#ClinicSpeak: chemobrain in MS

HSCT or BMT accelerates brain atrophy rates and disability worsening in SPMS. #ClinicSpeak #MSBlog #MSResearch

I am revisiting this old paper to make it a Saturday trilogy of posts on HSCT.

HSCT (hemopoetic stem cell transplantation) or BMT (bone marrow transplantation) requires chemotherapy to ablate or wipe-out your immune system to allow the stem cell transplantation. The chemotherapy drugs that are used are neurotoxic, i.e. they damage the brain.

PwMS who already have pre-existing damage to their brain and spinal cords are particularly susceptible to the neurotoxic effects of chemotherapy. This is also driven by age; the older you are the worse you handle chemotherapy. The oncologists refer to this observation as chemobrain, which is particularly prevalent in the elderly. 

The following study below in which I was involved with shows that when pwMS are given chemotherapy they undergo increased neuronal loss, which is associated with worsening of their EDSS and greater brain atrophy. The data speaks for itself. The picture below is what we call a survival curve of EDSS worsening; you can see that the pwMS who had high blood levels of neurofilaments were much more likely to worsen than those who did not have raised neurofilament levels. Similarly, brain atrophy rates in pwMS were in the order of 2.1% per year in those who had a HSCT compared to only 1.2% per year in pwSPMS who did not have HSCT; the upper limit of normal for brain atrophy in healthy adults is generally accepted to be 0.4% per year. The bottom line is that if you have SPMS HSCT is likely to accelerate your disease worsening. As a result of these and similar observations most units have stopped doing HSCT in people with more advanced MS. However, with the advent of highly-effective DMTs such as alemtuzumab, natalizumab, fingolimod, daclizumab, ocrelizumab and cladribine the number of pwMS needing to be referred for HSCT should be small. 



Petzold et al. Evidence for acute neurotoxicity after chemotherapy. Ann Neurol. 2010 Dec;68(6):806-15.

OBJECTIVE: Chronic neurotoxicity is a recognized long-term complication following chemotherapy in a range of diseases. Neurotoxicity adversely affects patients' quality of life. The objective of this study is to examine whether there is evidence of acute neurotoxicity.


METHODS: This prospective study included MSers with secondary progressive multiple sclerosis (SPMS-BMT, n = 14) and hematological malignancies (HM-BMT, n = 17) receiving chemotherapy as preconditioning for bone marrow transplant. The control groups included SPMSers matched for demographic and clinical data (SPMS-PL, n = 14) and healthy controls (n = 14). Neurodegeneration was assessed at baseline and longitudinally (months 1, 2, 3, 6, 9, 12, 24, and 36), combining a clinical scale for disability (Expanded Disability Status Scale [EDSS]), a serum protein biomarker for neurodegeneration (neurofilaments, NfH-SMI35), and brain atrophy measures (magnetic resonance imaging).

RESULTS: Disability progression was significantly more acute and severe following chemotherapy compared to placebo. Immediately after starting chemotherapy, serum NfH-SMI35 levels increased in 79% (p < 0.0001) of SPMS-BMT MSers and 41% (p < 0.01) of HM-BMT patients compared to 0% of SPMS-PL MSers or healthy controls. In SPMS-BMT serum NfH-SMI35 levels were > 100-fold higher 1 month after chemotherapy (29.73ng/ml) compared to baseline (0.28ng/ml, p < 0.0001). High serum NfH-SMI35 levels persisting for at least 3 months were associated with sustained disability progression on the EDSS (p < 0.05). Brain atrophy rates increased acutely in SPMS-BMT (-2.09) compared to SPMS-PL (-1.18, p < 0.05).

INTERPRETATION: Neurotoxicity is an unwanted acute side effect of aggressive chemotherapy.

CoI: Prof. G was a co-author on this study.

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