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.


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 are the most perplexing diseases that excite neurologists?

Neurologists typically see what they will call run-of-the-mill stuff. These are cases they don’t typically struggle too hard to make a diagnosis or to treat. These common cases don’t really keep us on our toes. No, what gets neurologists bristling, we admit, are the esoteric diseases. We are thrilled when we sniff a rarity in the air. We develop goosebumps when we think we are on the trail of the next case report. We are envious when such cases are presented at the neurological altar, the neuropathological conference.

"Une leçon clinique à la Salpêtrière" by André Brouillet - Photo prise dans un couloir de l'université Paris V. Licensed under Public Domain via Commons - https://commons.wikimedia.org/wiki/File:Une_le%C3%A7on_clinique_%C3%A0_la_Salp%C3%AAtri%C3%A8re.jpg#/media/File:Une_le%C3%A7on_clinique_%C3%A0_la_Salp%C3%AAtri%C3%A8re.jpg
“Une leçon clinique à la Salpêtrière” by André Brouillet – Photo prise dans un couloir de l’université Paris V. Licensed under Public Domain via Commons – https://commons.wikimedia.org/wiki/File:Une_le%C3%A7on_clinique_%C3%A0_la_Salp%C3%AAtri%C3%A8re.jpg#/media/File:Une_le%C3%A7on_clinique_%C3%A0_la_Salp%C3%AAtri%C3%A8re.jpg


But what are these mysterious cases that set our blood on fire? Which are the most perplexing? What are these diseases so rare only a few have the knowledge and experience to recognise them? To investigate, I had a quick look at the index of neurology checklists I have been labouring to produce, and I came up with a list of 75. I have grouped these into three depending on their degree of  perplexity.


"Pagoda Burr Puzzle" by Meronim - Own work. Licensed under CC BY-SA 3.0 via Commons - https://commons.wikimedia.org/wiki/File:Pagoda_Burr_Puzzle.jpg#/media/File:Pagoda_Burr_Puzzle.jpg
“Pagoda Burr Puzzle” by Meronim – Own work. Licensed under CC BY-SA 3.0 via Commons – https://commons.wikimedia.org/wiki/File:Pagoda_Burr_Puzzle.jpg#/media/File:Pagoda_Burr_Puzzle.jpg


To keep the list manageable I have left out conditions addressed in my previous posts on the most practical and helpful neurology guidelines and top all-time neurology review articles. I have also been selective in choosing the single reference that I think best reflects each condition. I must also confess that I cheated a little; many are paediatric conditions, but they are all neurological.

Gorilla Scratching Head. Eric Kilby on Flikr. https://www.flickr.com/photos/ekilby/18047130741
Gorilla Scratching Head. Eric Kilby on Flikr. https://www.flickr.com/photos/ekilby/18047130741


The first class of esoteric neurological diseases are conditions that should be familiar, or vaguely so, but the neurologist needs to do a bit of hard thinking and reading-up to solve.

  1. Aceruloplasminaemia
  2. Alexander disease
  3. Benign hereditary chorea
  4. CANVAS syndrome
  5. Cerebrotendinous xanthomatosis (CTX)
  7. Dentatorubral pallidolyusian atrophy (DRPLA)
  8. Fatal familial insomnia (FFI)
  9. Fragile X tremor ataxia syndrome (FXTAS)
  10. Generalized epilepsy with febrile seizures plus (GEFS+)
  11. Gerstmann Straussler Scheinker (GSS) syndrome
  12. Lafora body disease
  13. Menke’s disease
  14. Miller Dieker syndrome
  15. MNGIE
  16. Myofibrillar myopathy
  17. Neuro Sweet syndrome
  18. Ornithine transcarbamylase (OTC) deficiency
  19. Potassium aggravated myotonias
  20. Progressive encephalomyelitis rigidity and myoclonus (PERM)
  21. Pyridoxine-responsive epileptic encephalopathy
  22. Rapid onset dystonia parkinsonism (RDP)
  23. Refsum’s disease
  24. Rippling muscle disease (RMD)
  25. Tyrosine hydroxylase deficiency (THD)



The next set of 25 conditions are rather rare but a phone call to a nearby expert is likely to resolve the diagnostic and management difficulty. These are:

  1. Adult polyglucosan body disease
  2. Alpers syndrome
  3. Barth syndrome
  4. Biotin responsive basal ganglia disease
  5. Brown-Vialetto Von-Laere (BVVL) syndrome
  7. Facial onset sensory and motor neuronopathy (FOSMN)
  8. Hemiconvulsion hemiplegia (HH) syndrome
  9. Hereditary myopathy with early respiratory failure (HMERF)
  10. Jeavon’s syndrome (eyelid myoclonia with absences)
  11. Joubert syndrome
  12. Kufor Rakeb
  13. Landau Kleffner syndrome
  14. Melkersson Rosenthal syndrome
  15. Nemaline myopathy
  16. Neuronal ceroid lipofuscinosis (NCL)
  17. Ohtahara syndrome
  18. Panayiotopoulos syndrome (PS) 
  19. Pantethonate kinase associated neurodegeneration (PKAN)
  20. Perry syndrome
  21. Raeder’s paratrigeminal syndrome
  22. Rett syndrome
  23. Sialidosis
  24. Tangier disease
  25. Tarui disease


And below are probably the 25 most esoteric neurological conditions. I consider these among the conditions most neurologists would generally have very little knowledge or experience of, and there would probably be a few experts worldwide who would have experience in them.

  1.  17q deletion syndrome 
  2. 4H Syndrome
  3. Brody disease
  4. Calsequestrin storage myopathy
  5. Coffin Lowry syndrome 
  6. Congenital cataracts facial dysmorphism neuropathy (CCFDN)
  7. Curranino syndrome
  8. Danon disease
  9. Doose syndrome
  10. Nasu Hakola disease
  11. Pelizaeus Marzbacher disease 
  12. PHARC syndrome
  13. Pourfour du petit syndrome
  14. Sandhoff disease
  15. Satoyoshi syndrome
  16. Schwartz Jampel syndrome
  17. Sepiapterin deficiency
  18. SEPN-1 related myopathy 
  19. Sialic acid storage diseases
  20. Sjogren Larsson syndrome
  21. Unverricht Lundborg disease
  22. Vici syndrome
  23. Wolf Hirschhorn syndrome
  24. Woodhouse Sakati syndrome
  25. Zellweger syndrome

Here is a pdf of all 75 esoteric neurology conditions. The is a personal, non-evidenced, list; understandably there will be differing opinions-especially from our Ivory towers! The list is therefore not immutable so please post your comments; I am open to expanding or deflating it with justifiable reason. And don’t worry, there are checklists on all these esoteric conditions coming soon.