Treatment of nonproliferative diabetic retinopathy with Defibrotide in noninsulin-dependent diabetes mellitus: a pilot study.

PURPOSE: Microvascular alterations, impairment of coagulation, ischemia and diffuse endothelial damage are related to the progression of diabetic retinopathy. Defibrotide has been demonstrated to produce profibrinolytic, cytoprotective and vasofacilatory activities. The aim of the present study was to evaluate the therapeutic effect of Defibrotide in the treatment of nonproliferative diabetic retinopathy. METHODS: Two randomized age- and sex-matched groups (cases and controls) of 35 NIDDM patients presenting non-proliferative diabetic retinopathy were included in this study: cases were treated with Defibrotide (800-1600 mg daily) for two years. RESULTS: All tested parameters (ETDRS visual acuity; computerized perimetry; retinography; fluorescein angiography), improved significantly (p<0.001) in Defibrotide-treated patients compared to controls. In our opinion, Defibrotide's manifold effects on vascular endothelia may account for this improvement by stimulation of tPA, PGI2, PGE2, thrombomodulin and modulation of endothelin-1 release. CONCLUSIONS: Our preliminary data seem to suggest that Defibrotide could be proposed for medical treatment of nonproliferative diabetic retinopathy.

Plasma endothelin-1 concentrations in patients with retinal vein occlusions.

AIMS: To investigate whether plasma levels of endothelin-1 (ET-1), a potent vasoconstricting peptide that is crucial in regulating retinal blood flow, were elevated in patients with retinal vein occlusion (RVO). METHODS: ET-1 plasma concentrations were determined by radioimmunoassays in a double blind fashion in a group of 18 selected patients with RVO, in 20 healthy age matched non-smoking, normoglycaemic, normotensive control subjects, and in 15 patients with uncomplicated essential hypertension in the same age range. RESULTS: Patients with RVO had significantly increased ET-1 plasma levels (14.22 (SD 4.6) pg/ml) compared with both normal subjects (7.90 (1.6) pg/ml; p < 0.05) and hypertensive patients (8.50 (2.9) pg/ml; p < 0.05). The highest concentrations of circulating ET-1 were found in patients with RVO of the ischaemic type (16.97 (3.5) pg/ml; p < 0.01; n = 7). Systemic hypertension alone did not account for the observed increase in plasma ET-1 concentrations. CONCLUSIONS: These findings raise the possibility that the increased circulating ET-1 levels in patients with RVO may be a marker of the occlusive event, thereby suggesting that ET-1 homeostasis may be relevant to RVO pathogenesis and retinal ischaemic manifestations.

Circulating endothelin-1 in non-insulin-dependent diabetic patients with retinopathy.

Endothelin-1 (ET-1), a novel 21-amino acid vasoconstrictive peptide secreted by endothelial cells, has been thought to play a role in various forms of vascular disease. Diabetes mellitus is well known for its association with microvascular damage. To investigate whether ET-1 levels may be related to microangiopathy in diabetes mellitus, plasma ET-1 levels were measured in two groups of diabetic patients: A) 47 patients with non-insulin dependent diabetes mellitus (NIDDM) and retinopathy (28 M, 19 F; mean age 60.7+/-8.5 yrs) but without nephropathy (microalbuminuria < 30 mg/day) and hypertension (SBP < 140, DBP < 90 mmHg); group A was divided in three subgroups based on the severity of retinopathy: a) 16 with background retinopathy; b) 21 with pre-proliferative retinopathy; c) 10 with proliferative retinopathy. B) 8 patients with insulin-dependent diabetes mellitus (IDDM) recently diagnosed (6 M, 2 F; 16.4+/-3.8 yrs) without complications. C) 28 healthy subjects (HS) (16 M, 12 F; 47.8+/-11.8 yrs) as controls. In the NIDDM group the ET-1 concentration was significantly higher (17.3+/-2.4 pg/ml) than both in the HS (8+/-4.7 pg/ml) and IDDM patients (10.2+/-3.7 pg/ml) (p < 0.0001). In the subgroups with retinopathy the ET-1 levels were a) 15.1+/-4.3 pg/ml; b) 22.2+/-6.8 pg/ml and c) 16.6+/-5.1 pg/ml. These values were significantly elevated as compared to HS (p<0.001; p < 0.0001; p < 0.002, respectively), being the highest levels of ET-1 observed in the NIDDM patients with pre-proliferative retinopathy. In conclusion our study revealed that the ET-1 concentrations are elevated in NIDDM patients with retinopathy especially in those patients with pre-proliferative retinopathy.

The ocular phenotype of the Bardet-Biedl syndrome. Comparison to non-syndromic retinitis pigmentosa.

PURPOSE: To investigate 20 patients affected with Bardet-Biedl (BB) syndrome and compare them to an age-matched group of 70 non-syndromic patients with retinitis pigmentosa (RP) to identify hallmarks peculiar to the BB phenotype. METHODS: Patients were examined clinically and with functional tests (color vision, kinetic perimetry, electroretinography, ocular motility tests). Fundus findings were numerically graded for statistical purposes. RESULTS: Recurrent ocular features in BB patients were early and severe reduction of visual acuity, constantly altered color vision, high incidence of strabismus and nystagmus, mild-to-severe atrophic changes of the optic disc, and frequently absent or minimal pigmentary retinal changes. Visual acuity was more closely correlated to optic disc than to macular conditions. These findings were remarkably different from non-syndromic RP. CONCLUSIONS: This investigation further suggests that retinopathy in BB syndrome has features distinctive from those in non-syndromic RP. The early occurrence of optic disc atrophy in the BB syndrome, even in those patients with healthy maculas, suggests that optic atrophy could often be primary in nature and might play a major role in decreasing central vision in BB patients. Variability of some findings is in line with the documented heterogeneity of the BB syndrome.

Autosomal-dominant retinitis pigmentosa associated with an Arg-135-Trp point mutation of the rhodopsin gene. Clinical features and longitudinal observations.

PURPOSE: To report the clinical and functional characteristics of patients affected with autosomal-dominant transmitted retinitis pigmentosa (adRP) from a large Italian pedigree in which a point mutation predicting the Arg-135-Trp change of rhodopsin was identified by polymerase chain reaction-single-strand conformation polymorphism analysis. METHODS: Seven patients, ranging in age from 6 to 41 years, underwent a full clinical ophthalmologic evaluation, kinetic visual field testing, and electroretinographic testing. RESULTS: In agreement with previous reports, this rhodopsin mutation yielded a particularly severe phenotype, both clinically and functionally. The evaluation of patients from this pedigree in the first and second decade of life demonstrated that retinal function is still electroretinographically measurable at least until 18 years of age, although reduced to 2% to 4% of normal. Longitudinal measures showed that the rate of progression of the disease was unusually high, with an average 50% loss per year of electroretinographic amplitude and visual field area with respect to baseline. Later in the course of the disease, macular function is also severely compromised, leaving only residual central vision by the fourth decade of life. CONCLUSIONS: The phenotype associated with mutations in codon 135 of the rhodopsin molecule appears to have an unusually high progression rate and yields an extremely poor prognosis. These distinctive features make the Arg-135-Trp phenotype substantially different from the general RP population, and also from many of the other adRP pedigrees with known rhodopsin mutations reported to date.

Electroretinographic alterations in the Laurence-Moon-Bardet-Biedl phenotype.

Maximal 0.5-Hz and cone 30-Hz ERG responses were recorded from 19 patients showing a Laurence-Moon-Bardet-Biedl (LMDD) phenotype. Off-line averaging of 80 to 100 iterations was routinely performed. When needed, our previously described low-noise techniques and off-line fast Fourier transform procedures were used. The maximal ERG response was non-detectable in 52.6% of cases. About half of the recordable signals were below 5% of the lower normal amplitudes. Cone 30-Hz ERGs were measurable in 64.7% of cases. Of these, 63% of tracings were below 5% of the lower normal range. In most cases no dystrophic pattern was definable, due to severe reduction of both signals. Statistical analyses showed no correlation between ERG amplitudes and residual visual field areas. Clinical and electroretinographic observations suggest that retinopathy in most LMBB patients is a widespread form of degeneration, initially affecting rods but rapidly involving cones as well. However, there are also cases with a clear-cut cone-rod pattern, with fairly well preserved maximal ERG responses. The lack of correlation between maximal ERG responses and visual field residual areas, different from non-syndromic retinitis pigmentosa (RP) patients, could be related either to a low reliability of visual field testing in LMBB patients or to mechanisms accounting for the ongoing retinal degeneration in LMBB syndrome that are different from those of pure RP. Variable findings are in line with the documented genetic heterogeneity of the syndrome.

Correlation between Goldmann perimetry and maximal electroretinogram response in retinitis pigmentosa.

To evaluate the relationship between Goldmann perimetry and maximal electroretinographic responses in patients with retinitis pigmentosa, analyses were performed on 220 affected subjects and separately on two subgroups with autosomal dominant (n = 35) and autosomal recessive (n = 29) inheritance. Electroretinograms were recorded averaging 100 iterations elicited with a 20-lux/s, 0.5-Hz white flash ganzfeld stimulation. The peripheral isopters of the visual fields were delimited with I4e, IIIe and V4e targets, measured on conventional perimetry charts with a light pen and expressed in square centimeters. Unlike most previously published reports, this investigation showed a definite correlation (p = 0.0001) between maximal electroretinographic response amplitude and visual field areas. This correlation was more evident for I4e and IIIe isopters (r = 0.89 and 0.87, respectively) than for V4e isopter (r = 0.69). This phenomenon appears to be related to distortion occurring on standard isometric charts and to spatial summation effects in the peripheral field. Such correlations held for both the autosomal dominant and autosomal recessive subgroups. It appears that, if enough accuracy is provided, maximal electroretinographic responses and Goldmann visual fields are both good measures of the remaining functioning retina in nonsyndromic retinitis pigmentosa, irrespective of inheritance models and dystrophic patterns.

Clinical heterogeneity of dominant optic atrophy: the contribution of visual function investigations to diagnosis.

BACKGROUND: The variability of the visual function impairment in dominant optic atrophy (DOA) makes it difficult to diagnose the disease within genealogies. Physiologic investigations were conducted on a family with DOA to evaluate methods of detecting clinical and subclinical signs in obligate heterozygotes, in order to identify affected subjects within the genealogy and to formulate the individual and reproductive risks. METHODS: Investigations included tests for color vision, contrast sensitivity function (CSF), kinetic and static computerized perimetry, transient pattern reversal visual evoked potentials (VEPs) and steady-state flash VEPs. RESULTS: Eight subjects from the pedigree were diagnosed as having DOA. Two of them were unaware of their affection, and six showed wide clinical variability. CSF paralleled the central visual impairment, but was also slightly impaired in the two unaware subjects. Static computerized perimetry disclosed mild sensitivity defects in the central visual fields in these two patients. VEPs showed heterogeneous results as well, ranging from normal findings to severely altered tracings. CONCLUSIONS: This investigation suggests that combined clinical and functional evaluation is necessary to diagnose DOA. Particularly, the combined use of computerized perimetry, CSF, and VEPs allowed the identification of cases at a subclinical stage.

Autosomal dominant simple microphthalmos.

Congenital bilateral microphthalmos is a rare malformation of the eye, which ranges from extreme to mild reduction of total axial length. Microphthalmos may occur as an isolated ocular abnormality or as part of a systemic disorder, and different classifications of the condition have been attempted. We describe a large pedigree with 14 persons in four generations affected with bilateral microphthalmos without other ocular or systemic signs. An autosomal dominant trait with complete penetrance is proposed. Five subjects underwent a complete ophthalmological evaluation. The total axial length was measured by A scan ultrasonography in all persons. Ultrasonography showed a reduction of the total axial length (range 18.4-19.7 mm) and a reduced vitreous cavity length (range 11.4-13.5 mm) in all investigated patients. All the patients had microcornea (range 8-9.7 mm). No other ocular anomalies or associated systemic malformations were found. A review of published reports also suggests that simple, partial, posterior, pure microphthalmos and nanophthalmos are similar clinical entities sharing total axial length and vitreous cavity length reduction. Therefore, the term simple microphthalmos is proposed to identify these clinical conditions.

Comparison of apraclonidine and timolol in chronic open-angle glaucoma. A three-month study.

PURPOSE: To compare the safety and efficacy of apraclonidine ophthalmic solution 0.25% and 0.5% (both given 3 times daily) to timolol maleate (0.5%) given twice daily, in primary open-angle glaucoma or ocular hypertension. METHODS: This study was a 90-day prospective, multicenter, double-masked, randomized, parallel group trial. Intraocular pressure (IOP) measurements were made between 8:00 and 10:00 AM before the morning dose (i.e., up to 12 hours after the evening dose of glaucoma medication) and at 4:00 PM (i.e., 8 hours after the morning dose of glaucoma medication). Patients with off-therapy IOP of greater than 22 mmHg and less than 35 mmHg were entered into the study and were assessed 14, 30, and 90 days after treatment. RESULTS: Sixty-nine patients were enrolled; there were no significant demographic differences among the three study groups. All three treatments significantly reduced IOP over 90 days (P < 0.011). For apraclonidine 0.5%, IOP reductions from 25.8 +/- 3.2 mmHg (pretreatment) to 20.4 +/- 4.00 mmHg (day 90) were observed; for apraclonidine 0.25%, from 25.7 +/- 3.05 mmHg (pretreatment) to 22.1 +/- 4.24 mmHg (day 90); and for timolol 0.5% from 26.1 +/- 3.79 mmHg to 21.1 +/- 5.91 mmHg (day 90). The 90-day period of therapy was completed by 12 patients treated with apraclonidine 0.5%, 21 patients treated with apraclonidine 0.25%, and 23 patients treated with timolol 0.5%. There were no serious adverse events. Fourteen of 22 patients (0.5% apraclonidine) and 21 of 23 patients (0.25% apraclonidine) tolerated the drug well; ocular allergy developed in the remaining patients treated with apraclonidine, which resolved upon discontinuation. CONCLUSIONS: Apraclonidine effectively lowers IOP associated with open-angle glaucoma or ocular hypertension; these pilot results will need to be confirmed by a larger pivotal study. Long-term therapy for some patients may be inhibited by ocular allergy for which there was a higher incidence to the 0.5% apraclonidine solution than to the 0.25% solution in this study. Apraclonidine may be of value as an additional therapy for open-angle glaucoma in selected patients.

Serum angiotensin converting enzyme in diabetic retinopathy.

Serum levels of angiotensin converting enzyme (SACE) were measured in 118 diabetic patients divided into the following four groups: 44 insulin-treated diabetic patients with severe retinopathy, 38 non insulin-treated diabetic patients with severe retinopathy, 18 diabetic patients, including both insulin-treated and non insulin-treated subjects with background retinopathy, 18 diabetic patients, insulin-treated and non insulin-treated without signs of retinopathy. Nineteen retinopathic patients non diabetic were also studied in order to verify whether SACE levels are altered when retinopathy is present independently from diabetes. The control group was composed of 44 normal subjects. When the data from the above six groups of subjects were submitted to statistical tests (one-way ANOVA, T-test of Bonferroni and test of Student-Newman-Keuls), the study yielded the following results: i) a remarkable difference between the SACE levels in healthy subjects and those in the three groups of diabetic retinopathic patients considered; ii) a non statistically significant difference of SACE levels between normal subjects and diabetic patients without retinopathy; iii) a non statistically significant comparison of SACE levels of normal subjects versus non diabetic retinopathic patients. Therefore, we concluded that while primitive diseases of the retina are not associated with an increase of SACE levels, yet when diabetes and retinopathy coexist, the SACE levels increase remarkably (in rather an independent way from the type of diabetes, the age of subjects, the stage of retinal disease and the daily average insulin dose), suggesting that most of the enzyme's increase originates from the endothelium of peripheral vasa, widely involved in most of the retinopathic diabetic patients.

[Clinical significance of antinuclear antibodies in progressive systemic sclerosis]. / Significato clinico degli anticorpi antinucleari nella sclerosi sistemica progressiva.

Indirect immunofluorescence (IIF) was used to detect antinuclear antibodies (ANA) in 42 clinical cases. In each case cryostatic rat kidney slices and cultivated HEp-2 cells were used as substrates. Clinical diagnoses were as follow: Progressive Systemic Sclerosis (PSS) 25 cases, of which 8 were acrosclerotic, 8 diffuse, 5 CREST syndrome, 1 overlap PSS + Systemic Lupus Erythematosus (SLE) and 3 PSS + myopathy; Localised scleroderma (morphea): 3 cases; Mixed Connective Tissue Disease (MCTD): 3 cases; "Idiopathic" Raynaud's Disease (RD): 4 cases; Dermatomyositis (DM): 2 cases (1 paraneoplastic); SLE: 1 case; Unclassifiable Connective Tissue Disease (UCTD): 4 cases. The ANA-positive cases identified by the traditional technique were divided according to pattern into 4 categories: homogeneous, peripheral, speckled, nucleolar. In contrast those identified using HEp-2 cells were divided into 9 pattern groups: (nuclear type) centromere, fine speckled, coarse speckled, diffusely grainy, homogeneous: (nucleolar type) speckled, clumpy, homogeneous. The results demonstrated a higher general incidence of positivity with HEp-2 cells and confirmed the close connection between Anticentromere ANA and CREST syndrome. A similarly close connection was noted between MCTD and both nuclear diffusely grainy and nucleolar speckled patterns. A fairly clear connection was also noted between acrosclerotic or diffuse SSP and a fine speckled nuclear pattern. It is felt that ANA tests using IFI on HEp-2 cells should lead to significant progress in the field of diagnosis and prognosis and the study of PSS subsets.

[Current technics in surgery of retinal detachment in children. Surgical and anesthesiologic aspects]. / Techniques actuelles dans la chirurgie du décollement de la rétine chez les enfants. Aspects chirurgicaux et anesthésiologiques.

After some premises on the etiology of retinal detachment in children, the authors report their own surgical procedures. The indications, the advantages and disadvantages of the use of plastic or organic substances, with the effects of transitory or permanent plombages are discussed. Moreover, the anesthesiological problems concerning the preparation of young patients, the intraoperative phase and often numerous postoperative diagnostic controls are examined.

[Prevention of retinal detachment in subjects before and after being operated on for cataract]. / Prophylaxie du décollement de la rétine chez les sujets devant être ou ayant déjà été opérés de cataracte.

Some premises on the clinical aspects of retinal detachment in patients operated upon for cataract and in conditions of lens dislocation are made. The different aspects of the preoperative prophylaxis (indications, techniques, application time) are dealt with, and the technical procedures used during operation for cataract are described. The authors point out the necessity of a postoperative control of the aphakic eyes, at short-or long-term in order to avoid vitreo retinal alterations.