Clinical manifestations

Multiple sclerosis: an overview of phenotypes

Multiple sclerosis is a chronic autoimmune, inflammatory neurologic disease that leads to varying degrees of myelin and axonal injury and destruction in the central nervous system (18). Although multiple sclerosis is the most common disabling nontraumatic neurologic condition for young adults worldwide and affects up to 500,000 adults in the United States alone, worldwide estimates of multiple sclerosis prevalence and incidence are rising (04). Multiple sclerosis is twice as common in women as in men, and persons of Northern European descent fall in the highest category of risk for contracting the disease (20). Although the course of multiple sclerosis is varied and unpredictable, most people initially experience reversible neurologic deficits followed by progressive deterioration over time (18). In addition to debilitating motor symptoms (eg, spasticity, ataxia, dysesthesia), these neurologic deficits can include cognitive and neuropsychiatric changes (18).

In 1996, four clinical phenotypes of multiple sclerosis were defined: relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing (28). Over time, the diagnostic criteria for multiple sclerosis have come to be known as “the McDonald Criteria” and have changed to incorporate increasing use of MRI and other technologies to identify multiple sclerosis in earlier stages. In 2017, the latest revision of the McDonald Criteria was published inLancet Neurology and outlined four phenotypes: clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, and primary progressive multiple sclerosis (49). It is important to note, however, that all patients with CIS (ie, the initial episode of neurologic symptoms caused by CNS inflammation and demyelination) do not go on to develop multiple sclerosis. But, according to the 2017 McDonald Criteria, multiple sclerosis can be diagnosed in a person with CIS if evidence of earlier multiple sclerosis-like damage and active inflammation in a different location is found on MRI.

Cognition in multiple sclerosis

Cognitive impairment is common in multiple sclerosis, with prevalence rates ranging from 45% to 65% at both the earlier and later stages of the disease (12). Although cognitive decline is more common in the progressive form of multiple sclerosis, evidence suggests that cognitive impairment is a central feature regardless of phenotype. Most empirical evidence points to a waning instead of sparing of general intellectual ability in multiple sclerosis; however, some investigations have noted subtle declines to general intelligence (07). Frank dementia is rare in multiple sclerosis, but declines in advanced instrumental activities of daily living have been noted (07; 02; 51).

Course and phenotype. In a study by Brissart and colleagues, the course of cognitive decline was examined in 128 people with multiple sclerosis who were administered a neuropsychological test battery and classified according to five groups: early relapsing-remitting (< three years), late relapsing-remitting (> 10 years), secondary progressive, and primary progressive (05). The performance of the four multiple sclerosis groups was compared to a group of cognitively normal controls.

Results of the study showed that all four multiple sclerosis groups exhibited some level of cognitive impairment. For the relapsing-remitting group, cognitive impairment increased with disease duration. In the early relapsing-remitting group, cognitive decline was subtle and mostly related to phonemic/letter fluency. In the late relapsing-remitting group, cognitive decline was more pronounced and spanned a number of cognitive areas. In this group, slowed processing and declines in working memory accompanied the impaired phonemic/letter fluency seen in the early relapsing-remitting group. Cognitive deficits in the two progressive multiple sclerosis groups were more widespread and severe than in the two relapsing-remitting multiple sclerosis groups and spanned the cognitive areas of processing speed, verbal episodic memory, working memory, and executive function. The authors concluded that cognitive impairment increases in accordance with disease progression in multiple sclerosis and that different multiple sclerosis phenotypes are associated with different cognitive profiles.

Cognitive decline by cognitive domain. One of the most well-known reviews on cognitive function in multiple sclerosis was authored by Chiaravalloti and DeLuca (07). In this review, four areas of cognition affected by multiple sclerosis were identified: long-term memory, efficiency of information processing, executive functions, and visual perceptual functions. For the current review, the discussion of cognitive domains affected by multiple sclerosis will be revised somewhat to include processing speed, short-term memory and new learning (ie, ability to recall verbal information after a delay of 20 to 25 minutes), working memory and attention (immediate memory), executive functions, and visuospatial ability. The working memory and attention are equivalent to “immediate memory” by neurologists. For cognitive psychologists, the ability to recall verbal information after a delay is termed “long-term memory.” However, the term “short-term memory and new learning” is being used instead of “long-term memory” because most readers of this article will be neurologists and not cognitive psychologists. Also, short-term memory and new learning will be applied to this same cognitive ability; thus, “short-term memory and new learning” will refer to what cognitive psychologists often call “long-term memory.” Regardless, deficits in short-term memory and new learning are primary cognitive deficits in multiple sclerosis and occur in most people with multiple sclerosis with corresponding cognitive decline.

Processing speed. In a review of 157 studies published between January 2004 and December 2013, Costa and colleagues evaluated processing speed in samples of people with multiple sclerosis (08). In the review, the authors detailed a surprisingly wide range of study limitations. For example, about half of the studies utilized heterogeneous multiple sclerosis samples (ie, combining multiple sclerosis subtypes into one sample), whereas only 10% were designed to understand differences between disease courses (ie, compared multiple multiple scerosis subtypes). Assessments used to study processing speed in multiple sclerosis were also heterogeneous, with 62 different tasks used across the studies. Only 11% of articles evaluated multiple sclerosis samples at two time points (ie, longitudinally).

The authors also highlighted a need for clarification in the definition of processing speed in multiple sclerosis and proposed a new theoretical model, the tri-factor model of information processing speed (IPS). As stated by Costa and colleagues: “the tri-factor model of IPS impairments in [multiple sclerosis] was developed based on the following premises which evolved from past studies: (1) IPS refers to how fast one can execute a cognitive task or the amount of work one can do within a certain period of time; (2) processing of information is composed of several steps (sensorial, cognitive, and motor processing), each of which can be individually affected by brain pathology; and (3) IPS is not a unitary construct; it can be divided into simple and complex IPS” (08).

Although Costa and colleagues noted several limitations in the current research literature about processing speed in multiple sclerosis, the identified studies have provided evidence that processing speed deficits represent the most fundamental cognitive feature in multiple sclerosis across subtypes (08). For example, longitudinal studies have shown that declines in processing speed increase as the disease progresses and that people with secondary progressive multiple sclerosis are particularly prone to processing speed declines. In terms of baseline performance, multiple studies have found that people with relapsing-remitting multiple sclerosis perform similarly to people with clinically isolated syndrome but better than people with secondary progressive multiple sclerosis on processing speed measures. For people with primary progressive multiple sclerosis, some studies have noted poorer processing speed compared to relapsing-remitting multiple sclerosis and better processing speed in relation to secondary progressive multiple sclerosis. Significant differences were not noted, however, in other studies.

Short-term memory and new learning. In the review by Chiaravalloti and DeLuca mentioned earlier, the ability to learn new information and later recall that same information after a delay of 20 to 25 minutes was termed long-term memory (07).

Initial theories about memory deficits in multiple sclerosis emphasized the role of retrieval (40). Memory deficits were said to stem from an impaired ability to recall information from memory stores, whereas the ability to encode and store newly learned information was thought to remain intact. As techniques for studying the role of memory became more sophisticated, however, theories about the source of memory impairment in multiple sclerosis began to shift (50). It now appears that memory declines in multiple sclerosis are largely attributable to a poorer learning slope. For people with multiple sclerosis, it often takes an increase in information repetition for that information to be adequately stored. After the information has been adequately acquired, recall of this information is similar to that of cognitively normal peers.

Attention or working memory and immediate memory. The study of working memory in multiple sclerosis has been complicated by the reliance of traditional working memory measures on processing speed. Genova and colleagues state: “Although working memory impairments in [multiple sclerosis] have been well established, it is unclear whether the impairments evidenced are purely due to deficits in working memory alone or if they are confounded by processing speed deficits. Most studies designed to examine working memory in [multiple sclerosis] have been contaminated by the ‘speed versus accuracy confound,’ which states that as an individual is asked to process information more quickly, accuracy of performance generally decreases” (15). When taking this “speed versus accuracy confound” into account, however, the evidence appears to indicate that processing speed, and not working memory, represents the primary information processing deficit in multiple sclerosis and that the working memory performances of people with multiple sclerosis approach that of controls when slowed speed of processing is controlled for (15). Specifically to working memory, the evidence appears to indicate that the central source of impairment is within the central executive and not the phonological loop (26).

Parceling the effects of multiple sclerosis on the different facets of attention is difficult, and many attention tasks also rely somewhat on working memory, processing speed, or executive function for completion. As Chiaravalloti and DeLuca note, “Variability in the exact cognitive processes labeled ‘attention’ makes it difficult to draw conclusions about the effect of [multiple sclerosis] on attention processes: for example, some investigators label a task an ‘attention’ task when it might more accurately involve processing speed or executive control. In addition, the involvement of fatigue is not often accounted for, and this factor probably exerts a considerable effect on the performance of tasks that demand longer attention spans and that are typically used to identify deficits in sustained or divided attention. Finally, differences among studies in the description of various disease courses could affect conclusions about attention because the more complex forms of attention (ie, sustained and divided) are more likely to be affected by the progressive forms of MS” (07). Overall, however, attention deficits in multiple sclerosis appear to become more prevalent as the complexity of the attention task increases. Although deficits on tasks such as Digit Span Forward (ie, a test of basic attention and working memory requiring participants to repeat strings of digits that increase in length) are rare, deficits on complex tasks of sustained attention and divided attention (ie, simultaneously attending to one object while monitoring another object) are more common (07).

Executive function. The term executive function was first coined by the pioneering neuropsychologist Muriel Lezak to describe a set of cognitive abilities related to goal setting, action initiation and inhibition, planning, shifting, and verification (27). Initial estimates of executive dysfunction in multiple sclerosis were well below those of impairments in processing speed and memory (07). However, a study by Cerezo Garcia and colleagues (06) shows that executive dysfunction may be more widespread in multiple sclerosis than previously thought. In this study, several tests designed to tap executive functioning were administered to a group of 100 people with multiple sclerosis (06). In total, 85% of the multiple sclerosis group showed impaired performance on three or more tests, and 71% showed impaired performance on five or more tests. In relation to a group of healthy controls who were administered the same battery of executive function tests, performance was significantly lower for the multiple sclerosis group on at least some aspect of every measure. When analyzing only the multiple sclerosis group, those participants with a progressive course performed the poorest on the test battery. A factor analysis showed that the executive function test battery could be grouped into three cognitive abilities: cognitive flexibility, initiation, and abstraction. In sum, these results show that deficits in executive function may be more widespread than previously thought in multiple sclerosis. However, as noted by Chiaravalloti and DeLuca, “Measures of executive functioning are also particularly susceptible to the effects of depression in patients with MS, and this should always be considered in the interpretation of poor performance on executive tasks in individuals with MS” (07).

Visuospatial ability. In relation to other cognitive skills, visuospatial abilities have received less attention in multiple sclerosis. In one study, 31 neuropsychological tasks assessing spatial and nonspatial visuoperceptual abilities were administered to a group of 49 people with multiple sclerosis (52). Although 26% of the multiple sclerosis group exhibited visuoperceptual impairment (ie, deficits on four or more tasks), significant rates of impairment were observed on only four of the 31 visuospatial tasks. Tasks in which performance was poorest concerned color discrimination, perception of the Müller-Lyer illusion, and object recognition.

In another study of visuospatial ability in multiple sclerosis, 89 people with relapsing-remitting multiple sclerosis received visual assessment of contrast sensitivity and contrast visual acuity and were administered a neuropsychological battery (53). Results showed that contrast sensitivity was associated with performance on some cognitive measures. The authors concluded that cognitive impairment--particularly in the areas of processing speed and, to a lesser extent, memory—affected performance on visual tests.

Cognitive decline and medical and financial capacity. Evidence has indicated that the cognitive declines often seen in multiple sclerosis are associated with declines in the ability to make sound medical and financial decisions (02; 51). For example, one aspect of medical decision-making capacity (ie, understanding) is compromised in people with multiple sclerosis with corresponding cognitive impairment. In terms of cognitive areas, diminished new learning and executive function correlated with poorer understanding (02). In another study, people with multiple sclerosis with corresponding cognitive impairment were found to have declines in a number of financial skills in relation to both cognitively intact people with multiple sclerosis and a healthy control group (51). Neurocognitive correlates of financial capacity in the sample of cognitively impaired people with multiple sclerosis included mental flexibility and working memory.

Subsequent studies have further evaluated the medical and financial capacity in progressive multiple sclerosis. In a study by Gerstenecker and colleagues, a group of 22 people with progressive multiple sclerosis was found to have significantly lower performance on three treatment capacity consent standards (ie, appreciation, reasoning, understanding) than a group of healthy controls (17). In the progressive multiple sclerosis group, verbal fluency was the primary cognitive predictor for both reasoning and understanding consent standards. Verbal learning and memory was the primary cognitive predictor for appreciation. Multiple sclerosis severity was not significantly correlated with any medical decision-making capacity (MDC) variable (16). The same progressive multiple sclerosis group was also found to have significantly poorer financial capacity than a group of healthy controls, with approximately 50% of the multiple sclerosis sample showing some level of financial capacity impairment. Short-term verbal memory (ie, the ability to recall verbal information after a delay) was found to be the primary predictor of overall financial capacity in the multiple sclerosis sample. Written arithmetic ability was found to be a secondary predictor.

Cognitive reserve. As noted by Yaakov Stern, “the concept of reserve has been proposed to account the repeated observation that, across individuals, there is not a direct relationship between the severity of the factor that disrupts performance (such as degree of brain pathology or brain damage) and the degree of disruption in performance. One idea is that the variability that naturally exists across individuals in cognitive reserve might be translated into differential susceptibility to factors that disrupt performance. A related idea is that there may be individual differences in how people compensate once pathology disrupts the brain networks that normally underlie performance” (47)”.

The protective effects of “cognitive reserve” on cognitive decline in multiple sclerosis have been well documented (48). Heritable and environmental factors have been shown to represent protective factors or cognitive reserve against disease-related cognitive impairments. Heritable factors include such variables as larger maximal lifetime brain growth, whereas environmental factors include such variables as intellectual enrichment and higher education. However, it should be noted that cognitive reserve protection may become less effective as the disease progresses (01).

Treatment of cognitive decline. Cognitive rehabilitation refers to the training or relearning of cognitive skills that have declined as a result of neurologic disease or insult. Currently, no convincing evidence exists that pharmacological cognitive treatments are effective in multiple sclerosis (21). Thus, cognitive rehabilitation may represent a particularly important area of study in multiple sclerosis. However, evidence about the efficacy of cognitive rehabilitation in multiple sclerosis is mixed.

Mitolo and colleagues conducted a review of the literature pertaining to cognitive rehabilitation interventions in multiple sclerosis (29). In total, 33 studies were identified that were published between 1993 and 2014. Of the 33 studies, 23 focused on one or two specific cognitive domains and 10 used a nondomain-specific form of cognitive rehabilitation. Older studies focused on memory and new learning, whereas newer studies included other domains such as executive function, processing speed, and attention. Fifteen studies included heterogeneous samples of people with multiple sclerosis, 14 included people with relapsing-remitting multiple sclerosis, and four did not specify a multiple sclerosis subtype. Only seven studies were considered by Mitolo and colleagues to be properly designed randomized controlled trials.

A large proportion of the studies included in the review reported that cognitive rehabilitation had a positive effect in multiple sclerosis. However, reports regarding type, extent, and duration of benefit varied from study to study. Thus, the review’s authors concluded that “no definite conclusions could be drawn about the effect of different types of interventions on cognitive rehabilitation outcomes” (29). For future studies, Mitolo and colleagues recommended that more rigorous methodology be used with outcome measures that can evaluate short-term cognitive changes and changes in quality of life.

Studies have begun to investigate the role of exercise on hippocampal volume and function in older adults with multiple sclerosis. In a study investigating the effect of exercise on hippocampal volume in healthy older adults, increases in hippocampal volume were noted in those undergoing aerobic exercise (41). Hippocampal segmentation was conducted and changes were particularly strong in the right subiculum and left dentate gyrus. Similar research using multiple sclerosis samples is scarce. In a pilot study of two persons with multiple sclerosis with corresponding memory impairment, improvements in memory function and increased hippocampal volume were seen in the participant engaged in aerobic exercise but not in the participant undergoing nonaerobic stretching (25). In a more recent study, aerobic exercise (ie, progressive treadmill walking) was found to positively affect hippocampal shear stiffness and damping ratio in eight ambulatory females with multiple sclerosis (43).

Imaging and cognition. The relationship between cognitive dysfunction and brain imaging was reviewed by Rocca and colleagues (42). The authors took a broad approach to the classification of studies and grouped damage according to white matter damage and grey matter damage. Regarding white matter damage, Rocco and colleagues noted that the volume and location of white matter lesions is associated with poorer performance on neuropsychological tests in people with multiple sclerosis. Studies of this kind were noted to have highlighted the importance of disconnection syndrome on cognitive function in multiple sclerosis. However, Rocco and colleagues note significant limitations to assessing white matter lesions as a primary cause of cognitive dysfunction in multiple sclerosis. One of these limitations relates to “multiparametric studies, which have combined different MRI techniques to define the relative contributions of focal lesions or damage to the white or grey matter on cognitive performance of patients with MS, have consistently shown that white matter lesions play only a partial or complementary role compared with damage to normal appearing white matter and grey matter” (42).

Studies examining the relationship between normal appearing white matter and cognitive dysfunction in multiple sclerosis have shown more promise, with diffusion tensor imaging (DTI) and voxel-wise procedures showing particular promise (42). Using DTI metrics and voxel-wise procedures, performance on measures of attention, working memory, and processing speed have been shown to be related to disruptions in white matter tracts connecting prefrontal cortical regions. Interestingly, only partial overlap between tract abnormalities and white matter lesion location has been found. This evidence suggested that abnormalities to normal-appearing white matter are significant and independent contributors to cognitive dysfunction in multiple sclerosis.

Other evidence, however, has implicated the role of hippocampal and grey matter atrophy in multiple sclerosis-related cognitive decline. In a seminal paper published in BRAIN, Sicotte and colleagues found volume loss in the CA1 region of the hippocampus in patients with early-stage multiple sclerosis that was disproportionate to global brain atrophy (45). In correspondence with disease progression, hippocampal atrophy expanded from CA1 into other CA regions. Both regional and total hippocampal volume were found to be associated with performance on tests of verbal memory. In a later study, Damjanovic and colleagues compared patients with multiple sclerosis and cognitive impairment to those without cognitive impairment (11). Patients classified as cognitively impaired exhibited higher T2 and T1 lesion volumes on MRI, with white matter atrophy being predictive of level of disability. However, hippocampal and deep grey matter atrophy were better predictors of cognitive impairment. The authors concluded that hippocampal and deep grey matter atrophy are key factors associated with cognitive impairment in multiple sclerosis (11). The findings of a study by Eijlers and colleagues suggest a concurrent acceleration of cortical atrophy and cognitive decline throughout the progression of multiple sclerosis (14). The underlying factors contributing to cognitive decline transitioned from deteriorating lesional pathology in stable relapsing-remitting multiple sclerosis to deep gray matter atrophy in transitioning relapsing-remitting multiple sclerosis and, ultimately, to an escalated rate of cortical atrophy in progressive multiple sclerosis exclusively.

Neuropsychiatric features of multiple sclerosis

The neuropsychiatric features of multiple sclerosis are well discussed in a review by Paparrigopoulos and colleagues (32). The review noted that at least some level of neuropsychiatric symptomatology is present in up to 95% of people with multiple sclerosis. Paparrigopoulos and colleagues note that major depression is particularly common in multiple sclerosis, with rates being approximately three times higher in people with multiple sclerosis than in the general population. Although depressive symptoms in multiple sclerosis generally reflect a typical presentation, some studies have reported that rates of irritability are inflated in multiple sclerosis in relation to rates of guilt and poor self-concept. Depression in multiple sclerosis is associated with morbidity, mortality, quality of life, and suicidal ideation. Thus, clinicians working with people with multiple sclerosis should regularly screen for depressive symptoms. Optimal treatments for depression in multiple sclerosis include a combination of antidepressant medication and psychotherapy. For treatment-resistant depression, electroconvulsive shock therapy can sometimes be effective.

Paparrigopoulos and colleagues also note that other neuropsychiatric features are increased in multiple sclerosis (32). Comorbid anxiety is often experienced with depression in people with multiple sclerosis, with prevalence rates between 14% and 40%. The combination of anxiety and depression in people with multiple sclerosis is particularly negative and is associated with increased suicidal ideation and multiple sclerosis relapses. Bipolar disorder is twice as common in multiple sclerosis compared to the general population and cannot be fully accounted for by the use of steroids. Euphoria is found in 10% to 15% of people with multiple sclerosis and is associated with a number of negative markers (eg, increased disability, cognitive impairment, cerebral atrophy). Pseudobulbar affect is experienced in up to 10% of people with multiple sclerosis and is associated with increased disease burden and cognitive decline. In addition, pseudobulbar affect carries social and occupational ramifications and leads to distress among the patient and his or her family.

In the review by Paparrigopoulos and colleagues, it was stated that “Most studies have focused on a single or a few psychiatric symptoms in [multiple sclerosis] patients, such as depression and anxiety. Few studies have investigated the full range of neuropsychiatric syndromes assessed with specifically developed tools” (32). However, using the neuropsychiatric inventory (NPI) (10) and MRI, Diaz-Olavarrieta and colleagues evaluated a group of 44 people with multiple sclerosis who were stable between relapses and 25 healthy controls with demographic and cognitive profiles similar to the multiple sclerosis group (13). Neuropsychiatric symptoms were present in 95% of people with multiple sclerosis compared to only 16% of healthy controls. Depressive symptoms were most common and were rated as present in 79% of the multiple sclerosis group. Other neuropsychiatric changes were also common in the multiple sclerosis group, including agitation (40%), anxiety (37%), irritability (35%), apathy (20%), euphoria (13%), disinhibition (13%), hallucinations (10%), aberrant motor behavior (9%), and delusions (7%). Euphoria and hallucinations were associated with moderately severe MRI abnormalities.

Prognosis and complications

The prognosis for neurobehavioral symptoms appears to be just as variable as that for other neurologic symptoms. Worse prognostic factors include a shorter interval between the first two relapses, age of onset of older than 40 years, male sex, and the presence of pyramidal or cerebellar symptoms. The presence of cognitive symptoms or euphoria and eutonia are more likely to indicate a more extensive demyelinating lesion load. Moreover, multiple sclerosis patients with cognitive symptoms or euphoria and eutonia are less likely than multiple sclerosis patients without neurobehavioral symptoms to be employed, engaged in social activities, or independent in daily living activities (34; 03). Also, it has been determined that cognitive decline in patients with multiple sclerosis can significantly decrease their quality of life (30).

Clinical vignette

The 48-year-old male patient was diagnosed with multiple sclerosis in July 1995. He had an elementary level of education and was disabled. On July 22, 2002, he was hospitalized for severe weakness and frequent falling. On neurobehavioral testing, the patient was alert and cooperative. He provided his own history. He reported depression because of his illness and condition. He stated that he was in a hopeless situation, sometimes even cried during the night, but denied suicidal ideation.

No speech articulation defects were noted. Voice volume and speed were normal. No paraphasias were observed in spontaneous language. He could follow simple and 2-step commands and recognized right-left in his body and the examiner’s. Spontaneous language was correct in phonology, lexicon, and grammar. In the word generation test using phonological (letter) categories, he produced a total of two words using the letter A (abnormal). When using semantic categories (animals), he produced 10 animal names in one minute (low average for his age and education). His score in the Boston Naming Test was 42/60 (decreased). His total score in the MMSE was 19/30 (abnormal). He could report remote and recent events in a rather general way. His knowledge about recent events, however, was poor. Two different conditions were used in the Wechsler Memory Scale-Logical Memory subtest: immediate and delayed. In the immediate condition, the patient’s score was 6/50 (abnormal). No mixture of the two stories was observed. In the delayed recall condition, his score was 2/50 (abnormal). These scores pointed to an abnormal immediate verbal memory associated with significant defects in storing and retrieving verbal information. He had no delayed recall of the Rey-Osterrieth Complex Figure. Performance in the Hooper Visual Organization test was defective (50% of errors). He could not copy the Rey-Osterrieth Complex Figures and just drew some poorly integrated fragments. No neglect was noted. Difficulties in finding similarities between words were noted, pointing to abstracting difficulties and an inability to find supraordinate concepts when two words were presented. He failed all the mathematical operations that were presented. His score in the WAIS-III-Matrix Reasoning subtest was two standard deviations below the mean for his age group.

Biological basis

Etiology and pathogenesis

Multiple sclerosis is a chronic autoimmune, inflammatory neurologic disease that leads to varying degrees of myelin and axonal injury and destruction in the central nervous system (18). Thus, the cognitive and neuropsychiatric changes associated with multiple sclerosis are generally a byproduct of cerebral demyelination and disruptions to white and grey matter.

Epidemiology

Cognitive impairment is common in multiple sclerosis, with prevalence rates ranging from 45% to 65% at both the earlier and later stages of the disease (12), though with a trend toward higher percentages in later stages of the disease. Although cognitive decline is more common in the progressive form of multiple sclerosis, evidence suggests that cognitive impairment is a central feature of multiple sclerosis regardless of phenotype. In terms of psychiatric features, mood disorders dominate the clinical picture, with up to 80% of people with multiple sclerosis endorsing some level of depressive symptomatology (33). Other neuropsychiatric changes are also common in multiple sclerosis and include agitation, anxiety, irritability, apathy, euphoria, disinhibition, hallucinations, aberrant motor behavior, and delusions.

Prevention

There are no known methods for prevention of the neurobehavioral aspects of multiple sclerosis.

Diagnostic workup

Diagnostic procedures related to cognitive and neuropsychiatric features of multiple sclerosis are best assessed with a thorough clinical interview and comprehensive neuropsychological assessment conducted by a neuropsychiatrist or neuropsychologist. Standardized mood and personality measures may also be utilized.

Management

As noted in a review by Guimaraes and Jose Sa, using acetylcholinesterase inhibitors (eg, donepezil) has been studied as a treatment for multiple sclerosis-related memory decline. The authors reported that although some benefit was noted in an early study, subsequent studies have not found acetylcholinesterase inhibitors superior to placebo for reduction in multiple sclerosis-related cognitive impairment (19). Thus, no convincing current evidence exists that pharmacological cognitive treatments are effective in multiple sclerosis (21). Cognitive rehabilitation (ie, the training or relearning of cognitive skills that have declined due to neurologic disease or insult) may represent a particularly important area of study in multiple sclerosis. However, evidence about the efficacy of cognitive rehabilitation in multiple sclerosis is mixed.

In a review of the effects of disease-modifying treatments on cognitive dysfunction in multiple sclerosis, Niccolai and colleagues noted that disease-modifying treatments are used in multiple sclerosis to reduce relapses (31). Because these medications often reduce inflammation, it is theorized that the level and progression of cognitive decline might also be reduced. However, Niccolai and colleagues reported, “the studies with DMTs [disease modifying therapies] have shown weak positive effects on cognition, and the methodological limitations reduce the strength of the results. The majority of randomized controlled trials on DMT are not appropriate to detect cognitive changes. Cognition is not the primary outcome and often the only explorative measure of cognition is the PASAT… Observational studies on DMT are non-randomized, have included small sample of patients with different clinical characteristics, used heterogeneous cognitive assessment tools and outcome measures and have not considered the patients’ cognitive status at baseline. We can only speculate that early treatment may be the most effective way to preserve intact cognitive functioning and delay the development of cognitive impairment, on the basis of studies focusing on CIS and early RRMS patients” (31). A systematic review and meta-analysis including 55 studies revealed that disease-modifying therapies can enhance cognitive test performance in individuals with relapsing-remitting multiple sclerosis (23). However, the existing evidence does not support the notion of primarily escalating treatment to address cognitive deficits. Despite the extensive utilization of various disease-modifying therapies, there is a notable scarcity of data regarding the differential effects of these treatments on cognitive impairment.

Special considerations

Pregnancy

There is no evidence that pregnancy has a long-term negative effect on the neurobehavioral aspects of multiple sclerosis. Pregnancy may result in fewer relapsing attacks, and the postpartum period may result in greater relapsing attacks. The reproductive rate is not altered by multiple sclerosis.

Anesthesia

Anesthesia is not contraindicated and does not appear to aggravate the neurobehavioral aspects of multiple sclerosis.