Cognitive dysfunction is common in people with multiple sclerosis (MS), with rates varying according to disease type, affecting ~40% of individuals with relapsing-remitting MS (RRMS), 80% of individuals with secondary progressive MS, and 90% of individuals with primary progressive MS. Cognitive deficits begin early in the disease process. Cognitive impairment may be present in 30% of individuals with clinically isolated syndrome (CIS), a harbinger of MS.1 There is evidence that people with radiologically isolated syndrome—abnormal MRI findings suggestive of MS in the absence of any clinical MS-related symptoms—show cognitive impairment with rates similar to those seen in CIS.2
Cognitive dysfunction is important for multiple reasons. It is a robust predictor of a person’s ability to sustain employment, introduces limitations with respect to activities of daily living, and can compromise relationships. Cognitive dysfunction is a marker of increased neurologic impairment attributable to MS. For example, cognitive deficits in individuals with CIS predict an earlier conversion to RRMS. Prominent deficits in people with RRMS predict an earlier transition to progressive MS.3
Affected Cognitive Functions
A wide array of cognitive functions may be adversely affected, but the quintessential cognitive deficit is delayed information processing speed.4 Other cognitive domains involved include working memory, learning and memory in the verbal and visual domains, executive functioning, and visuospatial abilities. Agnosias and apraxias which are more typically found in people with Alzheimer disease are less common.
The central role played by processing speed in cognition is illustrated by findings that show processing speed deficits implicated in challenges with working memory and executive functioning. Data also suggest that processing speed in people with MS is susceptible to distraction.5 Cognitive paradigms that introduced controlled distractors into the testing process detected impairment in individuals who had been deemed cognitively intact on an array of tests without these distractors (Figure 1).
Cognitive Testing
The Symbol Digit Modalities Test (SDMT) has emerged as the sentinel cognitive test to evaluate processing speed in people with MS. The SDMT has excellent sensitivity and specificity, is easy and quick to administer (~90 seconds), is well-tolerated by people with MS, and comes with serial versions that minimize the effects of practice. The SDMT has been widely incorporated into clinical trials and is available across multiple languages with associated normative data.6
A number of well-recognized standardized batteries are available to detect cognitive dysfunction in people with MS. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) comprises 5 tests: the SDMT, the Paced Auditory Serial Addition Test (PASAT), the 10/36 Visual Memory Test, the Selective Reminding Test (for verbal memory), and the Controlled Oral Word Association Test (COWAT).7 The BRB-N takes ~30 to 40 minutes to complete, depending on the evaluee’s level of cognitive difficulty.
The Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS), a more comprehensive battery derived by consensus opinion among neuropsychologists working in the field, comprises the California Verbal Learning Test (CVLT), Delis-Kaplan Executive Function System (D-KEFS), Brief Visual Memory Test (BVMT), SDMT, PASAT, COWAT, and Judgment of Line Orientation (JLO).8 The MACFIMS takes ~90 minutes to administer to someone who is cognitively intact. By convention, a failure on 2 or more indices of this battery is considered indicative of global cognitive impairment. Failure is typically defined as a score of 1.5 standard deviations below age-, sex-, and education-matched normative data.
A spinoff from the MACFIMS is gaining traction in the MS clinical and research field. Three tests (SDMT, CVLT, and BVMT) comprise the Brief International Cognitive Assessment in MS (BICAMS).9 This screening battery takes ~10 minutes to complete, has been widely translated into multiple languages, and has normative data for these various languages. Serial versions of the tests make BICAMS useful for repeat measures, and, by extension, clinical trials and longitudinal studies in general (Table).
Structural and Functional Indices
Cognitive deficits correlate with structural and functional MRI indices. Brain metrics, such as total lesion volume and total white and gray matter volume, are modestly associated with cognitive deficits. The most robust structural index associated with cognitive impairment is thalamic volume.10 This is not routinely measured in a clinical setting, but an indirect marker of thalamic size may be found from inspection of the third ventricle, given the close proximity of the thalamus. Indeed, one of the earliest brain imaging–cognitive studies that predates the MRI era reported a fairly robust association between the width of the third ventricle and indices of visual and verbal memory.11 Subsequent, more sophisticated MRI brain volume metric measurements have confirmed this.12 The width of the third ventricle is a potentially useful clinical MRI marker of thalamic integrity (Figure 2).
Functional brain imaging findings complement the structural findings and reveal the degree to which the MS brain attempts to compensate for anatomic abnormalities. There is a clearly defined neural network for the SDMT encompassing the frontoparietal attentional network and occipital cortex, cuneus, precuneus, and cerebellum; it is apparent that in people with MS the activation within this particular network is dysfunctional, with ancillary brain areas recruited as a compensatory mechanism.13 Resting-state functional brain changes are also abnormal in people with MS, indicating the vulnerability of the brain to cognitive impairment even before the individual has been presented with a cognitively challenging task.
Whereas abnormal brain indices (eg, atrophy, total lesion load, dysfunctional neural networks) are the main driving force for cognitive impairment, other factors may play a role as well. Recently, data have emerged indicating that clinically significant depression can add to the cognitive burden in people with MS. This influence is magnified should depression be comorbid with anxiety.14 This point is highly relevant from a clinical perspective given that 1 in 2 people with MS experience a depressive illness over the course of their lifetime with MS.15 Along similar lines, impaired sleep may influence cognition, but the findings with respect to fatigue are mixed.
Cognitive Dysfunction Treatment
No good data supporting the use of medications to treat cognitive dysfunction in people living with MS are available. Memory-enhancing drugs, such as donepezil, which may be used in early stages of Alzheimer disease, are ineffective in people with MS.16 The same holds true for other memory-enhancing medications, such as rivastigmine. Disease-modifying therapy, which has transformed the therapeutic landscape for people with RRMS, generally does not have substantial cognitive benefit.
With medications proving largely ineffective for MS-related cognitive dysfunction, efforts have focused on cognitive rehabilitation. This can take 2 forms. The first involves teaching people cognitive compensatory tasks to help mitigate, and navigate around, cognitive deficits. Examples include using a smartphone as an aid to offer reminders to people with memory deficits. Practical suggestions, although potentially helpful, cannot by themselves lead to cognitive improvement. The latter may come about with cognitive remediation interventions.
There is emerging literature suggesting that people with MS who have cognitive deficits can show improvement in their cognitive abilities with these kinds of interventions.17 A number of programs are computerized, the most widely used being RehaCom (Hasomed GmbH, Magdeburg, Germany), which is available in multiple languages and contains individual modules for areas such as attention, processing speed, memory, and executive functioning. Administration of these interventions is typically over a 5-week period, 2 sessions per week, in which the person receives an individualized intervention that takes into account their level of cognitive functioning. Moderately strong data show that a program such as this can bring about cognitive improvement even in people with more advanced progressive MS. This was illustrated in a large international, multidisciplinary study of 311 people with progressive MS. Data from Canada, the United Kingdom, the United States, Italy, Denmark, and Belgium showed that almost 50% of study participants were able to improve their processing speed on the SDMT by >4 points, deemed clinically significant, after 12 weeks of therapy. These benefits remained in almost a third of people by 6 months after completion of the cognitive intervention.18
In addition to cognitive rehabilitation, there are promising data from the exercise literature indicating that aerobic exercise in particular may have cognitive as well as physical benefits for people with MS. Further data are needed to support this conclusion.
Conclusion
Cognitive deficits are common in people with MS and exert a negative effect across multiple domains. These deficits correlate modestly well with MRI changes and may be amenable to interventions, particularly cognitive remediation strategies. A priority for future research is to determine whether the cognitive improvements seen in the laboratory after interventions translate into real-world benefits.
