Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene

PURPOSE: To investigate the clinical features of subjects with glaucoma with the E50K mutation in the optineurin (OPTN) gene and to compare the onset, severity, and clinical course of these patients with a control group of subjects with glaucoma without this mutation. METHODS: The phenotype of well-characterized subjects from Moorfields Eye Hospital, London, who had been identified as carrying the OPTN E50K mutation was examined. A wide range of structural, psychophysical, and demographic factors were then compared with those in a control group of subjects with glaucoma without this mutation. RESULTS: Eleven subjects with glaucoma with the E50K mutation (nine in two families and two sporadic cases) were studied. All 11 subjects had normal tension glaucoma (NTG), with presenting and highest IOP of 15.3 +/- 3.0 and 16.5 +/- 2.5 mm Hg (+/-SD) on diurnal testing. Compared with 87 NTG control subjects who did not have this mutation, subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area (+/-SD; 0.5 +/- 0.28 mm2, P = 0.001) at diagnosis. The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields. In addition, seven E50K mutation-carrying individuals in two families (age range, 23-58 years) presented with normal optic discs and visual fields and, as yet, no signs of glaucoma. CONCLUSIONS: In this study, subjects with glaucoma who had the OPTN E50K mutation were found to have NTG that appeared to be more severe than that in a control group of subjects with NTG without this mutation. The findings emphasize the importance of early detection and treatment of glaucoma in such individuals, to minimize visual loss.     

Integrated visual fields: a new approach to measuring the binocular field of view and visual disability

Background We have developed a method of quantifying the central binocular visual field by merging results from monocular fields (Integrated visual field). This study aims to compare the new measure with the binocular Esterman visual field test in identifying patients with self-reported visual disability.Methods Forty-eight patients with glaucoma each recorded Humphrey 24-2 fields for both eyes and an Esterman on the same day, and each completed a binary forced-choice questionnaire relating to perceived visual disability. Computer software merged sensitivity values from monocular fields to generate an integrated visual field and a related score of the number of defects at the <10 dB and <20 dB level. Receiver operating characteristic (ROC) analysis was used to compare the integrated visual field score and the Esterman disability score with individual responses to the questions on perceived difficulty with visual tasks.Results Comparison of areas under ROC curves revealed that a score based on the integrated visual field was generally better (median area: 0.79) than Esterman scores (median area: 0.70) in classifying patients with or without a self-reported perceived difficulty with visual tasks.Conclusions The integrated visual field offers a rapid assessment of a glaucoma patients binocular visual field without extra perimetric testing. As compared to an actual binocular field test (Esterman), the integrated visual field provides a better prediction of a glaucoma patients perceived inability to perform certain visual tasks.     

Primary central nervous system lymphoma - A hospital based study of incidence and clinicopathological features from India (1983-2003)

Over the last two decades, an increase in the incidence of PCNSL cases has been reported in the West, both among immunosuppressed and immunocompetent patients. The present study was undertaken to assess the trend of incidence of PCNSL cases in India. To the best of our knowledge, only a single such report is available from India. All biopsy proven PCNSL cases obtained from the Neurosurgical databases of two large referral hospitals, one in Northern India (AIIMS, New Delhi) and another in Southern India (NIMHANS, Bangalore) from the period 1980 to 2003, were reviewed. Immunophenotyping was done and relevant clinical details collected. Appropriate statistical analysis was done to assess any change in trend of incidence or age at presentation. PCNSL cases constituted 0.95% and 0.92% of the total intracranial neoplasms at AIIMS and at NIMHANS, respectively. The mean age for cases diagnosed at AIIMS was 44.35 years, while that for NIMHANS was 39.51 years. Statistical analysis to evaluate any change in trend either of incidence or of age at presentation, over the study period, did not reveal any significant change. All the cases occurred in immunocompetent patients, except one case of HIV positive at NIMHANS, and one case of renal transplant at AIIMS. Frontal lobe was the most common site of involvement. Majority of the cases were diffuse, high grade, large cell lymphoma, B-cell immunophenotype. Thus, this multicentric hospital based study did not reveal any increase in incidence of PCNSL cases in India over the past 24 years. Further, in contrast to the West, majority of the cases in this Indian study were immunocompetent and a decade younger than in the West. The association of PCNSL with HIV/AIDS has been low in India, possibly due to early death in AIDS on account of opportunistic infections.This revised version was published online in April 2005 with corrections to the article title.     

Signal transduction pathways regulating cyclooxygenase-2 in lipopolysaccharide-activated primary rat microglia

Inflammatory processes play a key role in the pathogenesis of a number of common neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Abnormal iron accumulation is frequently noted in these diseases and compelling evidence exists that iron is involved in inflammatory reactions. Histochemical stains for iron repeatedly demonstrate that oligodendrocytes, under normal conditions, stain more prominently than any other cell type in the brain. Therefore, we examined the hypothesis that cytokine toxicity to oligodendrocytes is iron mediated. Oligodendrocytes in culture were exposed to interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha). Toxicity was observed in a dose-dependent manner for IFN-gamma and TNF-alpha. IL-1beta was not toxic in the concentrations used in this study. The toxic concentration of IFN-gamma, and TNF-alpha was lower if the cells were iron loaded, but iron loading had no effect on the toxicity of IL-1beta. These data provide insight into the controversy regarding the toxicity of cytokines to oligodendrocytes by revealing that iron status of these cells will significantly impact the outcome of cytokine treatment. The exposure of oligodendrocytes to cytokines plus iron decreased mitochondrial membrane potential but activation of caspase 3 is limited. The antioxidant, TPPB, which targets mitochondria, protected the oligodendrocytes from the iron-mediated cytotoxicity, providing further support that mitochondrial dysfunction may underlie the iron-mediated cytokine toxicity. Therapeutic strategies involving anti-inflammatory agents have met with limited success in the treatment of demyelinating disorders. A better understanding of these agents and the contribution of cellular iron status to cytokine toxicity may help develop a more consistent intervention strategy.     

Peripheral neuropathy in metachromatic leucodystrophy. A study of 40 cases from south India

BACKGROUND: There is a paucity of literature from India on metachromatic leucodystrophy (MLD), a rare metabolic disorder of childhood resulting from aryl sulfatase A (ASA) deficiency.Patients/ METHODS: Case records of histopathologically verified cases of MLD, evaluated over a period of 12 years at the National Institute of Mental Health and Neurosciences, Bangalore, India, were reviewed. RESULTS: The late infantile group (36) manifested with regression of milestones (all), delayed mile stones (14), gait abnormalities (14), and seizures (11). Despite spasticity (29), there was hypo/areflexia in 25 patients. Optic atrophy (six) was rare. Consanguinity was noted in 25 children and four had a history of similar illness in siblings. Behavioural problems dominated in the juvenile group (four), but associated cognitive decline and hyporeflexia provided a clue to the diagnosis. Low serum ASA (seven of 20), raised cerebrospinal fluid protein (five of 12), and urinary metachromatic granules (two of 32) were infrequent. Electrophysiological evidence of severe demyelinating and length dependent sensory motor neuropathy was observed in all, even in the presence of hyper-reflexia. In addition to metachromatic dysmyelinating neuropathy in all patients, sural nerve biopsy in 20 patients revealed orthochromatic deposits within perivascular macrophages, particularly among those patients with normal ASA values (11 of 14), suggesting the accumulation of other glycosphingolipids. CONCLUSIONS: This study produced some noteworthy observations: the high degree of consanguinity associated with MLD in India, the existence of MLD with normal serum concentrations of ASA, the deposition of orthochromatic lipids, and electrophysiological evidence of a partial conduction block.     

Interventional Radiology Strategies in the Treatment of Pseudomyxoma Peritonei

Purpose To describe percutaneous maneuvers to treat the unusual entity symptomatic pseudomyxoma peritonei (PMP).Methods Four patients with PMP were treated by interventional radiology techniques that included large catheters (20–30 Fr) alone (n = 3), multiple catheters (n = 4), and dextran sulfate as a catalytic agent through smaller catheters (n = 1). The causes of the PMP were tumors in the ovary (2 patients), appendix (1 patient), and colon (1 patient). Each patient previously had undergone at least two operations to remove the PMP, and all patients had symptomatic recurrence. An in vitro analysis of catalytic agents also was performed.Results All four patients improved symptomatically. Follow-up CT scans demonstrated marked reduction of PMP material in all cases. One patient underwent another interventional radiology session 5 months after the first; the other three patients had no recurrence of symptoms. One patient had reversible hypotension 2 hr after the procedure. The amount of material removed varied from 3 to 6 L.Conclusion These interventional radiology techniques were effective and safe for PMP and suggest options for this difficult medical and surgical problem.