Should Cognitive Function Decline Necessitate a Change in Multiple Sclerosis Therapy?


Physicians have debated whether or not cognition is a reliable marker for disease deterioration, and if it should necessitate a change in therapy.

Dr Bianca Weinstock-Guttman

Bianca Weinstock-Guttman, MD, from the Jacobs Comprehensive Center for Treatment and Research at the University at Buffalo

Bianca Weinstock-Guttman, MD

A pair of arguments for and against changing disease-modifying therapy (DMT) in the treatment of multiple sclerosis (MS) with the onset of a decline in cognitive function have pointed, ultimately, to the importance of determining cognitive decline’s reliability as a marker of disease deterioration.1-2

In light of the FDA’s recent warning regarding the halting of fingolimod (Gilenya, Novartis) as well as the potential of stroke and arterial lining tears associated with alemtuzumab (Lemtrada, Sanofi Genzyme), these disputes are possibly even more challenging than they were at their initiation.

In a series of essays, Bianca Weinstock-Guttman, MD, from the Jacobs Comprehensive Center for Treatment and Research at the University at Buffalo, and colleagues, argued in favor of the proposal that a decline in cognitive function should lead to a change in DMT.

Weinstock-Guttman and colleagues acknowledged that the American Academy of Neurology’s (AAN) 2018 recommendations make a consideration for switching therapies when a response is deemed suboptimal, based on published clinical trials.3

On the other hand, Emilio Portaccio, MD, from the IRCCS Don Gnocchi Foundation, countered that uncertainty about the method for measuring decline is among many factors that "limit the implementation of cognitive evaluation in the therapeutic-making process," though Portaccio agreed that cognitive decline would seem a useful measure of treatment response.

"If we accept that cognitive deficits in MS patients or cognitive decline from baseline reflect cerebral disease, then it would seem self-evident that this sign/symptom merits clinical attention as would any other indication of disease activity," Weinstock-Guttman and colleagues suggested.

In his argument, Portaccio pointed out that several neuropsychological evaluation batteries have been proposed, such as the Brief International Cognitive Assessment for MS, but that the need for brevity to be widely implemented precludes comprehensive measurement. He noted potential confounders such as fatigue and depression are necessarily omitted, and so can lead to an inaccurate assessment.

Additionally, although Weinstock-Guttman and colleagues considered various tools which could provide a brief assessment of cognitive function, they concluded that the Symbol Digit Modalities Test (SDMT) of information processing speed would measure the cognitive function which is of the most consequence to MS. They noted evidence in support of a clinically meaningful change in SDMT score at around 4 points—or 10%.

Portaccio, though, was not entirely convinced. He questioned whether or not an isolated 4-point decline on the SDMT—“with neither subjective complaints nor other clinical or MRI evidence of disease activity,” he wrote—was enough to decide to switch from a first-line to a possibly harmful second-line treatment.

Maria Amato, MD, from the Department NEDUROFARBA at the University of Florence, provided a judgment on the debate by agreeing with Portaccio. She stated that there is no current consensus on optimal cognitive decline measure. Although, she pointed out the SDMT has been extensively validated as a test of information processing speed, suggesting that it could represent an exception to the limitations cited by Portaccio.

"As more clinical trial data with SDMT are going to be presented, in the near future we will be enabled to consider whether SDMT decline is indicating suboptimal treatment response and should, therefore, lead to a change in disease-modifying therapy," Amato explained.

A version of this article first appeared on


1. Weinstock-Guttman B, Eckert S, Benedict RH. A decline in cognitive function should lead to a change in disease-modifying therapy - Yes. Mult Scler. 2018;24(13):1681-1682. doi: 10.1177/1352458518783364

2. Portaccio E. A decline in cognitive function should lead to a change in disease-modifying therapy - No. Mult Scler. 2018;24(13):1683-1684. doi: 10.1177/1352458518783357

3. Rae-Grant A, Day GS, Marrie RA, et al. Practice Guideline: Disease-modifying Therapies for Adults with Multiple Sclerosis. Neurology. 2018;90: 777-788. doi: 10.1212/WNL.0000000000005347

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