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The herald of secondary progression in multiple sclerosis (SPMS) is seen as a gloomy event by both patient and clinician, evoking the spectre of the wheelchair and an insidious loss of independent living. After the cut and thrust of the relapsing stage, when even unpleasant and disabling neurological constellations can potentially be reversed or ameliorated by corticosteroids, therapy intervention and natural history; where there is an ongoing dialogue as to exactly which disease modifying treatment would be appropriate at a particular time point; and where there exists the promise of upscaling to monoclonal strategies or commencing soon to be licensed oral agents. When both parties realise that progression has come, and will stay, there can be an uncomfortable autumnal chill in the consulting room.
The article by Koch et al1 helps to forewarn us when that moment is more likely to arrive than not (see page 1039). It takes as its base a large cohort of over 5000 patients enrolled over two decades, of which a third had reached SPMS at the time of analysis. Care was taken to censor on first exposure to immunomodulatory drugs (25% of total group), and since three-quarters of this population were drug naive, are likely to provide one of the last remaining datasets to outline the pure history of the disease. The headlines reveal that the median time from disease onset to this pivotal point was 21 years, with corresponding quartiles being 11 (fastest) to 32 (slowest) years. Median age was 54 years. Relatively poor prognostic indicators were male sex and motor onset syndromes. Younger patients took a longer time to reach SPMS but this occurred at a younger age.
This survey, which is in good agreement with other series about the timing of the secondary stage, can now be definitive about the gender hazard and reinforces the at risk neuroanatomical system.2
What then are we to do this information? Perhaps it should act as a low grade warning light. It is not absolute but the risks of progression in young males with motor onset disease are higher than the rest of their peers. On their behalf, we might wish to be more aggressive in current conventional treatments and be looking to enrol them early in trials of novel compounds, particularly when the transition is still occurring. Moreover, of course, if the tide cannot be turned, the outpatient conversation can start slowly rather than hastily, to prepare and educate them for life with SPMS. Some comfort can be taken that even if the divide has been crossed, much can be done with symptomatic treatments (eg, pain, sphincter dysfunction, fatigue), ensuring co-pathology has not been missed (eg, spinal stenosis), multi-therapy input and perhaps a final trial of corticosteroids, which can on occasion be very gratifying.
This work serves to highlight the dynamics of the pre-SPMS phase, it encourages us to find similar prognostic markers for the SPMS stage itself and, vitally, to search for possible agents to temper the gradient. Pathfinder trials which are currently taking place or recently finished include: cannabinoid (ongoing), myelin basic protein (negative), lamotrigine (mixed) and simvastatin (ongoing) (http://clinicaltrials.gov/).