When newly diagnosed pwMS enter a clinic room, they have read up about MS and are often focused on the daunting idea of ending up in a wheelchair or having to use a zimmer frame. From natural history cohorts before disease-modifying treatments (DMTs) were introduced, we know that for an untreated pwMS it takes a median 11.4 years to reach EDSS 4/not being able to walk unrestricted anymore, 23 years to reach EDSS 6/walking with a cane and 33 years to reach EDSS of 7/having to use a wheelchair. There is consistent evidence that our army of DMTs impacts on these hard disability endpoints, and delays them with several years. This is undeniably good news. However, what happens in two decades from now might not be what drives your life choices today and tomorrow.
This study of De Meo et al. performed extensive cognitive assessments among 1,212 pwMS and 196 healthy controls. This allowed them to delineate five different cognitive phenotypes:
- Preserved cognition
- Mild verbal memory or semantic fluency: This means your use of language becomes more restricted, your brain has to spend more energy on accessing less frequently used words.
- Severe executive/attention: This means you have difficulties multitasking. In practice, this means that cooking while keeping an eye on your offspring, putting laundry in the washing machine and answering a text might become very demanding. Similarly, also following conversations with multiple people at once might become tiresome.
- Mild multidomain: PwMS underachieving on all cognitive tests. Next to verbal memory and attention, there are also difficulties with visuo-spatial memory (i.e. difficulties with the board game ‘memory’) and cognitive inhibition which is your mind’s ability to tune out stimuli that are irrelevant to the task at hand.
- Severe multi-domain: cfr. Mild multi-domain but more pronounced.
Most striking is the frequency of these phenotypes among pwMS, and especially among – so called – “early RRMS” i.e. less than 5 years from symptom onset – and thus not diagnosis. In ‘early RRMS’, only 25% had preserved cognition, 38% had mild verbal memory or semantic fluency deficits, 14% had mild multi-domain deficits, 11% severe–executive/attention and 12% severe–multidomain deficits. The picture becomes more sombre in individuals with a longer disease duration where only 5% (SPMS) and 7% (PPMS) had preserved cognition.
In the beginning of the disease, pwMS often do not realise that MS-related cognitive deficits will be much more fundamental in how the disease impacts on their life than not being able to run. Cognitive impairment is one of the most important reasons for unemployment early in the disease course, with about 54% of pwMS with an EDSS <3 (i.e. pwMS that still have an unrestricted walking range) being unemployed in Europe. In many work environments, solutions can be found for physical disabilities (e.g. flexible hours to avoid busy commute, working from home one or two days a week, private transport to work, …) but bypassing cognitive disabilities is much more challenging. In practice, it often involves cutting back on working hours. Not being able to work, unwillingly affects your self-confidence, reduces common ground with many individuals from your social network and puts your disease at the center stage of your life.
At this point, it is unfortunately not possible to systematically categorise pwMS according to one of these cognitive subtypes in clinics. A cognitive test battery to determine cognitive status easily takes two to three hours to complete, and systematically repeating this examination over time as a monitoring tool is not realistic. Moreover, underperforming on a cognitive test has no clear consequences for your DMT management. This means that the effect of DMTs on the preservation or slowing down of cognitive deficits is not well studied. If an individual would have a lower score on a verbal memory test one year after a baseline measurement, we do not know whether a change in DMT would impact on preserving verbal function in the future.
The reason we do not have this information is because most DMT clinical trials have focused on relapse rate reductions and EDSS as primary endpoints. These are legitimate endpoints in MS but it is not necessarily what will determine whether you can stay at work and be integrated in society. Therefore, we need to know how and to what extent DMTs impact on cognitive decline: the cognitive efficacy. Hopefully, the mildly encouraging data on cognition in the siponimod trial will set the scene for more and better.
Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
Ermelinda De Meo 1 2 3, Emilio Portaccio 4 5, Antonio Giorgio 6, Luis Ruano 7 8, Benedetta Goretti 3, Claudia Niccolai 5, Francesco Patti 9, Clara Grazia Chisari 9, Paolo Gallo 10, Paola Grossi 11, Angelo Ghezzi 12, Marco Roscio 12, Flavia Mattioli 13, Chiara Stampatori 13, Marta Simone 14, Rosa Gemma Viterbo 14, Raffaello Bonacchi 1 2 15, Maria A Rocca 1 15, Nicola De Stefano 6, Massimo Filippi 1 2 15 16, Maria Pia Amato 3 5
- PMID: 33393981
- PMCID: PMC7783596 (available on 2022-01-04)
- DOI: 10.1001/jamaneurol.2020.4920
Importance: Cognitive impairment is a common and disabling feature of multiple sclerosis (MS), but a precise characterization of cognitive phenotypes in patients with MS is lacking. Objectives: To identify cognitive phenotypes in a clinical cohort of patients with MS and to characterize their clinical and magnetic resonance imaging (MRI) features. Design, setting, and participants: This multicenter cross-sectional study consecutively screened clinically stable patients with MS and healthy control individuals at 8 MS centers in Italy from January 1, 2010, to October 31, 2019. Patients with MS and healthy control individuals who were not using psychoactive drugs and had no history of other neurological or medical disorders, learning disability, severe head trauma, and alcohol or drug abuse were enrolled. Main outcomes and measures: Participants underwent a neurological examination and a cognitive evaluation with the Rao Brief Repeatable Battery and Stroop Color and Word Test. A subgroup of participants also underwent a brain MRI examination. Latent profile analysis was used on cognitive test z scores to identify cognitive phenotypes. Linear regression and mixed-effects models were used to define clinical and MRI features of each phenotype. Results: A total of 1212 patients with MS (mean [SD] age, 41.1 [11.1] years; 784 women [64.7%]) and 196 healthy control individuals (mean [SD] age, 40.4 [8.6] years; 130 women [66.3%]) were analyzed in this study. Five cognitive phenotypes were identified: preserved cognition (n = 235 patients [19.4%]), mild-verbal memory/semantic fluency (n = 362 patients [29.9%]), mild-multidomain (n = 236 patients [19.5%]), severe-executive/attention (n = 167 patients [13.8%]), and severe-multidomain (n = 212 patients [17.5%]) involvement. Patients with preserved cognition and mild-verbal memory/semantic fluency were younger (mean [SD] age, 36.5 [9.8] years and 38.2 [11.1] years) and had shorter disease duration (mean [SD] 8.0 [7.3] years and 8.3 [7.6] years) compared with patients with mild-multidomain (mean [SD] age, 42.6 [11.2] years; mean [SD] disease duration, 12.8 [9.6] years; P < .001), severe-executive/attention (mean [SD] age, 42.9 [11.7] years; mean [SD] disease duration, 12.2 [9.5] years; P < .001), and severe-multidomain (mean [SD] age, 44.0 [11.0] years; mean [SD] disease duration, 13.3 [10.2] years; P < .001) phenotypes. Severe cognitive phenotypes prevailed in patients with progressive MS. At MRI evaluation, compared with those with preserved cognition, patients with mild-verbal memory/semantic fluency exhibited decreased mean (SE) hippocampal volume (5.42 [0.68] mL vs 5.13 [0.68] mL; P = .04), patients with the mild-multidomain phenotype had decreased mean (SE) cortical gray matter volume (687.69 [35.40] mL vs 662.59 [35.48] mL; P = .02), patients with severe-executive/attention had higher mean (SE) T2-hyperintense lesion volume (51.33 [31.15] mL vs 99.69 [34.07] mL; P = .04), and patients with the severe-multidomain phenotype had extensive brain damage, with decreased volume in all the brain structures explored, except for nucleus pallidus, amygdala and caudate nucleus. Conclusions and relevance: This study found that by defining homogeneous and clinically meaningful phenotypes, the limitations of the traditional dichotomous classification in MS can be overcome. These phenotypes can represent a more meaningful measure of the cognitive status of patients with MS and can help define clinical disability, support clinicians in treatment choices, and tailor cognitive rehabilitation strategies.