Multiple Sclerosis is an inflammatory and degenerative disease of the central nervous system which includes the brain, spinal cord and also the optic nerves.
Clinical Characteristics
The most common form of multiple sclerosis is the relapsing remitting form ( RRMS) which is characterized by episodes of acute worsening symptoms with recovery and periods of remission in between. About 85% of patients are diagnosed with this form of multiple sclerosis. The typical patient is diagnosed in their 20s or 30s.
The other form is progressive multiple sclerosis. Progressive MS can be further classified as secondary or primary progressive.
Secondary progressive MS is what follows relapsing-remitting disease when one studies the natural history of the disease. Over time in patients with relapsing disease, the up and down course is replaced by a steady state with gradually worsening gait/fatigue/cognition. Inherently the rate and level of change in these problems is widely variable between individual patients. This is the untreated natural history of the disease, however in the era of early effective treatment, our goal in treating the RRMS patient is to prevent/delay the onset of secondary progression and prevent/decrease the level of disability. And with early optimal treatment our current medications are capable of achieving these goals.
Primary progressive MS on the other hand is not preceded by a relapsing-remitting phase before the onset of difficulty with gait. The onset is not acute and more insidious and here the problems tend to stay and not fully recover as in a relapse. This type of MS is typically diagnosed in patients in their 40s to 50s.
Pathological Features
A relapse in RRMS is caused by a new lesion in the brain, spinal cord or optic nerve. The presenting symptoms depend on the location of the lesion/s. A lesion is formed when harmful immune cells ( lymphocytes) cross the blood-brain barrier ( which is a fence that prevents everything in blood from entering the brain freely ) and enter the
tissue and cause inflammation. Normally the blood-brain barrier is not permeable to these cells. Once a lesion happens, over the next several days the healing process starts including remyelination, removal of the debris and recovery of neurons and repair of the breach in the blood- brain barrier, and this corresponds to improvement in symptoms. Though this is an over simplified explanation, this helps understand the predominant cause of worsening symptoms in RRMS.
The disease mechanisms in progressive MS on the other hand are very different from that of RRMS and much more complex. Often in patients with progressive MS, worsening symptoms are not associated with a new lesion or changes on MRI. There is no infiltration of lymphocytes from the blood into the brain through a breached blood-brain barrier that causes the worsening.
Rather than this kind of infiltration of immune cells from the periphery, there are resident immune cells within the brain or in the covering of the brain called meninges that propagate a low-grade inflammation. There is also activation of immune cells normally present in the brain called microglia into a destructive form. These cells can also cause damage in normal appearing white matter (NAWM) which is white matter on MRI scans that do not show a lesion and hence appears normal. Apart from this there is also more oxidative stress injury and age-related degenerative mechanisms that can play a role in disease worsening.
Given these differences, treatment approaches to progressive MS have to be geared towards targeting specific disease mechanisms involved. Our current treatments address some of them, but there are more avenues to be explored. Treatments that can modulate microglia, decrease oxidative stress, enhance remyelination and stem-cell therapy are being studied.