Jacqueline Bernard

Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial

BACKGROUND Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women. METHODS We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0.10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204. FINDINGS We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0.25 relapses per year (95% CI 0.17-0.37) in the estriol group versus 0.37 relapses per year (0.25-0.53) in the placebo group (adjusted rate ratio 0.63, 95% CI 0.37-1.05; p=0.077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0.0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0.0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy. INTERPRETATION Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial. FUNDING National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.

Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis

BACKGROUND Structural retinal imaging biomarkers are important for early recognition and monitoring of inflammation and neurodegeneration in multiple sclerosis. With the introduction of spectral domain optical coherence tomography (SD-OCT), supervised automated segmentation of individual retinal layers is possible. We aimed to investigate which retinal layers show atrophy associated with neurodegeneration in multiple sclerosis when measured with SD-OCT. METHODS In this systematic review and meta-analysis, we searched for studies in which SD-OCT was used to look at the retina in people with multiple sclerosis with or without optic neuritis in PubMed, Web of Science, and Google Scholar between Nov 22, 1991, and April 19, 2016. Data were taken from cross-sectional cohorts and from one timepoint from longitudinal studies (at least 3 months after onset in studies of optic neuritis). We classified data on eyes into healthy controls, multiple-sclerosis-associated optic neuritis (MSON), and multiple sclerosis without optic neuritis (MSNON). We assessed thickness of the retinal layers and we rated individual layer segmentation performance by random effects meta-analysis for MSON eyes versus control eyes, MSNON eyes versus control eyes, and MSNON eyes versus MSON eyes. We excluded relevant sources of bias by funnel plots. FINDINGS Of 25 497 records identified, 110 articles were eligible and 40 reported data (in total 5776 eyes from patients with multiple sclerosis [1667 MSON eyes and 4109 MSNON eyes] and 1697 eyes from healthy controls) that met published OCT quality control criteria and were suitable for meta-analysis. Compared with control eyes, the peripapillary retinal nerve fibre layer (RNFL) showed thinning in MSON eyes (mean difference -20·10 μm, 95% CI -22·76 to -17·44; p<0·0001) and in MSNON eyes (-7·41 μm, -8·98 to -5·83; p<0·0001). The macula showed RNFL thinning of -6·18 μm (-8·07 to -4·28; p<0·0001) in MSON eyes and -2·15 μm (-3·15 to -1·15; p<0·0001) in MSNON eyes compared with control eyes. Atrophy of the macular ganglion cell layer and inner plexiform layer (GCIPL) was -16·42 μm (-19·23 to -13·60; p<0·0001) for MSON eyes and -6·31 μm (-7·75 to -4·87; p<0·0001) for MSNON eyes compared with control eyes. A small degree of inner nuclear layer (INL) thickening occurred in MSON eyes compared with control eyes (0·77 μm, 0·25 to 1·28; p=0·003). We found no statistical difference in the thickness of the combined outer nuclear layer and outer plexiform layer when we compared MSNON or MSON eyes with control eyes, but we found a small degree of thickening of the combined layer when we compared MSON eyes with MSNON eyes (1·21 μm, 0·24 to 2·19; p=0·01). INTERPRETATION The largest and most robust differences between the eyes of people with multiple sclerosis and control eyes were found in the peripapillary RNFL and macular GCIPL. Inflammatory disease activity might be captured by the INL. Because of the consistency, robustness, and large effect size, we recommend inclusion of the peripapillary RNFL and macular GCIPL for diagnosis, monitoring, and research. FUNDING None.

Retinal Nerve Fibre Layer and Macular Thinning in Spinocerebellar Ataxia and Cerebellar Multisystem Atrophy

The spinocerebellar ataxias, like all neurodegenerative diseases, lack objective disease- and stage-specific biomarkers. Based on reports of clinically evident optic disc atrophy or retinal disease in some ataxia patients, and the discovery that pre-symptomatic retinal thinning occurs in other neurologic diseases such as multiple sclerosis, we tested the hypothesis that subclinical neuronal or axonal loss in the retina could occur in the degenerative ataxias. Spectral domain optical coherence tomography was performed on 29 ataxia patients with genetically proven spinocerebellar ataxia (SCA) 1, 2, 3, or 6, or multisystem atrophy type C (MSA-C) and 27 age-matched normal subjects. Ataxia patients were assessed using the scale for assessment and rating of ataxia. Compared with normal control subjects, retinal nerve fibre layer (RNFL) thickness was reduced for patients with SCA2 and SCA3, and thickness in the macular region was reduced for all SCAs but SCA2.

Post subthalamic area deep brain stimulation for tremors: a mini-review

Deep brain stimulation (DBS) in the thalamic ventrointermediate nucleus (VIM) is the traditional target for the surgical treatment of pharmacologically refractory essential tremor or parkinsonian tremor. Studies in recent years on DBS in posterior subthalamic area (PSA), including the zona incerta and the prelemniscal radiation, have shown promising results in tremor suppression, particularly for those tremors difficult to be well controlled by VIM DBS, such as the proximal postural tremor, distal intention tremor and some cerebellar outflow tremor in various diseases including essential tremor and multiple sclerosis. The adverse effect profile of the PSA DBS is mild and transient, without lasting or striking dysarthria, disequilibrium or tolerance, in contrast to VIM DBS, particularly bilateral DBS. However, the studies on PSA DBS so far are still limited, with a handful of studies on bilateral PSA, and a short follow up duration compared to VIM. More studies are needed for direct comparison of these targets in the future. A review here would help to gain more insight into the benefits and limits of the PSA DBS compared to that in VIM in the clinical management of various tremors, particularly for those difficult to be well controlled by traditional VIM DBS.

Homonymous hemimacular thinning: A unique presentation of optic tract injury in neuromyelitis optica

A 42-year-old African American woman with a 5-year history of neuromyelitis optica was found to have an incongruous homonymous hemianopia. Optical coherence tomography (OCT) showed corresponding left homonymous hemimacular thinning. Magnetic resonance imaging of the brain demonstrated a demyelinating lesion in the left optic tract (OT) just anterior to the lateral geniculate nucleus and diffusion tensor magnetic resonance tractography confirmed axonal fiber loss in the left OT. This case illustrates the complementary and confirmatory roles of visual field testing, macular OCT, and neuroimaging in an OT lesion, which caused selective hemimacular thinning through retrograde degeneration.

Immunologic mechanisms of fingolimod and the role of immunosenescence in the risk of cryptococcal infection: A case report and review of literature

BACKGROUND Fingolimod is a disease-modifying agent used in the treatment of relapsing/remitting multiple sclerosis. In MS clinical studies, the overall rate of infections in fingolimod group was overall similar to placebo, except for slightly more common lower respiratory tract infections and to a lesser extent HSV. Recently, an increasing number of cryptococcal infections associated with a long-term use of this medication have been reported. METHODS We reviewed literature for cases of cryptococcal infection associated with the use of fingolimod and reported a case at our institution, as well as carefully evaluated the established immune mechanisms of the medication and discussed new insights into its short-term and long-term immunologic effects that may become important in the context of risk of infection. RESULTS Unique characteristics of cryptococcal pathogen, its immune escape mechanisms, its ability to establish a latent infection with a potential for later reactivation, fingolimods effects on many lines of immune system, both quantitatively and qualitatively, duration of therapy, and long-term effects of fingolimod, not previously described, in conjunction with effects of natural immunosenescence of the patient population, that appears to be most at risk, may be meaningful in further understanding the risk of infection with long-term use of fingolimod in people of older age.

Retinal nerve fiber layer and macular thinning in systemic lupus erythematosus: an optical coherence tomography study comparing SLE and neuropsychiatric SLE.

Objective Due to the lack of reliable biomarkers in diagnosing and monitoring neuropsychiatric systemic lupus erythematosus (NPSLE), the aim of this study was to examine the utility of measurements obtained through spectral domain optical coherence tomography (SD-OCT) as a biomarker for NP involvement in SLE. Methods Retinal nerve fiber layer (RNFL) and macula scans were performed using SD-OCT on 15 NPSLE patients, 16 SLE patients without NP symptoms (non-NP SLE), and 16 healthy controls. Macular volume and thickness of the central macula and peripapillary RNFL were compared between the groups and to scores on two validated cognitive tests. Results NPSLE patients did not differ significantly from non-NP SLE patients in retinal thickness or macular volume. However, SLE patients as a whole showed significant RNFL and macular thinning compared to controls. Scores on the Trail Making Test B, a test of complex attention, showed significant correlation to temporal superior and temporal inferior RNFL thickness. Conclusion Our results demonstrate RNFL thinning in SLE, and confirm the previous finding of high incidence of abnormal brain scans in SLE. These findings suggest that OCT measurements may be indicative of neurodegeneration in SLE and may be a useful biomarker for early cognitive impairment in SLE.

Optical coherence tomography in Susac's syndrome

Susacs syndrome is an autoimmune endotheliopathy with predilection for brain, retina and cochlea (Susac, 1994). Optical coherence tomography (OCT) is a non-invasive method, which is increasingly used in the diagnosis of retinal as well as primary central nervous system diseases. OCT is suggested as a useful diagnostic tool in differentiating Susacs syndrome from multiple sclerosis (MS) (Brandt et al., 2012). This report demonstrates the OCT findings in 3 patients with Susacs syndrome in different stages of the disease. The OCT demonstrated decreased retinal nerve fiber layer (RNFL) thickness, which was patchy in nature and more prominent in the nasal quadrants. We also observed loss of the normal foveal contour, which is uncharacteristic for MS. The extent and degree of the OCT abnormalities in our patients correlated with the stage and severity of the disease and correlated with the findings on the visual field studies. We confirm that OCT is a useful diagnostic tool in Susacs syndrome and helps to differentiate it from MS. Furthermore, OCT may be a non-invasive alternative to fluorescein angiography in longitudinal follow up of these patients.

Severe early bilateral macular edema following fingolimod therapy.

We report a case of bilateral macular edema (ME) within 10 days of starting fingolimod 0.5mg therapy in a patient with Multiple Sclerosis (MS). The complication resolved without treatment as demonstrated by sequential Optical Coherence Tomography (OCT). Fingolimod is a sphingosine-1-phosphate receptor modulator that reduces lymphocyte presence in the CNS. In pivotal trials, ME, a known complication of fingolimod, typically occurred unilaterally with onset at approximately 3 months. A 60y/o AA female, diagnosed with MS in 1977, started oral fingolimod treatment on 05/31/2011. Baseline screening with OCT and ophthalmology evaluation showed no ME. On 06/10, she developed bilateral blurry vision and discontinued fingolimod. On 06/27, OCT revealed severe bilateral ME. Later OCT exams showed a progressive decrease in Central Foveal Thickness (CFT) and Macular Volume (MV), without specific treatment other than discontinuation of fingolimod. On 7/27, CFT, MV, and Visual Acuity (VA) were similar to baseline. This is the first reported case of bilateral, early onset ME following fingolimod treatment at the current FDA-approved dose of 0.5mg. Diabetes, a known risk factor for ME, may have contributed to her early, bilateral involvement. Our case provides further support for earlier OCT, in conjunction with ophthalmic examinations, for at-risk patients on fingolimod, and suggests that cessation of fingolimod may be associated with resolution of ME.

Natalizumab stabilizes physical, cognitive, MRI, and OCT markers of disease activity: A prospective, non-randomized pilot study

[This corrects the article DOI: 10.1371/journal.pone.0173299.].