Citations

Background Natural history of patients with incidentally discovered lesions that fulfill magnetic resonance imaging (MRI) criteria for multiple sclerosis (MS) in the absence of objective clinical symptoms suggestive of central nervous system (CNS) inflammatory-demyelinating disease is not well defined. Objective We evaluated the risk of developing symptomatic MS in patients with radiologically uncovered asymptomatic possible inflammatory-demyelinating disease (RAPIDD). Methods We identified and longitudinally followed a cohort of 22 patients from two tertiary care MS centers: Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey, and Mayo Clinic, Rochester, Minnesota, after an initial MRI study fulfilling the Barkhof–Tintore MRI criteria completed for other reasons unrelated to MS. Results Eight of 22 patients developed an objective clinical symptom consistent with a CNS inflammatory-demyelinating syndrome and fulfilled dissemination in space and time criteria for definite MS. Median age at the time of diagnosis of MS was 44.8 years (range 28.3–71.4 years). Time taken for the development of definite MS was studied by survival analysis. Cumulative event rates were; 12 months: 9%, 24 months: 15%, 36 months: 30.4%, and 60 months: 44.6%. Six of 22 patients were followed beyond 60 months. Two of these six patients developed MS later (at 66 and 112 months, respectively). Three patients remained asymptomatic despite follow-up of 10 years. Conclusions Patients with RAPIDD develop MS at a similar rate to treated patients (and less frequently than placebo groups) with clinically isolated syndromes from prior randomized controlled studies. Some patients with RAPIDD continue to have radiological evolution of subclinical disease without MS symptoms despite long follow-up periods.

AbstractTissue kallikrein KLK1 and the kallikrein-related peptidases KLK2–15 are a subfamily of serine proteases that have defined or proposed roles in a range of central nervous system (CNS) and non-CNS pathologies. To further understand their potential activity in multiple sclerosis (MS), serum levels of KLK1, 6, 7, 8 and 10 were determined in 35 MS patients and 62 controls by quantitative fluorometric ELISA. Serum levels were then correlated with Expanded Disability Status Scale (EDSS) scores determined at the time of serological sampling or at last clinical follow-up. Serum levels of KLK1 and KLK6 were elevated in MS patients (p≤0.027), with highest levels associated with secondary progressive disease. Elevated KLK1 correlated with higher EDSS scores at the time of serum draw and KLK6 with future EDSS worsening in relapsing remitting patients (p≤0.007). Supporting the concept that KLK1 and KLK6 promote degenerative events associated with progressive MS, exposure of murine cortical neurons to either kallikrein promoted rapid neurite retraction and neuron loss. These novel findings suggest that KLK1 and KLK6 may serve as serological markers of progressive MS and contribute directly to the development of neurological disability by promoting axonal injury and neuron cell death.