Wednesday, 8 June 2016

Brain shrinkage due to drugs used in HSCT

Lee H, Narayanan S, Brown RA, Chen JT, Atkins HL, Freedman MS, Arnold DL. Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis.Mult Scler. 2016. pii: 1352458516650992. [Epub ahead of print]

BACKGROUND:A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy.
OBJECTIVE:We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT.
METHODS:Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white-matter lesions.
RESULTS:Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was -0.23% per year, consistent with the rate expected from normal aging.
CONCLUSION:Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of "committed" tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.

We have been talking about HSCT and it is quite effective at inducing NEDA, but the drugs used to get rid of the immune system can be damaging. So in this study they see brain shrinkage. 

Whilst you may expect some shrinkage because the drugs will get rid of inflammation and swelling and eventually the rate of brain loss is at the level of age-related loss in healthly individuals. But they think that the drugs cause some nerve damage. They are probably right because ProfG showed that these drugs cause nerve damage.

Petzold A, Mondria T, Kuhle J, Rocca MA, Cornelissen J, te Boekhorst P, Lowenberg B, Giovannoni G, Filippi M, Kappos L, Hintzen R.Evidence for acute neurotoxicity after chemotherapy.
Ann Neurol. 2010;68:806-15. doi: 10.1002/ana.22169


  1. can/how does this compare with lemtrada data?

    my partner's ms clinic uses mri which measures brain atrophy. her pre treatment brain atrophy was normal relative to population but spine wasn't measured (she has about 12 lesions between spine and brain). i was really curious what would be found on the 6 month post treatment mri re atrophy, but it wasn't measured correctly or something so i'll have to wait 12 months to satisfy my curiosity (apparently, she doesn't want to have a second mri to satisfy my curiosity over something she has no control over lol). no bulsufan but lots of cyc lol

  2. For context, I think it's worth noting that the drugs used in non-myelo are nowhere near as harsh as Bulsaphan (as used in Dr Freedman's myeloablative protocol and this study).

    That's not to say they don't also lead to a degree of accelerated BVL though, and I guess the other question is whether non-myelo leads to the same normalisation to within the limits of normal aging.

    Fingers crossed - and it would seem logical based upon similar NEDA rates and the Lemtrada experience - but I've not seen this specifically studied in non-myelo protocols.

    1. there have been studies of brain atrophy post high dose Cyc but I have not found the numbers that would allow direct comparison with this small study (I haven't looked particularly hard either). For example,

      I'm confused about what this means - "The mean rate of long-term atrophy was -0.23% per year, consistent with the rate expected from normal aging." Is this saying that over the long term period (say 5 or more years) the atrophy actually actually stabilises to the average of the normal rate expected per year? Or is that that after the first 2 years, it stabilises to the normal rate but the initial loss is not mitigated by later slower losses? I hope that makes sense.

    2. I believe they are saying that with time the rate of atrophy goes to the rate of aging


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