J Furby

Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial

BACKGROUND Partial blockade of voltage-gated sodium channels is neuroprotective in experimental models of inflammatory demyelinating disease. In this phase 2 trial, we aimed to assess whether the sodium-channel blocker lamotrigine is also neuroprotective in patients with secondary progressive multiple sclerosis. METHODS Patients with secondary progressive multiple sclerosis who attended the National Hospital for Neurology and Neurosurgery or the Royal Free Hospital, London, UK, were eligible for inclusion in this double-blind, parallel-group trial. Patients were randomly assigned via a website by minimisation to receive lamotrigine (target dose 400 mg/day) or placebo for 2 years. Treating physicians, evaluating physicians, and patients were masked to treatment allocation. The primary outcome was the rate of change of partial (central) cerebral volume over 24 months. All patients who were randomly assigned were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT00257855. FINDINGS 120 patients were randomly assigned to treatment (87 women and 33 men): 61 to lamotrigine and 59 to placebo. 108 patients were analysed for the primary endpoint: 52 in the lamotrigine group and 56 in the placebo group. The mean change in partial (central) cerebral volume per year was -3.18 mL (SD -1.25) in the lamotrigine group and -2.48 mL (-0.97) in the placebo group (difference -0.71 mL, 95% CI -2.56 to 1.15; p=0.40). However, in an exploratory modelling analysis, lamotrigine treatment seemed to be associated with greater partial (central) cerebral volume loss than was placebo in the first year (p=0.04), and volume increased partially after treatment stopped (p=0.04). Lamotrigine treatment reduced the deterioration of the timed 25-foot walk (p=0.02) but did not affect other secondary clinical outcome measures. Rash and dose-related deterioration of gait and balance were experienced more by patients in the lamotrigine group than the placebo group. INTERPRETATION The effect of lamotrigine on cerebral volume of patients with secondary progressive multiple sclerosis did not differ from that of placebo over 24 months, but lamotrigine seemed to cause early volume loss that reversed partially on discontinuation of treatment. Future trials of neuroprotection in multiple sclerosis should include investigation of complex early volume changes in different compartments of the CNS, effects unrelated to neurodegeneration, and targeting of earlier and more inflammatory disease. FUNDING Multiple Sclerosis Society of Great Britain and Northern Ireland.

Magnetic resonance imaging measures of brain and spinal cord atrophy correlate with clinical impairment in secondary progressive multiple sclerosis

Background Neuroaxonal loss is a pathological substrate of disability in progressive multiple sclerosis (MS) and can be estimated in vivo by measuring tissue atrophy on magnetic resonance imaging (MRI). While there is some evidence that brain atrophy correlates better with disability than T2 lesion load in secondary progressive MS, the clinical relevance of atrophy within specific regions of the central nervous system requires further evaluation. Methods Clinical and MRI examinations were performed in 117 subjects with secondary progressive MS. MRI analysis included measures of normalized brain volume (NBV), normalized grey matter (NGMV) and white matter volume (NWMV), central cerebral volume (CCV), spinal cord cross-sectional area (SCCA), and brain T2 and T1 lesion volume. Clinical assessments included the expanded disability status scale (EDSS) and MS functional composite (MSFC). Results All MRI measures correlated significantly with the MSFC score, with the strongest correlation being for the NBV (r = 0.47; P < 0.001). NBV and SCCA were the only significant independent predictors of the MSFC score in a stepwise regression model containing all the MRI measures, and SCCA was the only MRI measure to show a significant association with the EDSS. While NGMV had stronger correlations with the clinical variables than NWMV, NBV was more correlated with clinical impairment than either measure. Conclusions This data suggests that measures of atrophy, particularly of the whole brain and spinal cord, are relevant and useful disease markers in secondary progressive MS.

Cervical cord and brain grey matter atrophy independently associate with long-term MS disability

In MRI studies of multiple sclerosis (MS), brain grey matter (GM) and spinal cord atrophy correlate with disability.1 2 However, it is uncertain whether they independently associate with long-term disability. We measured upper cervical cord cross-sectional area (UCCA) in a cohort of patients ∼20 years after presenting with a clinically isolated syndrome (CIS) suggestive of MS. Associations of brain GM atrophy and white matter (WM) lesion load with disability had been previously observed in the cohort.1 We now report UCCA measurements and independent associations of the cord and brain measures with disability. Seventy patients presenting with CIS had analysable brain and MRI scans acquired on a 1.5 T scanner after a median of 20 years (range 18–27). Clinically definite MS (CDMS) was diagnosed clinically.3 Disability was assessed with the expanded disability status scale (EDSS)4 and MS functional composite score (MSFC) plus its three components, paced serial auditory attention test (PASAT; 3 s interval), nine-hole peg test (9HPT) and 25-foot timed walk (T25FW). CDMS subgroups were defined as relapsing–remitting (RR) or secondary progressive (SP) MS; those with an EDSS ≤3 were classified as benign.5 At the 20-year follow-up, 27 remained CIS, 32 had RRMS (21 benign MS, 11 non-benign RRMS (EDSS>3)), and 11 had SPMS. UCCA and brain MR parameters were measured as previously described.1 2 UCCA was also measured in 17 healthy volunteers. Statistical analysis was performed using the SPSS Version 11.0 (SPSS, Chicago, Illinois) and Stata 9.2 (Stata Corporation, College Station, Texas). Subgroup comparisons of UCCA were performed …

Biomarker Report from the Phase II Lamotrigine Trial in Secondary Progressive MS – Neurofilament as a Surrogate of Disease Progression

Objective Lamotrigine 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. Methods SPMS 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. Results Treatment 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. Conclusions The 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.

Grey matter magnetization transfer ratio independently correlates with neurological deficit in secondary progressive multiple sclerosis

Although there is substantial brain grey matter pathology in secondary progressive multiple sclerosis (MS), there has been limited investigation of its contribution to disability.This study investigated the correlation of magnetization transfer ratio (MTR) measures taken from brain grey matter, normal appearing white matter (NAWM) and lesions with neurological deficit and disability in 113 people with secondary progressive MS. In order to adjust for the potential effects of focal white matter lesions and global brain atrophy, T2 lesion volume and normalized brain volume (NBV) were also calculated for each subject. Clinical measures included the expanded disability status scale (EDSS) and the multiple sclerosis functional composite (MSFC) scores. Linear regression analysis was used to assess the age- and gender-adjusted correlation of MTR histogram mean, peak height and peak location with the MSFC and individual component measures. Logistic regression analysis was used to determine whether imaging measures could be used to predict if subjects were in the higher disability group (EDSS ≥ 6.5).Significant correlations were detected between MSFC composite and mean MTR in (i) normal appearing white matter (NAWM; r = 0.327, p < 0.0001), (ii) grey matter (r = 0.460, p < 0.0001) and (iii) lesions (r = 0.394, p < 0.0001). Although NBV and T2 lesion volume correlated significantly with MSFC, grey matter histogram mean emerged as the best predictor of MSFC score. None of the MRI measures significantly predicted higher EDSS.These results suggest that brain grey matter pathology plays an important role in determining neurological impairment. The apparent paucity of correlation between MRI measures and EDSS is likely to represent the relative insensitivity of the latter measure in this study group.

Different white matter lesion characteristics correlate with distinct grey matter abnormalities on magnetic resonance imaging in secondary progressive multiple sclerosis.

Background Although MRI measures of grey matter abnormality correlate with clinical disability in multiple sclerosis, it is uncertain whether grey matter abnormality measured on MRI is entirely due to a primary grey matter process or whether it is partly related to disease in the white matter. Methods To explore potential mechanisms of grey matter damage we assessed the relationship of white matter T2 lesion volume, T1 lesion volume, and mean lesion magnetisation transfer ratio (MTR), with MRI measures of tissue atrophy and MTR in the grey matter in 117 subjects with secondary progressive multiple sclerosis. Results Grey matter fraction and mean grey matter MTR were strongly associated with lesion volumes and lesion MTR mean (r = ±0.63–0.72). In contrast, only weak to moderate correlations existed between white matter and lesion measures. In a stepwise regression model, T1 lesion volume was the only independent lesion correlate of grey matter fraction and accounted for 52% of the variance. Lesion MTR mean and T2 lesion volume were independent correlates of mean grey matter MTR, accounting for 57% of the variance. Conclusions Axonal transection within lesions with secondary degeneration into the grey matter may explain the relationship between T1 lesions and grey matter fraction. A parallel accumulation of demyelinating lesions in white and grey matter may contribute to the association of T2 lesion volume and lesion MTR with grey matter MTR.