Abstract
ObjectiveLamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment.MethodsSPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12–24 and 0–24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored.ResultsTreatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12–24 months p = 0.043, Nfh 0–24 months p = 0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin.ConclusionsThe relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration.
Highlights
Sodium channel blockade is postulated to protect axons from anoxia-induced injury secondary to neuroinflammation
Treatment effect by comparing differences in NfH, NOx, GFAP, BDNF and NGF values based on lamotrigine serum adherence and tablet compliance
Reduction in NfH levels by measuring differences 0–12, 12–24 and 0–24 m between lamotrigine adherent and non-adherent groups revealed significant differences between the two groups at NfH 12–24 and NfH 0–24 m, p = 0.043 and p = 0.023, respectively. This was further supported by measuring rate of change, where lamotrigine adherent group showed a significant change between 0–24 m in NfH levels (p = 0.041), with NfH levels at 12– 24 m having a p-value of 0.055
Summary
Sodium channel blockade is postulated to protect axons from anoxia-induced injury secondary to neuroinflammation. The Phase II lamotrigine trial in secondary progressive MS encountered an unexpected result with lamotrigine causing early cerebral volume loss that partially corrected after discontinuation of treatment. This effect may have been due in part to reversible fluid shifts or a reduction in inflammation due to the treatment. Neurofilament proteins are the scaffolding proteins of neurons and are markers of neuro-axonal injury [1,2]. CSF neurofilament (NfH) have been shown to be higher in all sub-types of MS compared to control subjects and elevated during the active [3] as well as the progressive phases correlating with clinical scales EDSS and MSFC [1,4]. NfH is detectable in the blood but has only been studied in one retrospective study evaluating response to interferon-b therapy, with no significant differences between the responders and the non-responders [5]
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