AAN 2019 posters #3


All good things unfortunately come to an end, and sadly this is the last in the series of three on AAN 2019 posters. What has captured my attention from this years AAN has been the varied interests of the clinician scientists who have presented their work here. This is a good sign, because without varied interests, science and ultimately progress slowly comes to a standstill. I call it the ‘great stagnation’. But, is science really hitting the wall? Probably not if AAN 2019 is anything to go by.

I’m often asked about diet by my MS patients, and beyond Vitamin D and Omega-3 fatty acids there is very little evidence behind the exclusionary diets. But here’s one that gives you food for thought.

1. Dietary intake and the effect on disease progression in people with MS. Meier-Gerdingh et al., RUHR-University, Germany

We know that diet is an important metabolic determinant in the general population (e.g. diabetes), but PwMS are at even greater risk of metabolic disorders. Diet influences many of the mechanisms implicated in MS (immune function, gut microbiota etc.). But, is there an association between diet an disability levels?

In a cross-sectional study, 135 PwMS filled in a detailed 102-item food frequency questionnaire. Diet quality (DASH score) was scored based on quality of the foods (favorable – fruits, vegetables, nuts and legumes, whole grains and diary; unfavorable – salt, sugar-sweetened beverages (SSBs), red and processed meats).

Overall, DASH scores were not found to be associated with disability status (see Figure 1a below). However, in an analysis of individual DASH score components, those with a higher intake of SSBs had a greater risk of severe versus mild-moderate disability (see Figure 1b below, p-value for trend 0.01). Those in the top quartile of SSB intake consumed on average 292 kcal from SSBs while people in the bottom quartile consumed on average 7 kcal from SSBs per day.

Although, this is preliminary work, the potential trend between SSBs and higher disability in MS is an interesting. But, it is also possible that having severe MS impedes a healthy diet and this is a potential confounder.

Figure 1: DASH scores and disability levels

2. Neurofilament light chain levels in pregnant multiple sclerosis patients. Cuello et al., University Hospital Basel.

NfL, which is a marker of neuro-axonal injury was assessed in the blood during pregnancy and puerperium in 39 PwMS with RRMS (P-MS), 5 non-pregnant PwMS (NP-MS) and 21 pregnant women without MS (HPW). 8 P-MS suffered relapses during pregnancy.

NfL levels tended to be higher in P-MS than HPW (see Figure 2 below). However, it is only the P-MS with a relapse (RP-MS) that had higher NfL values in the third trimester, but this was no different to NP-MS. P-MS without relapses had lower NfL values compared to NP-MS at first and third trimesters and during puerperium.

Although, a relatively small study, longitudinal NfL levels may have potential as a biomarker to monitor MS during pregnancy.

Figure 2: Serum neurofilament light chain levels in pregnancy with relapse, no relapse, non-MS pregnancy (controls) and non-pregnant PwMS.

3. Adjusting neurofilament light levels using an MRI-based estimate of total axonal bulk improves its prediction of MS progression. Phillips et al. NIH.

NfL measurements are proving to be good biomarker of disease progression in MS, however, in some instances there are significant overlaps in measurements with that of healthy controls. This may be because not all factors in the brain that lead to the final result can be accounted for. But, by measuring the total brain volume as a representation of total neuronal content it may be possible to account for some of these factors.

These group of investigators have therefore devised a methodology for estimating total brain neuronal bulk (see Figure 3 below). They then used this as a correction to adjust NfL values and found it better delineated the different MS subtypes from non-MS cases (not shown), and had greater predictive value in relation to MS progression by MS-DSS scale (see Figure 4 below).

Figure 3: Method for adjusting NfL values
Figure 4: Unadjusted and adjusted NfL values and disability scores (MS-DSS)

4. Impact of cervical stenosis on multiple sclerosis lesion distribution in the spinal cord. Gratch et al., University of Pennsylvania Health System.

Narrowing of the spinal canal (called canal stenosis) with degenerative spine changes is not unusual with ageing in both MS and non-MS cases. Often the two can co-exist and cause diagnostic challenges. There have also been suggestions in the past that the stenosis can cause underlying damage to the spinal cord (see Figure 5, displayed as Figure 2 below) and MS lesions may be more common in these areas. No one has really systematically checked whether this is the case.

Here, they looked at exactly this comparing 100 co-existing MS/stenosis cases and 100 MS-only controls. Surprisingly, they found that MS lesions were more likely to occur in the lower cervical regions in those with both MS and stenosis (See Figure 6, displayed as Figure 3 below) and appeared to be related to the distribution of the cervical stenosis (see Figure 7, displayed as Figure 4 below).

They hypothesize that the repetitive trauma caused by the stenosis may lead to blood brain barrier injury and influx immune cells leading to MS plaque formation. One hypothesis you’ll never be able to convincingly prove!

Figure 5: MS lesion versus stenosis-related cord damage
Figures 5, 6: The association between cervical cord MS lesions and existence of cervical stenosis

5. Oligoclonal band number correlates with relapses and progression in multiple sclerosis. Perrone et al., University of Pennsylvania.

The oligoclonal bands (OCBs) in the CSF depicting antibody production by the immune system is a reliable marker of MS, found in greater than 90% of PwMS. In fact last year, the OCBs were incorporated into the latest version of the McDonald Criteria for diagnosing MS. Some have even suggested that the number of bands visualized may have prognostic value – wherein those with a lower number had a more favorable prognosis.

In this work, they looked at 128 PwMS. 92% were OCB positive, and were divided into those less than 10 bands and greater than 10 bands. Looking at their clinical activity over a two year period, those with >10 bands had a greater annualized clinical and MRI relapse rate (see Figure 7 below). Moreover, the use of a new or more advanced assistive device was more likely in those with >10 bands.

Quantification of OCB bands may therefore help identify those that require a more active DMT earlier on in their disease course.

Figure 7: Greater relapses and progression in PwMS with >10 OCBs

6. Leprosy in two patients with relapsing remitting multiple treated with fingolimod. Balasa et al., Baylor College of Medicine.

If you ever wandered if Leprosy is still around, here is proof that it never went away, and for those of you that haven’t heard about leprosy, it is well worth doing your research on the topic.

Fingolimod like other immunosuppressants leads to an increased risk of infections, but with fingolimod the sustained lymphopenia means that additional quirky infections need to be also considered.

Here, they report two cases, both female, with lymphopenia following fingolimod treatment for ~35 months (see Figure 8, displayed as Figure 1 below). Both were potentially exposed to armadillo feces!

Figure 8: Leprosy affecting skin and joints

7. Serious adverse events in rituximab-treated patients with multiple sclerosis and related disorders. Wallach et al., New York University School of Medicine.

Rituximab, like ocrelizumab is an anti-CD20 and targets B cells, depleting them. Unlike, ocrelizumab it has been used for many years in other disorders with FDA approval in 1997 for lymphomas. But, there is limited long-term data for its use in MS.

Here, data of almost 1000 cases is presented. The cumulative dose of rituximab was ~4g over this period. The most frequent serious adverse events were infections ~7% (see Figure 9 below), of which ~8% had lymphopenia (unfortunately IgG levels were only available in half of the patients, and was present in ~23% of those measured). So, surprisingly the infections were not always related to the lab abnormalities.

The occurrence of other autoimmune disorders (Crohn’s, coeliacs etc) was 0.6%, with a mean time to diagnosis of 1.3y, whilst mortality was 1.4% within 12 months of the last rituximab dose, although none were felt to be related to rituximab by their clinicians.

Figure 9: Infections on rituximab resulting in hospitalization

8. CNS T cell lymphoproliferative diseases following treatment with alemtuzumab. Horton et al., Rocky Mountain MS Center.
?We know all about the autoimmune disorders related to alemtuzumab, but what of the other potential effects on the immune system. In CAMMS223, CARE-MS I and II and their extensions studies, non-EBV associated Burkitt’s lymphoma, Castleman’s disease (a pre-lymphomatous state resulting in activation of plasma cells) have been reported very rarely.

Here, the authors report what they believe to be the first case of CNS T-cell lymphoma, which unfortunately was fatal. The MRI images are available below (see Figure 10).

We know that after alemtuzumab B cells re-populate as early as three months, whilst T cells may take much longer, as much as 60 months. It’s possible that this prolonged CD4+ lymphopenia may be an issue in some cases.

Figure 10: MRI pre and post treatment with alemtuzumab. A- 8 months prior to treatment, B- 18 months after initiation of 1st alemtuzumab infusion. FLAIR with progressive confluent, asymmetric white hyperintensities with patchy enhancement. Started on rituximab and high dose steorids, C- 22 months post alemtuzumab, D-24 months post alemtuzumab, post treatment with rituximab, high dose methotrexate, procarbazine, vincristine, methylprednisone, and cytosine arabinoside.

9. INROADS: A Phase 3 study to assess the efficacy and safety of ADS-5102 (Amantadine) extended release capsules in multiple sclerosis patients with walking impairement. Cameron et al., Oregon Health & Science University, Portland.

Approximately 50% of PwMS become dependent on walking aids after 15years. ADS-5102 is designed to produce a slow rise in amantadine in the blood, so that when taken before going to bed, peak drug levels occur in the morning around awakening and is sustained throughout the day (this is different to Amantadine immediate release).

The authors report on the results of a 4-week phase II study (see Figure 11 below) in 60 PwMS that shows significant improvement in walking compared to placebo. The team are still enrolling for a larger Phase III study (INROADS), and results are expected by the end of the year.

Amantadine is licensed for the treatment of dyskinesia (fidgety movements) in Parkinson’s disease, and sometimes used off-label in MS for fatigue management.

Figure 11: Statistically significant improvement in walking in the ADS-5102 group versus placebo in the T25F walk

About the author

Neuro Doc Gnanapavan


  • Thanks NDG for all your effort feeding back your thoughts on the key research presented. MS research appears to be in the doldrums at the moment. When I was diagnosed in 2009 I was pretty optimistic with initiatives such as the NMSS Promise 2010 and the emphasis on protection and repair. This programme has delivered neither. I was also optimistic about the projects funded by the UK MS Society such as the Cambridge Centre for Myelin Repair – I’ve yet to see any benefits for patients. MS Research has helped deliver some effective anti inflammatory drugs, but the car has stalled. We don’t seem to be making any headway with cause, disease processes, neoroprotection or repair. There is a big focus for on measurement eg nfl levels etc, but a patient doesn’t just need a measure to say that they are getting worse, but treatments to stop the worsening or reverse it. Is there a sense at these meetings from those you meet that MS research is just treading water at the moment?

    • So the brain is the most difficult organ to crack in terms of understanding function and disease. But if you look at MS, back in the mid 90s it was at the same position as where Alzheimer’s, Parkinsons and motor neurone disease are. Yet though investment in research has moved ahead of these conditions. So it is worth pushing forward those small gains.

      Promise 2010 had as part of it the Lamtorigine trial in SPMS that on subsequent post hoc analysis showed stabilisation in the walking of those who were blood drug level compliant with the medication. This later spurred on the phenytoin study in optic neuritis that showed reduction in the loss of RNFL in those on phenytoin versus placebo. At the same period there was the high dose simvastatin study that showed reduction in brain volume loss versus placebo. This is now going onto a larger phase III study. The studies I have listed have all been clinician led and have not proceeded beyond Phase II studies, because of funding issues. But, efforts need to focus on the work that has been done and have given a read out and progressed further.

      Other studies in Progressive MS that have shown promise is Ibudilast and Biotin.

      I have to admit I didn’t expect the remyelination programme to work as MS at a fundamental level has axonal damage, which is even more at the later stages of MS. It’s like trying to insulate the pipe when there are portions that are missing.

      • ” So it is worth pushing forward those small gains.”

        At least your honest…some say those small gains are mountains.

      • “Other studies in Progressive MS that have shown promise is Ibudilast and Biotin.”

        They have…seemed like small rewards..?

  • A more obvious (and, indeed, rather stupid) confounder in the diet study is that it lumps highly nutritious red meat on the ‘bad’ list with the crisps and the fizzy pop instead of the ‘good’ list where it has much more right to be than do grains, for instance. Daft.

  • NDG I would like to ask an irrelevant to the post question: Does early cortisone impove the outcome of a relapse or it just speeds up the recovery time? The official brochures say the second but I remember you saying that you would want to administer cortisone the soonest possible (for better outcomes?). Thank you!

  • Number 8. (CNS atypical T-cell lymphoproliferative disease following treatment with alemtuzumab) looks a lot like my own case (https://nn.neurology.org/content/5/5/e483) in which I (an MS patient) developed CNS atypical T-cell lymphoproliferative disease following treatment with Fingolimod (Gilenya).
    Unfortunately, the email address of the authors of the paper is nowhere to be found, otherwise I would have sent them an email.

  • Thanks very much for chewy research summaries. Nutrition obviously very complicated to study, but am a little bewildered by how dairy [assume that’s what is meant by ‘diary’ above] finds its way into the ‘favourable’ end of the researchers’ healthy eating axis, given that it’s anathema to all the more or less respectable MS diets (Swank, OMS, Wahls etc). Would love to know the rationale, as cheese and cream are fondly missed old friends.

    • So, by traditional dietetics training diary products land in the healthy spectrum. Remember, majority of the world relies on diary to provide sufficient calories and calcium for the bones. Last year when I was clamouring around in Tibet at ~5200m on a trek I drank yak milk with ghee; the stuff was atrocious and wouldn’t wish it on my worst enemy, but gave me the energy that I regularly needed at high altitude! Everything is relative, as long as you balance what has worked before in so far as diet is concerned with exercise you should be fine. The occasional cake is also a boost to the endorphins!!



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