Primary progressive multiple sclerosis
Valerie L Stevenson, neurologist
National Hospital for Neurology and Neurosurgery, London
Open Door - February 2007 pages 10-11
What is primary progressive MS?
Most people with MS will be diagnosed with relapsing remitting MS. However about 10-15% of people will gradually notice increasing disability without any clear relapses or remissions and will be described as having primary progressive MS. Most commonly this is seen as increasing stiffness and weakness of the legs (progressive spastic paraparesis), but other symptoms can occur such as unsteadiness, tremor or visual loss.
Who gets primary progressive MS?
Although primary progressive MS is a rare form, there are still estimated to be more than 8,000 people affected in the UK. People with primary progressive MS are more likely to be older at onset and, unlike relapsing remitting MS, it is equally as common in men as in women.
One condition or two?
Several studies have compared primary progressive MS to other forms of MS to see if there is any evidence that it is a different condition altogether.
Magnetic Resonance Imaging (MRI)
When compared to relapsing remitting MS or secondary progressive MS, people with primary progressive MS tend to have fewer, smaller lesions (see figure 1); few new lesions over time; and less enhancement with gadolinium - a marker that is injected before an MRI scan to show areas of inflammation.
However these findings vary between people so it is impossible to tell what type of MS a person has from the MRI scan alone.
Figure 1 - Often fewer lesions are seen in primary progressive MS (left) than in relapsing remitting MS (right)
Pathological studies
Small studies have compared the post mortem examinations in people who have died with (not from) primary progressive MS:
Inflammation is present but less so than in secondary progressive MS
More lesions show loss of oligodendrocytes (the cells that form the myelin sheath) and reduced myelin repair compared to other MS subtypes
Immunology
Studies have failed to show any consistent findings to differentiate between MS subtypes.
Genetics
MS (mainly relapsing remitting MS) has been associated with specific genetic markers. However studies in primary progressive MS have involved small numbers and have given inconsistent results.
Whether primary progressive MS should be treated differently is an interesting question. Most treatments work in relapsing remitting MS by reducing inflammation. However there is evidence from both MRI and pathological studies that there is less inflammation in primary progressive MS. Most of these studies have however been performed in people who have had primary progressive MS for many years.
Recently it has been suggested that perhaps inflammation does occur in some people or alternatively it may occur in all people with primary progressive MS but only in the earliest stages. Work is ongoing to explore this theory but early results suggest that MRI scans of people within five years of the onset of any symptoms do show more inflammation than expected. If this is the case, then treating people with primary progressive MS at an early stage with anti-inflammatory drugs may be effective.
What about treatment now?
Unfortunately there are currently no licensed treatments to delay the progression in primary progressive MS; however there has been a lot of research interest in recent years.
Interferon beta-1a
A trial in 50 people found no definite effect, although there was a trend for reduced changes on the MRI scan and better hand function in the group receiving 30mcg of Avonex.
Interferon beta-1b
One study looked at 73 people for two years but found no difference in disability progression. However, the group receiving treatment had reduced MRI changes and scored better on a scale looking at hand dexterity, cognitive function and walking.
Glatiramer acetate
The PROMiSe trial was a multi-national, double-blind, placebo-controlled trial in 943 people with primary progressive MS over three years. Unfortunately the study was terminated early as interim analysis showed it was unlikely to yield statistically significant results. When it was stopped, 757 people had completed two years; there was a trend for reduced levels of gadolinium enhancement and lesion load in the treated group.
Mitoxantrone
A placebo-controlled study has been performed over two years in 61 people. Preliminary results do not show a benefit for treatment in measures of function or disability; the MRI results are awaited.
Riluzole
A small study involving 16 people did not show any definite effect. There was a trend for a reduction in MRI changes but not in clinical measures of disability.
Intravenous immunoglobulin (IVIG)
In a trial of 231 patients with progressive MS (only 34 with primary progressive MS), preliminary results show no treatment effect in the whole group but a possible effect in the primary progressive MS subgroup. Full results are awaited.
Rituximab
In a small study of this monoclonal antibody, temporary changes were seen in the cerebrospinal fluid (CSF) of four people, suggesting it may be effective. A large double-blind, placebo-controlled trial in 435 patients is now underway to test it further.
Other agents
In trials in mixed populations (people with any form of MS or in 'progressive' MS - both primary and secondary), azathioprine has shown a small beneficial effect but no significant effects were seen in the primary progressive MS subgroup. Similarly cladribine, methotrexate and perfenidone showed possible small effects but not in the primary progressive group.
In a study of 22 people with primary progressive MS receiving haematopoietic stem cell transplantation, two-thirds showed no progression after three years, however there was no control group and two people died.
The CUPID trial is looking at the role of cannabis based medicines in reducing progression in people with progressive MS. This three year trial is still recruiting around the UK.
Thoughts for the future
Inflammation is the main target for available treatments in MS. Although less inflammation is seen in primary progressive MS than in other subtypes, it may be important in the early stages of the condition. This has therapeutic implications and should be borne in mind for future treatment trials in primary progressive MS.
In addition to therapies aimed at reducing inflammation, other important areas for future research studies include neuroprotection aimed at preventing degeneration as well as remyelination and repair.
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