The onset of secondary-progressive multiple sclerosis (SPMS) may be seen as the time at which progressive disability accumulation becomes clinically evident. The process of irreversible disability likely begins much earlier during the relapsing phase; however, a diagnosis is typically made only after relapses have ceased or a level of disability has been reached, which results in a considerable diagnostic delay (Katz Sand et al. Mult Scler 2014;20:1654-1657) (see also Part 1 of this article).
A common opinion is that a threshold of disability accumulation is required (e.g. EDSS >4.0) before an SPMS diagnosis can be made (Cree et al. Neurology 2021;97:378-388), an indication that progression is largely defined by ambulation rather than other symptoms. A higher EDSS score may improve diagnostic accuracy (Lorscheider et al. Brain 2016;139(Pt 9):2395-2405) but the delay comes at the cost of ongoing neurodegenerative damage. Physicians may opt to err on the side of caution, but a premature diagnosis is arguably less detrimental than a delayed diagnosis.
As some authors have noted, the limited effectiveness of treatments for progressive MS may be the result of being employed too late in the disease process (Soelberg Sorensen et al. Curr Opin Neurol 2020;33:262-270). This problem is seen in SPMS trials (e.g. ASCEND, EXPAND), which enrolled patients in their late forties. In more recent studies (e.g. MS-SMART, SPRINT-MS), patient were in their late fifties, after the window of opportunity had surely closed.
One reason often cited for delay is the clinician’s reluctance to diagnose due to a lack of therapeutic options (Torkildsen et al. Neurodegener Dis Manag 2021;11:9-19). This may change now that a number of effective therapies (depending on the jurisdiction) for progressive MS have been approved.
A further factor may be the perception that patients are reluctant to receive an SPMS diagnosis. However, recent surveys reported that the greater difficulty for patients was uncertainty: the diagnosis was not communicated clearly; and a care plan was not described (Giovannetti et al. PLoS ONE 2020;15:e0228587. Solari et al. Front Neurol 2019;10:916). As a result, patients may be unclear about whether they will still receive adequate care. This concern appears to be justified: a European survey reported that up to 30% of patients are no longer seen by their neurologist after an SPMS diagnosis (Torkildsen 2021). This may be due in part to loss of drug reimbursement with an SPMS diagnosis in some countries.
An interesting observation from surveys was that patients were often aware of SPMS onset before they received the formal diagnosis (Bamer et al. Mult Scler 2007;13:1033-1037). A European survey found that patients reported a mean age at SPMS onset that was 2.7 years earlier than when they were diagnosed (Solari 2019).
A number of early signs and symptoms can alert clinicians and patients to the onset of SPMS. These include gradual symptom worsening; lack of clear recovery; increased symptom severity; and the development of new symptoms (Ziemssen et al. Mult Scler Relat Disord 2020;38:101861). Non-ambulatory symptoms that were associated with early progression were worsening cognition, visual symptoms, bladder symptoms and worsening fatigue. Detailed history-taking was also important to uncover circumstances strongly suggestive of progression, such as a recent change in employment status or a need for assistance in performing activities of daily living (ADL) (Inojosa et al. Front. Neurol 2021;11:628542. Ziemssen 2020).
A recent innovation has been the use of digital tools in clinical practice. For example, the MS Progression Discussion Tool (MSProDiscuss, https://msprodiscuss.com/) was developed by clinicians in Canada, the U.S. and Germany to help evaluate early signs of progression and to facilitate patient discussions about SPMS. In the validation study, the web-based tool took about two minutes to complete (Ziemssen et al. Med Internet Res 2020; 22:e16932). Included were questions on disease activity, symptoms (intermittent/improving/stable/worsening), and impact of symptoms on ADL. In a recent follow-up survey of physicians and nurses, respondents said the questions were similar to those asked in a regular visit; 85.8% said they would be willing to integrate the tool into their practice (Ziemssen et al. J Med Internet Res 2021;23:e29558). The MSProDiscuss has been advocated by some physician groups (Boyko et al. Mult Scler Relat Disord 2021;50:102778) and is now being used in two ongoing real-world studies, AMASIA (Ziemssen et al. JMIR Res Protoc 2020;9:e19598) and PANGAEA 2.0 Evolution (Ziemssen et al. ECTRIMS 2019; EP1456).
Interestingly, the validation study reported that SPMS onset was more likely to be associated with cognitive impairment (45-66% with SPMS vs. 18% with RRMS) and bowel/bladder symptoms (57-65% vs. 20%). The onset of self-care difficulties was also an important factor that discriminated between RRMS (29%) and patients transitioning to SPMS (79%) (Ziemssen 2020).
These findings suggest that the recognition of a pattern of worsening symptoms and ADL limitations can facilitate the earlier diagnosis of SPMS, which would provide patients with more time to better accommodate the transition.