Monday, 13 April 2015

Treat PPMS Early with Neuroprotectives.

Abdel-Aziz K, Schneider T, Solanky BS, Yiannakas MC, Altmann DR, Wheeler-Kingshott CA, Peters AL, Day BL, Thompson AJ, Ciccarelli O.Evidence for early neurodegeneration in the cervical cord of patients with primary progressivemultiple sclerosis.
Brain. 2015. pii: awv086. [Epub ahead of print]

Spinal neurodegeneration is an important determinant of disability progression in patients with primary progressive multiple sclerosis. Advanced imaging techniques, such as single-voxel 1H-magnetic resonance spectroscopy and q-space imaging, have increased pathological specificity for neurodegeneration, but are challenging to implement in the spinal cord and have yet to be applied in early primary progressive multiple sclerosis. By combining these imaging techniques with new clinical measures, which reflect spinal cord pathology more closely than conventional clinical tests, we explored the potential for spinal magnetic resonance spectroscopy and q-space imaging to detect early spinal neurodegeneration that may be responsible for clinical disability. Data from 21 patients with primary progressive multiple sclerosis within 6 years of disease onset, and 24 control subjects were analysed. Patients were clinically assessed on grip strength, vibration perception thresholds and postural stability, in addition to the Expanded Disability Status Scale, Nine Hole Peg Test, Timed 25-Foot Walk Test, Multiple Sclerosis Walking Scale-12, and Modified Ashworth Scale. All subjects underwent magnetic resonance spectroscopy and q-space imaging of the cervical cord and conventional brain and spinal magnetic resonance imaging at 3 T. The differences in imaging measures between groups and the relationship between magnetic resonance imaging measures and clinical scores, correcting for age, gender, spinal cord cross-sectional area, brain T2 lesion volume, and brain white matter and grey matter volume fractions were assessed. Although patients did not show significant cord atrophy when compared with healthy controls, they had significantly lower total N-acetyl-aspartate (mean 4.01 versus 5.31 mmol/l, P = 0.020) and glutamate-glutamine (mean 4.65 versus 5.93 mmol/l, P = 0.043) than controls. Patients showed an increase in q-space imaging-derived indices of perpendicular diffusivity in both the whole cord and major columns compared with controls (P < 0.05 for all indices). Lower total N-acetyl-aspartate was associated with higher disability, as assessed by the Expanded Disability Status Scale (coefficient = -0.41, 0.01 < P < 0.05), Modified Ashworth Scale (coefficient = -3.78, 0.01 < P < 0.05), vibration perception thresholds (coefficient = -4.37, P = 0.021) and postural sway (P < 0.001). Lower glutamate-glutamine predicted increased postural sway (P = 0.017). Increased perpendicular diffusivity in the whole cord and columns was associated with increased scores on the Modified Ashworth Scale, vibration perception thresholds and postural sway (P < 0.05 in all cases). These imaging findings indicate reduced structural integrity of neurons, demyelination, and abnormalities in the glutamatergic pathways in the cervical cord of early primary progressive multiple sclerosis, in the absence of extensive spinal cord atrophy. The observed relationship between imaging measures and disability suggests that early spinal neurodegeneration may underlie clinical impairment, and should be targeted in future clinical trials with neuroprotective agents to prevent the development of progressive disability.


So we can read the conclusions  "early spinal neurodegeneration may underlie clinical impairment, and should be targeted in future clinical trials with neuroprotective agents" to prevent the development of progressive disability.and it should come as no big shakes that this is what is needed. It is so obvious. 

The question you and I are asking is what are they going to use in clinical trials. There are some neuroprotective trials ongoing and due to start in PPMS.

 It is obvious the sooner you stop nerve damage the better that is going to be. In this study they cannot detect shrinkage of the spinal cord, but the animal studies clearly show that nerve atrophy can occur before the spinal cord actually shrinks and so beware this is probably a misleading surrogate and underestimates the problem.

33 comments:

  1. Hi Team G

    Are you aware if Avastin (Bevacizumab) can falsely make an MRI look normal when there is a cervical cord lesion/atrophy.
    IN my case there is a debate as to whether I have PPMS or delayed radiation myelpathy. I had avastin treatment for DRM and this normalized the MRI in June 2013 only for it to return in October 2013.
    Thankyou

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  2. Have there been any studies involving the use of creatine as a neuroprotective? Given the potential impact of Biotin on energetics, and the emphasis in certain diets on creatine intake, would high-dose creatine supplementation be something that could also have a beneficial impact? Thanks for your consideration.

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    1. There have been studies on the use of creatine as neuroprotective, but there is no evidence that high dose creatine supplementation is beneficial in MS as yet. There have been studies in other conditions andthe question again is how high is high dose.

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  3. In particular, creatine-AKG appears to have some impact during the Krebbs cycle.

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  4. Are there any plans to research this that you are aware of? I also note that a recent 2015 paper about Tysabri found:

    "Patients treated with natalizumab showed an increase in total N-acetylaspartate, creatine and phosphocreatine, and glutamate in lesional white matter. These increasing metabolite concentrations might be a sign of enhanced axonal metabolism."

    Perhaps this deserves further study?

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    Replies
    1. I don't know precisely but there is research into energy metabolism for sure

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  5. Is it worth chucking doses of creative into our food then?

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    1. I doubt it, otherwise where to do you stop, it is so plausible to develop a rationale to supplement with a variety of different things, but dose will be key and this is where studies are lacking.

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  6. Well hopefully biotin( md1003) will come to the rescue :) praying for us all !

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  7. With progressive types does the rate of profession stay the same throughlut the disease
    I.e I have gone from having no symptoms to trouble walking over 200m with stiff legs in less than 4 months!
    Would this plateau at all or will this continue at this rate? It almost feels like prms, is lemtrada etc accepted for prms?

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  8. What about treating PPMS early with either MSCT or hsct? We know early on in PPMS patients can have active inflammation?
    We also know that early in the disease process the chances of success are better? Surely in a case like above, the possible benefit of hsct etc far outweighs the risk of the future and how fast it's progressing?

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    1. They are still working out how best to do these treatments and treatment failures can knock back the programme. I am sure some PPMSers will have some benefit but I don't think it will stop the progression however it needs a proper trial because otherwise we are no the wiser.

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  9. MD what would you do in my position from 0-edss 4/5 in 4 months? With no sign of relenting and no time to wait for trials?
    The institute in Russia are claiming around a 60% success rate which drops a touch if no enhancing lesions?

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    1. I'm not MD, however suggest in the first instance your diagnosis is being reviewed. EDSS 0 to 4 or even 0 to 5 within 4 months is very uncommon in PPMS. Current diagnostic criteria require at least 1 year of disease deterioration from onset - was this the case? Else, I would be reluctant to call this PPMS, but rather rapidly progressive or perhaps progressive-relapsing MS? If the latter were correct, I would probably recommend a drug used in people with relapsing MS, with Natalizumab topping my list pending your specific situation. Or perhaps you could join a HSCT trial?

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    2. My reply was to going to be to talk to DrK...which I did over lunch and thank you for giving me an idea as I did have a think what I would do and hopefully we can get a study off the ground

      Also there is the Laquinimod PPMS trial ongoing but

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    3. Anon 10.20am - if you haven't already had it done, you should get a thorough Vit B12 check-up done

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    4. DR K where you suggest joining a Hsct trial
      Is this for both rapidly progresive and progresive relapsing?
      What if hsct was available as a private patient on a paid basis would you suggest this?

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  10. Hi DrK Thankyou ever so much for the reply
    Having someone else's opinion on this matter is a help beyond belief
    The fact you guys take time to update let alone answer us is something we can never explain the gratitude for

    Should I email you the case of an objective case as I know you can't give specific advice?
    Your time is as always appreicated

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  11. Also would lemtrada be as beneficial as natalizumab ?

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  12. I'll be happy to be involved in any study personal or otherwise
    I would also be happy to fund a treatment for myself should it be needed
    It's either you guys or the Russians that get my money

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  13. Dr k with what you suggested what would you do if it was not the latter of the two?
    Are there any treatments ? As you can gather I'm up against it here and will try anything

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  14. I've had the b12 check it came up as 350, I was supplementing at the time but told that won't make a difference

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    1. I'm assuming you are the same Anon from the earlier posting on April 16 at 10.20am. If you mean 350 pg/ml that is actually in the grey zone and warrants further investigation, if you mean 350 pmol/L then that is an OK level. I'm not suggesting that B12 deficiency is necessarily the cause of your problems, but I had similar issues with worsening symptoms and no apparent reason for this (i.e. no relapses). I was taking extra B12 but because I had an unidentified folate deficiency caused by medications my supposedly adequate Serum B12 levels were actually false high readings due to the folate deficiency. Once the folate deficiency was addressed my B12 levels then sorted themselves out, and subsequent tests showed that my Active B12 (a test not usually done unless you specifically ask for it) had become the correct 20% of Serum B12 (which is the usual test done). While I had the folate deficiency some of my symptoms were a lot worse, but subsequently improved. However, I must note that my MS was diagnosed a couple of years before the folate deficiency was identified and I already had deficits and disability (3.5 EDSS), but my symptoms (especially coordination and fatigue) were worsening quite a lot until the folate problem was fixed. There’s quite a bit of info on B12 etc in the April Unrelated Blogger comments.

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  15. Mouse Dr k
    Which treatment would you suggest is most beneficial to ppms early
    Hsct or MSCT

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    1. There is not good evidence for either HSCT is about immune replacement msct is largely immunosuppression

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  16. I have read a lot about MSCT bejng successful in ppms?
    Thankyou anon for the b12 info
    I have read that 350 isn't great but didn't think it could cause all this? It was also during a time when I was supplementing b12 with a high dose vitamin but not sure it makes a difference

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    1. I’m not saying that B12 deficiency is the cause of your problems/symptoms, but after being told I had MS I started trying to find out more about MS as I was completely ignorant about it. What worried me was that I found out that B12 (and other B vitamin) blood tests were supposed to be part of the standard diagnostic workup for MS to rule out B12 deficiency as a cause of neurological symptoms – but for me not a single blood test was done for anything. Being put onto an expensive MS drug with nasty side effects was a catalyst for me to find out more, as I did not want to join the admittedly small “misdiagnosis club”, and B12 deficiency is a recognised MS mimic. I was lucky to have a very supportive GP who accepted that I’d done my research very thoroughly, and ordered the blood tests which then showed up the anomalies. If I had just sat back and accepted as gospel what I was told by various clinicians I would be in a right mess now. My medication related folate deficiency did produce a false high B12 test result, which was exacerbated by me taking the additional B12 I had been recommended to take (even though my B12 had not been tested). The B Group vitamins all work together and need to be in balance – and mine were not.
      Doctors are not infallible, they are human, and the current overloaded state of health systems around the world means that many of them just don’t get the time they really need with their patients, and the sad fact is that shortcuts are taken or assumptions made. Sometimes you have to take some responsibility for becoming informed about your problems, and become your own advocate so that you can make the most of the time you do get with your doctor/s. The internet can be your best friend or your worst enemy as there are plenty of charlatans and hope peddlers out there with their own barrows to push. I hope you are able to get some answers to your problems, and find a way forward.

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  17. Don't worry you have biotin just done a phase 3 for ppms

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  18. I read that it looks good !
    I wonder if it works for rapid cases though?

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  19. Even Mouse Dr probably doesn't have this data but fingers crossed it does work in rapid cases

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  20. Also Biotin won't be ready until 2017 by all
    Accounts

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