Clinically isolated syndrome
A clinically isolated syndrome (CIS) can be defined as the heralding manifestation of MS.
The clinical diagnosis of MS requires identifying two relapses, separated in time and involving different areas of the central nervous system (CNS). With the advent of MRI of the brain and spinal cord, it is now possible to identify people at risk of developing MS as they show a CIS. Multiple studies have now made it possible to better define the risk of “converting” from a CIS to MS. There is evidence that initiating a disease-modifying treatment (DMT) at the CIS stage delays both conversion to MS and onset of the progressive phase.
Natural history
The clinical presentation of initial symptoms is highly variable. However, typically people with a CIS are young Caucasian adults (average age of onset being 30 years). In 46% of CIS cases, the lesion sits in the spinal cord, more frequently presenting with sensory than with motor signs. The optic nerve is the second most frequent site, as 21% of people with CIS have an acute optic neuritis. Multifocal symptoms (involving more than one site in the CNS) are encountered in 23% of cases. Others will have a lesion in the brainstem, or in the cerebral hemispheres. After a few weeks, these symptoms remit partially or completely.
The natural long-term history of people with CIS is now better known, through the observation of groups with CIS followed over periods of up to 20 years. Some demographic or early clinical variables are strong predictors of an individual’s risk profile. Female gender, early age at onset, sensory symptoms only, and a complete recovery usually carry a good prognosis. Optic neuritis, as published recently by the Optic Neuritis Study Group, is associated with an overall 50% risk of developing MS 15 years after onset. On the other hand, cerebellar or multifocal symptoms and poor recovery are usually associated with a poor prognosis.
Diagnosis
Since a CIS is a possible prelude to MS, it is of utmost importance to rule out other conditions. This is done through history, clinical examination, and blood testing (to exclude systemic and other autoimmune conditions). The two main tests are MRI of the brain and spinal cord, and examination of the cerebrospinal fluid (CSF). MRI will show inflammatory lesions with features compatible with demyelination in up to 90% of CIS cases.
These lesions validate the clinical suspicion of MS and have an impact on the risk of conversion to RRMS and, subsequently, to SPMS. One study of 107 people concluded that 80% of people with CIS with an abnormal MRI, and 20% with a normal MRI, will develop clinically confirmed MS after an average of 20 years. A higher number of lesions carries a higher risk of converting to MS and of an earlier phase of secondary progression.
CSF testing is commonly used to support a clinically defined MS (CDMS) diagnosis, mainly through the detection of oligoclonal bands (OBs). These bands are not specific to MS, but occur in over 95 per cent of people with CDMS. They are found in two thirds of those with CIS. In a trial of 52 people with CIS, their detection was associated with a sensitivity of 91 per cent and a specificity of 94 per cent for the risk of converting to CDMS. (Sensitivity measures the proportion of people correctly identified as having the condition and specificity the proportion correctly identified as not having it). About 70 per cent of people with CIS with more than two OBs will eventually evolve to MS, independently from the presence of MRI lesions. In some countries, lumbar punctures are done less commonly in establishing a diagnosis of CDMS and rarely for CIS.
Treatment
Steroids, usually high doses of IV methylprednisolone, are used to treat acute exacerbations that cause new symptoms or worsen existing symptoms.
Multiple clinical trials with interferon beta preparations have established their effectiveness in reducing the frequency of relapses and delaying the progression of the disease. Interferon beta has anti-inflammatory properties and is able to improve the integrity of the blood-brain barrier. The placebo arm of these trials (the subjects in a study who are not on the active treatment) also established that the longer the treatment is delayed, the higher the risk of disability progression. Three clinical trials have shown that interferon beta can reduce the risk of a second episode by 50% over two years. In fact, 40% of untreated people with CIS will evolve to CDMS within two years. If therapy is initiated two years after the CIS, the risk for CDMS is higher when compared to patients who received early treatment (49% for those with delayed treatment versus 36% for those treated early, after five years). Identifying those who have high risk CIS and initiating early disease-modifying therapy is then of major importance.
Similar results, in people with CIS and MS, have been achieved with glatiramer acetate, a synthetic form of a myelin protein which induces a suppressive response against lymphocytes reactive to CNS antigens.
Natalizumab, a humanised monoclonal antibody which prevents the infiltration of activated lymphocytes through the blood-brain barrier into the CNS, has not been tried in people with CIS.
In conclusion, CIS is now recognised as an initial manifestation of MS. People with CIS who have inflammatory lesions on MRI of the brain or spinal cord, coupled with OB in the CSF, are at a high risk of early conversion to clinically definite MS, possibly also to an earlier phase of secondary progression. Treating these people with an interferon beta or with glatiramer acetate delays these events.
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