Pearl S. Rosenbaum

Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury

Erythropoietin (EPO) plays an important role in the brains response to neuronal injury. Systemic administration of recombinant human EPO (rhEPO) protects neurons from injury after middle cerebral artery occlusion, traumatic brain injury, neuroinflammation, and excitotoxicity. Protection is in part mediated by antiapoptotic mechanisms. We conducted parallel studies of rhEPO in a model of transient global retinal ischemia induced by raising intraocular pressure, which is a clinically relevant model for retinal diseases. We observed abundant expression of EPO receptor (EPO-R) throughout the ischemic retina. Neutralization of endogenous EPO with soluble EPO-R exacerbated ischemic injury, which supports a crucial role for an endogenous EPO/EPO-R system in the survival and recovery of neurons after an ischemic insult. Systemic administration of rhEPO before or immediately after retinal ischemia not only reduced histopathological damage but also promoted functional recovery as assessed by electroretinography. Exogenous EPO also significantly diminished terminal deoxynucleotidyltransferase-mediated dUTP end labeling labeling of neurons in the ischemic retina, implying an antiapoptotic mechanism of action. These results further establish EPO as a neuroprotective agent in acute neuronal ischemic injury.

Necroptosis, a novel form of caspase-independent cell death, contributes to neuronal damage in a retinal ischemia-reperfusion injury model

Necroptosis is programmed necrosis triggered by death receptor signaling. We investigated whether necroptosis contributes to neuronal damage and functional impairment in a model of retinal ischemia. Methods: Sprague‐Dawley rats were subjected to raised intra‐ocular pressure for 45 min and received intravitreal injections of the specific necroptosis inhibitor, Nec‐1, its inactive analogue (Nec‐1i) or vehicle. Seven days after ischemia, ERGs were performed and then the eyes were enucleated for histological analysis. In other animals, retinas were subjected to propodium iodide, TUNEL staining or Western Blotting and probed with anti‐LC‐3 antibody. Results: Retinal ischemia resulted in selective neuronal degeneration of the inner layers. Pretreatment with Nec‐1 led to significant preservation in thickness and histoarchitecture of the inner retina and functional improvement compared with vehicle‐treated controls. Pretreatment with Nec‐1i did not provide histological or functional protection. Post‐treatment with Nec‐1 also significantly attenuated the ERG b‐wave reduction compared with ischemic vehicle controls. Nec‐1 had no effect on the number of caspase or TUNEL‐labelled cells in the ischemic retina but did inhibit the induction of LC‐3 II and reduced the number of PI‐labelled cells after ischemia. Conclusion: Necroptosis is an important mode of neuronal cell death and involves autophagy in a model of retinal ischemia.

Cell‐specific caspase expression by different neuronal phenotypes in transient retinal ischemia

Emerging evidence supports an important role for caspases in neuronal death following ischemia‐reperfusion injury. This study assessed whether cell specific caspases participate in neuronal degeneration and whether caspase inhibition provides neuroprotection following transient retinal ischemia. We utilized a model of transient global retinal ischemia. The spatial and temporal pattern of the active forms of caspase 1, 2 and 3 expression was determined in retinal neurons following ischemic injury. Double‐labeling with cell‐specific markers identified which cells were expressing different caspases. In separate experiments, animals received various caspase inhibitors before the induction of ischemia. Sixty minutes of ischemia resulted in a delayed, selective neuronal death of the inner retinal layers at 7 days. Expression of caspase 1 was not detected at any time point. Maximal expression of caspase 2 was found at 24 h primarily in the inner nuclear and ganglion cell layers of the retina and localized to ganglion and amacrine neurons. Caspase 3 also peaked at 24 h in both the inner nuclear and outer nuclear layers and was predominantly expressed in photoreceptor cells and to a lesser extent in amacrine neurons. The pan caspase inhibitor, Boc‐aspartyl fmk, or an antisense oligonucleotide inhibitor of caspase 2 led to significant histopathologic and functional improvement (electroretinogram) at 7 days. No protection was found with the caspase 1 selective inhibitor, Y‐vad fmk. These observations suggest that ischemia‐reperfusion injury activates different caspases depending on the neuronal phenotype in the retina and caspase inhibition leads to both histologic preservation and functional improvement. Caspases 2 and 3 may act in parallel in amacrine neurons following ischemia‐reperfusion. These results in the retina may shed light on differential caspase specificity in global cerebral ischemia.

Cockayne Syndrome in Adults: Review With Clinical and Pathologic Study of a New Case

Cockayne syndrome and xeroderma pigmentosum—Cockayne syndrome complex are rare autosomal recessive disorders with poorly understood biology. They are characterized by profound postnatal brain and somatic growth failure and by degeneration of multiple tissues resulting in cachexia, dementia, and premature aging. They result in premature death, usually in childhood, exceptionally in adults. This study compares the clinical course and pathology of a man with Cockayne syndrome group A who died at age 31½ years with 15 adequately documented other adults with Cockayne syndrome and 5 with xeroderma pigmentosum—Cockayne syndrome complex. Slowing of head and somatic growth was apparent before age 2 years, mental retardation and slowly progressive spasticity at 4 years, ataxia and hearing loss at 9 years, visual impairment at 14 years, typical Cockayne facies at 17 years, and cachexia and dementia in his twenties, with a retained outgoing personality. He experienced several transient right and left hemipareses and two episodes of status epilepticus following falls. Neuropathology disclosed profound microencephaly, bilateral old subdural hematomas, white-matter atrophy, tigroid leukodystrophy with string vessels, oligodendrocyte proliferation, bizarre reactive astrocytes, multifocal dystrophic calcification that was most marked in the basal ganglia, advanced atherosclerosis, mixed demyelinating and axonal neuropathy, and neurogenic muscular atrophy. Cellular degeneration of the organ of Corti, spiral and vestibular ganglia, and all chambers of the eye was severe. Rarely, and for unexplained reasons, in some patients with Cockayne syndrome the course is slower than usual, resulting in survival into adulthood. The profound dwarfing, failure of brain growth, cachexia, selectivity of tissue degeneration, and poor correlation between genotypes and phenotypes are not understood. Deficient repair of DNA can increase vulnerability to oxidative stress and play a role in the premature aging, but why patients with mutations in xeroderma pigmentosum genes present with the Cockayne syndrome phenotype is still not known. (J Child Neurol 2006;21:991—1006; DOI 10.2310/7010.2006.00088).

Retinal ischemia leads to apoptosis which is ameliorated by aurintricarboxylic acid

Transient retinal ischemia results in a delayed cell death of the inner retinal layers. This study demonstrates that this ischemic cell death occurs, at least in part, through apoptosis. The general endonuclease inhibitor, aurintricarboxylic acid, protected rat retinal cells from ischemic cell damage when administered before the onset of ischemia and, more importantly, when administered 6 hr after the insult. Thus, the demonstration that transient retinal ischemia results in cell damage as a result of apoptosis opens new therapeutic strategies aimed at lessening retinal damage as a result of this process.

Functional and morphologic comparison of two methods to produce transient retinal ischemia in the rat.

Objectives Much of our knowledge of the pathophysiology of retinal ischemic injury is from a multitude of studies that use in vitro or in vivo animal models of retinal ischemia followed by reperfusion. The objective of this study was to compare histopathologic and electrophysiologic (electroretinography) parameters using two different models of transient retinal ischemia: high intraocular pressure (HIOP) and suture ligation of the optic nerve (SL). Methods Transient retinal ischemia was induced using the HIOP model or the SL model in the Sprague–Dawley rat for either 30 or 60 minutes. Histopathologic outcome was determined at 1 and 7 days after ischemia. In addition, electroretinography (ERG) was performed at 2 hours, 1 day, 3 days, and 7 days after ischemia. Results At 1 and 7 days after 30 minutes of ischemia, there were no significant histopathologic abnormalities in the retina with either model, except for a slight decrease of the cell count in the ganglion cell layer (GCL) with the SL method. After 60 minutes of ischemia, there was significant thinning of the inner retina. There was a significant early dropout of cells at 1 day in the inner nuclear layer (INL) in the HIOP method compared to the SL method where the dropout was delayed and gradually progressive. Dropout of cells in the GCL was early (1 day) and gradually progressive in both models but more severe in HIOP than SL. There was a significant decrease in the ERG b-wave amplitudes as early as 2 hours after both 30 and 60 minutes of ischemia compared to preischemic baselines. Conclusions The degree of retinal injury after transient retinal ischemia was more severe at 1 day after reperfusion in the HIOP method compared to the SL method but was similar at 7 days in both models. Furthermore, our data suggests that functional assessment of ischemic damage by electroretinography may be a more sensitive parameter than conventional histopathologic quantification. The timing of either measurement relative to the ischemic stimulus is critical because histologic measurements performed too early after ischemia may underestimate the degree of injury.

Deleterious Role of TNF-α in Retinal Ischemia–Reperfusion Injury

PURPOSE Tumor necrosis factor (TNF)-alpha is a mediator of neuronal cell death and survival in ischemia-reperfusion injury. This study was conducted to further elucidate the role of TNF-alpha and its receptor in an in vivo model of retinal ischemia-reperfusion injury by investigating its effects on retinal histopathology and function. METHODS Retinal ischemia-reperfusion injury was performed on p55 and p75 knockout (KO) mice and Sprague-Dawley rats using the high intraocular pressure METHOD The temporal expression of TNF-alpha was ascertained with immunohistochemical staining. Separate rats received intravitreal recombinant TNF-alpha or neutralizing antibody before or after ischemia. TUNEL labeling was performed to assess for cell death, and electroretinography was performed to assess function. RESULTS TNF-alpha expression peaked at 12 to 24 hours after ischemia-reperfusion injury. TUNEL staining was diminished after intravitreal TNF-alpha antibody. Both transgenic KOs demonstrated significantly less functional impairment. Rats receiving recombinant TNF-alpha 48 hours after ischemia showed exaggerated functional impairment. Animals treated with TNF-alpha antibody before ischemia displayed significant functional improvement. CONCLUSIONS TNF-alpha plays a largely deleterious role in ischemia-reperfusion injury in an in vivo model of retinal injury. Direct neutralization of this cytokine partially preserves retinal function. The diverse characteristics of TNF-alpha are attributed in part to the timing of its expression after injury. TNF-alpha receptor expression and function, along with combination treatments targeting death receptor-mediated apoptosis, should be further explored to develop neuroprotective therapeutic strategies for acute retinal ischemic disorders.

Simultaneous intraocular and orbital non-Hodgkin lymphoma in the acquired immune deficiency syndrome

BACKGROUND Non-Hodgkin lymphoma is more common in patients with the acquired immune deficiency syndrome (AIDS), and the incidence of non-Hodgkin lymphoma in the AIDS population has been increasing as the life expectancy of these patients has increased. Nevertheless, intraocular lymphoma, as part of primary central nervous system lymphoma and orbital non-Hodgkin lymphoma, has rarely been reported in patients with AIDS. Co-existent intraocular and orbital lymphoma is exceptionally unusual. The clinical and histopathologic findings are reported in a patient with AIDS who had simultaneous intraocular and orbital non-Hodgkin lymphoma. The clinical funduscopic findings initially were attributed to a viral retinitis. METHODS A left orbital biopsy followed by enucleation of the left eye was performed and studied by light microscopy. Immunophenotyping of the orbital biopsy also was performed. FINDINGS Simultaneous intraocular and orbital large cell malignant lymphoma was present with neoplastic spread directly along the scleral canal of the ciliary nerve. Massive necrosis involving the retina, retinal pigment epithelium, choroid, and optic nerve, as well as several solid retinal pigment epithelial detachments, were observed. Immunophenotyping of the orbital tumor disclosed positive staining for Leu 4 (T cells, 30%) and Leu 14 (B cells, 60%). Immunostaining for light and heavy chains was precluded by tumor necrosis. CONCLUSION Non-Hodgkin lymphoma should be included in the differential diagnosis of acute retinitis, and proptosis in patients with AIDS.

Sinus histiocytosis with massive lymphadenopathy involving the orbit : Reversal of compressive optic neuropathy after chemotherapy

A 38-year-old woman from Antigua had compressive optic neuropathy of the right eye caused by orbital involvement with sinus histiocytosis. There was also nasal sinus involvement and massive cervical lymphadenopathy resulting in radiographic compression of the airway and carotid sheath. Because of the compressive optic neuropathy and threat to the airway and carotid perfusion, the patient underwent a 6-month chemotherapeutic regimen of cyclophosphamide, vincristine, and prednisone. After chemotherapy, the visual dysfunction resolved in correlation with diminution of the orbital mass, and marked regression of the cervical lymphadenopathy. This case demonstrates the potential efficacy of chemotherapy in the treatment of compressive optic neuropathy in cases of orbital sinus histiocytosis with massive lymphadenopathy.

Advancing wave-like epitheliopathy : Clinical features and treatment

PURPOSE The purpose of the study is to describe an entity referred to as advancing wave-like epitheliopathy and successful treatment of this keratopathy with 1% silver nitrate solution. METHODS Eleven eyes of 7 patients were identified with advancing wave-like epitheliopathy. A thorough history and physical examination was performed on each patient, and attempts were made to identify the cause for the epitheliopathy. Six eyes with associated visual loss due to the epitheliopathy involving the visual axis were treated with 1% silver nitrate solution to the superior conjunctival limbus. RESULTS Possible causes for the epitheliopathy included use of antiglaucomatous medications or contact lens care solutions (6 of 11 eyes), soft contact lens wear (4 of 11 eyes), a history of ocular surgery (3 of 11 eyes), or the presence of an underlying dermatologic or inflammatory disorder (3 of 11 eyes). All patients treated with 1% silver nitrate solution (6 of 6 eyes) experienced resolution of their symptoms with either complete or partial resolution of the epitheliopathy. CONCLUSIONS Advancing wave-like epitheliopathy is a keratopathy characterized by centripetally advancing waves of coarse, irregular epithelium arising from the superior limbus. The cause appears to be multifactorial. Symptoms include ocular redness, irritation, and a decrease in visual acuity if the visual axis is involved. Application of 1% silver nitrate solution to the superior limbus is well tolerated and effective in treating this condition.