Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) 
demyelinating disease and a leading cause of permanent disability. Patients most 
often present with a relapsing-remitting disease course, typically progressing 
over time to a phase of relentless advancement in secondary progressive MS 
(SPMS), for which approved disease-modifying therapies are limited. In this 
review, we summarize the pathophysiological mechanisms involved in the 
development of SPMS and the rationale and clinical potential for natalizumab, 
which is currently approved for the treatment of relapsing forms of MS, to exert 
beneficial effects in reducing disease progression unrelated to relapses in 
SPMS. In both forms of MS, active brain-tissue injury is associated with 
inflammation; but in SPMS, the inflammatory response occurs at least partly 
behind the blood-brain barrier and is followed by a cascade of events, including 
persistent microglial activation that may lead to chronic demyelination and 
neurodegeneration associated with irreversible disability. In patients with 
relapsing forms of MS, natalizumab therapy is known to significantly reduce 
intrathecal inflammatory responses which results in reductions in brain lesions 
and brain atrophy as well as beneficial effects on clinical measures, such as 
reduced frequency and severity of relapse and reduced accumulation of 
disability. Natalizumab treatment also reduces levels of cerebrospinal fluid 
chemokines and other biomarkers of intrathecal inflammation, axonal damage and 
demyelination, and has demonstrated the ability to reduce innate immune 
activation and intrathecal immunoglobulin synthesis in patients with MS. The 
efficacy of natalizumab therapy in SPMS is currently being investigated in a 
randomized, double-blind, placebo-controlled trial.