Silvana Guerriero

Idebenone Treatment In Leber's Hereditary Optic Neuropathy

Sir, We have read with great interest the results presented by Klopstock et al. (2011) concerning the RHODOS study on a clinical trial with idebenone in Lebers hereditary optic neuropathy (LHON) and we would like to share our own experience of idebenone therapy in LHON. Idebenone has been an approved drug (Mnesis®, Takeda Italia Farmaceutici) in Italy since the early 1990s and, after the initial report by Mashima et al . (1992) on its possible efficacy in LHON, we offered this therapeutic option to all of our new consecutive patients with LHON, almost all of whom accepted treatment. Idebenone was given after informed consent following the regulation for ‘off-label’ drug administration and was provided for free by the National Health Service, under the legislation for certified rare disorders. Patients were initially treated with 270 mg/day (Cortelli et al ., 1997; Carelli et al ., 1998 a , b ), but following the reports on idebenone treatment in Friedreich ataxia, the dosages were increased to 540–675 mg/day (Rustin et al ., 1999; Kearney et al ., 2009). To evaluate retrospectively the efficacy of idebenone therapy, we reviewed all of our patients with LHON, idebenone treated and untreated, after approval of the institutional Internal Review Board. Inclusion criteria for treated patients were the initiation of therapy within 1 year after visual loss in the second eye, and for all patients (treated and untreated) age at onset of at least 10 years and a follow-up of at least 5 years. We included only patients treated within 1 year after onset because this is the time frame to reach the nadir of the visual loss and the probability of spontaneous recovery of vision is highest in the following 5 years (Nikoskelainen et al ., 1983; Barboni et al ., 2005, 2010; …

Acanthamoeba T4 and T15 genotypes associated with keratitis infections in Italy

Thus far there is little data available concerning Acanthamoeba associated amoebic keratitis (AK) from Italy. In order to understand the incidence of Acanthamoeba in patients with ocular infections and to characterize the isolates at the molecular level, ocular specimens and contact lenses or lens case solutions from 140 patients were analysed by culture and by an 18S rRNA (Rns) gene-based PCR method. Nineteen (13.6%) patients showed Acanthamoeba culture positive samples. Eleven out of the 14 genetically characterized isolates were assigned to the T4 genotype. Three isolates, two of them from patients with keratitis responding to specific anti-Acanthamoeba therapy, were identified as belonging to the T15 genotype. This finding represents the first association between the T15 genotype and human amoebic keratitis. PCR amplification of the 18S ribosomal DNA proved to be a sensitive method, potentially able to detect Acanthamoeba without the need of long culture incubation, and thus considerably useful for clinical applications.

LDL-Apheresis Accelerates the Recovery of Nonarteritic Acute Anterior Ischemic Optic Neuropathy

Abstract:  Nonarteritic acute anterior ischemic optic neuropathy (NAION) is a disabling disease which impairs visual function. It is presumed to result from disturbances of microcirculation in the anterior portion of the optic nerve head due to hemodynamic factors derived from excessive blood viscosity, or restriction of the vasal lumen in hypertensive, hypercholesterolemic, diabetic patients. We aimed to determine whether acute reduction of plasma fibrinogen and serum low‐density lipoprotein (LDL) cholesterol is effective for treatment of NAION. We recruited 11 patients (7 females, 4 males) with a mean age of 57.2 ± 19.6 years. All except one of them presented risk factors for atherosclerosis. The mean values of LDL‐cholesterol and fibrinogen before treatment were 144 ± 32 mg/dL and 341 ± 80 mg/dL, respectively. All were treated with standard therapy (prednisone, salicylate, pentoxiphyllin) and underwent three sessions of LDL‐apheresis (HELP system—B Braun) that can reduce plasma LDL‐cholesterol and fibrinogen by more than 50% in a very short time. In all patients we observed a drastic reduction of LDL cholesterol and fibrinogen and a clear improvement in the visual functional data. In fact, mean values of corrected vision increased from 3.7/10 ± 3/10 to 7.9/10 ± 2.2/10 (P = 0.002) after the third session, while the scotomatous portion of the visual field regressed after the first session, and in 5 patients further regressed after the third session. This improvement had remained stable after 3 months. Thanks to its effect of antagonizing hemorheologic disorders of the ocular microcirculation, fibrinogen/LDL‐apheresis seems to be an efficacious treatment of NAION.

Mitochondrial DNA copy number differentiates the Leber's hereditary optic neuropathy affected individuals from the unaffected mutation carriers.

Sir, We read with great interest the article by Giordano and colleagues (2014) reporting that cellular activation of compensatory mitochondrial biogenesis, as measured by mitochondrial DNA (mtDNA) copy number, is a major determinant of incomplete penetrance in Leber’s hereditary optic neuropathy (LHON), a mitochondrial disease characterized by bilateral subacute loss of central vision due to optic atrophy (Carelli et al. , 2004; Yu-Wai-Man et al. , 2011). In most known mitochondrial diseases due to mtDNA mutations the penetrance or the severity of the condition depends on the level of heteroplasmy of the mutation (Schon et al. , 2012). However, LHON is due to mtDNA mutations that exemplify a different paradigm. The three primary mutations, namely the m.3460G>A/ND1, m.11778G>A/ND4 and m.14484T>C/ND6, are generally found as homoplasmic. One of the three primary mtDNA mutations is necessary but not sufficient to cause optic neuropathy and disease penetrance can vary in different families harbouring the same mutation, and even within different branches of the same family (Howell and Mackey, 1998). The study by Giordano and colleagues (2014) highlights how in large LHON cohorts of individuals of European descent, higher mtDNA content in blood cells discriminates the unaffected mutation carriers from LHON affected and control subjects. A significantly higher mtDNA copy number was observed in asymptomatic maternal relatives, hereafter called ‘Carriers’, moving progressively towards lower values from carriers to affected subjects to controls. Previously, different data were reported on this …

High mitochondrial DNA copy number is a protective factor from vision loss in heteroplasmic leber’s hereditary optic neuropathy (LHON)

Purpose Lebers hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. It is characterized by as yet undisclosed genetic and environmental factors affecting the incomplete penetrance. Methods We identified 27 LHON subjects who possess heteroplasmic primary LHON mutations. Mitochondrial DNA (mtDNA) copy number was evaluated. Results The presence of centrocecal scotoma, an edematous, hyperemic optic nerve head, and vascular tortuosity, as well as telangiectasia was recognized in affected subjects. We found higher cellular mtDNA content in peripheral blood cells of unaffected heteroplasmic mutation carriers with respect to the affected. Conclusions The increase of cellular mtDNA content prevents complete loss of vision despite the presence of a heteroplasmic state of LHON primary mutation, suggesting that it is a key factor responsible for penetrance of LHON.

Deep sequencing unearths Nuclear mitochondrial Sequences under Leber's hereditary optic neuropathy-associated false heteroplasmic mitochondrial DNA variants

Lebers hereditary optic neuropathy (LHON) is associated with mitochondrial DNA (mtDNA) ND mutations that are mostly homoplasmic. However, these mutations are not sufficient to explain the peculiar features of penetrance and the tissue-specific expression of the disease and are believed to be causative in association with unknown environmental or other genetic factors. Discerning between clear-cut pathogenetic variants, such as those that appear to be heteroplasmic, and less penetrant variants, such as the homoplasmic, remains a challenging issue that we have addressed here using next-generation sequencing approach. We set up a protocol to quantify MTND5 heteroplasmy levels in a family in which the proband manifests a LHON phenotype. Furthermore, to study this mtDNA haplotype, we applied the cybridization protocol. The results demonstrate that the mutations are mostly homoplasmic, whereas the suspected heteroplasmic feature of the observed mutations is due to the co-amplification of Nuclear mitochondrial Sequences.

Orbital pseudotumor in a child: diagnostic implications and treatment strategies

Orbital pseudotumor is a benign, idiopathic, non-infectious and non-neoplastic clinical syndrome characterized by the presence of an inflammatory mass at orbital level with no identifiable cause. The disease is rarely observed in the pediatric population. This article describes a relapsing bilateral orbital pseudotumor in a young girl. The diagnostic implications and treatment strategies are discussed.

Retinal circulation after carotid artery revascularization.

Doubts still exist concerning the mechanisms involved in ocular ischemic syndrome (OIS) and its dependence on carotid disease. We report findings from 14 surgical patients undergoing carotid artery reconstruction for symptomatic cerebrovascular disease. All of them had fluorescein angiography (FA) of the eye ipsilateral to the carotid operation before surgery and 3 months after to provide information regarding retinal circulation time. Before the surgical procedure, the mean circulation time was 29.4 ± 9.4 seconds (CI 95%: 24.5-34.3). After 3 months, a significant (P < .001) decrease in the circulation time was observed: 18.9 ± 8.4 seconds (CI 95%: 14.5-23.4). The present series demonstrates that carotid revascularization surgery improved retinal flow in approximately 80% of the patients.

Retinal Abnormalities in Newly Diagnosed Adult Acute Myeloid Leukemia

Retinal abnormalities (RA) are very frequently observed in adult patients with acute myeloid leukemia (AML), but the clinical significance of these findings has not been fully investigated. We examined the fundus oculi in a cohort of 122 adult patients with AML at presentation and analyzed some clinical and biological features to assess whether there was any association with RA. For this purpose, we subdivided the patients into two groups according to the presence or absence of RA (groups 1 and 2, respectively). We considered current laboratory parameters such as white blood cell (WBC) count, hemoglobin (Hb), platelets and serum lactate dehydrogenase (LDH). Moreover, we subdivided the patients into two groups according to age <60 (group A) or ≧60 years (group B) to evaluate a possible association between RA and response to treatment and/or overall survival (OS). In our series, a higher median age and a lower Hb value were associated with group 1 (p = 0.001 and p = 0.04, respectively); the median LDH value was 812 U/l (range 224–5,551) and 607 (range 181–5,244) for groups 1 and 2, respectively (p = 0.02). There was no association between RA and karyotypic alterations. In terms of outcome, in group A (<60 years), 80% patients who achieved complete remission (CR) were in group 2 vs. 13% nonresponders (NR) (p < 0.0001). Median OS of group 2 patients was 49.7 months compared with 7.2 months for those in group 1 (p = 0.002). In group B, 58% patients who achieved CR were in group 1 vs. 15% NR (p < 0.006). Median OS of patients in group 2 was 14.6 months compared with 2.9 months in group 1 (p = 0.02). Our data show that RA are significantly associated with some biological features and with shorter OS in AML patients and this parameter seems to be an effective clinical sign of poor prognosis in terms of CR.

Ten-Year Retention Rate of Infliximab in Patients with Behçet’s Disease-Related Uveitis

ABSTRACT Purpose: To evaluate the 10-year drug retention rate of infliximab (IFX) in Behçet’s disease (BD)-related uveitis, the effect of a concomitant use of disease modifying anti-rheumatic drugs (DMARDs) on drug survival and differences according to the lines of biologic treatment. Methods: Cumulative survival rates were studied using the Kaplan-Meier plot, while the Log-rank (Mantel-Cox) test was used to compare survival curves. Results: Forty patients (70 eyes) were eligible for analysis. The drug retention rates at 12-, 24-, 60- and 120-month follow-up were 89.03%, 86.16%, 75.66% and 47.11% respectively. No differences were identified according to the use of concomitant DMARDs (p = 0.20), while a statistically significant difference was observed in relation to the different lines of IFX treatment (p = 0.014). Visual acuity improved from baseline to the last follow-up visit (p = 0.047) and a corticosteroid-sparing effect was observed (p < 0.0001). Conclusions: IFX retention rate in BD-uveitis is excellent and is not affected by concomitant DMARDs.