Blood-retina barrier permeability and its relation to the progression of diabetic retinopathy in type 1 diabetics. An 8-year follow-up study.

Blood-retina barrier (BRB) permeability and its relation to the progression of diabetic retinopathy was studied over an 8-year period in 50 insulin-dependent diabetic patients. Initially, the patients underwent an ophthalmological examination, including measurement of best corrected visual acuity, fundus photography and vitreous fluorometry for determination of BRB permeability. After 8 years the patients were reexamined and their retinal status and clinical course were evaluated. We found a positive correlation between a high initial permeability value and an unfavorable clinical course using the parameter photocoagulation. A decrease in follow-up visual acuity was also associated with high initial permeability; however, this correlation was not statistically significant. A significant difference in mean blood pressure was found between values measured in laser-treated patients vs a group that did not undergo such therapy. Thus, in patients showing the same initial retinal morphology, high permeability seems to indicate an unfavorable disease course. The extent to which BRB permeability can be a valuable supplement to fluorescein angiography and three-mirror examination in the clinical decision process needs to be further evaluated.

Clinical course and prognosis of pseudotumor cerebri. A prospective study of 24 patients.

In a prospective study, 24 consecutive patients with pseudotumor cerebri were followed for an average of 49 months with regular neurologic and ophthalmologic examinations. At the first examination the intracranial pressure was between 18 and 45 mm Hg; several patients had pressure waves up to 70 mm Hg and decreased conductance to cerebrospinal fluid outflow. In the majority, medical treatment, usually with diuretics and acetazolamide, induced a rapid relief of symptoms, but about 25% had a more protracted disease course with persistent headache, asthenia and memory disturbances interfering with daily life. Five patients required a shunt operation. Chronic changes of the optic disc developed in nearly half the patients, and one had optic atrophy and severe visual impairment. Repeated measurements of the intracranial pressure and conductance to cerebrospinal fluid outflow showed that abnormalities can persist for a long time, even in cases without symptoms of intracranial hypertension.

Blood-retinal barrier permeability versus diabetes duration and retinal morphology in insulin dependent diabetic patients.

The blood-retinal barrier permeability to fluorescein was quantitated in 54 patients (22 females and 32 males) with insulin dependent diabetes mellitus (IDDM) of different duration. Correlation was demonstrated between permeability and diabetes duration. A normal permeability was measured in patients with up to ten years diabetes duration. A pathologically increased permeability was measured with ten to 15 years diabetes duration and during the next decade the permeability increased rapidly to 5-10 times the normal value. Onset of diabetes in the decade before and after puberty did not change the pattern. However, the pathologically increased permeability after ten years duration of the disease could not be demonstrated in diabetics with onset of the disease after the age of 30 years. The permeability of the blood-retinal barrier correlated well with changes in retinal morphology as seen by ophthalmoscopy and fluorescein angiography. However, there was an overlap in permeability between groups with different retinal appearance. A significant factor was the presence of macular edema, which also apparently indicated a preproliferative state.

Breakdown of the blood-retinal barrier in multiple sclerosis measured by vitreous fluorophotometry.

Periphlebitis retinae in multiple sclerosis appears as transitory cellular infiltrations around veins in an otherwise normal retina. Similar cellular infiltrations have been found around veins in the central nervous system. In the present study the blood-retinal barrier has been investigated by vitreous fluorophotometry. Eight multiple sclerosis patients with actual periphlebitis retinae and 9 patients with previous but not active periphlebitis retinae were included in this study. Abnormal leakage of fluorescein was manifest in the group of multiple sclerosis patients with periphlebitis retinae. Permeability (1.8 +/- 0.2 X 10(-7) cm/sec; mean +/- SEM) but not in the control group as a whole permeability (1.3 +/- 0.1 X 10(-7) cm/sec; mean +/- SEM) compared to 17 normals (permeability 1.1 +/- 0.005). It is thus concluded that breakdown of the blood-retinal barrier may be transitory when connected with periphlebitis retinae in multiple sclerosis.

The blood-retinal barrier permeability to fluorescein in normal subjects and in juvenile diabetics without retinopathy.

The blood-retinal barrier permeability to fluorescein was determined in 20 eyes from 17 normal volunteers (mean age 31 years) and in 20 eyes from 19 juvenile diabetics without apparent retinopathy (mean age 35 years - mean duration of diabetes 6 years). The permeability was in normal subjects (1.1 +/- 0.4) X 10(-7) cm/sec (mean +/- 2 X SD) and in juvenile diabetics (1.1 +/- 0.7) X 10(-7) cm/sec (mean +/- 2 X SD). Thus a break-down of the blood-retinal barrier cannot be demonstrated as a very early and general phenomenon in the early course of the diabetic disease. The fluorescein diffusion coefficient in the vitreous body was determined and juvenile diabetics without apparent retinopathy showed a diffusion coefficient of (0.80 +/- 0.25) X 10(-5) cm2/sec (mean +/- 2 X SD), which was the same as in normals where the diffusion coefficient was (0.69 +/- 0.46) X 10(-5) cm2/sec (mean +/- 2 X SD).

Carriers of X-linked retinitis pigmentosa. A fluorophotometric determination of the permeability of the blood-retinal barrier.

The blood-retinal barrier permeability to fluorescein was studied in a single family with X-linked retinitis pigmentosa by an elaborate vitreous fluorophotometric method. Affected males showed a ten times increase of permeability compared with normals. In a group of seven obligate carriers the mean permeability was significantly increased by 45% compared with the mean permeability in a group of normals. Five of the seven carriers had permeabilities higher than the normal mean permeability + 2 SD, while two carriers had a permeability within the normal mean +/- 2 SD. Thus, this study supported that carriers of X-linked retinitis pigmentosa show deterioration of the blood-retinal barrier. However, the phenomenon is not present in all carriers and the permeability cannot be used as a completely safe indicator of the carrier state.

Treatment of keratoconjunctivitis sicca with Elmiron.

Ten women with primary Sjögren's syndrome were treated with sodium pentosan polysulfate (Elmiron) 150 mg X 2 daily for 4 months in an open investigation. No subjective or objective improvement was recorded.

Quantitative vitreous fluorophotometry applying a mathematical model of the eye.

A slit-lamp fluorophotometric method is presented that permits calculation of a blood-retinal barrier permeability to fluorescein (P) and a diffusion coefficient for fluorescein in the vitreous body (D). The calculations are performed by relating the time course of the free--not protein bound--fluorescein concentration in the bloodstream with the fluorescein concentration profile in the vitreous body. The combination is performed automatically on a computer by applying a simplified mathematical model of the eye. P refers to the area of the barrier of the model eye. In a group of six normal persons, the mean P was (1.1 +/- 0.4) X 10(-7) cm/sec (mean +/- SD), while in six diabetic patients with background retinopathy and macular edema the mean P was (7.1 +/- 3.8 ) X 10(-7) cm/sec. The mean D was (7.4 +/- 3.4) X 10(-6) cm2/sec in the normal group and (9.6 +/- 2.0) X 10(-6) cm2/sec in diabetic patients, corresponding as a first approximation to free diffusion in water. Model calculations show that knowing the fluorescein concentration in the bloodstream is considerably significant for the calculation of the permeability, contributing factors up to 50%. For the low-permeation situation, subtraction of the preinjection scan contributes a factor of 50% for both permeability and diffusion coefficient. The exact placement in the vitreous body of the concentration profile, by applying a formalism that transforms slit-lamp movement to intraocular distance, contributes a factor of 20% on the diffusion coefficient. The permeability obtained with the model can be calculated as the ratio between area of vitreous and plasma fluorescein concentration curves within 20%. Active transport of fluorescein across the blood-retinal barrier in the direction of vitreous to blood does not seem to be significant within the first 2 hr after fluorescein injection.

Visual evoked potentials in pseudotumor cerebri.

Pattern reversal visual evoked potentials in 13 patients with pseudotumor cerebri were significantly delayed (99 +/- 7.3 ms [mean +/- SD]) compared with the findings in 20 normal subjects (94 +/- 2.7 ms), although only four patients had latencies outside the normal range. There was, however, a significant correlation between the intracranial pressure and the latency of visual evoked potentials. After medical treatment of the intracranial hypertension, visual evoked potential latencies decreased in patients who recovered and in whom the papilledema disappeared. In one patient with progressive visual failure, the visual evoked potentials were abnormal before disturbances of visual fields and visual acuity were evident. Repeated examinations of visual evoked potentials might be of value in patients with pseudotumor cerebri to ensure neurosurgical intervention in due time to prevent visual loss in patients with impending optic nerve atrophy.

Photometric oculometry: a slit-lamp technique for determination of intraocular distances.

The optics of slit-lamp fluorophotometry were analyzed. This analysis forms the basis of the formulation of a slit-lamp technique called photometric oculometry, which makes it possible to measure intraocular distances. A comparison between ultrasonography and photometric oculometry in the determination of the ocular axial length was carried out. Measurements in 11 eyes showed statistical agreement, with a mean of 22.90 mm, SD +/- 1.815 (ultrasound), and a mean of 23.17 mm, SD +/- 1.667 (photometry). The principle involved in photometric oculometry is of special importance for the calculation of the blood-retinal barrier permeability to fluorescein by vitreous fluorophotometry, since the method allows the volume of the vitreous body to be estimated directly from the slit-lamp fluorophotometer recording.

The blood-retinal barrier permeability to fluorescein in juvenile diabetics treated with continuous subcutaneous insulin infusion.

To determine possible quantitative changes of the blood-retinal barrier permeability in juvenile diabetics treated with continuous subcutaneous insulin infusion (CSII), we studied seven patients (three females and four males, mean age 36 years) with a mean duration of the disease of 19 years. The pump treatment was continued for seven to eight days and during the treatment mean blood glucose level decreased to near-normal values (before 13.7 mmol per liter - during 6.2 mmol per liter). There was no changes in retinal appearance during treatment. Determination of the blood-retinal barrier permeability showed no quantitative changes during the one week treatment with CSII (mean permeability before 7.6 10 divided by 7 cm/sec - mean permeability during 7.8 10 divided by 7 cm/sec). In order to quantitate possible long-term reversibility of break-down of the blood-retinal barrier we have design to extend the treatment period.

Ophthalmologic prognosis in benign intracranial hypertension.

In a prospective study twenty patients with benign intracranial hypertension, 15 females and five males with mean age 34 years (range 12-61 years), were followed up from 12 to 61 months (mean 22 months). Initially all patients showed marked papilledema, normal visual acuity, considerable enlargement of the blind spot area, and significantly delayed pattern reversal visual evoked potentials. During medical treatment eleven patients showed within 3-6 months a rapidly regression and normalization of papilledema, blind spot area, and visual evoked potentials. Eight patients continued in showing papilledema including disc gliosis, enlargement of blind spot area, and pathological visual evoked potentials. One patient developed optic nerve atrophy. The results indicated that repeated examinations of visual evoked potentials, when suspect of threatening visual loss has come up (papilledema, increased blind spot area, and field defects), might increase the change of diagnose of an optic nerve atrophy as early as possible.

Calculation of the permeability of the blood-retinal barrier to fluorescein.

A method is presented, for calculation of the permeability of the blood-retinal barrier to fluorescein which is based upon simultaneous determination of the free fluorescein concentration in plasma and the fluorescein concentration profile in the vitreous body. By aid of a simplified mathematical model of the eye the blood-retinal barrier permeability is calculated automatically on a computer from corresponding values of the fluorescein concentration in plasma and in the vitreous body. The present method eliminates some of the factors of uncertainty, which have been present in earlier applied fluorophotometric methods, thus contributing to increasing the exactness of the fluorophotometric method for the estimation of the permeability of the blood-retinal barrier to fluorescein. Apart from the permeability of the barrier, the diffusion coefficient for fluorescein in the vitreous body is also estimated by the present method.

Photometric oculometry. I. An analysis of the optical principles in slit-lamp fluorophotometry.

The optical principles of slit-lamp fluorophotometry are analysed by aid of a mathematical model of the optical system. The analysis forms the theoretical basis for a slit-lamp technique called photometric oculometry, which makes possible an estimation of intraocular axial distances and axial length. The technique is based on a calculation--by aid of a mathematical model of the eye--of the ratio between intraocular movement of the slit-lamp focal plane and corresponding movement of the slit-lamp. Intraocular axial distances can be calculated by aid of this ratio and a direct measurement of the slit-lamp movement when the focal plane is moved in the optical axis from retina to cornea. These items are prerequisites for a quantitative determination of the blood-retinal barrier permeability to fluorescein during vitreous fluorophotometry.

Photometric oculometry. II. Measurement of axial ocular distances with slit-lamp microscopy. Clinical evaluation, and comparison with ultrasonography.

Photometric oculometry is a slit-lamp technique, which makes possible an estimation of intraocular axial distances and axial length. The technique is based on a transformation of a sagittal slit-lamp movement into intraocular axial distances when the slit-lamp focal plane is moved in the optical axis from retina to cornea. Determination of the axial length in 50 eyes (refractive range +4.75 to -5.25 D) showed that the axial length varied from 21.9 mm in hypermetropic eyes to 26.0 mm in myopic eyes, with the emmetropic eyes being approximately 24 mm. A comparison of intraocular axial distances determined by photometric oculometry and by ultrasonography on a small series of eyes showed no significant differences between the axial length, the length of the vitreous body, and the lens thickness, whereas a significant difference between the anterior chamber depth was observed (photometry giving slightly larger values than ultrasound).

The blood-retinal barrier permeability in essential hypertension.

In a series of 8 patients with recently discovered moderate essential hypertension the blood-retinal barrier permeability to fluorescein was determined by aid of quantitative vitreous fluorophotometry before and after normalization of the systemic blood pressure. The permeability before medical treatment was 1.69 X 10(-7) cm/sec (+/- SEM = 0.14) and after medical treatment and normalization of the blood pressure 1.27 X 10(-7) cm/sec (+/- SEM = 0.12), corresponding to the permeability in a normal population. Thus the blood-retinal barrier permeability is pathologically increased even in moderate degrees of essential hypertension, but this increase in permeability is reversible.

Fluorescein in human plasma in vivo.

In connection with corpus vitreum fluorophotometric examinations fluorescein was injected iv and fluorescein in the blood stream was studied with respect to protein binding and elimination kinetics. It was shown by ultrafiltration that in blood obtained during the examination most of the fluorescein was protein bound, and only a minor fraction (10-20%) was free in the water phase. While the free fraction was approximately constant over a wide concentration range when studied in vitro the free fraction increased by a factor of about 2 during a 2 h examination period in vivo. The curve describing the elimination of fluorescein from blood showed a polyexponential decline course. The area under this curve showed only a small variation for the same normal person examined 3 times over a period of 6 months. The area under the bolus has a magnitude, which is 30-40% of that under the rest of the curve.

Fluorescein in human plasma in vitro.

A method to determine fluorescein in human plasma is described. By aid of ultrafiltration a separation between fluorescein bound to plasma proteins and fluorescein free in the water is obtained. Both fractions are quantitated. Fluorescein is bound to plasma proteins. The protein binding is reversible, not sensitive to practically appearing changes in pH, temperature and gas tensions. For a normal person it appeared that at a total plasma concentration between (10(-6) - 10(-4))g . ml-1 approximately 15% was free while at a total concentration of 10(-3) g . ml-1 45% was free, pointing towards a limited amount of protein binding sites.

The blood-retinal barrier permeability in diabetic patients.

By the of aid an extended corpus vitreum fluorophotometric technique, the blood-retinal barrier permeability for fluorescein was studied in diabetologically well characterized patients with insulin dependent diabetes mellitus. The method, which involves simultaneous determination of the fluorescein concentration in corpus vitreum and plasma, is described and discussed. A clear correlation was found between the degree of retinopathy and permeability (P). Patients with normal visus, ophthalmoscophy, fundus photo and fluorescence angiography exhibited P-values of 1.10(-7) cm . sec-1. This was similar to P-values found in normal volunteers. Simplex retinopathy without macular oedema showed values of 2.5 . 10(-7) cm . sec-1 while simplex retinopathy with macular oedema showed P-values of 10 . 10(-7) cm . sec-1.