Most people with MS have relapsing symptoms that last days or weeks before resolving; however, one in ten do not. Instead, from the beginning, these people have a progressive and continuous accumulation of neurological symptoms, with occasional plateaus and temporary minor improvement but without typical relapses. People who show a gradual worsening of MS from the onset of the disease are considered to have primary progressive multiple sclerosis (PPMS).
The cause of PPMS is still unknown. Various theories attempt to combine the available data into plausible explanations but, thus far, none has proved definitive.
Clinical characteristics
People with PPMS tend to be older than people with a relapsing-remitting form at onset of the disease (an average of 40 years old). The clinical features often suggest involvement of the spinal cord which often bears the brunt of the disease.
The most common symptom is a progressive weakness of the lower limbs with spasticity (spastic paraparesis), which is seen in 80% of people with PPMS.
Another common symptom is difficulty with coordination and balance (known as ataxia) due to progressive cerebellar involvement, which is found in 15% of individuals. Other symptoms may include changes in sensation, muscle weakness, muscle spasms, difficulty in moving, problems in speech or swallowing, visual problems, fatigue, pain and bladder and/or bowel difficulties.
Pathological, immunological and MRI findings
The lesions seen in people with PPMS show a loss of oligodendrocytes (the cells that form the myelin sheath) and a reduction in myelin repair when compared to other MS subtypes. Widespread inflammation (though less than in relapsing forms) with diffuse axonal damage in white brain matter and demyelination of cortical tissue are also found. Axonal damage is the basis of irreversible and progressive disability.
There is limited information regarding immunological findings compared with other forms of the disease. The most frequently reported is the increased intrathecal synthesis of IgG antibodies and the appearance of oligoclonal bands in the cerebrospinal fluid of approximately 90% of people with PPMS. Another immunological finding includes the observation by some researchers of auto-antibodies, part of the body’s immune system, that mistakenly target proteins of the brain. Although several studies have attempted to investigate this issue, immunological patterns that differentiate PPMS have not yet been described.
Despite their increased disability that occurs over time, people with PPMS usually have fewer brain MRI abnormalities than people with other subtypes of MS, and those lesions tend to be smaller. Another characteristic of MRI findings is that those with PPMS have a lower frequency of gadolinium-enhancing lesions when compared with other MS subtypes, and fewer new lesions developing over time. However, as these findings vary from person to person, it is impossible to determine what type of MS a person has from an MRI scan alone.
Diagnosis
As PPMS does not have relapsing symptoms, it is important to listen to the person’s own story of the disease and combine this with tests (MRI and oligoclonal bands) in order to determine a diagnosis of PPMS.
The story of gradually progressive neurological symptoms, including paraparesis or unsteadiness, is characteristic. To make the diagnosis of PPMS, the condition must have been present for one or more years; this protracted diagnosis can be very stressful. A neurological examination should demonstrate abnormalities related to brain or spine disease, for example, spasticity, Babinski sign (a reflex action in which the big toe moves upward and the other toes fan out when the sole is stroked – a normal reflex in infants but an indication of CNS damage in adults) or hyperreflexia (overresponsive reflexes). MRI should show lesions, especially in the brain and cervical spine. The spinal fluid normally shows oligoclonal bands; however, a small group of people have no immunological abnormalities in CSF. The McDonald criteria contain a section on diagnosing PPMS.
Treatment
To date, there is no proven or licensed disease modifying treatment to slow the course of PPMS.
Two small studies of interferon beta could not demonstrate a delay in the progression of the disease. A large study with glatiramer acetate also failed to demonstrate a substantial reduction in the proportion of people who showed progression. Other studies have evaluated different
medications for the treatment of PPMS.
Medications such as intravenous cyclophosphamide and methylprednisone, azathioprine, methotrexate, cladribine, rituximab, immunoglobulin and autologous stem cell transplantation have not proven effective in modifying the course of PPMS, although some of these treatments continue to be investigated. Future treatment options, including the monoclonal antibodies natalizumab and alemtuzumab, have received much attention; however, as their mode of action appears to be mediated through a decrease in cerebral inflammation, their role in PPMS may be limited.
Finally, strategies to promote remyelination or to repair or replace damaged axons are under investigation.
Because there is no proven disease-modifying treatment for PPMS, it is highly relevant to consider symptomatic treatment in order to improve quality of life. Treatment often includes rehabilitation and symptomatic therapies.
Prognosis
In general, the prognosis in PPMS differs from that of the relapsing form of the disease. In PPMS, people usually start experiencing symptoms at 40 to 45 years (a more advanced age than in the relapsing MS form) and are able to walk years after diagnosis, although they tend to worsen over time. This worsening ability to walk is a common disabling symptom in nearly all people with PPMS.
Conclusions
People with PPMS represent about ten per cent of all those with MS. Despite an increased interest in PPMS in recent years, the pathophysiology of this disorder is still poorly understood. Research priorities include a better understanding of the mechanism of the disease and its natural history, as well as a search for new therapeutic approaches that may delay progression. Above all, it is important to be aware of symptom management strategies so that the quality of life of people with PPMS may be improved.
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