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Different MS Cognitive Phenotypes Could Help Guide Care

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Researchers have developed a new classification of cognitive function for patients with multiple sclerosis (MS) that is based on the identification of five cognitive phenotypes.



Dr Ermelinda De Meo

“This is the first time there has been a complete categorization of cognitive profiles in MS patients,” lead author Ermelinda De Meo, MD, IRCCS San Raffaele Scientific Institute, Milan, Italy, told Medscape Medical News.

“In addition to physical disability, we should also be thinking about cognitive disability,” she said. “They are not always the same. Such measures of cognitive profiles could be considered as a measure of disease progression along with physical disability scores.”

Until now, there have been two categories of cognitive function for MS patients ― impaired, or not impaired, De Meo noted. “This dichotomous categorization is not relevant to the real world where patients do not easily fit into those black and white boxes,” she added.

The five profiles follow a rough gradient. Patients are more likely to reach higher-level phenotypes with progressive disease and disease of longer duration, De Meo reported.

“But we need more data on exactly how these classifications relate to disease progression. In addition, disease-modifying treatments may well influence cognitive profiles too, and this is something that needs to be monitored and investigated,” she said.

The five phenotypes are described in an article published online in JAMA Neurology on January 4.

“This new categorization of cognitive deficits may integrate the EDSS [Expanded Disability Status Scale] score in defining clinical disability, support clinicians in treatment choices, and help tailor cognitive rehabilitation strategies,” the researchers conclude in their article.

They say that the defining of cognitive phenotypes may represent a step toward personalized treatment and improving understanding of the pathophysiologic mechanism of MS-related cognitive changes.

To identify the phenotypes, the researchers conducted a cross-sectional study that included 1212 clinically stable MS patients from eight Italian MS centers and 196 healthy control individuals. MS patients who experienced relapses or who had used corticosteroids within 4 weeks before a neuropsychological assessment were excluded.

All study participants underwent a neuropsychological evaluation with the Rao Brief Repeatable Battery and the Stroop Color and Word Test to evaluate the most frequently impaired cognitive domains.

Scores were corrected for age, sex, and education in accordance with normative values and were standardized on the basis of the healthy control individuals. Fatigue was assessed using the Fatigue Severity Scale, and depression was evaluated using the Montgomery-Åsberg Depression Scale.

All patients underwent a same-day neurologic examination with the EDSS score and definition of clinical subtype, and patients were classified in accordance with disease duration. A subgroup of participants also underwent a brain MRI.

The researchers categorized the MS patients into five phenotypes:

  1. Preserved cognition, which was characterized by preserved functioning in all cognitive tests and that was characteristic of patients during the early stages of the disease. The only imaging feature noted in this group was slightly lower thalamic volume compared with healthy control individuals.

  2. Mild reductions in verbal memory and semantic fluency, which was associated with hippocampal atrophy on imaging.

  3. Mild multidomain, characterized by mild decreased cognitive performance on several different tests. It was associated with cortical atrophy on imaging.

  4. Severe–executive/attention, which was characterized by decreased performance on all tests, particularly those assessing attention and executive function. This phenotype was characterized by higher fatigue scores compared with all of the others. Imaging features included a higher white matter lesion load.

  5. Severe–multidomain, which was characterized by severely decreased performance on all cognitive tests. These patients had severe brain atrophy on MR that involved all explored tissue compartments. They also experienced severe depressive symptoms.

Although the most severe cognitive phenotype (number 5) was more frequent in the late stages of MS, it was also observed in patients with short disease duration and low physical disability, a finding that underscores the importance of cognitive assessment of patients with MS from the early disease stages, the authors note.

They suggest that their findings may have several implications for clinical management and decision making.

“This categorization of cognitive features could help in planning rehabilitative strategies tailored to subgroups of cognitively homogeneous patients. This categorization could be particularly relevant to patients with mildly impaired profiles who may be the ideal candidates for rehabilitative treatments because they may have higher brain plasticity resources,” they write.

“Transition to a more severe phenotype may support the clinical decisions on changes in the pharmacological treatment,” they add.

Use of these cognitive phenotypes can also represent a step forward in research, allowing a better selection of candidates for cognitive rehabilitation trials as well as fostering future studies on the pathophysiologic mechanism of cognitive changes in MS by using more advanced MRI techniques and deep-learning approaches, they add.

Although current knowledge does not allow for a complete understanding of the meaning of these phenotypes, their definition represents a starting point for future studies, the authors conclude.

“This is just a cross-sectional study ― it is the first step to establishing such cognitive profiles,” De Meo added. “We aim to continue to follow these patients to see how their cognitive profiles change over time and if there is evolution, but we did show in this study that there is a relation between disease duration and cognitive profile.”

She says her group is ready to use this classification in clinical practice. She noted that the battery of cognitive tests that they used are well established and are familiar to most neuropsychologists.

The researchers are now developing an instrument for automated classification, such that clinicians could enter scores from the various tests, and the machine would determine which profile was applicable to each patient.

“It would be useful for all MS patients to be profiled in this way every couple of years so we can track progression,” De Meo commented.

De Meo has disclosed no relevant financial relationships. Coauthors’ financial relationships are listed in the original article.

JAMA Neurol. Published online January 4, 2021. Abstract

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