Primary-Progressive Multiple Sclerosis

The Less Talked-About Form of MS

Historically, primary-progressive multiple sclerosis (PPMS) has seemingly taken a back seat to other types of multiple sclerosis (MS). By far, the largest amount of information published about research and treatments for multiple sclerosis (MS) has been in reference to relapsing-remitting and secondary-progressive forms of MS (RRMS and SPMS respectively). No disease-modifying therapies have been approved for the long-term treatment of PPMS, although many experimental medications are being studied with this form of MS in clinical trials.

The emphasis has been on RRMS and SPMS for a number of reasons. First, 85 percent of individuals diagnosed with MS begin with the RRMS form, and after many years, RRMS usually advances to SPMS – so clearly the vast majority of patients fall under these categories. Second, RRMS, with its trademark flare-ups and remissions, is the easiest to identify, measure, and observe changes – both in terms of symptoms and diagnostic/ evaluative testing. And third, unlike PPMS (and eventually SPMS), constant flare-ups of inflammation play a vital role in RRMS.

This inflammation in RRMS occurs within the brain and spinal cord (components of the central nervous system [CNS]), and gives researchers a specific target for potential drug and treatment therapies. Disease flare-ups as well as ongoing subclinical disease activity (referring to changes occurring inside the body without any new or worsening symptoms) are frequently observed and measured through the use of magnetic resonance imaging (MRI) technology.

In contrast to RRMS, only 10 percent of individuals with MS are diagnosed with PPMS, and only five percent have a form known as progressive-relapsing MS (PRMS). These types of MS often begin (or present to the doctor) with a very gradual accumulation of walking difficulties. At the same time, PPMS (and early PRMS) patients do not experience any type of exacerbation, or flare-up of symptoms.

Equally confounding for the treating physician is the fact that little or no abnormalities will be visible on the gadolinium-enhanced MRI scan – which is a standard diagnostic tool for identifying lesions (areas of inflammation) in RRMS. Gadolinium is a chemical agent used to highlight areas of inflammation. It is administered to a patient prior to having an MRI scan performed. Since PPMS patients have little or no known inflammation, these types of scans can often appear normal, with little or no evidence of active MS.

The reason for a normal-appearing MRI of the brain as well as the presenting symptom of gradual walking difficulties, is the fact that most of the disease’s effects are thought to take place in the spinal cord for individuals with PPMS. An MRI of the spinal cord shows a slowly worsening spinal cord syndrome, also known as progressive myelopathy, in at least 60 percent of those diagnosed with this type of MS. Atrophy (cell death) is often apparent in the spinal cord, along with loss of tissue, largely caused by the degeneration of nerve fibers.

Two features are necessary for a doctor to diagnose PPMS. First, the patient must be experiencing a slow and gradual worsening in his or her symptom(s), and second, she or he must have never had a flare-up of symptoms (also known as a clinical relapse, exacerbation, or attack). Some individuals who are initially diagnosed with PPMS, unexpectedly begin experiencing acute flare-ups of their symptoms. This is what distinguishes a person as having PRMS, and the diagnosis at that time is changed from PPMS to PRMS. As mentioned earlier, approximately five percent of individuals with MS are eventually diagnosed with PRMS – but these patients always begin as having PPMS.

Not everyone with PPMS experiences walking difficulties and has disease activity largely limited to the spinal cord. A portion of individuals with PPMS are found to have progressive cerebellar syndrome. People who are diagnosed with this type of PPMS show significant changes on their brain MRI, often similar to someone with SPMS. And rather than presenting with problems walking (in terms of strength), someone with progressive cerebellar syndrome will typically have difficulties with balance as well as a disabling tremor.

Do the Various Forms of MS Differ Biologically?

Obvious differences exist in the demographics of who is initially diagnosed. Twice as many women are diagnosed with RRMS than men, whereas PPMS is divided equally between the genders, and some sources report a slight tendency toward more men than women being diagnosed with this form of MS. Individuals are typically diagnosed or experience initial symptoms of RRMS as a young adult, often in one’s teens or 20s. The onset of PPMS is generally after age 35, with many people being diagnosed in their 40s or 50s.

For several years, experts in the field of MS have suggested that at least two different types of disease pathologies are involved with MS. One mode of action is inflammation, as seen as gadolinium-enhanced active lesions on an MRI scan and as a flare-up of symptoms. This is believed to occur as myelin (protective nerve covering) and axons (nerve fibers) are attacked by one’s own immune-system.

Certain types of immune-system cells and chemical responses promote inflammation and damage to the CNS, with resultant flare-ups of symptoms. To a certain extent the myelin may be repaired (remyelination) and function returned (remission). Over time, however, eventual accumulation of deficits usually occurs. The flare-ups and remissions are the defining disease behaviors for RRMS. Inflammation is thought to also be involved to a certain extent with the other types of MS that may exhibit flare-ups and remissions (PRMS and SPMS).

The second mode of action is degeneration, which may be defined as the deterioration of specific cells. As with inflammation, degeneration is thought to be caused by one’s own immune system. This process does not promote extensive inflammation, but rather is thought to pre-program healthy cells for an early death. And as the myelin and axons die off, deficits relating to these areas of damage slowly progress. This appears to be the type of disease activity with PPMS, PRMS, and SPMS, although the latter two may have more inflammatory component because PRMS patients and some SPMS patients experience flare-ups.

These two modes of action – inflammation and degeneration – help to differentiate RRMS from PPMS. Finding treatments for these different types of MS may well involve different approaches.

Future Research with PPMS

Looking to future treatments, researchers point out that the next line of MS drugs and therapies may be aimed at repairing and regenerating lost myelin and nerve fibers (axons). This would have the potential for a return of function, which is a vital goal in MS research. Some agents are showing this type of action in animal studies, but making the leap from animal studies to human trials can be a long and difficult transition.

Neuroprotection is another area of great interest for the treatment of all types of MS. If successful, this type of treatment would potentially protect the central nervous system from damage caused by an attack from the body’s immune-system cells. Theoretically, nerves and myelin would remain more intact, and patients would have fewer symptoms.

While scientists may need several years to accomplish such mighty goals, today’s approved drugs for MS are effective in slowing down disease activity for individuals with relapsing forms of the disease. This has been a dramatic step toward a cure, and with studies now being directed to PPMS as well, researchers believe it will only be a matter of time before individuals with PPMS may also have access to several effective disease-modifying treatments.

By Susan Wells Courtney, MSAA Senior Writer
Reviewed by Dr. Jack Burks,MSAA Chief Medical Officer