How does MS progress over time?

85% of cases of MS begin as "Relapsing Remitting" MS (RRMS), which consists of acute attacks of neurological dysfunction (relapses or exacerbations), separated by periods of disease stabilization (remission)[5, 6].

A relapse or exacerbation (from here on referred to simply as a relapse for the sake of clarity) is defined as "the unprovoked and unanticipated occurrence of a new symptom or recurrence of an old symptom, lasting for a period of greater than 24 hours." The time and course of a typical relapse is relatively consistent: symptoms usually develop over a matter of days, remain constant for 3 to 4 weeks, and then slowly resolve over a period of about one month. It has been established that each relapse is associated with new areas of demyelination in the CNS[7].

A remission is a period during which the patient returns to the level of health (or close to that level) that existed before their last attack - it does not mean that all the symptoms of MS disappear completely. Indeed, during these periods of apparent clinical stability the underlying disease is usually still active, as can be demonstrated by Magnetic Resonance Imaging (MRI).

As the condition progresses, full recovery after a relapse becomes less common. The effects of repeated relapses accumulate to cause worsening disability, and eventually the disease may enter the "progressive" phase, in which the pace at which disability occurs is greatly accelerated. The result is that many MS patients end up needing to resort to wheelchairs or other forms of assisted mobility.

The pathology behind this clinical pattern is complex and results from the two types of neural damage that occur: demyelination and axonal damage. Myelin that has been destroyed is replaced to some extent by scar tissue, which is not as efficient at transmitting nerve impulses as the original nerve tissue. Initially the CNS adapts by using alternative pathways, causing periods of remission during which patients may experience partial or complete recovery of function, but eventually these alternative pathways also become damaged and scarified, leading to gradual accumulation of permanent disability.

In addition to demyelination, however, axonal damage occurs. It used to be thought that this type of damage only occurred in the later stages of the disease, but recent research has shown that this is not the case and that it begins in the very earliest stages[3, 8]. This finding is extremely important because axons cannot be replaced at all. As one recent editorial in Neurology put it, "What is lost is not regained"[2].

The fact that axonal loss begins at the very onset of the disease has been confirmed by the use of Magnetic Resonance Spectroscopy (MRS), while studies using Magnetic Resonance Imaging (MRI) have revealed that brain atrophy occurs concurrently. It has also been observed that brain atrophy continues to increase during the relapsing-remitting stage without concurrent disability progression. This suggests that compensatory mechanisms maintain neurologic function despite progressive brain tissue loss and consequently mask it from clinical observation. Eventually a threshold is reached, however, beyond which further axonal loss leads to continuously progressive neurologic disability[8-11].

It is clear, therefore, that relapses, particularly early relapses, sound a serious warning. This warning must be heeded if the accumulation of axonal loss and permanent irreversible disability are to be minimized. In order to ensure the best possible therapeutic outcome, therefore, patients should receive aggressive therapy with an effective disease-modifying agent starting as soon as possible after a definitive diagnosis of MS has been made, before extensive axonal loss has had a chance to occur[3].

Although it is impossible to anticipate the nature, severity or timing of disease progression for a specific patient, different general categories of the disease have been identified based upon the pattern and frequency of relapses. These are set out in Table 2.

Table 2. The different types of MS

Type	Frequency of cases	Disease course
Relapsing- remitting (RRMS)	50% of MS patients	Characterized by relapses, followed by periods of remission, with or without complete recovery. RRMS is the most common form of the disease (80-90% of MS patients initially have RRMS) and is usually diagnosed in individuals between the ages of 20 and 40. Symptoms may evolve over several days or weeks and then fully or partially disappear. Some people will experience a relapse every few months and others only once every few years. In the latter case the disease is sometimes called benign MS (see below), but this is always a retrospective diagnosis. The pattern in which attacks occur is unpredictable even in a single individual. 50% of RRMS patients will develop Secondary Progressive MS (SPMS) within 10-15 years of initial diagnosis.
Benign (retrospective diagnosis)	10% of MS patients	Characterized by complete recovery from exacerbations, which are isolated and rare. Patients do not become disabled.
Secondary progressive (SPMS)	30 - 40% of MS patients	Similar to RRMS, and usually develops from it about 10 to 15 years after onset. Characterized by progressive worsening of neurologic symptoms with some relapses showing incomplete recovery at the beginning, followed by a slow steady progression of disability without further attacks. These patients will eventually become moderately or severely disabled. Relapses may occur at first, but then they stop completely and a slow but steady progression of disability takes place. Approximately 30-40% MS patients have SPMS.
Primary progressive	10% of MS patients	Characterized by the occurrence of progression from the beginning, with or without rare relapses. In PPMS symptoms worsen over time but there are no relapses or remissions. Some people with PPMS have brief periods during which their symptoms either stay the same or improve slightly. This type of MS is most often diagnosed in people over the age of 40 years.

There are also certain factors that provide an indication that the disease will progress more slowly with a tendency to less severe disability in the long term:

• Few attacks in the first years after diagnosis
• Long intervals between attacks
• Complete recovery from attacks
• Small numbers of brain lesions seen on MRI
• Symptoms that are sensory in nature (i.e. numbness or tingling).

Conversely, other factors indicate that the disease will progress more rapidly with a poorer long-term prognosis:

• Frequent attacks
• Poor recovery from attacks
• Detection of many lesions on MRI
• Onset of symptoms after the age of 40 years
• Male gender
• Several symptoms in parallel
• Muscle spasms and stiffness (spasticity), paralysis or problems with balance and coordination early in the disease.

Although severely debilitating for many patients, MS is not contagious or fatal. At present there is no cure, but over the years MS has become increasingly manageable with the help of treatments that relieve symptoms and, in particular, modify the disease process so that the number and frequency of attacks is reduced and the progression of MS is delayed..