by Elena Moro
For November 2016 we have selected: Cree BAC, Gourraud P-A, Oksenberg JR, et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol 2016:80;499-510.
Studies describing the natural history of multiple sclerosis (MS) before the availability of disease-modifying treatments have reported a progression of the disease from the relapsing-remitting form to the secondary progressive form in about 50% of patients at 19 years after the onset. Little information is available on the impact of the new treatments on MS progression in the long-term.
The long-term course of MS has been prospectively evaluated in this single-center observational study (EPIC) including 517 patients (18-65 year-old) between July 2004 and September 2005. Patients with both clinically defined MS or clinically isolated syndrome were recruited. Clinical measures at baseline, every year up to 5 years, and at 10 years included brain MRI, blood samples for biomarkers and genomics, neurological assessments with the Expanded Disability Status Scale (EDSS), the times 25-foot walk (T25W), the 9-hole peg test (9HPT), and the paced serial auditory addition test (PASAT-3). The patients were treated with disease-modifying therapies, including interferon therapy, glutiramer acetate, steroids, azathioprine, and escalation to high-potency therapy such as natalizumab, rituximab, mitoxantrone, and cyclophosphamide. No evidence of disease activity (NEDA) was defined as no relapses, no clinically significant increase in EDSS, no new or expanding T2 lesions, and no gadolinium-enhanced lesions on brain MRI from baseline to the 2-year end-point.
At the 10-year end-point, 471 patients were available (91%), with a median time of 16.8 years since the disease onset. Of these, 407 patients had relapsing-remitting MS (RMS), and 64 patients had progressive forms of MS (PMS). In 55.3% of the RMS patients there was a significant increase of the EDSS scores. The different levels of EDSS score at baseline did not predict the worsening. Instead, more than 75% of PMS patients showed a worsening, and those with baseline EDSS scores Within the first 2 years of the study, 82.1% of RMS patients presented with clinical and/or MRI disease activity. Thus, only 17.9% satisfied the NEDA criteria. However, NEDA at 2 years did not predict the EDSS outcome at 10 years, and NEDA patients had a trend towards a worsening in EDSS score within the years. Moreover, the finding of new or expanding T2 lesions from baseline up to year 2 was not related to further worsening of clinical assessments.
An increase in the EDSS score within the first 2 years was unexpectedly linked with a lower risk of progressive worsening, possibly due to treatment escalation. Serum level of 25-OH vitamin D was coupled with risk of focal disease activity, but not with long-term disability.
“This prospective study following over 10 years MS patients who have been treated with disease-modifying treatments has shown that 41% of this population did not progress in disability, but remained stable or improved. These results are very encouraging when compared to data coming from the pretreatment era (only 10.1% of RMS patients transitioned to SPMS in this study compared to the 30-50% in the pretreatment time)”, says Prof. Jera Kruja, Department of Neurology, University of Medicine Tirana, Albania. “Moreover, the evolution to sustained disability was slower than expected, since only 10.7% of patients had an EDSS score ≥6 at the 10-year end point, compared with the 50% reported from previous studies concerning the MS natural history.”
“The presence of brain MRI new T2 lesions or gadolinium enhanced lesions, and of the increase in the EDSS scores within the first 2 years of the study did not have any predictive value on the long-term outcomes,” says Prof. Maria Trojano, Department of Neurology, University of Bari, Italy. “These findings also challenge the concept of NEDA, that was similarly not associated with the long-term outcomes, and overall support the need of other biomarkers as predictors of disease progression. The study has several limitations, such as being a single-center observational study, and including a relatively small number of participants. Moreover, in the next future, it needs to be determined by a comparative effectiveness observational study whether high-intensity therapy started at time of the diagnosis further improve the long-term progression and disability in comparison to an escalation therapy.”
The other nominees for the November 2016 Paper of the month are:
– Elias WJ, Lipsman N, Ondo WG, et al. A randomized trial of focused ultrasound thalamotomy for essential tremor. N Engl J Med 2016;375:730-739. Seventy-six patients with essential tremor were randomized to undergo unilateral focal ultrasound thalamotomy or sham procedure. At 3-month follow-up patients with thalamotomy had significant benefit in contralateral hand tremor compared to sham patients. Improvement was maintained at 1-year time point. Permanent gait disturbances and paresthesias occurred in 9% and 14% of the lesioned patients, respectively.
– Saver JL, Goyal M, van der Lugt A et al., for the HERMES Collaborators. Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke. A meta-analysis. JAMA 2016;316:1279-1288. This meta-analysis involving 1,278 patients with large-vessel ischemic stroke (634 of them with endovascular thrombectomy) enrolled in 5 trials, shows that the odds of better disability outcomes at 3 months in the 634 patients decreased with longer time from symptom onset to endovascular treatment. There was no benefit from thrombectomy after 7.3 hours from symptom onset.
– Hutchinson PJ, Kolias AG, Timofeev IS, et al., for the RESCUEicp Trial Collaborators. Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med 2016;375:1119-1130. Four-hundred and eight patients with traumatic brain injury and refractory intracranial hypertension were randomly operated on with decompressive craniectomy (201) or managed with medical care (188). At 6-month follow-up surgical patients had reduced mortality, and higher rates of vegetative status. Moderate disability and good recovery rates were similar between the two groups of patients.