Tuesday, 2 May 2017

Neuro Doc Gnanapavan's round up of AAN 2017, Boston

This year the American Academy of Neurology (AAN) conference was held at the Boston Convention & Exhibition Center, South Boston, MA. Nearby, in the Boston Harbor are the Boston Tea Party Ships & Museum; for those of you who are unaware of the history between the Brits and the Americans on this one - it makes a riveting read. A few parallels can even be drawn to the current trade agreement being negotiated by the UK with the US in the wake of 'Brexit'. Despite the history of Boston, it is ironically also known as the most British of American cities (also known as New England's gateway city), and people queue...

But I digress, what of AAN? For those of you who have been following my live tweets, you'd have a fair idea of the highlights:

Number One
1. Progressive MS 

SIPONIMOD (Selective S1P1 and S1P5 receptor modulator) IN SECONDARY PROGRESSIVE MS (SPMS) - presented by Prof Ludwig Kappos, MD

In RRMS (relapsing-remitting MS) Phase 2 BOLD study, siponimod 2mg reduced active MRI lesions at 3mth by 72% and annualized relapse rate at 6mth by 66%. A further study has now been done in SPMS. It is a randomized, placebo-controlled (i.e. there was dummy arm) study with time to 3-month confirmed disability progression (CDP) assessed by EDSS (disability scoring system) as its primary endpoint. Efficacy was reported as a hazard ratio, which quantifies the risk reduction under siponimod treatment versus dummy treatment. 

The subjects included in the study were aged 18-60y, had prior RRMS, were SPMS (defined as progressive disability of at least 6mths in the absence of relapses or independent of relapses), EDSS score of 3.0-6.0 [these criteria will define future licensing of siponimod]. The EDSS scores were matched between the two arms, as was the number of Gd+ lesions, but the siponimod arm tended to have less relapses in the 2y prior to screening than the dummy arm (64 vs 80%). 

Outcomes: Time to 3mth CDP; risk reduction of 21% in the siponimod arm. This was influenced by the number of relapses 2y prior to screening (i.e. favored siponimod in this study). However, the timed 25foot walk at 3mth (as confirmed worsening by ⋟20% from baseline) was not significantly different between the two arms - this may because of the difficulty walking those with higher disability and the day to day variability in walking SPMS, or simply 3mths is too early to see an effect on walking. When they divided the trial up with those ⋞ EDSS 5.5, there was a trend favoring siponimod in the times 25foot walk, but this was not significant (i.e. the lower your disability the more likely you are to benefit from siponimod). There was an 81% reduction in new and enlarging T2 lesions and 86% reduction in Gd+ lesions in the siponimod arm vs. placebo.

Overall, I feel the siponimod trial outcomes are promising, but I will have to be realistic with my MS patients in saying that they may not see clear objective improvments in the short term.


  • Most important - will the inflammatory component reactivate upon cessation? Does discontinuation depend on the treatment being taken i.e. highly active therapies vs. moderately active therapies?
  • Even in progressive MS there is a need to preserve function, for example upper limb function, cognition (intelligence & memory), vision, bowel/bladder function etc.
  • Neuronal reserve - what is the consequence of another relapse? Can make the difference of requiring a stick to being hoisted from the bed. 
  • Time to first relapse in stoppers is similar to stayers when there is a long period of relapse freedom (Kister et al. JNNP 2016 Oct p1133).
  • Relapses within the first 5y of disease impact on disease progression only over the short-term, long-term impact is minimal (particularly with disease duration >10y or already in SPMS) [Tremlett et al. Neurology 2009 Nov p1616].

Number Two
2. Imaging


Background - the ability to differentiate demyelination or non-specific white matter disease (NSWM) due to aging, migraine headaches or small vessel ischaemia is limited in the traditional 2D MRI images of brain lesions. Their objective was to describe MS lesions using 3D imaging and surface characteristics and see whether this can be used to differentiate MS from NSWM. They found MS lesions were more associated with asymmetry and complex surface morphology and were more likely to be multi-lobular and elongated. In addition, protruded and sloped lesions were only observed in MS (see figure below).

Figure: Cross-sectional MRI FLAIR images of the brain (on the left, top and bottom) and 3D printed regions of interest of 9 unique PwMS. Primary MS lesion features (top image) are demonstrated with asymmetric (A-D), symmetric (E-H), complex surfaces (I-L), and simple surfaces (M-P). Secondary MS lesion features (bottom image) are demonstrated of multi-lobular (A-D), elongated (E-H), protrusion (I-L), sloped edge (M-P) traits observed.

CHARACTERIZATION OF SPINAL CORD LESIONS IN MS USING HIGH FIELD MRI [Ouellete et al. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown]

Although spinal cord lesions pay an important contribution to disability in MS, little is known about them because they are difficult to visualize using conventional MRI. Using high-field MRI (in this case 7T MRI) allows for an improvement in signal-to-noise ratio permitting better delineation of gray (GM) and white matter (WM) areas.

They found over time there is increasing involvement of the spinal cord GM as a result of lesion accumulation and atrophy (volume loss). Although, generally there is contribution from both GM and WM lesions to clinical disability; the degree of involvement of the GM depicted by cross-sectional area is the best predictor of disability.

Figure: Spinal cord imaging of upper cervical levels in a 42y old non-MS female (marked as control going through C1-C4 top to bottom), 45y old RRMS male (marked RRMS, disease duration 4y, EDSS 2), and 36y old SPMS male (marked SPMS, disease duration 20y, EDSS 6.5).

Number Three
3. EBV - Epstein Barr Virus

FINNISH MATERNITY COHORT STUDY ON EBV [Ascherio A et al. Harvard school of public health, Boston]

Background - EBV antibodies cross the placenta and may provide protection against primary EBV infection in early childhood (similar results observe with maternal EBNA1 antibodies [the viral protein associated with EBV). 

Children born between 1983-1991 and diagnosed with MS before 2009 were studied. 176 MS cases and 326 control cases were identified. 

They found an association between maternal VCA IgG (the presence of VCA IgG antibodies indicate that EBV infection has occurred recently or in the past) level during pregnancy and risk of MS in the offspring. Similarly, there was an association between maternal EBNA-1 (the presence of EBNA-1 IgG indicate that EBV infection occurred in the past, antibodies form 6-8 weeks after infection and are then present for life) and EA-D IgG (the presence of D early antigen IgG antibodies indicate recent or current EBV infection) level during pregnancy and risk of MS in the offspring. This effect was independent of the association between maternal vitamin D levels and offspring MS risk.

Of course, the findings need confirmation in other population groups. Moreover, the biological mechanism is unclear, but I'll make a crazy assumption that the exposure risk may be primed in utero! 

Now, for those of you already bored reading the above, here are some pictures that I took!

 Boston Tea Party Ship
 Boston Harborwalk
Center piece at the mfa Museum of Fine Arts


  1. Regarding siponimod:
    How is it possible they measured relapses and Gd+ lesions to SPMS? Isn't the definition of SPMS that patients don't relapse anymore, but they are getting progressively worse?

    1. You can still have superimposed relapses, this is called relapsing progressive MS. One study found that when people switch from RRMS to SPMS there are relapses for 5y into the SPMS phase. Imaging is often not done in progressive MS but you can see from this study that there is ongoing MRI activity.

  2. Bitterly disappointed to read that Siponimod will be restricted to people with an EDSS score of 3.0-6.0 I missed the boat for RRMS and the same again for me with SPMS. Right now my EDSS is 6.5.

    Sounds like I will just have to bugger along as best I can. Mind you it will be a few years before NICE give the nod and I might have fallen off my perch by then.

  3. Reasons to continue DMT

    Even in progressive MS there is a need to preserve function, for example upper limb function, cognition (intelligence & memory), vision, bowel/bladder function etc.

    But none of this matters of you're in wheelchair?.........

    How is that fair if legs are only things affected????

    1. I entirely agree, which is why we are asking the US & UK MS Societies to support our submission to the NIHR for funding of our 'CHARIOT MS' trial for people with an EDSS of 6-8.5, and upper limb function, among others, as outcome.

    2. This is about doing trials in wheelchair users, Dr K has been trying to get funding to do a study in the higher EDSS scores for cladrabine for sometime now...

    3. I knew about this trial last year and contacted Prof G who in turn copied KS in on his response.
      Is the funding any nearer and how best to be considered?

    4. Unfortunately, we're not as close to CHARIOT MS as we wish to.

      There's a dog-chasing-tail story to it. If a drug has been left by the wayside – as cladribine had been following the EMA rejection in 2011, until about 2015 – charities and public funders are reluctant to support a trial because they are initially suspicious of the reason of rejection, which is understandable, however often remain so even after giving evidence-based answers to every question on the planet, which is perhaps less understandable.

      Despite making the case that serendipity is presenting a huge opportunity to change the lives of pwMS across the Globe, and at every stage of their MS, the belief in "what big pharma does must be right" is overwhelming. As a result, nothing much happens, apart from some lip service support.

      Once pharma resurrects the drug as a potentially big earner, nothing will happen outside pharma even if the regulatory license may be very narrow (say relapsing but not including progressive disease), and the company had no intention of extending it by undertaking new trials, for example to include people in wheel chairs. We won’t give up, however only after the summer (at the earliest) will we know where we stand.

      Compassionate use remains an option, and we have done this at BartsMS on a number of occasions.

    5. thanks for the reply. When you mention compassionate use can neurologists still use compassion as a means to prescribe drugs for wheelchair users since blueteq or does blueteq only prevent neurologists prescribing high end drugs compassionately?

  4. Hi can Klaus please reply to the last post re compassion and Blueteq please. I've received my ms drugs most probably through compassion but will Blueteq put an end to that?

    1. Apologies...
      It's either Blueteq, which applies to DMT for which you have to fulfill NHSE eligibility criteria, or compassionate of drugs that are not commissioned via Blueteq/NHSE because they are not licensed for MS. Hence, unless you find a neurologist who enters false evidence in the Blueteq form to enable you access to NHSE approved drugs, you will have to find somebody prepared to treat you with off-label medication.


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