What is the impact of Vitamin D on the complicated course of MS?

Some general neurologists get away with not having to think too much about multiple sclerosis (MS). This is because they have an ‘MSologist‘ at hand to refer all their patients with ‘demyelination‘. Many general neurologists however care for people with MS because they do not have a ‘fallback guy‘ to do the heavy lifting for them. This therefore makes it imperative for neurologists to keep up with everything about this often disabling and distressing disorder.

MS prevalence map. By AdertOwn work and [1], CC BY-SA 3.0, Link
The management of MS is however very tricky, and it is challenging to get a grip of it all. This is partly because the clinical course is varied, and the diagnostic process tortuous. The patient first goes through an onerous retinue of tests which include an MRI, a lumbar puncture, evoked potentials, and a shedload of blood tests. This is all in a bid to secure the diagnosis and to exclude all possible MS mimics.

MRI scan. NIH Image Galley on Flikr. https://www.flickr.com/photos/nihgov/30805879596

Then comes the head-scratching phase of determining if the patient actually fulfils the diagnostic criteria for MS, or if they just have clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS). To secure the diagnosis of MS, the neurologist turns to the McDonald criteria which stipulate dissemination in time and place of inflammatory events. As simple as this should be, this is no easy task at all. This is because, at different times, the criteria have meant different things to different people. The guidelines have also gone through several painful, and often confusing, iterations. Indeed the McDonald criteria have only recently been re-revised-to the delight of MSologists but the chagrin of the general neurologist!

Steampunk Time and Space Machine. Don Urban on Flikr. https://www.flickr.com/photos/donpezzano/3230179951

Once the diagnosis of relapsing remitting MS (RRMS) is reasonably established, the patient is taken through a guided tour of the ever-expanding available treatment options. These are typically to prevent relapses, but more recently to prevent disease progression as well. People with mild to moderate MS are nudged towards interferons, glatiramer acetate, dimethylfumarate, or terifluonamide. Those with more aggressive disease, on the other hand, are offered a menu of fingolimod, natalizumab, or alemtuzumab. Other newer agents include daclizumab and cladribine. And, just stepping into the arena, there is ocrelizumab for primary progressive (PPMS). Whichever option is chosen, the course of treatment is long, and it is fraught with risks such as infections and immune suppression.

https://pixabay.com/en/syringe-pill-bottle-morphine-small-1884784/

Once the bigger questions have been settled, the neurologist then braces for the ‘minor’ questions her enlightened patients will ask. The easier questions relate to the treatment of symptoms, and some of the most vexing concern the role of Vitamin D deficiency. Such questions include, ‘Is vitamin D deficiency a cause of MS?‘, ‘Do people who are vitamin D deficient experience a worse outcome?‘, and ‘Should patients with MS be on Vitamin D supplementation?‘.

Pandora’s box. Michael Hensman on Flikr. https://www.flickr.com/photos/mycael/3664900435

To attempt to resolve these questions I plunged into some of the literature on Vitamin D and MS. And this is like opening Pandora’s box. Here are some of the things I found.

***

Is MS associated with Vitamin D deficiency?

It therefore appears that there is an association of vitamin D deficiency with MS, but it is far from certain that this is a causative relationship. One hypothesis is that vitamin D deficiency is the outcome, rather than the cause, of MS. The deficiency presumably results becuase the very active immune system in people with MS mops up the body’s Vitamin D. This so-called reverse causation hypothesis asserts that vitamin D deficiency is a consumptive vitaminopathy

Sunshine Falls. Dawn Ellner on Flikr. https://www.flickr.com/photos/naturesdawn/4299041739

Does Vitamin D deficiency worsen MS progression?

There is therefore no single answer to this question, but the emerging consensus is that Vitamin D deficiency adversely affects the course of MS. 

Milk splash experiment. Endre majoros on Flikr. https://www.flickr.com/photos/boneball/24597145866

Should people with MS be on Vitamin D supplementation?

Even if Vitamin D deficiency doesn’t cause MS, the evidence suggests that it negatively influences the course of the disease.

Salmon salad nicoise. Keith McDuffee on Flikr. https://www.flickr.com/photos/gudlyf/3609052894

What to do?

This is the million dollar question eloquently posed by a recent editorial in the journal Neurology titled Preventing multiple sclerosis: to (takevitamin D or not to (takevitamin D? The reasonable consensus is to encourage vitamin D replenishment to prevent MS, starting from preconception. It is also generally agreed that people with MS should be on vitamin D supplementation in the expectation that it will slow the disease activity.

A practical approach to Vitamin D replacement is the Barts MS team vitamin D supplementation recommendation. This is to start with 5,000IU/day vitamin D, and aim for a plasma level of 100-250 nmol/L. Depending on the level, the dose is then adjusted, up or down, to between 2-10,000IU/day. They also advise against giving calcium supplementation unless there is associated osteoporosis.

What is a general neurologist to do? To follow the prevailing trend, and hope it doesn’t change direction too soon!

Vitamin D Pills. Essgee51 on Flikr. https://www.flickr.com/photos/sg51/5224823967

 

What is the state of Parkinson’s disease biomarkers?

Neurologists are always cautious when making a diagnosis of Parkinson’s disease (PD). This shouldn’t be the case because PD is not difficult to recognise-at least not most of the time. For one, PD has classical clinical signs- the trio of resting tremor, slow movements (bradykinesia), and stiffness (rigidity). For another, it is asymmetrical, starting and remaining worse on one side of the body.

All these features are however vague in the early stages of PD. To make matters worse, there are many other diseases that mimic PD. These include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Lewy body disease (LBD), corticobasal degeneration (CBD), and even SWEDDS (if it exists at all!). And always lurking in the shadows, waiting to catch the neurologist out, are dystonic tremor and essential tremor.

Marking Parkinson's. EMSL on Flikr. https://www.flickr.com/photos/emsl/4704802544
Marking Parkinson’s. EMSL on Flikr. https://www.flickr.com/photos/emsl/4704802544

 

These PD mimics challenge and intrigue neurologists in equal measure. They contribute to the delayed and missed diagnosis of PD in 20% of cases. Are there shortcuts out there to improve our diagnostic accuracy? A simple test perhaps? Maybe some biomarker? Here are 6 budding contestants.

1. Dopamine transporter (DAT) scans

Dopamine. John Lester on Flikr. https://www.flickr.com/photos/pathfinderlinden/211882099/in/photolist-jHXaD
Dopamine. John Lester on Flikr. https://www.flickr.com/photos/pathfinderlinden/211882099/in/photolist-jHXaD

DAT scans are now in general, even if not universal, use. They help to distinguish PD from conditions such as essential tremor or drug-induced Parkinsonism. DAT scans are however expensive, and they do not distinguish PD from many of its other mimics such as MSA, PSP, (you know the roll call). There are indications that DAT scans may be normal in cases of PD. We therefore clearly need better, cheaper (and newer!) PD biomarkers than DAT scans.

2. Cerebrospinal fluid (CSF) biomarkers

© Nevit Dilmen [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
© Nevit Dilmen [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
Perhaps the answer is in a spinal tap or lumbar puncture (LP). A lumbar puncture is a simple but dreaded test. It is however useful for giving us access to the cerebrospinal fluid (CSF) that bathes the brain and spinal cord. Analysis of the CSF often gives the game away in many neurological disorders. It is not surprising therefore that researchers looked at a panel of nine CSF biomarkers that may identify PD. The paper, published in the JNNP, suggests that there may be biomarker roles for neurofilament light chain (NFL), soluble amyloid precursor protein (sAPP), and α-synuclein (of course). CSF α-synuclein is the focus of another paper in BioMedCentral which reports that one form, oligomeric α-synuclein, is the one to watch out for.

Another set of CSF biomarkers is related to blood vessel formation (angiogenesis). I came across this in a paper in Neurology titled Increased CSF biomarkers of angiogenesis in Parkinson disease. The authors are referring to vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2. Others are placental growth factor (PlGF), angiopoietin 2 (Ang2), and interleukin-8. Enough to keep researchers busy for a while.

3. Peripheral blood biomarkers

Even the most compliant patient would prefer to have a blood test rather than a spinal tap. Thankfully there are some blood-based biomarkers in the offing. One set are called α-synuclein blood transcripts (SNCA transcripts). The authors of an article published in the journal Brain report that SNCA transcripts are consistently reduced in the blood of people with early PD. The accompanying editorial however cautions on the utility of these SNCA transcripts because low levels are also seen in some people who do not have PD. The true value of SNCA transcripts may lie in their ability to predict cognitive decline, but how many people really want to know that?

Other potential blood based biomarkers mentioned are uric acid and epidermal growth factor (EGF).

4. Retinal optical coherence tomography (OCT)

CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=525623
CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=525623

Even better than blood and spinal fluid biomarkers would be something totally painless. And to the rescue comes retinal optical coherence tomography (OCT). OCT uses light waves to take pictures of the retina. This allows measurement of the size of different parts of the retina; the area of interest in PD is called the foveal pit. A paper in Movement Disorders reports that OCT is a sensitive marker of PD. The authors show that the foveal pit in PD has a unique form; it is shallow in the superior-inferior and the nasal-temporal slopes. Perhaps neurologists will soon be running to ophthalmologists, cap-in-hand, to save their blushes.

5. Salivary gland α-synuclein

Public Domain, https://commons.wikimedia.org/w/index.php?curid=1074079
Public Domain, https://commons.wikimedia.org/w/index.php?curid=1074079

 

Back to painful biomarkers I’m afraid, all in aid of clinching an early diagnosis you must understand. This time it’s salivary gland biopsy. Some eager researchers took biopsy samples of the submandibular salivary glands of people with early PD. They then looked for, and found, α-synuclein in about 75% of them. Their paper is published in Movement Disorders titled Peripheral Synucleinopathy in Early Parkinson’s Disease: Submandibular Gland Needle Biopsy Findings. Unfortunately  20% of control subjects without PD also had α-synuclein in their salivary glands. Could these people have pre-manifest PD? We must await larger and longer studies before we start needling away at the salivary glands of the worried-well.

6. Intestinal tract α-synuclein

What if the answer is not in the salivary glands? Then we should be really afraid because α-synuclein has popped up in …the intestines. A review paper in Movement Disorders describes this in the brilliantly titled Gut Feelings About α-Synuclein in Gastrointestinal Biopsies: Biomarker in the Making? Another paper published in PLOS One takes things further, reporting an association between intestinal α-synuclein with increased gut permeability. I’ll make no further comments on the gut; not with the threat of cameras and scopes going up all sorts of body openings.

α-synuclein staining of a Lewy body. By Marvin 101 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7533521
α-synuclein staining of a Lewy body. By Marvin 101Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7533521

Below is a link to an open access article in Movement Disorders with more potential PD biomarkers

Are there any other biomarkers out there? Please leave a comment.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

neurochecklists-image

Migraine and its strange and surprising associations

By Sasha Wolff from Grand Rapids - Can't Concentrate: 14/365, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=11343038
By Sasha Wolff from Grand Rapids – Can’t Concentrate: 14/365, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=11343038

I am casting my sight on the scourge of millions around the world-migraine. This post is a prelude to a piece I am working on titled How is migraine research soothing the pain of neurology? In doing this, I came across a few curiosities which I thought would do nicely as a separate post. Therefore, before the real stuff, here are 8 strange and surprising migraine associations.

α. Migraine and the weather

Texture: Thunder Clouds. Virginia Moerenhout on Flikr. https://www.flickr.com/photos/yndra/4784553320
Texture: Thunder Clouds. Virginia Moerenhout on Flikr. https://www.flickr.com/photos/yndra/4784553320

Some migraineurs know that their migraine attacks are related to changes in the weather. For them therefore, the science is just catching up. This piece from the American Migraine Foundation summarises some recent articles which discuss the weather alterations that may trigger migraine headaches. The fingers are pointing at low barometric pressure, high environmental temperature, strong winds, and…wait for it…> 3hours of sunshine!

β. Migraine and irritable bowel syndrome (IBS)

This is not even officially out yet, but a press release announcing the American Academy of Neurology’s April 2016 meeting whets our appetites. The findings of a study to be unveiled in Vancouver reports that migraine is probably genetically linked to irritable bowel syndrome (IBS). Not only that, the two may also share genetic markers with tension type headache (TTH). And the link is thought to be the serotonin transporter, and the serotonin receptor 2A, gene. The association of migraine and IBS will really put the cat among the pigeons; dealing with migraine alone is hard enough but combine the two and…

γ. Migraine and Parkinson’s disease (PD)

By Marvin 101 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7533521
By Marvin 101Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7533521

Migraine sufferers will really balk at the scary report of migraine as a risk factor for Parkinson’s disease (PD). This is the conclusion of a research work published in the journal Cephalalgia (really just a fancy word for headache). The authors followed up >40,000 people to see if those with migraine are more likely to develop PD than those without. Curious indeed! I have to confess, whatever the hazard ratios say, that I was not impressed by the difference in numbers developing PD of 148 versus 101.

δ. Migraine and radiotherapy

Varian radiation therapy machine. Dina-Roberts Wakulczyk on Flikr. https://www.flickr.com/photos/littlesister/490643515
Varian radiation therapy machine. Dina-Roberts Wakulczyk on Flikr. https://www.flickr.com/photos/littlesister/490643515

I’m not trying to be smart, but SMART syndrome is real. It is an acronym for Stroke-like migraine attacks after radiation therapy. It is easy for neurologists to miss this condition because it sets in years after the radiation treatment. There is however a clue in the MRI of people with SMART syndrome: cortical thickening and gadolinium enhancement in the area of brain treated with radiation. It’s simple really!

ε. Migraine and raised intracranial pressure

By Jonathan Trobe, M.D. - University of Michigan Kellogg Eye Center - The Eyes Have It, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=16115920
By Jonathan Trobe, M.D. – University of Michigan Kellogg Eye Center – The Eyes Have It, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=16115920

An article in Journal of Neurology reports that many people with unrelenting migraine have raised pressure in the brain (raised intracranial pressure or ICP). The article, titled association of unresponsive chronic migraine and raised intracranial pressure, showed that reducing the pressure by a spinal tap (lumbar puncture) leads to sustained remission of migraine. Neurologists diagnose raised ICP by look into the back of the eye for a sign called papilledema. This article however throws a spanner in the works because >75% of the people with migraine and raised ICP in the study did not have papilledema. What do the headache gurus have to say about this, I wonder?

ζ. Migraine and stroke

Neurologists really haven’t sorted this one out yet. We struggle to give our patients a straightforward answer to their simple question, ‘does migraine cause stroke?‘ This is because the literature on this is all smoke and mirrors, and recent papers do little to clear the air. Take this paper in a recent issue of Neurology titled Age-specific association of migraine with cryptogenic TIA and stroke. The authors could only conclude that there is probably a causal or shared risk, and this only in older people. The accompanying editorial, titled Migraine and cryptogenic stroke: the clot thickens, concludes that there may be a higher risk of stroke in migraineurs, but this is in those with other traditional stroke risk factors in the first place. A shaky association I say, but one not to be dismissed too hastily.

η. Migraine and teeth-grinding

By Mik81 - Photography of author, original description page was here., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2478383
By Mik81 – Photography of author, original description page was here., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2478383

I did say these are strange links. Teeth grinding or bruxism is not something neurologists would give a second thought to, but a review article in Practical Neurology says we should think again. Titled Bruxism in the Neurology Clinic, the review says bruxism is closely linked to migraine, and sleep bruxism is only associated with migraine. There is much more to bruxism and neurology; the authors suggests that bruxism may be a form of oromandibular dystonia, and it may arise from dysregulation in the basal ganglia. Quite a lot to chew! Dentists out there should be very worried-the neurologists are out to expand their territory.

θ. Migraine and hiccups

Try this Flikr. Bart on Flikr. https://www.flickr.com/photos/cayusa/3029282000
Try this Flikr. Bart on Flikr. https://www.flickr.com/photos/cayusa/3029282000

And finally a report which links migraine and hiccups. Again from Cephalalgia, this is a case series of people with migraine who report hiccups as aura of migraine. Strange and surprising indeed!

migraine aura 2 - when it's light and shimmery. Joanna Roja on Flikr. https://www.flickr.com/photos/cats_mom/2758240218
migraine aura 2 – when it’s light and shimmery. Joanna Roja on Flikr. https://www.flickr.com/photos/cats_mom/2758240218

=========================================================================

screen-shot-2016-12-19-at-18-32-39