Multiple Sclerosis and Related Disorders (2014) 3, 1–2

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Editors' welcome Something for everyone Regular readers may have noticed that the number of articles and size of the printed version has increased steadily, to such extent that from 2014 we will publish 6 issues per year. The current issue has something for everyone with contributions on ophthalmology, epidemiology, new medication, psychology and molecular pathology. Simon Hickman and colleagues provide a comprehensive review of visual changes in MS. They make many valuable points. For example, many readers will not be aware that the development of a complete or partial homonymous hemianopia in a patient receiving Natalizumab (Tysabri) may be the first sign of progressive multifocal leukoencephalopathy. Also, chronic optic neuropathy should be regarded as a major Red Flag. It is very rare in definite MS and raises the question of other disorders such as the Harding's syndrome which is a mitochondrial disorder akin to Leber's optic neuropathy. The paper from Thailand by Apiwattanakut and Kasemsuk emphasizes the rarity of MS in their country and that most visual disorders that they deal with are due to neuromyelitis optica (NMO). MRI of the spinal cord and Aquaporin-4 antibody titers readily distinguished NMO from MS. Burton and colleagues appraise the role of vitamin D in MS and emphasize the usefulness of the anterior visual pathway (AVP) model as a means of evaluating its role in demyelination. The AVP model is a combination of clinical evaluation, neurophysiologic tests on the optic nerve and retina, MRI of the anterior visual structures and optical coherence tomography (OCT). In the first of their two papers in the current issue, Sandhoff et al. likewise examine the AVP in MS and discover that total macular volume (but not retinal nerve fiber layer thickness) correlates with physical activity as measured by an accelerometer. The mechanism is unclear but the clear implication is that physical activity should be encouraged. The NODAMUS multicentre study investigated whether impairment of glutamate homeostasis might be relevant to NMO and tested for polymorphisms in the Excitatory Amino Acid Transporter2 (EAAT2/SLC1A2) gene in 81 French subjects. They found no significant variants in the coding region for the EAAT2 gene that could impair glutamate expression. Susac's syndrome is a difficult diagnosis and a recognized simulator of MS. The predominance of deafness and retinal infarcts usually helps clinch the diagnosis especially if the MRI shows characteristic ‘snowball’ lesions in 2211-0348/$ - see front matter & 2013 Published by Elsevier B.V.

the corpus callosum. Further help may be provided by OCT according to the unique article by Bernard and colleagues. In their three patients, OCT revealed patchy reduction in the retinal nerve fiber layer especially in the nasal quadrants and a loss of the normal foveal contour. These features would be atypical for MS and might help with the diagnosis of Susac's syndrome, and other focal retinal pathologies, especially where fluorescein angiography is contraindicated because of allergy etc. and where longitudinal studies were required. With an epidemiology focus, the investigation by Pandey and co-workers is well worth a read. 35 Subjects with primary or secondary progressive MS were followed up for 7 years. Their findings are tempered by the observational nature of the survey and the fact this came from a tertiary referral center, however a significant number did not progress as often or as rapidly as expected and a few appeared to improve. Hawkes and Boniface pursue their theory that people who are destined to suffer MS are prior risk-takers (e.g. alcohol, smoking, cannabis, gambling, more partners and pregnancies) and describe their case-control study that addresses these social characteristics. The authors conclude that there might be a particular personality profile that brings a person into contact with whatever causes MS. Krokki and co-workers examine co-morbidity in their cohort of 491 MS patients from FInland. They found a significant association between: MS and epilepsy; women with benign MS and headache; peripheral nervous system disorder (polyneuropathy) and primary progressive MS. In a meta-analysis of nearly 4000 MS cases from Arica, Asia, Australia and New Zealand, Makhani and associates report as expected, a high MS incidence and prevalence in Australia and particularly low level in Africa and Asia. The poor quality of data from these last two low rate areas is emphasized. Turning now to new medications, we have two articles on 4-aminopyridine (4-AP). Hadavi and colleagues describe SR-Fampridine, the European-badged sustained release form of 4-AP. Initial studies show that this improves walking speed significantly in a subgroup of patients who respond to the drug. A known limiting factor with 4-AP is a tendency to cause seizures at high doses, an effect that was indeed observed with the maximum evaluated dose of SR-Fampridine (20 mg twice day). The authors emphasize the potential risk of falls, dizziness, insomnia, fatigue, nausea, and balance disorders, all of which were seen primarily in the high dose group. Despite a stormy passage, this new drug at last has been approved by the

2 US and European regulatory authorities. The importance of proper patient selection is stressed as not all are responders. The USA equivalent preparation (Dalfampridine) which is likewise slow release 4-AP was evaluated from the aspect of unpleasant ‘positive’ phenomena by Thaera and partners. In their retrospective case review there were 5/76 who developed side-effects: two experienced recurrence of trigeminal neuralgia that failed to settle after drug withdrawal; there was one seizure, one patient with leg pain and another who developed multifocal paroxysmal paresthesias. Clearly these unwanted effects demand caution in prescribing (especially in the presence of renal impairment) but the authors do not correlate side effects with doses administered and there is no information about benefits on walking or fatigue. On the psychologic front Dr Walker and co-workers administered high dose immunosuppression and autologous hemopoietic stem cell transplantation to 7 patients with rapidly progressive MS. Although brain atrophy measures did not correlate with cognitive assessment, at 24 months there appeared to be no further cognitive deterioration in some subjects, raising the possibility that the disease might have been stabilized. Sandroff and associates examined the effect of everyday activity as recorded by a portable accelerometer, on cognitive processing speed and the Timed 25 foot (7.6 m) walk. They found an unadjusted improvement in cognitive processing speed but this may have been confounded by elevated mood. Finally, Gupta and partners looked at the connection between self-reported MS severity and its association with health outcomes, in a large questionnaire-based survey. Not surprisingly, in the MS group there was significantly more activity impairment, decreased work productivity, increased use of healthcare resources and a lower health-related quality of life. All these measures correlated with disease severity. Lastly there are three papers that deal with possible biomarkers and molecular mechanisms. Many would not think readily of Vitamin A in the MS casual pathway, but it is known that this vitamin can inhibit the formation of Th17 cells which are probably involved in relapses. Thus, Runia and co-workers

B. Banwell et al. measured mean vitamin A levels and found them significantly lower in patients but there was no clear association with relapses and vitamin A level shifts. There was a weak correlation between low levels of vitamins A and D which the authors attribute to dietary input. Is it possible that all fat-soluble vitamins (A, D, E and K) are involved with MS? Jun-Ichi Satoh discusses the role of transcription-factor nuclear-factor B (NF-kB) in immune-related-conditions including MS. Using ChiP sequencing (a method of analyzing protein interactions with DNA) the binding sites of NF-kB overlapped with some areas of the genome connected with MS immune functions. It is suggested that aberrant regulation of NF-kB mediated gene expression might be associated with the development and progression of MS. Graham et al. discuss the concept of metabolic support of axons by oligodendrocytes. The loss of myelin and oligodendrocytes would eliminate the metabolic support provided in the form of energy sources such as lactate to axons, which is likely to compound the energy gap imposed by the alteration in sodium channels in demyelinated axons. They question the relevance of oligodendrocyte mitochondrial abnormalities in MS. One possibility is that astrocytes with healthy mitochondria may protect oligodendrocytes with abnormal mitochondria. The final paper by David Baker et al. provides questionnaire data related to the acceptability of various MS descriptors. The majority of respondents were British and US patients and disliked being called a client, sufferer, patient or person living with MS; they preferred ‘person with MS’ but the most popular (43%) was ‘MSer’. MSer in this context is a noun, as in farmer or IBMer, and is not an abbreviation for the often used term MS sufferer. It is suggested that this term is now used in all articles that may be accessed by patients, sorry, MSers. Have a good read! Brenda Banwell Gavin Giovannoni Christopher Hawkes Fred Lublin

Editors' welcome.

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