Gauthier Calais

Herpes encephalitis during natalizumab treatment in multiple sclerosis

In this case report we describe the first non-fatal herpes simplex virus encephalitis (HSE) case with natalizumab for multiple sclerosis (MS). A 36-year-old woman, previously treated with immunomodulatory and immunosuppressive drugs for MS, developed acute encephalitis after 6 monthly natalizumab perfusions. Brain imaging demonstrated suggestive bi-temporal lesions. Herpes simplex virus type-1 DNA was detected in cerebrospinal fluid. The patient improved gradually after a 21-day course of intravenous acyclovir, but neuropsychiatric changes remained 5 months later. Our non-fatal case of HSE and other reported cases of herpes infections provide evidence of an increased risk with natalizumab and point to the need for clinicians to maintain awareness.

Tear analysis in clinically isolated syndrome as new multiple sclerosis criterion.

In clinically isolated syndrome (CIS), the detection of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is critical for space dissemination validation when magnetic resonance imaging (MRI) diagnostic criteria are not fulfilled. However, lumbar puncture for CSF collection is considered relatively invasive. Previous studies have demonstrated applicability of OCB detection in tears to the diagnosis of multiple sclerosis (MS). The objective of the present study was to assess concordance between OCB detection in tears and in CSF. We have prospectively included patients with CIS and compared results of CSF and tear OCB detection by isoelectric focusing (IEF). Tears were collected using a Schirmer strip. We included 82 patients. For 69 of them, samples were analysable. OCBs were detected in CSF for 63.8% and in tears for 42% of patients. All patients with tear OCBs had CSF OCBs. We suggest that tear OCB detection may replace CSF OCB detection as a diagnostic tool in patients with CIS. This would circumvent the practice of invasive lumbar punctures currently used in MS diagnosis.

Differential processing of natural scenes in posterior cortical atrophy and in Alzheimer’s disease, as measured with a saccade choice task

Atrophy of the medial temporal lobe structures that support scene perception and the binding of an object to its context (i.e., the hippocampus and the parahippocampal cortex) appears early in the course of Alzheimer’s disease (AD). However, few studies have investigated scene perception in people with AD. Here, we assessed the ability to find a target object within a natural scene in people with AD and in people with posterior cortical atrophy (PCA, a variant of AD). Pairs of color photographs were displayed on the left and right of a fixation cross for 1 s. In separate blocks of trials, participants were asked to categorize the target (an animal) by either moving their eyes toward the photograph containing the target (the saccadic choice task) or pressing a key corresponding to the target’s location (the manual choice task). Isolated objects and objects within scenes were studied in both tasks. Participants with PCA were more impaired in detection of a target within a scene than participants with AD. The latter’s performance pattern was more similar to that of age-matched controls in terms of accuracy, saccade latencies and the benefit gained from contextual information. Participants with PCA benefited less from contextual information in both the saccade and the manual choice tasks—suggesting that people with posterior brain lesions have impairments in figure/ground segregation and are more sensitive to object crowding.

Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial

Background This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. Methods and findings NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimers Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease–specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, −0.07–1.64) at 13 weeks, 6.41 (5.33–7.49) at 52 weeks, and 9.63 (8.33–10.93) at 78 weeks and on nilvadipine was 0.88 (0.02–1.74) at 13 weeks, 5.75 (4.66–6.85) at 52 weeks, and 9.41 (8.09–10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. Conclusions The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. Trial registration Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Tear analysis: response to letter from Lolli and Franciotta

To answer to Professors Lolli and Franciotta’s comments tear isofocusing effectively remains experimental for the moment and this technique needs better standardization and quality control. Obviously, pH gradient variability between different fluids can occur and remains a shortcoming of every isofocusing study. However, oligoclonal bands (OCB) seem to be visually the same in tear and in cerebrospinal fluid (CSF), despite lower resolution in tears. The figure shown in our paper omitted to point out OCB. With this letter we are including the same figure (Figure 1), but with OCB indicated. Difficulty in visually fixing OCB by camera is certainly due to the lower proteic concentration in tears compared to CSF. Further studies are needed to effectively confirm these results. Our isofocusing results are semiquantitative and results are always provided in terms of presence or absence of at least three OCB for the moment. This could possibly change in the future with better standardization of technique.