Marco A. Zarbin

Diabetic Macular Edema: Pathogenesis and Treatment

Diabetic macular edema is a major cause of visual impairment. The pathogenesis of macular edema appears to be multifactorial. Laser photocoagulation is the standard of care for macular edema. However, there are cases that are not responsive to laser therapy. Several therapeutic options have been proposed for the treatment of this condition. In this review we discuss several factors and mechanisms implicated in the etiology of macular edema (vasoactive factors, biochemical pathways, anatomical abnormalities). It seems that combined pharmacologic and surgical therapy may be the best approach for the management of macular edema in diabetic patients.

Posterior Capsule Opacification in Pseudophakic Eyes

Posterior capsule opacification following extracapsular cataract extraction is a manifestation of proliferation of anterior lens epithelium onto the posterior capsule. In addition to Elschnig pearl formation, vision is decreased in two ways. Multiple layers of proliferated epithelium produce a frank opacity. Also, the lens cells show myofibroblastic differentiation and their contraction produces numerous tiny wrinkles in the posterior capsule resulting in visual distortion. Because the cells that proliferate are anterior lens epithelial cells and because proliferation begins at the site of apposition of anterior capsular flap and the posterior capsule, a wide anterior capsulectomy should help reduce the risk of and delay the onset of visual loss from this complication of extracapsular surgery. Polishing the posterior capsule at the time of surgery will not help in this regard unless there is a complicated cataract with pre-existing posterior migration of lens epithelium. The presence of a potential cleavage plane between the proliferating epithelium and the posterior capsule provides a therapeutic alternative to surgical or laser discission.

Drusen in age-related macular degeneration: pathogenesis, natural course, and laser photocoagulation-induced regression.

Drusen are subretinal pigment epithelial deposits that are characteristic of but not uniquely associated with age-related macular degeneration (AMD). Age-related macular degeneration is associated with two types of drusen that have different clinical appearances and different prognoses. Hard drusen appear as small, punctate, yellow nodules and can precede the development of atrophic AMD. Areolar atrophy of the retinal pigment epithelium (RPE), choriocapillaris, and outer retina develop as the drusen disappear, but drusen can regress without evidence of atrophy. Soft drusen appear as large (usually larger than 63 microm in diameter), pale yellow or grayish-white, dome-shaped elevations that can resemble localized serous RPE detachments. They tend to precede the development of clinically evident RPE detachments and choroidal neovascularization. Drusen characteristics correlated with progression to exudative maculopathy include drusen number (five or more), drusen size (larger than 63 microm in diameter), and confluence of drusen. Focal hyperpigmentation in the macula and systemic hypertension also are associated with an increased risk of developing choroidal new vessels (CNVs). Large drusen are usually a sign of diffuse thickening of Bruchs membrane with basal linear deposit, a vesicular material that probably arises from the RPE, constitutes a diffusion barrier to water-soluble constituents in the plasma, results in lipidization of Bruchs membrane, and creates a potential cleavage plane between the RPE basement membrane and the inner collagenous layer of Bruchs membrane through which CNVs can grow. Disappearance of drusen spontaneously and in areas adjacent to laser photocoagulation scars was first noted by Gass (Gass JD: Arch Ophthalmol 90:206-217, 1973; Trans Am Acad Ophthalmol Otolaryngol 75:580-608, 1971). Subsequent reports have confirmed these observations. Photocoagulation-induced drusen regression might prevent patients with drusen from developing exudative maculopathy. The mechanism for spontaneous drusen regression probably involves RPE atrophy. The mechanism for photocoagulation-induced drusen regression is unknown. If photocoagulation-induced drusen regression is anatomically similar to atrophy-associated drusen regression, then the former will be associated with dissolution of basal linear deposit and a residuum of basal laminar deposit. Sarks and coworkers (Sarks JP, Sarks SH, Killingsworth MC: Eye 11:515-522, 1997) proposed that this in turn will eliminate the potential cleavage plane between the RPE basement membrane and inner collagenous layer of Bruchs membrane through which CNVs grow, thus retarding the growth of CNVs.

Cholecystokinin receptors: Presence and axonal flow in the rat vagus nerve

Abstract Cholecystokinin (CCK) receptors have been detected in the rat vagus nerve. Ligation experiments have revealed a time dependent build up of the receptors at the ligature which is blocked by colchicine. Thus, at least a fraction of the receptors are being transported peripherally, presumably by fast flow. The possible involvement of these vagal CCK receptors with the ability of CCK to induce satiety is discussed.

Muscarinic cholinergic receptors: Autoradiographic localization of high and low affinity agonist binding sites

Previous studies have shown that muscarinic cholinergic agonists bind to 3 distinct receptor sites in brain, each being distinguished by their affinity for the agonists. Antagonists, on the other hand, bind to these sites with the same high affinity. The relative concentrations of the two high and the low affinity agonist sites are known to vary in different brain regions. The goal of this study was to localize separate populations of high and low affinity receptor sites in brain at the light microscopic level. All muscarinic receptors in slide-mounted intact tissue sections were labeled with [3H]N-methyl scopolamine ([3H]NMS), but in some experiments carbachol was added to selectively inhibit the binding of [3H]NMS to the high affinity sites. Autoradiograms of these tissue sections were generated by the apposition of emulsion-coated coverslips. Certain brain areas showed a relatively large displacement of [3H]NMS by carbachol indicating high concentrations of high affinity agonist binding sites. These areas included lamina IV of the cerebral cortex, nucleus tractus diagonalis, some thalamic nuclei, the zona incerta and the dorsal lateral geniculate body.

Age-related macular degeneration: review of pathogenesis.

Age-related macular degeneration is a condition (a) characterized by accumulation of membranous debris on both sides of the retinal pigment epithelium (RPE) basement membrane. Clinical manifestations of drusen, atrophy of the RPE/choriocapillaris, RPE detachment, and choroidal new vessel (CNV) formation occur after age 50 years. A hypothetical pathogenic sequence of events consistent with known data is: 1) RPE dysfunction (e.g., precipitated by an inherited susceptibility and/or environmental exposure); 2) accumulation of intracellular material in the RPE (e.g., accumulation of normal substrate material that is not enzymatically degraded properly vs. abnormal substrate material); 3) abnormal accumulation of extracellular material (basal laminar and basal linear deposit); 4) change in Bruchs membrane composition (e.g., increased lipid deposition and protein crosslinking); 5) change in Bruchs membrane parmeability to nutrients (e.g., impaired diffusion of water soluble plasma constituents across Bruchs membrane); and 6) response of the RPE to metabolic distress (i.e., atrophy vs. CNV growth). Histopathological and clinical studies indicate that areas of choroidal ischemia often are seen near CNVs in AMD patients. In response to decreased oxygen delivery/metabolic “distress”, the RPE may elaborate substances leading to CNV growth. Perhaps RPE atrophy, followed by choriocapillaris and photoreceptor atrophy, is a response to decreased nutrients/increasing metabolic abnormalities in areas of excessive accumulation of extracellular debris. Unanswered questions regarding AMD include: 1) is AMD an ocular manifestation of a systemic disease or purely an ocular disease?; 2) what determines whether CNVs vs.atrophy of the RPE-choriocapillaris-photoreceptors develops?; and 3) what induces the maturation of CNVs into an inactive scar, and what limits the growth of most CNVs to the area centralis?

Autoradiographic localization of high affinity GABA, benzodiazepine, dopaminergic, adrenergic and muscarinic cholinergic receptors in the rat, monkey and human retina.

High affinity gamma-aminobutyric acid, benzodiazepine, strychnine (glycine), dopamine, spirodecanone, alpha 1-adrenergic, alpha 2-adrenergic, beta-adrenergic and muscarinic cholinergic binding sites were localized by semiquantitative autoradiography in rat and, in some instances, in monkey and human retinae using [3H]muscimol, [3H]flunitrazepam, [3H]strychnine, [3H]spiperone, [3H]prazosin, [3H]para-aminoclonidine, [3H]dihydroalprenolol and [3H]quinuclidinyl benzylate, respectively. In nearly every case, the inner plexiform layer (IP) contained a high receptor density. The distribution of alpha 1 sites was unusual in that binding was concentrated in the outer plexiform layer (OP). Dopaminergic and, to a lesser extent, beta-adrenergic binding was diffusely distributed in the outer nuclear layer, the OP, the inner nuclear layer and the IP. The ganglion cell layer displayed significant benzodiazepine binding. The intraretinal distribution of pre- and postsynaptic markers of these neurotransmitters is discussed.

Distribution of opiate receptors in the monkey brain: an autoradiographic study.

By employing both in vivo and in vitro labeling techniques, opiate receptors were labeled with tritiated diprenorphine in the monkey brain and localized by light microscopic autoradiography. Both methods of labeling gave similar results, allowing a description of discrete areas having opiate binding sites. High concentrations of opiate receptors were found in the substantia gelatinosa of the spinal cord, nucleus tractus solitarius, area postrema, lateral parabrachial nucleus, substantia grisea centralis, several nuclei of the thalamus and hypothalamus, substantia innominata and in the amygdala. In the monkey pituitary, receptors were found in the neurohypophysis. These results correlate well with those found in autoradiographic studies of the rat brain although there are a few notable differences. Many of the opiate receptor distributions can be correlated with anatomical loci of brain functions known to be influenced by administration of opiate compounds.

Management of Traumatic Hyphema

Hyphema (blood in the anterior chamber) can occur after blunt or lacerating trauma, after intraocular surgery, spontaneously (e.g., in conditions such as rubeosis iridis, juvenile xanthogranuloma, iris melanoma, myotonic dystrophy, keratouveitis (e.g., herpes zoster), leukemia, hemophilia, von Willebrand disease, and in association with the use of substances that alter platelet or thrombin function (e.g., ethanol, aspirin, warfarin). The purpose of this review is to consider the management of hyphemas that occur after closed globe trauma. Complications of traumatic hyphema include increased intraocular pressure, peripheral anterior synechiae, optic atrophy, corneal bloodstaining, secondary hemorrhage, and accommodative impairment. The reported incidence of secondary anterior chamber hemorrhage, that is, rebleeding, in the setting of traumatic hyphema ranges from 0% to 38%. The risk of secondary hemorrhage may be higher in African-Americans than in whites. Secondary hemorrhage is generally thought to convey a worse visual prognosis, although the outcome may depend more directly on the size of the hyphema and the severity of associated ocular injuries. Some issues involved in managing a patient with hyphema are: use of various medications (e.g., cycloplegics, systemic or topical steroids, antifibrinolytic agents, analgesics, and antiglaucoma medications); the patients activity level; use of a patch and shield; outpatient vs. inpatient management; and medical vs. surgical management. Special considerations obtain in managing children, patients with hemoglobin S, and patients with hemophilia. It is important to identify and treat associated ocular injuries, which often accompany traumatic hyphema. We consider each of these management issues and refer to the pertinent literature in formulating the following recommendations. We advise routine use of topical cycloplegics and corticosteroids, systemic antifibrinolytic agents or corticosteroids, and a rigid shield. We recommend activity restriction (quiet ambulation) and interdiction of non-steroidal anti-inflammatory agents. If there is no concern regarding compliance (with medication use or activity restrictions), follow-up, or increased risk for complications (e.g., history of sickle cell disease, hemophilia), outpatient management can be offered. Indications for surgical intervention include the presence of corneal blood staining or dangerously increased intraocular pressure despite maximum tolerated medical therapy, among others.

Pathway-based therapies for age-related macular degeneration: An integrated survey of emerging treatment alternatives

Purpose: To review treatments under development for age-related macular degeneration (AMD) in the context of current knowledge of AMD pathogenesis. Methods: Review of the scientific literature published in English. Results: Steps in AMD pathogenesis that appear to be good targets for drug development include 1) oxidative damage; 2) lipofuscin accumulation; 3) chronic inflammation; 4) mutations in the complement pathway; and 5) noncomplement mutations that influence chronic inflammation and/or oxidative damage (e.g., mitochondria and extracellular matrix structure). Steps in neovascularization that can be targeted for drug development and combination therapy include 1) angiogenic factor production; 2) factor release; 3) binding of factors to extracellular receptors (and activation of intracellular signaling after receptor binding); 4) endothelial cell activation (and basement membrane degradation); 5) endothelial cell proliferation; 6) directed endothelial cell migration; 7) extracellular matrix remodeling; 8) tube formation; and 9) vascular stabilization. Conclusion: The era of pathway-based therapy for the early and late stages of AMD has begun. At each step in the pathway, a new treatment could be developed, but complete inhibition of disease progression will likely require a combination of the various treatments. Combination therapy will likely supplant monotherapy as the treatment of choice because the clinical benefits (visual acuity and frequency of treatment) will likely be superior to monotherapy in preventing the late-stage complications of AMD.