Sunday Digest


Here are links to a few papers that some of you may find interesting

This is one for the neuros reading or anyone interested in imaging 

Arevalo O, Riascos R, Rabiei P, Kamali A, Nelson F.

The advent of magnetic resonance imaging has improved our understanding of the pathophysiology and natural course of multiple sclerosis (MS). The ability of magnetic resonance imaging to show the evolution of MS lesions on sequential scans has brought it to be one of the endpoints in clinical trials for disease-modifying therapies. Based on the most updated consensus guidelines from the American (Consortium of MS Centers) and European (Magnetic Resonance Imaging in MS) boards of experts in MS, this document shows the most relevant landmarks related to imaging findings, diagnostic criteria, indications to obtain a magnetic resonance, scan protocols and sequence options for patients with MS. Although incorporating the knowledge derived from the research arena into the daily clinical practice is always challenging, in this article, the authors provide useful recommendations to improve the information contained in the magnetic resonance report oriented to facilitate communication between radiologists and specialized medical teams involved in MS patients’ multidisciplinary care.

Brain iron and disability is a theme, we have agents that block iron induced toxicity should we do try them?

Zivadinov R, Tavazzi E, Bergsland N, Hagemeier J, Lin F, Dwyer MG, Carl E, Kolb C, Hojnacki D, Ramasamy D, Durfee J, Weinstock-Guttman B, Schweser F. Brain Iron at Quantitative MRI Is Associated with Disability in Multiple Sclerosis. Radiology. 2018 Jul 17:180136. doi: 10.1148/radiol.2018180136. [Epub ahead of print].
Purpose To study deep gray matter susceptibility in multiple sclerosis (MS) by using quantitative susceptibility mapping (QSM) and to assess the relationship between susceptibility and clinical disability. 
Materials and Methods For this prospective study between March 2009 and November 2013, 600 participants with MS (452 with relapsing-remitting MS and 148 with secondary progressive MS) and 250 age- and sex-matched healthy control participants were imaged with 3.0-T MRI to measure magnetic susceptibility. Deep gray matter susceptibility (in parts per billion) was analyzed by using region of interest and voxelwise methods. QSM and MRI volumetric differences between study groups and associations with clinical outcomes were assessed. Analysis of covariance, multivariable linear regression, and voxelwise analyses, controlling for age and sex, were used to compare study groups and to explore associations between MRI and clinical outcomes. 
Results Compared with control participants, participants with MS presented with lower thalamic susceptibility (-7.5 ppb vs -1.1 ppb; P < .001) and higher susceptibility of basal ganglia (62 ppb vs 54.8 ppb; P < .001). Lower thalamic susceptibility was associated with longer disease duration (β = -0.42; P = .002), higher degree of disability (β = -0.64; P = .03), and secondary-progressive course (β = -4.3; P = .009). Higher susceptibility of the globus pallidus was associated with higher disability (β = 2; P = .03). After correcting for each individual structural volume in voxelwise analysis, lower thalamic susceptibility and higher susceptibility of the globus pallidus remained associated with clinical disability (P < .05). 
Conclusion Quantitative susceptibility mapping (QSM) suggests that altered deep gray matter iron is associated with the evolution of multiple sclerosis (MS) and on disability accrual, independent of tissue atrophy.

BoTox is good for alleivating bladder problems. You know all of this already, but here is a phase III study to demonstrate it.

Tullman M, Chartier-Kastler E, Kohan A, Keppenne V, Brucker BM, Egerdie B, Mandle M, Nicandro JP, Jenkins B, Denys P. Low-dose onabotulinumtoxinA improves urinary symptoms in noncatheterizing patients with MS. Neurology. 2018 Jul 20. pii: 10.1212/WNL.0000000000005991. OBJECTIVE:To evaluate the efficacy and safety of onabotulinumtoxinA 100 U in noncatheterizing patients with multiple sclerosis (MS) with urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO).
METHODS:In this randomized, double-blind phase III study, patients received onabotulinumtoxinA 100 U (n = 66) or placebo (n = 78) as intradetrusor injections via cystoscopy. Assessments included changes from baseline in urinary symptoms, urodynamics, and Incontinence-Quality of Life (I-QOL) total score. Adverse events (AEs) were assessed, including initiation of clean intermittent catheterization (CIC) due to urinary retention.
RESULTS:OnabotulinumtoxinA vs placebo significantly reduced UI at week 6 (-3.3 vs -1.1, p < 0.001; primary endpoint). Significantly greater proportions of onabotulinumtoxinA-treated patients achieved 100% UI reduction (53.0% vs 10.3%, p < 0.001). Significant improvements in urodynamics (p < 0.01) were observed with onabotulinumtoxinA. Improvements in I-QOL score were significantly greater with onabotulinumtoxinA (40.4 vs 9.9, p < 0.001) and ≈3 times the minimally important difference (+11 points). The most common AE was urinary tract infection (25.8%). CIC rates were 15.2% for onabotulinumtoxinA and 2.6% for placebo.
CONCLUSION: In noncatheterizing patients with MS, onabotulinumtoxinA 100 U significantly improved UI and quality of life with lower CIC rates than previously reported with onabotulinumtoxinA 200 U

You want to know about myelination. We know that clearing of debris is central to repair and macrophages/microglia are important in this process. In this study they show that macrophage colony stimulating factor can influence macrophages so they don’t cause so much demyelination and so they promote repair. Could this be used in MS. I would have to say I think very cautiously as you have macrophages all over the body and giving them a growth and survival factor may be bad news. However without doing the experiment we will never know.

Laflamme N, Cisbani G, Préfontaine P, Srour Y, Bernier J, St-Pierre MK, Tremblay MÈ, Rivest S. mCSF-Induced Microglial Activation Prevents Myelin Loss and Promotes Its Repair in a Mouse Model of Multiple Sclerosis. Front Cell Neurosci. 2018;12:178.

A pathological hallmark of multiple sclerosis (MS) is myelin loss in brain white matter accompanied by compromised remyelination. Demyelinated lesions are deeply associated with oligodendrocyte apoptosis and a robust inflammatory response. Although various studies point towards a noxious role of inflammation in MS, others emphasize a positive role for the innate immune cells in disease progression. A cytokine well-known to stimulate cell survival, proliferation and differentiation of myeloid cells, macrophage colony-stimulating factor (mCSF), was administered to mice during a 5 week-long cuprizone diet. Treated mice exhibited reduced myelin loss during the demyelination phase, together with an increased number of microglia and oligodendrocyte precursor cells in lesion sites. Tamoxifen-induced conditional deletion of the mCSF receptor in microglia from cuprizone-fed mice caused aberrant myelin debris accumulation in the corpus callosum and reduced microglial phagocytic response. mCSF therefore plays a key role in stimulating myelin clearance by the brain innate immune cells, which is a prerequisite for proper remyelination and myelin repair processes.

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