[Giant cell arteritis (temporal arteritis, Horton's arteritis): clinical characteristics and management]. / Morbus Horton (Arteriitis temporalis, Riesenzellarteriitis): Klinik, Diagnostik, Histologie, Therapie.

Giant cell arteritis can cause diagnostic difficulties due to its heterogeneous symptomatology. Characteristic ophthalmic and systemic symptoms of Horton's disease are discussed. The clinical course is described on the basis of typical patients, which shows that generic symptoms do not have to coexist. The Horton's arteritis potentially represents a systemic vasculitis that requires early diagnosis and treatment in order to avoid dramatic ophthalmic consequences, in worst cases blindness. The erythrocyte sedimentation rate (ESR) represents the most important laboratory parameter. Although temporal artery biopsy remains the only confirmatory procedure for a definite diagnosis, imaging procedures such as sonography, magnetic resonance imaging, ultrasound biomicroscopy are useful in supporting the clinical diagnosis. Highly dosed corticosteroid therapy should always be indicated when suspicious clinical symptoms are present, even without any dramatic laboratory parameter changes. Initial high dosages are indicated up to 1 gram daily depending on the severity of the disease. Subsequently a slow ESR titrated reduction of the dose is necessary under control of inflammation values, symptomatology and side effects. Occasionally a lifelong immunsuppressive therapy is indispensable. The long-term treatment should take place in close cooperation with the general practitioner, rheumatologist, neurologist and if necessary further specialists.

[A comparison of rebound tonometry (ICare) with TonoPenXL and Goldmann applanation tonometry]. / Evaluierung der Reboundtonometrie (ICare) im Vergleich zum TonopenXL und dem Goldmann-Applanationstonometer.

BACKGROUND: Goldmann applanation tonometry and dynamic contour tonometry (PASCAL) are two well established slit lamp mounted tonometric methods. Intraocular pressure measurement in bedridden patients and children is often only possible using hand held tonometers (TonoPenXL, Perkins tonometer, Draeger tonometer). This study was performed to evaluate the hand held ICare tonometer, which is based on the rebound method. METHODS: A total of 102 eyes were examined by two highly experienced ophthalmologists for: 1) ophthalmological status, 2) central corneal power (Zeiss IOL-Master), 3) central corneal thickness (Tomey ultrasound pachymetry, five successive measurements, SD<5%), 4) intraocular pressure (IOP) measurement with the Goldmann applantation tonometer (GAT) 1x, 5) TonoPenXL (1x), 6) ICare with three successive measurement series of 6 single measurements. RESULTS: The mean IOP(GAT) was 13.2+/-3.0 mmHg compared with the mean IOP(TonoPenXL) (13.4+/-3.1 mmHg) and with the IOP(ICare) (mean value of first measurement series: 13.4+/-3.1 mmHg). The series of measurements with the ICare showed a tonography effect (decrease of IOP from 14.6 mmHg at the first measurement and 14.2 mmHg at the second to 14.0 at the third measurement). The ICare-measurements were highly reliable (Cronbach's alpha=0.974) and showed a good correlation between the measurement series (r=0.592-0.642; p<0.001). There was a great intra-individual variability of up to 17 mmHg between the GAT, TonoPenXL and ICare methods. CONCLUSIONS: The ICare tonometer is easy to handle and high reliability. The data are comparable with those from the Goldmann tonometer. A tonography effect of 0.6 mmHg in the successive measurement series was found.

bcl-2 gene therapy exacerbates excitotoxicity.

The protooncogene bcl-2 can block neuronal death from both naturally occurring apoptosis and exogenous insults. bcl-2 is therefore a promising candidate for the prevention of excitotoxic neuronal death. Using an adeno-associated viral vector, we delivered the bcl-2 gene to the ganglion cell layer of the rat eye. We hypothesized that infection with bcl-2 would protect ganglion cells against excitotoxic cell death. However, retinal infection with bcl-2 increased ganglion cell susceptibility to both axonal injury and intravitreal NMDA. Our study--intended to explore the possibility of bcl-2 transduction as an in vivo therapeutic approach--revealed a deleterious effect of bcl-2 transduction.

Concurrent downregulation of a glutamate transporter and receptor in glaucoma.

PURPOSE: Elevated levels of extracellular glutamate have been implicated in the pathophysiology of neuronal loss in both central nervous system and ophthalmic disorders, including glaucoma. This increase in glutamate may result from a failure of glutamate transporters, which are molecules that ordinarily regulate extracellular glutamate. Elevated glutamate levels can also lead to a perturbation in glutamate receptors. The hypothesis for the current study was that glutamate transporters and/or receptors are altered in human glaucoma. METHODS: Immunohistochemical analyses of human eyes with glaucoma and control eyes were performed to evaluate glutamate receptors and transporters. These molecules were also assayed in rat eyes injected with glial-derived neurotrophic factor (GDNF). RESULTS: Glaucomatous eyes had decreased levels of both the glutamate transporter, excitatory amino acid transporter (EAAT)-1, and the glutamate receptor subunit N-methyl-D-aspartate (NMDA)-R1. Eyes treated with GDNF had elevated levels of both EAAT1 and NMDAR1. CONCLUSIONS: The loss of EAAT1 in glaucoma may account for the elevated level of glutamate found in glaucomatous vitreous and lead to a compensatory downregulation of NMDAR1. Inasmuch as GDNF can increase levels of both EAAT1 and NMDAR1, it may be a useful therapeutic approach to restore homeostatic levels of these in glaucoma.

Ethambutol is toxic to retinal ganglion cells via an excitotoxic pathway.

PURPOSE: Ethambutol is an essential medication in the management of tuberculosis. However, it can cause an optic neuropathy of uncertain etiology. Ethambutol toxicity was therefore studied in rodent retinal cells, and agents that might block its toxicity were considered. METHODS: The toxicity of ethambutol and related agents was evaluated in rodent retinal dissociated cell preparations and whole eyes. Calcium fluxes and mitochondrial function were evaluated by fluorescent and staining techniques. For in vivo assays, adult rats were administered oral ethambutol over a 3-month period. Cell survival was assessed by stereology. RESULTS: Ethambutol is specifically toxic to retinal ganglion cells in vitro and in vivo. Endogenous glutamate is necessary for the full expression of ethambutol toxicity, and glutamate antagonists prevent ethambutol-mediated cell loss. Ethambutol causes a decrease in cytosolic calcium, an increase in mitochondrial calcium, and an increase in the mitochondrial membrane potential. CONCLUSIONS: The visual loss associated with ethambutol may be mediated through an excitotoxic pathway, inasmuch as ganglion cells are rendered sensitive to normally tolerated levels of extracellular glutamate. Ethambutol perturbs mitochondrial function. Its toxicity may depend on decreased ATPase activity and mitochondrial energy homeostasis. Glutamate antagonists may be useful in limiting the side effects seen with ethambutol.

Systemic L-kynurenine administration partially protects against NMDA, but not kainate-induced degeneration of retinal ganglion cells, and reduces visual discrimination deficits in adults rats.

PURPOSE: Kynurenic acid (KYNA), an endogenous tryptophan metabolite, is an N-methyl-D-aspartate (NMDA) antagonist active at the glycine-binding site of the NMDA-receptor complex. The authors investigated whether systemic administration of a biochemical precursor of KYNA, L-kynurenine (L-Kyn), could block NMDA- or kainic acid (KA)-induced cell death in adult rat retinal ganglion cells (RGCs) and protect NMDA-treated animals from lesion-induced visual deficits. METHODS: Rats were injected with 20-nmol NMDA or 5-nmol KA intraocularly. To quantify the number of surviving RGCs, the retrograde tracer horseradish-peroxidase was injected into the superior colliculus contralateral to the lesioned eye. Surviving RGCs were counted on wholemounted retinae in a centroperipheral gradient, as well as in the four quadrants, using a computer-assisted image analysis system. RESULTS: The NMDA-injections resulted in an approximately 82% RGC loss in the adult rat retina compared with control retinae and a cell loss of approximately 50% in KA-treated retinae. Pretreatment with L-Kyn significantly reduced NMDA-induced RGC degeneration to values of approximately 60%, but KA toxicity was not significantly affected by L-Kyn pretreatment. Intraocular injections of NMDA resulted in an impairment of visual discrimination behavior, which partially recovered within a period of approximately 3 weeks. However, when treated systemically with L-Kyn, brightness discrimination was significantly improved as compared with NMDA-treated rats. CONCLUSIONS: These findings show that systemic administration of L-Kyn in adult rats can block NMDA-induced retinal ganglion cell death in vivo and preserves brightness discrimination performance.

Ganglion cell loss after optic nerve crush mediated through AMPA-kainate and NMDA receptors.

PURPOSE: Glutamate antagonists can block ganglion cell death due to optic nerve crush. Although most investigators have focused on blockade of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, we have chosen to evaluate the efficacy of blockade of the AMPA-kainate (KA) receptor in this experimental paradigm. METHODS: The optic nerves of rats were crushed, and ganglion cell survival was assessed. Groups of animals were treated with an NMDA antagonist, an AMPA-KA antagonist, or both. RESULTS: The AMPA-KA antagonist DNQX was more effective, although not additive in preserving retinal ganglion cells after optic nerve crush than the NMDA antagonist MK801. CONCLUSIONS: Activation of the AMPA-KA subtype of glutamate receptor may play a role in glutamate-mediated cell death after optic nerve crush.

The contribution of various NOS gene products to HIV-1 coat protein (gp120)-mediated retinal ganglion cell injury.

PURPOSE: There is growing evidence that the neuronal pathology seen with HIV-1 is mediated, at least in part, through an excitotoxic/free radical pathway. Nitric oxide (NO) plays a critical role in the nervous system, in both normal and pathologic states, and appears to be involved in a variety of excitotoxic pathways. Whether isoforms of nitric oxide synthase (NOS) are involved in gp120-mediated neuronal loss in the retina was therefore explored. METHODS: To determine which (if any) of the various isoforms of NOS are critical in gp120-mediated damage in the retina, neuronal NOS-deficient [nNOS(-/-)], endothelial NOS-deficient [eNOS(-/ -)], and immunologic NOS-deficient [iNOS(-/-)] mice were subjected to intravitreal injections of gp120. RESULTS: Retinal ganglion cells in the nNOS(-/-) mouse were relatively resistant to gp120, manifesting attenuation of gp120-induced injury compared with wild-type mice. The iNOS(-/-) and eNOS(-/-) mice were as susceptible to gp120 toxicity as control animals. NOS inhibitors were protective against this toxicity. CONCLUSIONS: The presence of nNOS is a prerequisite for the full expression of gp120-mediated loss in the retina; eNOS and iNOS do not appear to play a significant role.

Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine.

PURPOSE: It is well known that acute exposure to high concentrations of glutamate is toxic to central mammalian neurons. However, the effect of a chronic, minor elevation over endogenous glutamate levels has not been explored. The authors have suggested that such chronic exposure may play a role in glaucomatous neuronal loss. In the current study, they sought to explore whether a chronic, low-dose elevation in vitreal glutamate was toxic to retinal ganglion cells and whether this toxicity could be prevented with memantine, a glutamate antagonist. METHODS: Rats were injected serially and intravitreally with glutamate to induce chronic elevations in glutamate concentration. A second group of rats was treated with intraperitoneal memantine and glutamate. Control groups received vehicle injection with or without concurrent memantine therapy. After 3 months, the animals were killed, and ganglion cell survival was evaluated. RESULTS: Intravitreal injections raised the intravitreal glutamate levels from an endogenous range of 5 to 12 microM glutamate to 26 to 34 microM. This chronic glutamate elevation killed 42% of the retinal ganglion cells after 3 months. Memantine treatment alone had no effect on ganglion cell survival. However, when memantine was given concurrently with low-dose glutamate, memantine was partially protective against glutamate toxicity. CONCLUSIONS: These data suggest that minor elevations in glutamate concentration can be toxic to ganglion cells if this elevation is maintained for 3 months. Furthermore, memantine is efficacious at protecting ganglion cells from chronic low-dose glutamate toxicity.

The role of neuronal and endothelial nitric oxide synthase in retinal excitotoxicity.

PURPOSE: Nitric oxide synthase (NOS) plays an essential role in neuronal function and is critical in the brain for normal and pathologic responses to glutamate. The role of NOS in the retina is less well understood. The retina provides an experimental system in which the intrinsic circuitry is well defined; retinal excitotoxic damage has been well characterized. METHODS: To determine whether neuronal NOS (nNOS) and endothelial NOS (eNOS) are critical in excitotoxic damage in the retina, nNOS- and eNOS-deficient mice were subjected to intravitreal injections of N-methyl-D-aspartate (NMDA) or to arterial occlusions. RESULTS: Retinal ganglion cells in the nNOS-deficient mouse were relatively resistant to NMDA and to arterial occlusion. In contrast, the damage in the eNOS-deficient mouse retina was not distinguishable from that in control animals. Preinjection with an NOS inhibitor was partially protective. CONCLUSIONS: The presence of nNOS is a prerequisite for the full expression of excitotoxicity in the retina; eNOS does not appear to play a significant role.

Depression of retinal glutamate transporter function leads to elevated intravitreal glutamate levels and ganglion cell death.

PURPOSE: Elevated levels of extracellular glutamate have been implicated in the pathophysiology of neuronal loss in both central nervous system and ophthalmic disorders, including glaucoma. This increase in glutamate may result from a failure of glutamate transporters (molecules that ordinarily regulate extracellular glutamate; E:xcitatory A:mino A:cid T:ransporter; EAAT). Elevated glutamate levels can also lead to alterations in glutamate receptor expression. It was hypothesized that selective blockade of glutamate transporters would be toxic to retinal ganglion cells. METHODS: Glutamate transporters were blocked either pharmacologically or with subtype-specific antisense oligonucleotides against EAAT1. Glutamate levels, transporter levels and ganglion cell survival were assayed. RESULTS: Pharmacological inhibition of glutamate transporters with either an EAAT2 specific inhibitor or a nonspecific inhibitor of all the subtypes of transporters was toxic to ganglion cells. Treatment with oligonucleotides against the glutamate transporter EAAT1 decreased the levels of expression of the transporter, increased vitreal glutamate, and was toxic to ganglion cells. CONCLUSIONS: These results demonstrate that normal function of EAAT1 and EAAT2 is necessary for retinal ganglion cell survival and plays an important role in retinal excitotoxicity. Manipulation of retinal glutamate transporter expression may become a useful tool in understanding retinal neuronal loss.

Pilocarpine toxicity in retinal ganglion cells.

PURPOSE: Muscarinic agents reduce intraocular pressure by enhancing aqueous outflow, probably by stimulating ciliary muscle contraction. However, pilocarpine is a well characterized neurotoxin and is widely used to generate animal seizure models. It was therefore investigated whether pilocarpine was also toxic to retinal ganglion cells. METHODS: Dissociated whole retinal preparations were prepared from postnatal day 16 to 19 rats. Retinal ganglion cells had been previously back-labeled with a fluorescent tracer. Retinal cells were incubated with pilocarpine, lithium, and inositol derivatives, and viability of the retrogradely labeled retinal ganglion cells was assayed after 24 hours. RESULTS: Pilocarpine was toxic to retinal ganglion cells in a dose-dependent fashion. This toxicity was potentiated by lithium and blocked by epi- and myo-inositol. CONCLUSIONS: Pilocarpine is toxic to retinal ganglion cells in a mixed culture assay. This toxicity appears to depend on the inositol pathway and is similar to its mode of action in other neurons. However, 0.4 mM pilocarpine (the lowest concentration that did not affect ganglion cell survival) is roughly 1000-fold higher than the vitreal concentration and 20-fold higher than the scleral concentration that can be obtained with topical administration of 2% pilocarpine in the rabbit eye.

Co-expression of c-Jun and ATF-2 characterizes the surviving retinal ganglion cells which maintain axonal connections after partial optic nerve injury.

The expression of c-fos, c-jun, jun-b, jun-d, srf and pc4 mRNA was examined after partial optic nerve crush in the adult rat retina by in situ hybridization. Optic nerve injury led exclusively to the upregulation of c-jun, with cellular label indicative for c-jun mRNA in the retinal ganglion cell layer after two days, three days and one week post-injury. This expression pattern was in accordance with the appearance of c-Jun immunoreactivity in retinal flat mounts. Injection of an antisense but not a missense oligonucleotide against c-jun after partial crush resulted in a reduced number of connected retinal ganglion cells (RGCs) as shown by retrograde labeling. Prelabeling of RGCs with fluorogold before optic nerve section and subsequent antisense targeting against c-jun, however, led to a slightly higher number of surviving but axotomized RGCs. C-Jun antibody staining of retinal whole mounts pre- or postlabeled after crush by intracollicular administration of fluorogold showed strong c-Jun immunoreactivity in connected RGCs and also in a population of disconnected RGCs. Double labeling with an antibody directed against the transcription factor ATF-2 revealed strong co-expression of c-Jun and ATF-2 in connected RGCs but not in axotomized cells. Taken together these data indicate that both RGCs in continuity and those in discontinuity with the superior colliculus respond both equally to the noxious stimulus with c-Jun expression. Moreover, the co-expression of c-Jun with high levels of ATF-2 appears to be essential for either the continuity or survival of RGCs which remain connected with their target. In disconnected RGCs, however, low levels of ATF-2 and the co-expression of c-Jun may be related to cell death.

An experimental basis for implicating excitotoxicity in glaucomatous optic neuropathy.

Most therapy for glaucoma is directed at the management of the intraocular pressure (IOP). Conventional wisdom holds that excessive pressure within the eye leads to the ganglion cell loss/optic nerve damage seen in this disease. Both glutamate and elevated IOP can selectively damage the retinal ganglion cells in the mammalian eye. We have identified an elevated level of glutamate in the vitreous humor of glaucoma patients (27 microM as compared to 11 microM in the control population). This concentration of glutamate suffices--on its own--to kill retinal ganglion cells. It is plausible that the IOP may represent an initial insult that precipitates the production of excessive glutamate. Therefore, even if glutamate elevation is an epiphenomenon associated with the course of the disease, it may contribute to ganglion cell loss in humans. Lowering the IOP may slow down glutamate production, but if nothing is done to block the toxic effects of glutamate as well, visual loss may result despite excellent IOP control. If interventions can be found to retard the production or toxic effects of glutamate, it may be possible to slow glaucomatous visual loss.

Infection with adeno-associated virus may protect against excitotoxicity.

Gene therapy has developed as a promising approach for therapy in a broad variety of conditions. Viral vectors have been developed that may replace a defective gene, prevent expression of a mutant gene, or deliver a protective gene and thereby delay cellular loss. Using adeno-associated virus containing green fluorescent protein (AAV-GFP) we were able to specifically transduce cells located in the inner retina and induce over-expression of GFP in adult rat retinae. The delivery and expression of GFP had no influence themselves on retinal ganglion cell survival. Administration of the reporter vector AAV-GFP provided retinal ganglion cells with slight but significant protection from intravitreal NMDA. This was a locally mediated phenomenon; greater protection was seen in regions with more transduced cells. Any evaluation of the efficacy of a putative viral vector should consider the possible protective or toxic effect of the native virus.

Cation channel control of neurite morphology.

The development of neuronal polarity and morphology is essential for a functioning nervous system. The present study was undertaken to explore whether blockade of specific channels alter neuronal morphology. Retinal ganglion cells were cultured in the presence of antagonists to NMDA, AMPA/kainate, L-, N-, P-, and Q-type voltage-dependent calcium channels (VDCCs). Five parameters were measured under these conditions: the number of neurites at the cell body, total neurite length, the length of the longest neurite, the number of branch points per neurite, and the diameter of the cell soma. Antagonists to NMDA and L-type VDCCs reduce the number of neurites at the cell body; antagonists to P- and Q-type VDCCs increase the number of neurites. Antagonists to the N-type VDCCs increase total neurite outgrowth, while antagonists to the NMDA and P-type channels reduce total neurite length. Antagonists to the NMDA and L-type channels increase the length of a single neurite, while decreasing the number of branch points; antagonists to the P- and Q-type VDCCs do essentially the opposite-increase the number of neurites, while decreasing the length of each. Blockade of one or more cation channels in developing retinal ganglion cells significantly perturbs neurite morphology. This study may help elucidate part of the role that cation channel signaling plays in neuritic development.

Thy-1 is critical for normal retinal development.

In the mammalian retina, Thy-1, the most abundant mammalian neuronal surface glycoprotein, is found predominantly if not exclusively on retinal ganglion cells. We hypothesized that Thy-1 plays a significant role in retinal development. Neurite outgrowth of retinal ganglion cells from Thy-1(-) mice over multiple substrates was compared to that seen with wild-type controls. Adult mouse retinas were histologically compared between Thy-1(-) and three strains of Thy-1 positive mice. Thy-1(-) retinal ganglion cells had significantly less neurite outgrowth than controls. The inner nuclear, inner plexiform, ganglion cell and outer segment/pigment epithelium layers were thinner in Thy-1(-) retinae than in controls. Thy-1 appears to be critical for normal retinal development.

Nitrate therapy may retard glaucomatous optic neuropathy, perhaps through modulation of glutamate receptors.

Nitrates have been a major part of the internist's pharmacopoeia for more than 100 years, predominantly for the relief of anginal symptoms. The effects of nitroglycerin on the eye and specifically on intraocular pressure has been investigated with diverse results. However, nitroglycerin may also serve to protect retinal ganglion cells against glutamate mediated toxicity--a form of cell death that may be critical in glaucomatous blindness. Consequently, we therefore sought to evaluate whether nitroglycerin preparations, taken for non-ophthalmic reasons, had an effect on glaucomatous damage.