[Non-invasive determination of intracranial pressure. Physiological basis and practical procedure]. / Die nicht-invasive Bestimmung des Hirndruckes durch den Augenarzt: physiologische Grundlagen und Vorgehen in der Praxis.

It has been shown in some recently published papers that the intracranial pressure can be determined by dynamometric measurement of the outflow pressure of the central retinal vein (VOP). The knowledge gained by the basic experiments of Baurmann in 1925 has been forgotten by the ophthalmic community for many years. In this paper the basic phenomena of venous collapse are outlined which are fundamentally different from the biomechanics of the arterial collapse phenomenon observed by ophthalmodynamometry. A practical guideline is given for the dynamometric measurement of venous outflow pressure which equals the intracranial pressure. Performing dynamometry of the central retinal vein enables the ophthalmologist to determine intracranial pressure in a non-invasive way.

New insights into the pathogenesis of diabetic retinopathy--hormonal rather than metabolic factors are important.

Diabetic retinopathy has traditionally been viewed as a metabolite-driven, occlusive vasculopathy that affects both retinal microvascular haemodynamics and stricture; analogies to cholesterol-driven occlusive atherosclerosis of the macrovascular circulation were drawn. However this paradigm may no longer be appropriate. Recent evidence suggests that diabetic retinopathy from the beginning is the consequence of a complex hormonal dysfunction, which is related to insulin-dependent up- and downregulation of growth factors, to which metabolic, haemodynamic, endocrine, paracrine, and autocrine mechanisms contribute.

Reversion of 'early worsening' of diabetic retinopathy by deliberate restoration of poor metabolic control.

Acutely lowering long-standing severe hyperglycaemia can trigger progression ('early worsening') of diabetic retinopathy, most likely by up-regulation of the circulating insulin-like growth factor 1 (IGF-1). This condition, also called 'florid retinopathy', rarely responds to standard laser coagulation treatment. In this retrospective report, 2 young patients with type 2 diabetes are described, in whom deliberate restoration of poor diabetes control reduced the serum IGF-1 levels and improved 'early worsened' diabetic retinopathy.

Measurement of venous outflow pressure in the central retinal vein to evaluate intraorbital pressure in Graves' ophthalmopathy: a preliminary report.

PURPOSE: To evaluate the intraorbital pressure in patients with Graves' ophthalmopathy (GO) in relation to the intraocular pressure (IOP) and proptosis and to find out whether optic nerve compression is predictable. METHODS: The venous outflow pressure (VOP) in the central retinal vein was measured by the perviously described technique of oculodynamometry.1 Since the central retinal vein passes through the orbit, the VOP cannot be lower than the intraorbital pressure if outflow is to be guaranteed. The IOP was measured either in primary position or with slight chin elevation to avoid restriction of the globe. Fifty-seven patients underwent a complete ophthalmologic examination, including VOP measurements, Hertel exophthalmometry and visual fields. RESULTS: The IOP in primary position ranged between 10 and 29 mmHg and in most (n=54) cases the VOP was 0-4 mmHg higher than the IOP. These patients had neither scotomas nor visual deterioration during an observation period of up to 2 years. In those cases (n=3) where the difference between IOP and VOP was 35 mmHg, the patients developed scotomas and visual deterioration and had to be treated (high-dose steroids or orbital decompression). The elevation in VOP did not correlate with the degree of proptosis. In one unilateral case, treatment of high IOP (32 mmHg) with dorzolamide drops led to a decrease in visual acuity of two lines, inferior field depression and relative afferent pupillary defect. The difference between IOP and VOP was 10 mmHg. Stopping treatment normalized visual function, the IOP rose to its original level and the difference between IOP and VOP was 4 mmHg. CONCLUSION: The increased IOP in GO is not caused by primary glaucoma but by elevated intraorbital pressure. The difference between IOP and VOP must be <5 mmHg to guarantee normal perfusion. We interpret these findings to suggest that loss of visual acuity and visual field defects may not only be caused by optic nerve compression at the apex but also by deterioration of optic nerve head perfusion.

[Development of neovascularization of the optic papilla, retina and iris. Dependence on site and extent of retinal ischemia]. / Entstehung von Neovaskularisationen an Papille, Netzhaut und Iris. Abhängigkeit von Lokalisation und Ausdehnung der retinalen Ischämie.

BACKGROUND: Is it possible to find a correlation between the localisation of neovascularisations and the localisation and extension of the retinal ischemia? Ischemia was recognized not as capillary non-perfusion but as impaired retinal perfusion. MATERIALS AND METHODS: Patients with retinal ischemia like in diabetic retinopathy (n = 95), central retinal vein occlusion (n = 9), ischemic ophthalmopathia (n = 8) and branch vein occlusion (n = 5) who had neovascularisations were examined. The localisation of retinal ischemia and the localisation of neovascularisations were diagnosed by fluorescein angiography and biomicroscopy. RESULTS: Neovascularisations at the different places were observed with different frequencies depending on localisation and extension of retinal ischemia. Panretinal ischemia caused by diabetic retinopathy type B was followed by neovascularisations at iris in 69.2% with participation of the anterior chamber angle in 61.1%. In diabetic retinopathy type A with limited retinal ischemia neovascularisations of iris and chamber angle were significantly less frequent (31.7%/25%). On the contrary panretinal ischemia caused by central retinal vein occlusion was followed by neovascularisations elsewhere in 11.1%; in diabetic retinopathy type C with limited retinal ischemia neovascularisations elsewhere were observed only in 66.7%. CONCLUSIONS: There is a relationship between the localisation of the neovascularisations and the localisation and the extension of the retinal ischemia. The differentiation of PDR in different ischemic types is confirmed by different frequencies of the neovascularisation sites depending on the ischemic type. The explanation for the frequent finding of neovascularisations at the disk caused by the peripheral type of diabetic retinopathy is a communication via Cloquet's canal between periperal retina and papilla.

Systemic levels contribute significantly to increased intraocular IGF-I, IGF-II and IGF-BP3 [correction of IFG-BP3] in proliferative diabetic retinopathy.

Increased intraocular levels of angiogenic growth factors such as insulin-like growth factor I (IGF-I) have been demonstrated in proliferative diabetic retinopathy (PDR). It is unclear whether increased leakage of the blood retina barrier or local synthesis primarily determine intraocular levels of IGFs in man, which is of special interest regarding possible therapeutic options with somatostatin analogues in PDR. This is the first study investigating parallelly serum and vitreous levels of IGF-I/II, IGF-BP3 and the liver-derived permeability marker albumin to determine in vivo the amount of circulation-derived intraocular IGFs. A control group without retinal proliferation and patients with PDR were compared. Levels of IGF-I/II, IGF-BP3 and albumin were determined by immunological methods. Vitreous levels of albumin were 2.2-fold elevated in patients with PDR (254.1 +/- 37.2mg/dl; n = 27; p = 0.0027) compared to controls (115.7 +/- 36.2mg/dl; n =10), whereas serum levels were slightly decreased in diabetes patients (5049 +/- 196 mg/dl vs. 4330 +/- 186 mg/dl; p = 0.0283). This was comparable to an increase of IGF-I/11 and IGF-BP3 in vitreous from PDR patients (IGF-I: 2.3 +/- 1.1 ng/ml p = 0.005. IGF-II: 37.9 +/- 4.9 ng/ml; p = 0.0003. IGF-BP3: 97.9 +/- 26.9 ng/ml; p = 0.0001; n = 34) compared to controls (IGF-I: 0.7 +/- 0.1 ng/ml. IGF-II: 21.3 +/- 4.2 ng/ml. IGF-BP3: 31.3 +/- 4.9 ng/ml: n = 19). Serum levels did not differ significantly among the groups regarding IGF-I, II and IGF-BP3. Intraocular albumin and IGF-I levels calculated as percentage of the respective serum levels correlated significantly (r = 0.42; p = 0.012). This study demonstrates that influx of IGF-I, II and IGF-BP3 in PDR quantitatively parallels influx of the liver derived serum protein albumin suggesting that leakage of the blood retina barrier and serum levels of IGF primarily determine intravitreal IGF levels rather than local synthesis. Suppression of systemic IGF levels by new, highly effective somatostatin-analogues therefore provides a promising approach to prevent PDR.

Deficient activation and different expression of transforming growth factor-beta isoforms in active proliferative diabetic retinopathy and neovascular eye disease.

An increased expression and secretion of angiogenic growth factors was proposed to occur in proliferative diabetic retinopathy and other neovascularizing retinal diseases. However, a loss of anti-angiogenic factors also might promote retinal neovascularization. Therefore we investigated the active and latent vitreous levels of the subtypes of the endothelial anti-mitogen transforming growth factor-beta in vitreous of 58 patients. Four groups of patients were compared: Controls without retinal hypoxia, patients with quiescent and active proliferative diabetic retinopathy (PDR), and patients with severe retinal hypoxia resulting in rubeosis iridis. Whereas the amount of total TGF-beta in the four groups did not differ significantly, latent TGF-beta isoform expression showed complex alterations in ocular vitreous. Levels of active TGF-beta of patients with active PDR (79.5 +/- 28 pg/ml; n = 8) were decreased to 20% of the control levels (378 +/- 55 pg/ml; n = 12; p = 0.0005) and 25% of the mean concentration in quiescent PDR (346 +/- 64 pg/ml; n = 9; p = 0.0021). Levels in rubeosis (52 +/- 10 pg/ml; n = 10) did not differ significantly from those found in active PDR but were decreased to 15% of those in patients with quiescent PDR (p = 0.0004). Furthermore a highly significant inverse correlation between active TGF-beta and alpha2-antiplasmin, a liver produced inhibitor of the activation of TGF-beta by plasmin was noted (r = -0.59; n = 28; p = 0.001). We conclude that deficient activation of TGF-beta occurs in active proliferative diabetic retinopathy and in hypoxic angiogenesis most likely as a consequence of a blood retina barrier breakdown and influx of alpha2-antiplasmin from serum. The disinhibition of endothelial cell proliferation may be a central component in the process of neovascularization.

Growth factor alterations in advanced diabetic retinopathy: a possible role of blood retina barrier breakdown.

Chronic hyperglycemia may cause growth factor alterations that are likely to participate in tissue remodeling typical for diabetic late complications. However, few details of such events are known. The ocular vitreous fluid allows studies of growth factor levels in human eyes (after vitrectomy). The vitreous is highly inert and protected by the blood-retina barrier and thus probably reflects growth factor production by the normal retina. Vitreous from patients with proliferative diabetic retinopathy (PDR) was compared with vitreous obtained from patients with nonproliferative eye disease and with vitreous from patients without diabetes but with marked neovascular proliferations due to ischemia. This design permits us to distinguish diabetes-related from non-diabetes-related alterations. Insulin-like growth factor I (IGF-I), IGF-II, IGF binding protein 2 (IGFBP-2), and IGFBP-3 were elevated 3- to 13-fold in nondiabetic retinal ischemia and 1.5- to 3-fold in PDR, indicating that the changes were not restricted to diabetes. These changes may partially be explained by leakage of serum into the vitreous, since IGFs and IGFBPs are 20- to 50-fold higher in serum than in vitreous, and vitreous protein content was 1.5-fold elevated in PDR subjects and 5-fold in ischemia patients compared with control subjects. TGF-beta is a proposed antiangiogenic factor in the eye. TGF-beta2 was the predominant subtype in vitreous, and its total amount was not altered in PDR patients. More importantly, the active fraction of TGF-beta was decreased by 30 and 70% in PDR and nondiabetic retinal ischemia patients, respectively. Since plasmin may control TGF-beta activation, the serum protein alpha2-antiplasmin was measured and found to be significantly elevated to 150 and 250% of control values in PDR and ischemia patients, respectively. Thus, influx of serum proteins due to microvascular disturbances and hypoxia is proposed as a possible cause for vitreous alterations of IGF-I and of active TGF-beta. These changes seem to occur late in the sequence of events leading to PDR and are not specific for diabetes, but they were also observed in other diseases characterized by retinal hypoxia.

Central retinal venous outflow pressure.

BACKGROUND: Does the venous collapse phenomenon provide the possibility of venous dynamometry? METHOD: A technical model is presented which allows analysis of the conditions of the collapse of the central retinal vein in vitro. The conditions of the venous collapse were analysed with regard to intraocular pressure, intravasal pressure in the outflow of the central retinal vein and the overall perfusion. For clinical measurements dynamometry of the venous collapse is performed parallel to the experimental setting. RESULTS: The experiment reveals identical results for venous outflow pressure measured by venous dynamometry and by intravasal pressure detector. Venous dynamometry in vivo means that we use the onset of the venous collapse phenomenon to register the pressure in the central retinal vein at the point where it leaves the eye. Using this technique, retroocular obstruction of the venous outflow may be assessed. The venous outflow pressure itself depends on the venous flow resistance, intracranial pressure and arterial perfusion pressure. Any disorder of these three parameters may be assessed when the absolute venous outflow pressure is registered. CONCLUSION: The venous collapse phenomenon enables us to determine the venous outflow pressure. Clinical applications have proven promising.

[TNF-alpha level in the vitreous body. Increase in neovascular eye diseases and proliferative diabetic retinopathy]. / TNF-alpha-Spiegel im Glaskörper. Anstieg bei neovaskulären Augenkrankheiten und proliferativer diabetischer Retinopathie.

BACKGROUND: Deficient retinal capillary perfusion results in angioneogenesis of the eye. Its extension depends on the degree of ischemia. Mild stages are restricted to the retina, while marked ischemia results in neovascularization of the iris (rubeosis iridis). The neovascularization may be induced by the release of growth factors into the vitreous. Tumor necrosis factor alpha seems to be an important angiogenetic growth factor. PATIENTS AND METHODS: The patients were divided up into three groups with different retinal stages of ischemia, as judged by the extension of new vessel formation of the eye: a control group without angioneogenesis, a diabetes group with less severe to moderate angioneogenesis of patients with proliferative diabetic retinopathy and a rubeosis group with massive angiogenesis (rubeosis iridis) resulting from different causes. TNF-alpha was determined by immunological methods. RESULTS: The TNF-alpha level of vitreous in rubeosis (25.8 pg/ml; n = 6) was 2-fold elevated compared to controls (13.1 pg/ml; n = 10; p < 0.05) and 1.4-fold elevated compared to the diabetes group (18.2 pg/ml; n = 17). The values ranged from unmeasurable values to 41.25 pg/ml. Within the rubeosis group similar changes were observed independently of the causes of ischemia. There was no correlation between TNF-alpha-levels in the diabetes group and serum creatinine. CONCLUSIONS: 1. TNF-alpha is upregulated in ischemia. 2. TNF-alpha seems to be a mediator of angiogenesis in the eye. 3. Changes in diabetes may be secondary to local ischemia rather than being specific for diabetic retinopathy.

[Paralytic ectropion: lower lid suspension to the upper eyelid]. / Paralytisches Ektropium: Unterlidsuspension am Oberlid.

BACKGROUND: All operative procedures to improve paralytic ectropion leave problems and disadvantages concerning stability, tear dropping and cosmetic aspect. Our proposed surgical procedure tries to consider all consequences of a 7th nerve palsy concerning the eye: loss of static tonus with atony of the lower and upper lid followed by ectropion of the lower lid, enlargement of palpebral fissure and rising of the upper lid margin as well as loss of dynamic functions with incomplete lid closure, diminished associated movements of the lower and upper eye lid in upward and downward look. METHODS: 1. Symmetric tightening of lower and upper lid by fixation of the temporal tarsal ends at the origin of the lateral canthal tendon with combined shortening of the temporal angle. 2. Suspension of the lower lid by the upper lid achieved by connecting the free temporal tarsal ends and the medical canthal tendons 1-2 mm medial of the lacrimal puncta. PATIENTS AND RESULTS: Thus the following objectives are improved: 1. The lower lid follows the upper lid in upward look. 2. By the gravity of the lower lid the up-rise of the upper lid margin is repaired. 3. For the same reason the upper lid follows the eye movement in downward look. 4. Lid closure is improved. By our method functional and cosmetic results were satisfying in all 34 patients. Tear dripping of varying amount is to be mentioned most often as persisting problem. CONCLUSION: Our procedure disclosed a high stability. In a follow-up of 1 to 5 years no additional repair was necessary.

[Ischemic or non-ischemic central artery occlusion. An explanation for the development or lack of development of neovascularization]. / Ischämischer oder nicht ischämischer Zentralarterienverschluss. Eine Erklärung für das Auftreten oder Fehlen von Neovaskularisationen.

In a retrospective study we analyzed 29 central retinal artery occlusions (CRAO) with reference to the findings of ophthalmodynamometry (ODM) and fluorescein angiograms (FLA). We tried to find explanations for the relatively low rate of neovascularization in CRAO and predictive constellations for CRAO that will develop neovascularization. In 5 eyes the pathologic findings were classed as ischemic ophthalmopathy because of carotid or ophthalmic artery stenosis: 2 of these 5 eyes showed iris neovascularization (rubeosis iridis), while the other 3 "only" showed a CRAO with no clinical signs of ischemic ophthalmopathy. Of the remaining 24 eyes with CRAO there were 2 eyes with rubeosis iridis, which could be attributed to the CRAO itself (8.3%). FLA revealed ischemic perfusion of the retina in these 2 cases. ODM revealed reperfusion of the central artery (CRA) in 17 of 25 eyes with CRAO (71%) within the first 2 weeks. In 2 blind eyes that were re-examined 3 and 5 months after CRAO no iris or retinal neovascularization was found despite persisting malperfusion of CRA. In these 2 cases the minimal retinal perfusion needed because of complete retinal necrosis was sufficient explanation for the nonevolution of neovascularization. If ischemia is the essential condition for neovascularization, we can propose two explanations for non-development of neovascularization after CRAO: either there is adequate recanalization (majority of cases) or the need for perfusion is minimal or zero. Only in cases of persisting malperfusion and partially surviving retinal tissue (function!) will neovascularization perhaps develop. ODM is an adequate method of estimating the perfusion of CRA.

Vitreous levels of the insulin-like growth factors I and II, and the insulin-like growth factor binding proteins 2 and 3, increase in neovascular eye disease. Studies in nondiabetic and diabetic subjects.

Retinal capillary nonperfusion results in neovascularization of the eye, which is restricted to the retina in less severe cases and progresses to the anterior chamber and the iris angle in the most advanced case, called rubeosis. This angioneogenesis may be induced by the release of retinal growth factors into the vitreous. This study compared levels of the IGF-I and IGF-II, and of the IGF binding protein-2 (IGFBP-2) and IGFBP-3 in vitreous from three groups with different degrees of retinal ischemia, as judged by the extent of neovascularization: a control group without new vessel formation, retinal neovascularization in patients with proliferative diabetic retinopathy, and massive ischemia of various causes resulting in rubeosis. IGF-I and IGFBP-3 were increased 10- and 13-fold in rubeosis (P << 0.01) compared with no ischemia (n = 10), while IGF-II and IGFBP-2 were elevated 2.7- and 4.3-fold (P < 0.01). Within the rubeosis group similar changes were observed independently of the cause of ischemia, which was central vein occlusion, ischemic ophthalmopathy, or intraocular tumor in seven cases and diabetic retinopathy in three samples from two patients. Vitreous from patients with proliferative diabetic retinopathy but without rubeosis (n = 16) contained 2.5- and 2.2-fold elevated levels of IGF-I and of IGFBP-2 (P < 0.05), while IGF-II and IGFBP-3 were increased 1.4- and 1.6-fold, which was not significant. We conclude that: (a) ischemia appears to be a strong stimulus for the local production of IGF-I and -II and of IGFBP-2 and -3 in the eye. (b) Changes in IGF-I and IGFBP-2 in proliferative diabetic retinopathy may be secondary to local ischemia rather than being specific for diabetic retinopathy. (c) IGF-I and IGFBP-3 may play a role in mediating angioneogenesis in the eye.

[Retinal photocoagulation in hemorrhagic retinal branch vein thrombosis. A new treatment technique]. / Retinale Photokoagulation bei hämorrhagischen Venenastthrombosen. Eine neue Behandlungstechnik.

In branch vein occlusions involving the macula, the loss of macular function cannot be due to hypoperfusion of the involved capillaries, because if this were so the uninvolved part of the macula would presumably be unimpaired. The impairment of the macula is explained as follows. Congestion of the blood caused by the thrombosis means that the capillaries are exposed to high blood pressure. In the border zone of the thrombotic area capillaries that are normally drained are exposed to capillary hypertension. For this reason, the border zone of a retinal thrombosis is also affected. The perifoveal capillary network is usually in this border zone. We treated branch vein occlusions by perimacular photocoagulations on the blood in the inner retinal layer within the zone of the thrombosis. Our explanation for the gain in visual acuity following this procedure is that we occlude the retinal capillaries that are, passing on the high pressure into the perifoveal capillaries. Our proposed photocoagulation procedure is restricted to cases in which hemorrhage has led to enough blood in the inner retinal layer to coagulate. The destruction of the nerve fiber layer by this kind of photocoagulation has to be taken into account. The possible gain of visual acuity has to be balanced against the loss of function caused by destruction of parts of the nerve fiber layer.

A fluorescein angiographic study on patients with proliferative vitreoretinopathy treated by vitrectomy and intraocular daunomycin.

Fluorescein angiographic findings in patients with proliferative vitreoretinopathy treated by victrectomy, silicone oil tamponade and intraocular daunomycin are compared to findings in patients who received the same treatment but no intraocular drug. A difference between drug treated and untreated eyes was not discovered. We observed, however, a delayed arteriovenous passage time, cystoid macular edema, ectopia of the foveolar region and late hyperfluorescence of the optic disk; these findings might partly explain the visual results. Reduction of redetachment and thus prevention of reoperations by treatment with antiproliferative drugs may decrease the rate of cystoid macular edema and thus improve the functional results of surgical treatment.

[Photocoagulation treatment in hemorrhagic branch vein occlusion involving the macula. A new approach]. / Traitement par photocoagulation des occlusions hémorragiques de branches veineuses avec retentissement maculaire. Une nouvelle approche.

Hemorrhagic infarction of the inner retinal layer in vein occlusion disables the ophthalmologist from placing the photocoagulation at the "usual" level of the pigment epithelium. On the other hand, resorption of the photocoagulation energy by hemoglobin gives the change of placing coagulation in the inner retinal layer with complete destroying of the retinal capillaries. The not affected part of the macula in branch vein occlusions can thus be prevented from being destroyed by the chronic edema. A photocoagulation barrier is placed between the macula and the affected side. The unavoidable destruction of parts of the nerve-fiber-layer has to be taken into account. If therapy does not start too late, excellent results can be obtained.

[Occlusion site and occlusion time of central artery occlusions: diagnostic references caused by changes in the collapse phenomenon of the central artery in ophthalmodynamometry]. / Verschlussort und Verschlusszeit bei Zentralarterienverschlüssen: diagnostische Hinweise durch Veränderungen des Kollapsphänomens der Zentralarterie bei der Ophthalmodynamometrie.

The collapse of the central retinal artery in ophthalmodynamometry is typically altered in cases of central retinal artery occlusion. The alterations of the collapse phenomenon can be used to obtain the following information: (1) location of the occlusion; (2) duration of the occlusion. This information is of great value in determining the pathogenesis and therapy of central retinal artery occlusion.