Ageing brain – lessons from childhood MS

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Childhood onset MS has some unique features compared to adult onset MS. Firstly, it tends to be more active than adult onset MS with a greater number of relapses and more MRI activity, but equally has better reparative capacity and a later onset of progressive disease. But this is as far as the dis-similarities go.

If it walks like a duck and quacks like a duck, I call that bird a duck!

In a two year study of 37 paediatric MS, Bartels et al. recently found that paeds cases had smaller brain volumes at first presentation, and follow-up scans revealed persistent brain volume loss (see figure below). Moreover the brain volume loss appears to correlate with relapses, i.e. disease severity.

Failure of brain growth over 2-year follow-up. Mean brain volume z-scores at onset (first clinical presentation) and at follow-up after 2 years (mean ± SEM). Whole brain volume and white matter volume z-scores show significant reduction over 2 years, indicating accelerated brain volume loss in MS patients compared to healthy controls. Accordingly, patients show a significant increase in ventricular CSF volume (vCSF) z-scores over 2 years: (a) whole brain volume, (b) white matter volume, (c) grey matter volume, (d) peripheral grey matter volume, and (e) ventricular CSF volume.

If we look at adult MS we find the same; firstly brain volume loss is present at all stages of MS, be it CIS, RRMS, SPMS or PPMS, and secondly, the early clinical features matter (see figure below).

A greater number of lesion volume in the first five years means you reach hard disability milestones much faster (Fisinuku et al. Brain 2008)

So what we’re observing in MS, regardless of onset is that it’s a disorder of pathological ageing. If you’re not convinced have a look at the figure below, the neurofilament release in the various sub-types of MS captures this beautifully (see figure below).

Accelerated ageing in MS as reflected by axonal loss (Disanto et al. Ann Neurol 2017).

ABSTRACT
Mult Scler. 2019 Apr 4:1352458519829698. doi: 10.1177/1352458519829698. [Epub ahead of print]

Childhood multiple sclerosis is associated with reduced brain volumes at first clinical presentation and brain growth failure.

Bartels F, Nobis K, Cooper G, Wendel E, Cleaveland R, Bajer-Kornek B, Blaschek A, Schimmel M, Blankenburg M, Baumann M, Karenfort M, Finke C, Rostásy K.

BACKGROUND: Paediatric multiple sclerosis (pedMS) patients at a single site were shown to have reduced brain volumes and failure of age-expected brain growth compared to healthy controls. However, the precise time of onset of brain volume loss remains unclear.

OBJECTIVE: To longitudinally study brain volumes in a multi-centre European cohort at first presentation and after 2 years.

METHODS: Brain volumes of high-resolution magnetic resonance imaging (MRI) data from 37 pedMS patients at first presentation prior to steroid therapy and at 2-year follow-up ( n = 21) were compared to matched longitudinal MRI data from the NIH Paediatric MRI Data Repository.

RESULTS: Patients showed significantly reduced whole brain, grey and white matter and increased ventricular volumes at initial presentation and at follow-up compared to controls. Over 2 years, patients exhibited significant reduction of whole brain and white matter volumes, accompanied by increased ventricular volume. Brain volume loss at follow-up correlated with a higher number of infratentorial lesions, relapses and an increased Expanded Disability Status Scale (EDSS) score.

CONCLUSIONS: In pedMS patients, brain volume loss is present already at first clinical presentation and accelerated over 2 years. Increased disease activity is associated with more severe brain volume loss. MRI brain volume change might serve as an outcome parameter in future prospective pedMS studies.

About the author

Neuro Doc Gnanapavan

7 comments

  • Secondary endpoints
    Two patients experienced a clinical relapse post HSCT, both
    occurring about 2 years after the procedure. Both patients also
    had simultaneously appearing gadolinium-enhancing lesions.
    These patients were classified as secondary progressive MS
    (SPMS) patients. One further patient with relapsing-remitting MS
    had subclinical disease with new T2-lesions and gadoliniumenhancing
    lesions in the absence of relapses. Unfortunately, one
    patient did not have follow-up MRI and data were missing for two
    additional patients. As a consequence, it was difficult to assess
    freedom from disease activity, but evidence of post-HSCT disease
    activity was present in only 3 out of 18 evaluable patients. Notably,
    four patients had follow-up for 10 years or more, with no records
    of recurring disease activity.

    Although often seen as benign in the short term, pediatric onset
    MS is a particularly severe form of MS with impact on
    development, acquisition of skills and education, necessary for a
    normal adult life. Treatment of children with MS should therefore
    aim at early disease control and the threshold for treatment
    escalation should be low. In 2012, the International Pediatric
    Multiple Sclerosis Study Group put forth guidelines for assessment
    of treatment efficacy. In the guidelines inadequate treatment is
    defined by either an increase or no reduction in relapse rate, new
    T2 or contrast enhancing lesions on MRI, or two or more
    confirmed clinical exacerbations within a 12-month period or
    less.24 aHSCT is a promising alternative for children failing
    standard therapy, with the advantages of immediate disease
    control and functional improvement in a majority of patients.
    Furthermore, this one time procedure offers the advantage of
    avoiding adverse events associated with the continuous administration
    of disease-modifying drugs, which could affect school
    performance and have a negative impact on quality of life. On the
    downside, aHSCT is associated with risk of serious adverse events,
    such as potentially dangerous infections, secondary autoimmunity
    and decreased fertility. A more precise estimation of such risks
    should be subject to further study; meanwhile, we advocate that
    this procedure be performed at experienced centers only.

    Autologous hematopoietic stem cell transplantation for
    pediatric multiple sclerosis: a registry-based study of the
    Autoimmune Diseases Working Party (ADWP) and Pediatric
    Diseases Working Party (PDWP) of the European Society for
    Blood and Marrow Transplantation (EBMT)

    Bone Marrow Transplantation (2017), 1–5
    © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0268-3369/17

  • “So what we’re observing in MS, regardless of onset is that it’s a disorder of pathological ageing.”

    What does this mean in layman’s terms (the pathological ageing bit)?

    It sounds bad. My arrogant neuro told me that I had taken the diagnosis badly. Given the quote above, I believe I was right.

    • Hi Kevin, the brain losses volume as you age. It normally occurs at a rate of 0.1-0.3% per year. This is because the Bain is losing neurones (neurofilament release in the CSF with ageing captures a bulk of this, you can see this in the figure above). With MS this occurs at a faster rate, and PwMS reach the ageing milestones faster because of the brain volume loss. As you can see in the neurofilament graph those with progressive disease (PPMS/SPMS) are at greater risk of more neuronal loss (ie have greater neurofilament loss) at the same ages compared to controls. That is what I mean by pathological ageing.

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