Multiple sclerosis (MS) takes a large chunk of neurological practice. This is not only because it is common, but also because of its devastating impact. It predominantly affects the young, and deals a blow that reverberates through the wider family and society. This is why it is a top priority in neurology.
A lot however remains uncertain and controversial in MS. The cause of MS for instance remains unknown although the list of risk factors is a mile long (see my previous blog listing the top 6 MS risk factors). MS is a well-known condition but it features prominently in the most controversial questions in neurology. The pathology and subtypes of MS are subjects of intense debate, and the best tests and treatments are still being worked out.
The uncertainties in MS are quite fundamental. Take these two recent publications in high impact journals arguing opposites sides of an MS risk factor. One says there is no association of multiple sclerosis activity and progression with EBV or tobacco use, and the other says smoking cessation improves prognosis of multiple sclerosis. Another research article in the JNNP published this year suggests that we are still not sure what constitutes pathological brain atrophy in MS.
But it’s not all controversy and conflict in the world of MS. There is real progress shining a light to a brighter future in MS ,and here are a 11 I have found.
1. Interferons, with twists
Interferons have been the mainstay of MS treatment for decades. They are still standing their grounds despite inconclusive evidence of their effectiveness, their side effects, and the challenge from newer treatments. One way they hope to carry on into the future is by joining forces with oral contraceptives. This is according to a paper published in Neurology last year titled Oral contraceptives combined with interferon β in multiple sclerosis. The authors report that ethinylstradiol and desogestrel aid interferon-ß to reduce the number of new lesions in women with relapsing remitting multiple sclerosis.
We are also learning a little bit more about the types of patients who do worse on interferons. The Journal of Neuroimmunology reports that MS subjects with obesity do less well on interferons, and never achieve the valued status of NEDA, no evidence of disease activity. Another paper in JAMA Neurology, on the other hand, suggests that MS subjects with low Vitamin D levels have poorer disease control when treated with interferon.
2. Vitamin D
There is a lot of uncertainty about the significance of Vitamin D deficiency in MS. A big question is if vitamin D should be given routinely to prevent and treat MS. The potential benefit of Vitamin D was recently the subject of an article published in Journal of Cell Biology titled Vitamin D receptor–retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. The University of Cambridge researchers who carried out the study showed that Vitamin D activates a protein receptor, retinoid X receptor γ (RXR-γ), and this plays a role in the repair of myelin, the fatty nerve sheathing that is damaged in multiple sclerosis. The University of Cambridge statement announcing the finding makes for a simpler read: Vitamin D could repair nerve damage in multiple sclerosis.
An article in Scientific Americanfirst highlighted an association between seasonal MS relapses and melatonin. The science is rather complex, but the idea is based on the recognition that people with MS have fewer relapses in the darker months of the year, and this is when production of the hormone, melatonin, peaks. The research paper itself is published in Cell under the title Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses. The researchers proved their hypothesis by demonstrating that melatonin levels are lowest during an MS relapse than at other times. Furthermore, the pathology of the disease improves in MS mice treated with melatonin. For a simplified read, try this, perhaps over-enthusiastic, take from MD titled Melatonin Could One Day Treat MS.
4. Helicobacter pylori
In what may be an attempt at rehabilitation, H pylori is attempting to make a good name for itself. Notorius for causing stomach ulcers, it now wants to be known as the patron saint of MS. It is a tenuous link I have to say, but I can’t argue against the research paper published in the prestigious Journal of Neurology, Neurosurgery and Psychiatry (JNNP). The article has a refreshingly self-explanatory title Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females. The authors show that people with MS are less likely to be infected with H. pylori than control subjects. But I will not rush to swim in that dirty-looking pool yet, the margin is thin; 16% versus 21% in control subjects. It however raises the intriguing relationship between infections and autoimmunity, a subject explored brilliantly in the accompanying editorial, the hygiene hypothesis of multiple sclerosis.
Phenytoin is very familiar to neurologists because it was a leading epilepsy medication for decades. Although it still has pride of place in the treatment of status epilepsy, it has largely fallen out of favour-mainly for its cosmetic and cognitive side effects. It is therefore surprising to see phenytoin resurrecting in the world of multiple sclerosis. In a large trial published in Lancet Neurology this year, researchers showed a neuroprotective effect of phenytoin on optic neuritis, a common symptom of MS. Neuroprotection, if you must know, is the holy grail of neurology. The article is titled Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. But you might as well read the distilled, and not over-sensational title, in The Telegraph, Cheap epilepsy drug could prevent nerve damage in Multiple Sclerosis. I think the findings require a long stretch of the imagination, but I am happy to do this to remain positive.
Pramipexole is a dopamine agonist, a group of drugs used in the treatment of Parkinson’s disease. They are not as popular as they once were, partly again due to side effects. They may however take on an important role in MS. I first came across this in the Barts MS Blog titled Dopamine modulation – a novel target for MS. This refers to an article published in Molecular Neurobiology, Pramipexole, a Dopamine D2/D3 Receptor-Preferring Agonist, Prevents Experimental Autoimmune Encephalomyelitis Development in Mice. I fail to understand why our ivory towers love these long-winded titles! The bottom line however is that Pramipexole can modulate the immune system thereby limiting the damage it inflicts on the nervous system. Don’t ask me how it does this-I dare you to go read the abstract!
Ozanimod is a sphingosine-1-phosphate receptor modulator, and it has shown promise in trials of relapsing remitting MS. This was the conclusion of a recent randomised, placebo-controlled, phase 2 trial of Ozanimod in MS published in Lancet Neurology. Heart-warmingly called the RADIANCE study, the authors demonstrated the effectiveness of Ozanimod in subjects across 55 centres spread over 13 countries. This feat was rewarded with demonstrable reduction in MRI lesion load in the treated subjects. The phase 3 trial therefore promises a lot…but will it deliver?
8. Anoctamin 2 (ANO2)
Researchers are veritable hunters, looking for weak spots in their prey, diseases. They then hone in on their victims vulnerabilities, and pounce. In this way they develop treatment strategies. One such weak spot, recently reported in Proceedings of the National Academy of Sciences (PNAS), is connected to the chloride channel protein Anoctamin 2 (ANO2). The paper, Anoctamin 2 identified as an autoimmune target in multiple sclerosis, reports that subjects with MS have high antibody activity against ANO2. It’s rather complex biochemistry, and for a digested read see the version in Multiple Sclerosis News Today titled New Protein, Anoctamin 2, Identified as a Target of Autoantibody Production in MS. If ANO2 has anything to do with causing MS, you can be sure treatment strategies will follow. If this turns out to be an important pathway in MS, the armoury of MSologists will soon contain stronger firepower.
9. Intrathecal CD20
I know, getting into unfamiliar territory now, but the future always feels that way. In a study titled Intrathecal anti-CD20 efficiently depletes meningeal B cells in CNS autoimmunity, researchers injected CD20 into the spinal fluid of mice. They then showed that this depletes the B cells that cause the inflammation in MS. The article is published in Annals of Clinical and Translational Neurology, (I know, I haven’t heard of it before now myself). It is a significant enough step for JAMA Neurology to ask, Is intrathecal anti-CD20 a therapeutic option in treating MS relapse? Whether this would translate into clinical benefit is not clear from the article, but it is promising.
10. Haematopoietic cell transplant (HCT)
There have been reports in the lay press of subjects with MS getting up and walking, almost miraculously. There is however actually some science behind it all, for a change. An article in JAMA Neurology titled, rather clumsily, High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS), illustrated the benefits of haematopoietic cell transplant in MS. The 3 year interim analysis shows that HCT successfully induces sustained remission in MS-what more can we expect from an emerging treatment!
MS is as much a neurological, as it is a radiological, condition. The diagnosis of MS is heavily reliant on what is, or is not, a lesion on MRI scans; what is new and what is old; and what is getting bigger or smaller. Believe me, this is hardly ever straightforward. It is therefore gratifying to read an article (OK, I admit it, an abstract) in the American Journal of Neuroradiology titled FLAIR2: A Combination of FLAIR and T2 for Improved MS Lesion Detection. The authors report that they greatly improved the detection of MS lesions by combining two standard magnetic resonance imaging (MRI) techniques called T2 and FLAIR. This technique, FLAIR2, the authors say, is ‘a simple approach of obtaining CSF suppression with an improved contrast-to-noise ratio’, whatever that means! It does make one worry- how much we are actually missing now? FLAIR2 to the rescue.
12. Developing prospect
I know I said 11, but for those who like things to be even I will take you out of your misery and make it an even dozen. Look out for the Amiloride Clinical Trial In Optic Neuritis (ACTION). Something for the future!