Microperimetry and swept-source optical coherence tomography in the assessment of the preferred retinal locus in a child with macular retinoblastoma in the remaining eye.

Assessing the visual capabilities that remain to children affected with bilateral retinoblastoma has relied on psychophysical tests based on recognition visual acuity. We report a case in which fundus-driven perimetry and swept-source optical coherence tomography was performed in a patient with a macular tumor in the remaining eye as a novel way of further assessing fixation after oncological disease and treatment.

Focal laser treatment in addition to chemotherapy for retinoblastoma.

BACKGROUND: Retinoblastoma is the most common primary intraocular malignancy of childhood. Systemic chemotherapy is a common treatment for intraocular retinoblastoma, and laser treatment is used as adjuvant therapy during or immediately after chemotherapy courses in selected cases. OBJECTIVES: To compare the effectiveness and safety of adding focal laser therapy to systemically-delivered chemotherapy in treating intraocular retinoblastoma. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 9), MEDLINE Ovid (1946 to 20 October 2016), Embase Ovid (1980 to 20 October 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 20 October 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 20 October 2016, ClinicalTrials.gov (www.clinicaltrials.gov); searched 20 October 2016, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 20 October 2016. We did not use any date or language restrictions in the electronic searches for trials. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of systemic chemotherapy with versus without adjuvant laser therapy for postequatorial retinoblastoma. DATA COLLECTION AND ANALYSIS: We planned to use standard methodological procedures expected by Cochrane. We planned to meta-analyse the primary outcome, that is the proportion of eyes with recurrence of tumours within three years from treatment MAIN RESULTS: No studies met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: No evidence from randomised controlled trials was found to support or refute laser therapy in addition to systemic chemotherapy for postequatorial retinoblastoma.

Primary intravenous chemotherapy for group D retinoblastoma: a 13-year retrospective analysis.

BACKGROUND: Eye salvage rate for group D retinoblastoma using intravenous chemotherapy (IVC) as a primary modality is <50%. To report on 13 years' experience with the use of primary IVC for group D retinoblastoma. METHODS: A retrospective analysis of 64 group D eyes (52 patients) treated with primary IVC, from 2002 to 2014. RESULTS: The median age at presentation was 11.0 months (mean: 18.6, range: 0.6-144.0), 35 (67%) patients had bilateral disease, 38 (73%) germline disease and 8 (15%) cases were familial. In addition to IVC, patients received a median number of three treatments (mean: 6, range: 0-24), including thermotherapy/cryotherapy, plaque radiotherapy, intra-ophthalmic artery chemotherapy (IAC) and/or intravitreous chemotherapy. External beam radiotherapy (EBRT) was used in five eyes, all of which were eventually enucleated. In a median follow-up time of 55 months (mean: 64, range: 14-156), 63% of eyes were salvaged. By the Kaplan-Meier survival analysis, globe salvage rate was 83%, 70%, 59% and 45% at 1, 3, 5 and 10 years, respectively. There were no cases of metastatic spread from intraocular retinoblastoma and no deaths. IVC-related adverse events included febrile neutropenia in 21 (40%) patients and anaphylactic reaction to carboplatin in 2 (4%), all conservatively resolved. Of the patients receiving IAC, third and sixth nerve palsies were documented in two (10%) and one (5%) eyes, respectively. CONCLUSIONS: Primary IVC for group D eyes, with adjuvant treatments as required, was found to be a safe and efficient approach, achieving 63% eye salvage rate, no metastatic spread from intraocular retinoblastoma and no deaths. IAC has now replaced EBRT as a successful salvage treatment.

Glatiramer acetate for treatment of relapsing-remitting multiple sclerosis.

Glatiramer acetate (GA; Copaxone(®), Teva Pharmaceuticals Inc.), approved in the USA in 1996 and EU in 2001 as first-line treatment for relapsing-remitting multiple sclerosis, is now available in 51 countries and recently gained approval for delaying conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes. Over the last 10-15 years, abundant research has better characterized the immunomodulatory activities and clinical efficacy and safety of GA. Relapsing-remitting multiple sclerosis patients taking GA continuously for up to 22 years as disease-modifying monotherapy experience minimal disability progression, and more than 1 million patient-years of experience attest to GA safety and tolerability. GA does not generate neutralizing antibodies, has no known drug interactions - making it a good candidate for combination therapy - and new formulations under evaluation may reduce injection frequency and injection-site reactions. The place of GA in the growing multiple sclerosis armamentarium will depend on its demonstrated benefit-risk ratio relative to that of newer investigational drugs.

Burden of a multiple sclerosis relapse: the patient's perspective.

BACKGROUND: Relapses are a common feature of relapsing-remitting multiple sclerosis (RRMS) and increasing severity has been shown to be associated with higher healthcare costs, and to result in transient increases in disability. Increasing disability likely impacts work and leisure productivity, and lowers quality of life. OBJECTIVE: The objective of this study was to characterize from the patient's perspective the impact of a multiple sclerosis (MS) relapse in terms of the economic cost, work and leisure productivity, functional ability, and health-related quality of life (HR-QOL), for a sample of patients with RRMS in the US treated with immunomodulatory agents. METHODS: A cross-sectional, web-based, self-report survey was conducted among members of MSWatch.com, a patient support website now known as Copaxone.com. Qualified respondents in the US had been diagnosed with RRMS and were using an immunomodulatory agent. The survey captured costs of RRMS with questions about healthcare resource utilization, use of community services, and purchased alterations and assistive items related to MS. The Work and Leisure Impairment instrument and the EQ-5D were used to measure productivity losses and HR-QOL (health utility), respectively. The Goodin MS neurological impairment questionnaire was used to measure functional disability; questions were added about relapses in the past year. RESULTS: Of 711 qualified respondents, 67% reported having at least one relapse during the last year, with a mean of 2.2 ± 2.3 relapses/year. Respondents who experienced at least one relapse had significantly higher mean annual direct and indirect costs compared with those who did not experience a relapse ($US38 458 vs $US28 669; p = 0.0004) [year 2009 values]. Direct health-related costs accounted for the majority of the increased cost ($US5201; 53%) and were mainly due to increases in hospitalizations, medications, and ambulatory care. Indirect costs, including informal care and productivity loss, accounted for the additional 47% of increased cost ($US4588). Accounting for the mean number of relapses associated with these increased costs, the total economic cost of one relapse episode could be estimated at about $US4449, exclusive of intangible costs. The mean self-reported Expanded Disability Status Scale (EDSS) score, derived from the Goodin MS questionnaire, was significantly higher with relapse than with a clinically stable state (EDSS 4.3 vs 3.7; p < 0.0001), while the mean health utility score was significantly lower with relapse compared with a clinically stable state (0.66 vs 0.75; p = 0.0001). The value of these intangible costs of relapse can be estimated at $US5400. The overall burden (direct, indirect, and intangible costs) of one relapse in patients treated with immunomodulatory agents is therefore estimated conservatively at $US9849. CONCLUSIONS: This study shows that from a patient's perspective an MS relapse is associated with a significant increase in the economic costs as well as a decline in HR-QOL and functional ability.

Glatiramer acetate and the glatiramoid class of immunomodulator drugs in multiple sclerosis: an update.

IMPORTANCE OF THE FIELD: MS is a chronic progressive inflammatory and neurodegenerative disease associated with autoimmune dysregulation. Glatiramer acetate (GA), a complex polypeptides mixture and first member of the glatiramoid class, is a first-line therapy for relapsing MS. New glatiramoids are under development. AREAS COVERED IN THIS REVIEW: Studies from a PubMed search with terms 'glatiramer' and 'glatiramoid' were evaluated, focussing on studies conducted between 2007 and 2010. WHAT THE READER WILL GAIN: We review newly discovered GA effects on innate and acquired immunity and results of recent clinical studies. GA delays conversion from a clinically isolated syndrome to definite MS and has clinical benefits comparable to those of IFN-beta drugs, but is more cost-effective and improves quality of life. Preclinical studies of protiramer, a higher molecular mass glatiramoid, showed unexpected toxicity in animals, resulting in discontinuation of drug development. TAKE HOME MESSAGES: GA is a cost-effective, safe and efficacious MS treatment with pleiotropic immunomodulation activity, is best prescribed early and may safely enhance outcomes when used with other immunomodulators. Protiramer experience indicates the potential for unexpected toxicity associated with new glatiramoids. The safety, efficacy and immunogenicity of new glatiramoids must be evaluated thoroughly.

Risks vs benefits of glatiramer acetate: a changing perspective as new therapies emerge for multiple sclerosis.

An understanding of the risks, benefits, and relative value of glatiramer acetate (GA) in multiple sclerosis (MS) has been evolving based on recently completed head-to-head studies: REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease); BEYOND (Betaseron Efficacy Yielding Outcomes of a New Dose); and BECOME (BEtaseron vs COpaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3-Tesla MRI Endpoints). Outcomes in the primary endpoints of these trials showed no significant differences between GA and high-dose beta-interferons (IFNbetas). Results of the PreCISe (Early GA Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis [CDMS] in Subjects Presenting With a Clinically Isolated Syndrome [CIS]) trial led to the US Food and Drug Administration approval of GA in patients with a CIS. Furthermore, the ongoing follow-up study to the original pivotal GA trial, now extending beyond 15 years, continues to support the safety of GA. Currently, GA and IFNbetas are no longer the only immunomodulators available for MS. Introduction of the monoclonal antibody, natalizumab (Tysabri((R)); Biogen Idec, Inc., Cambridge, MA, USA) provides an alternative immunomodulator for MS and has changed the therapeutic landscape dramatically. However, the rare but serious cases of progressive multifocal leukoencephalopathy that have occurred with natalizumab have raised concerns among clinicians and patients about using this agent and some of the emerging agents. The potential risks and benefits of the emerging therapies (cladribine, alemtuzumab, rituximab, fingolimod, laquinimod, teriflunomide, and dimethyl fumarate) based on phase II/III trials, as well as their use for indications other than MS, will be presented. This review provides available data on GA, natalizumab, and the emerging agents to support new developments in our understanding of GA and how its long-standing role as a first-line therapy in MS will evolve within the increasingly complex MS therapeutic landscape.

Benefits of glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis.

Relapsing-remitting multiple sclerosis is a chronic, progressive disorder marked by repeated exacerbations that lead to increases in neurological disability. Glatiramer acetate and the IFN-betas are recommended as first-line agents for relapsing-remitting multiple sclerosis owing to their potential to reduce frequency and severity of relapses, decrease development of new brain lesions and delay permanent disability. After three decades of study, the preponderance of the evidence suggests that the efficacy of glatiramer acetate is similar to the IFN-betas and new data collected in more naturalistic settings suggest that it may provide improved quality of life, increased productivity and cost-effectiveness. This article will review this evidence including data from very recent head-to-head clinical trials and pharmacoeconomic analyses of cost-effectiveness.

Glatiramer acetate and interferon beta-1b: a study of outcomes among patients with multiple sclerosis.

INTRODUCTION: To study the medical cost and probability of relapse in patients with multiple sclerosis (MS) treated with either glatiramer acetate (GA) or interferon beta-1b (IFN beta.1b). METHODS: Data were obtained from the i3 InVision Data Mart Database from July 2001 to June 2006. We established an "intent-totreat" (ITT) cohort (n=842) of patients diagnosed with MS who began treatment with either GA or IFN beta-1b and had continuous insurance coverage from 6 months before to 2 years after the date when they began taking the medication. We also created a "continuous use" (CU) cohort (n=418) of individuals who, in addition to the criteria listed above, used either GA or IFN beta-1b within 28 days of the end of the 2-year postperiod. Using multivariate regressions, we examined both the 2-year total average direct medical costs and the likelihood of relapse within this period associated with the use of each of these MS medications. We defined relapse as being either hospitalization with a principal diagnosis of MS or having an outpatient visit with a diagnosis of MS and then prescribed steroids within a 7-day period. All regression analyses controlled for a wide range of factors that may potentially affect outcomes. RESULTS: In the ITT cohort, patients who started treatment with GA had a significantly lower 2-year estimated risk of relapse (13.54% vs. 5.31%; P=0.0006). In the CU cohort, patients who used GA also had a significantly lower 2-year estimated risk of relapse (10.91% vs. 2.09%; P=0.0018), as well as significantly lower average total medical costs ($53,157 vs. $48,130; P=0.0345). CONCLUSIONS: Results from this study indicate that users of GA have a significantly lower probability of 2-year relapse than users of IFN beta-1b. In addition, among continuous users, the 2-year total average direct medical costs are significantly lower for users of GA than for users of IFN beta-1b.

Glatiramer acetate versus interferon beta-1a for subcutaneous administration: comparison of outcomes among multiple sclerosis patients.

INTRODUCTION: We compared the outcomes of multiple sclerosis (MS) patients treated with either glatiramer acetate (GA) (Copaxone, Teva Pharmaceutical Industries, Israel) or interferon beta-1a for subcutaneous administration (IFN beta-1a-SC) (Rebif, Merck Serono, Switzerland). METHODS: Data were obtained from i3's Lab Rx Database from July 2001 to June 2006. We established an 'intent-to-treat' (ITT) cohort (n=845) of patients diagnosed with MS who began therapy on either GA (n=542) or IFN beta-1a-SC (n=303) and had continuous insurance coverage from 6 months before to 24 months after the date they began taking the medication. We also created a 'continuous use' (CU) cohort (n=410) of individuals who, in addition to the criteria listed above, used either GA or IFN beta-1a-SC within 28 days of the end of the 2-year-post period. Using multivariate regressions, we examined both the 2-year total direct medical costs and the likelihood of relapse associated with the use of these two MS medications. We defined relapse as either being hospitalised with a diagnosis of MS, or being diagnosed with MS during an outpatient visit and then prescribed steroids within a 7-day period. All regressions controlled a wide range of factors that have potentially affected outcomes. RESULTS: In the ITT cohort, patients who started therapy on GA had a significantly lower 2-year risk of relapse (5.92% versus 10.89%; P=0.0305), as well as significantly lower 2-year total medical costs (US$41,786 versus US$49,030; P=0.0002). In the CU cohort, patients who used GA also had a significantly lower 2-year risk of relapse (1.94% versus 9.09%; P=0.0049) and significantly lower total medical costs (US$45,213 versus US$57,311; P<0.0001). CONCLUSIONS: Results indicate that, compared with the use of IFN beta-1a-SC, use of GA is associated with significantly lower probability of relapse as well as significantly lower 2-year total direct medical costs. In addition, these results are more pronounced among patients defined as continuous users.

Natalizumab (Tysabri) treatment for relapsing multiple sclerosis.

BACKGROUND: Natalizumab (Tysabri), a humanized monoclonal antibody which binds to the alpha4beta1 integrins of leukocytes, blocks attachment to cerebral endothelial cells, thus reducing inflammation at the blood-brain barrier. Two pivotal randomized trials, 1 comparing active treatment to placebo and 1 comparing active treatment to placebo in relapsing multiple sclerosis (MS) patients receiving intramuscular interferon beta1alpha (Avonex), demonstrated significant efficacy for relapse control, decrease in sustained disability, and reduced numbers of new lesions on MRI. REVIEW SUMMARY: Because of safety issues raised by the appearance of 2 cases of progressive multifocal leukoencephalopathy in MS patients exposed to natalizumab for relapsing MS treatment has been restricted. This review briefly outlines the inflammatory nature of MS plagues, the mechanism of action of natalizumab and the pathogenesis of progressive multifocal leukoencephalopathy. The mandatory guidelines for natalizumab use in the treatment of MS with natalizumab are explained. Special concerns facing the therapist electing to prescribe natalizumab are mentioned. CONCLUSION: Natalizumab recently joined glatiramer acetate and beta interferon as an approved therapy for controlling relapsing MS. Unresolved safety issues currently restrict its use to monotherapy in patients who have had inadequate response to the other immunomodulating agents.

Control of multiple sclerosis relapses with immunomodulating agents.

Relapses in multiple sclerosis (MS) have wide-ranging consequences for patients and should be actively controlled with an appropriate immunomodulating agent provided soon after the diagnosis of MS. Several agents with varying mechanisms of action are approved for use in treating MS. Here we take a brief look at several short- and long-term comparative trials, examining the established strengths and weaknesses of the available immunomodulators. By reviewing the existing comparisons, clinicians will better understand the factors determining when to initiate therapy with an immunomodulator and how to determine which of these treatments may best suit their patients' needs.

Cognitive function in relapsing multiple sclerosis: minimal changes in a 10-year clinical trial.

BACKGROUND: Although cognitive impairment is common in patients with multiple sclerosis (MS), its value as a clinical trial endpoint remains uncertain. For example, in the randomized, blinded, pivotal trial of glatiramer acetate (GA) in patients with relapsing MS, improvements occurred in neuropsychological test scores during 2 years of treatment regardless of whether patients received GA or placebo, likely due to practice effects. OBJECTIVES: To assess long-term changes in neuropsychological status following 10 years of prospective evaluation in a typical immunotherapy trial cohort. METHODS: Participants in the ongoing open-label GA extension study repeated the Brief Repeatable Battery of Neuropsychological Tests an average of 10.6+/-0.4 years after their initial baseline evaluation. RESULTS: Mean scores on tests of memory and semantic retrieval were not significantly changed over 10 years of follow-up, but tests of attention showed declines for the group as a whole. Using a threshold of a 0.5 SD decline to define significant worsening, individual tests showed declines in 27-49% of participants and a composite score showed worsening in 19%. Controlling for age, gender, and education level, cognitive tests tended to worsen more in participants with better baseline cognitive test scores and higher EDSS scores. Changes in cognitive test scores during the first 2 years of observation were predictive of 10-year changes. CONCLUSIONS: Most patients with relapsing MS had stable cognitive performance during 10 years of prospective evaluation, some of which may be related to a therapeutic effect of GA. Because cognitive changes occur slowly on average, they may not be responsive enough to serve as useful endpoints in studies of course-modifying therapies in relapsing MS.

Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: meta-analysis of three double-blind, randomized, placebo-controlled clinical trials.

Three randomized, double-blind, placebo-controlled trials have shown that glatiramer acetate (GA) is effective in reducing relapse rate in patients with relapsing-remitting (RR) multiple sclerosis (MS). Using raw data pooled from 540 patients, we performed a meta-analysis of these three trials, to investigate whether the extent of GA efficacy varies according to disease-related variables at study entry. Three regression models were developed to assess the efficacy of GA on the annualized relapse rate (primary outcome measure), on the total number of on-trial relapses and on the time to first relapse. We also explored the efficacy of GA on accumulated disability and the potential role of baseline clinical variables as predictors of relapse-rate variables and treatment efficacy. The mean adjusted annualized relapse rate on study was 1.14 in the pooled placebo-treated subjects and 0.82 in the pooled GA group (P = 0.004), indicating an average reduction in annualized relapse rate of 28%. About a one third reduction of the total number of on-trial relapses was also observed in patients receiving GA (P < 0.0001), who had a median time to the first relapse of 322 days versus a median time to the first relapse of 219 days seen in those receiving placebo (P = 0.01). A beneficial effect on accumulated disability was also found (risk ratio of 0.6; 95%; CI = 0.4-0.9; P = 0.02). The drug assignment (P = 0.004), baseline EDSS score (P = 0.02) and number of relapses during the two years prior to study entry (P = 0.002) were significant predictors of on-trial annualized relapse rate. No other demographic or clinical variable at baseline significantly influenced the treatment effect. This meta-analysis reaffirms the effectiveness of GA in reducing relapse rate and disability accumulation in RRMS, at a magnitude comparable to that of other available immunomodulating treatments. It also suggests that GA efficacy is not significantly influenced by the patients' clinical characteristics at the time of treatment initiation.

Glatiramer acetate-reactive peripheral blood mononuclear cells respond to multiple myelin antigens with a Th2-biased phenotype.

One favored mechanism of action of glatiramer acetate (GA) in multiple sclerosis (MS) involves the induction of GA-reactive Th2 cells that are believed to enter the central nervous system and mediate bystander suppression in response to cross-reactive myelin antigens. To test this hypothesis, we examined the proliferative response and cytokine release from peripheral blood mononuclear cells (PBMCs) of 12 MS patients treated with GA, in response to 16 myelin peptides that were previously described as immunodominant or encephalitogenic and a tetanus peptide as a control antigen. Interferon-gamma (IFN-gamma) and IL-5 (markers of Th1 and Th2 responses, respectively) were assayed by enzyme-linked immunosorbent assay (ELISA). GA-stimulated PBMCs from 9 of 12 patients (75%) proliferated to one or more myelin peptides. Among the 16 peptides tested, GA-stimulated PBMCs from the majority of the patients proliferated in response to MOG(21-44). PBMCs from two thirds of the patients produced IL-5 in response to myelin peptides, while half of them produced IFN-gamma. Th1/Th0/Th2 cytokine phenotypes demonstrated that responses from 10 of 12 patients were either Th0- or Th2-biased. Responses from two patients were Th1-biased. Conversely, some myelin-specific T-cell lines (TCLs) responded to GA by proliferation (3 of 21 TCLs), IL-5 release (11 of 21 TCLs), and IFN-gamma release (3 of 21 TCLs). These results indicate that GA-reactive TCLs can respond to a spectrum of myelin peptides in a Th2-biased fashion, which is consistent with the concept of bystander suppression. Furthermore, some myelin-specific TCLs are able to recognize GA, with a tendency to produce more IL-5 than IFN-gamma, which would suggest a systemic modulatory effect of the drug.