Multiple Sclerosis Research Repository

1. An argument for broad use of high efficacy treatments in early multiple sclerosis: James M. Stankiewicz, MD

-the amount of damage to the brain that MS causes is underappreciated

-In addition, the above-referenced study by Sinnecker et al. reported that every T2 hyperintensity visualized in the brain was hypointense on magnetization prepared rapid acquisition with gradient echo at 7T, suggesting that all MS lesions are in fact “black holes.” Even then, 7T imaging is an imperfect tool. Pitt et al.12 reported that 7T MRI visualized 82%–93% of cortical lesions apparent at pathology.

-Measures of whole-brain atrophy and gray matter atrophy correlate cross-sectionally better with clinical disability than conventional measures such as T2 lesion volume, T1 hypointensities, and gadolinium enhancing lesions,13

-Novel imaging techniques such as diffusion tensor imaging (DTI), magnetization transfer ratio (MTR), and 23Na MRI imaging all demonstrate that more damage is present than is visualized on conventional MRI.

-23Na MRI imaging allows direct visualization of ongoing cellular dysfunction and cell death.

-A study of 45 patients with newly diagnosed relapsing-remitting MS found a decrease of whole-brain cerebral viscoelasticity relative to matched healthy volunteers and suggested a more widespread disturbance of tissue integrity than expected from the few visible T2 lesions.16 A measure of macromolecular integrity, MTR is reduced in normal-appearing white and gray matter from patients even at the earliest clinical stages of the disease17 with reduced MTR correlated with disability18 and cognitive impairment.19

-Recent patient survey work and disability claims reveal significant disability over time. In the North American Research Committee on Multiple Sclerosis (NARCOMS) database of patients mostly treated at 15 years after diagnosis, only 13% of patients reported no or mild symptoms. Moderate or greater disability was reported by >40% of patients in hand function, vision, cognition, bowel/bladder function, spasticity, pain, fatigue, and coordination. At 30 years, moderate or greater disability was reported for mobility in 69%, hand function in 60%, vision in 47%, cognition in 50%, bowel/bladder function in 70%, spasticity in 65%, pain in 64%, depression in 35%, fatigue in 72%, and tremor/coordination in 51%.21

-A recent survey of NARCOMS participants with a mean age of 55 years found that 58% of patients were not working, with 48.5% of those surveyed received disability benefits. Of those employed, 27% reported missing 6 days or more of work a year. Moderate to severe cognitive impairment, fatigue, and hand function problems were associated with both disability and absenteeism.22

-Of adults 65 years or older, 15% of patients without MS reported using an assistive device, whereas 81% of patients with MS required an assistive device in the NARCOMS cohort, a 6-fold difference.23,24

-More efficacious MS drugs, which better control inflammatory disease, are not a panacea. Studies of even the most effective agents available for MS indicate that no evidence of disease activity (NEDA) is achieved in only 47.7% of ocrelizumab-treated patients29 when followed up for 96 weeks and 29.5% of natalizumab-treated patients followed up for 2 years.30 So, even with best possible efficacy, an argument can be lodged that our treatments are not fully adequate.

– A population-based cohort in the United Kingdom found that patients (n = 104) treated initially with highly effective therapy had a lower mean change in EDSS at 5 years and a higher median time to sustained accumulation of disability than those treated with moderately effective therapies (n = 488). This effect persisted after adjustment for covariates including age and sex.50

-Once patients reach a DSS of 4, progression to cane dependence (DSS of 6) occurs independent of relapses.54

-a rational interpretation of the published literature might be to use a HETA in patients younger than 40 years of age

-The MSBase consortium recently analyzed a cohort of 1,555 patients with MS and found that individuals treated with higher efficacy agents developed secondary progressive disease later.55-In addition, a neurologist waiting for “efficacy failure” may be engaged in a frivolous exercise. Our current ability to monitor disease using clinical and radiologic measures is fair at best. Studies evaluating the prognostic value of NEDA find that it is poorly predictive of the outcome over the longer term.57,58 Ongoing brain structural damage (as measured by DTI) has been reported in patients who meet NEDA criteria.59 As such, a neurologist looking for overt signs of drug failure as manifest by clinical or MRI change may be ill advised.