One patient out of two with relapsing-remitting multiple sclerosis (RRMS) is expected to develop secondary progressive disease secondary progressive multiple sclerosis (SPMS) after about 15 years from the first onset of symptoms [1]. After 30 years of RRMS, two-third of patients will progress to SPMS.

Progressive disease is defined as a steadily increasing neurologic dysfunction or disability, independent of relapses and without unequivocal recovery [2], [3]. This progression is subject to periods of fluctuation and stability. Moreover, clinical relapses and activity on MRI can also occur in patients with SPMS, but mainly in the early stages. Four phenotypic sub-classifications for SPMS have therefore been proposed: active SPMS with progression, non-active SPMS with progression, active SPMS without progression, SPMS without progression or activity (stable disease) [2], [4].

The diagnosis of SPMS is often retrospective, non-reproducible and delayed. The period of diagnostic uncertainty around the changing pattern from RRMS to SPMS has been estimated to be around three years [5], [6]. SPMS is also underdiagnosed. Up to two-thirds of patients with insidious worsening of disability are still considered to have RRMS. The main problem is that during this uncertainty period, patients may remain on some disease-modifying therapies (DMTs) for RRMS, which could be ineffective for slowing SPMS [5]. From the physician's point of view, making the diagnosis of SPMS remains challenging [3]. The mechanisms of progression to SPMS are not clearly understood and the disease appears to evolve on a continuum [7]. Moreover, the concept of progression independent of relapse activity (PIRA) may contribute to this uncertainty as even in RRMS, patients can worsen independently of relapses without necessarily having a disease evolution considered to be secondary progressive [8].

There are also no clear clinical, imaging, immunologic or pathologic criteria that determine the advent of SPMS [3]. From the patient's point of view, the diagnosis of SPMS may be confirmation of them entering the final phase of the disease, and given the limited treatment options, this can elicit a highly emotional response.

Lorscheider et al. attempted to establish an objective definition of SPMS [9]. Using the MSBase neuro-immunology registry, the accuracy of 576 definitions of SPMS was analyzed. The best definition of SPMS identified (at an accuracy of 87%) was a worsening in the Expanded Disability Status Scale (EDSS) of +1.0 point with a previous EDSS ≤ 5.5 or +0.5 point with a previous EDSS ≥ 6.0, in the absence of relapse, with a minimum EDSS score of 4.0 and a minimum pyramidal functional system score of 2. The worsening should be confirmed over at least 3 months on the same functional system score that leads to progression. Interestingly, this definition enabled a diagnosis of SPMS three years earlier than the diagnosis date assigned by the treating physicians in the study.

This work is extremely relevant as it has established reliable diagnostic criteria that can be used in clinical practice. However, the proposed criteria may lack sensitivity: for example, a minimum EDSS score of 4.0 is required for a diagnosis of SPMS, although a secondary progressive disease course is possible with an EDSS of 2.0 and above.

The early signs of progression are often subtle and are sometimes not noticed by patients. The patient reported outcomes could be already modified long before the diagnosis of SPMS, up to 3 years before the diagnosis for disability and up to 4 years for a steadily decreasing quality of life [10]. To help clinicians detect symptoms of progression earlier and more accurately, several SPMS predictor tools have been developed, such as MSProDiscuss™ [3], [11].

Currently, there is a pressing need to define diagnostic criteria for SPMS that are applicable for clinical practice in order to facilitate earlier, more accurate and routine diagnosis of SPMS. Early SPMS may represent a window of opportunity for patient treatment, as new potential therapies have recently emerged for SPMS [3], [12]. The rational for this consensus paper was to address this need for clarity and consistency in SPMS diagnostic criteria, which are suitable for clinical practice.