment with ivermectin.

Lacrimal conjunctivitis.

In the course of an acute phase of pneumococcal conjunctivitis, a serpiginous corneal ulcer has never been reported to develop. However, if there is a pneumococcal chronic dacryocystitis and a resultant lacrimal conjunctivitis, the association with pneumococcal serpiginous ulcers is significant. This is most likely due to the fact that those serological types that are particularly virulent for the cornea have an affinity to colonize and infect the lacrimal sac.