Consecutive patients with clinically isolated syndrome (CIS), relapsing-remitting MS, secondary progressive MS, or primary progressive MS (PPMS), according to the 2010 McDonald’s criteria, were recruited from our outpatient clinic (18). Main exclusion criteria were relapses and/or steroid treatment within the preceding 2 months and additional diseases or conditions apart from MS that affect behavioral changes or compromise the adequate performance of the study procedures.

This was a single-center, cross-sectional study. Patient characteristics were obtained from the last visit in the outpatient clinic including the Expanded Disability Status Scale (EDSS) that was performed by certified level C raters (http://neurostatus.net) (19).

All additional tests were performed in one extra session by a neuropsychologist (SK-E). Each patient provided written informed consent prior to study entry, and the study was approved by the ethics committee of the canton of Bern, Switzerland.

The used tests were primarily selected to assess the main neuropsychological functions. Unless otherwise stated, tests were taken from “Materials and Norms for the Neuropsychological Diagnostics,” and normal values were available for all tests (20). Tests for verbal and visual short-term memory included the Digit Span Forward and a Block Tapping test. To measure learning and long-term memory, the Rey Auditory Verbal Learning test, the Rey Visual Design Learning test, and the delayed recall of Logical Memory of the Wechsler Memory Scale and the delayed recall (30′) of Rey’s Complex Figure were used. Performance on executive functions were assessed with a Word and Design fluency task, Stroop’s Color-Word test, a Planning (tower) test, and the Kramer’s test, i.e., a Card Sorting test. Tests for measuring different aspects of attention included two subtests (alertness and divided attention) of the computerized test battery of Zimmermann and Fimm (21), the Test des Deux Barrages (assessing focused attention), and an extended German version of part A of the Trail Making test. Visuospatial constructional ability was tested by means of copying the Complex Figure of Rey. A test called Spatial test assessed mental rotation.

Tests without normative data included the Bells test (assessing neglect; cut-off: 6 of maximum 36 omissions); the test of upper limb apraxia (TULIA; cut-off: 194 of maximum 240 points); language tasks assessing comprehension (short version of the token test); naming, reading, and writing (each of these maximum 10 points); and the Cortical Vision Screening test (maximum 38 points) (22).

The FrSBe assesses behavioral changes related to frontal lobe disturbances, which includes apathy, disinhibition, and executive dysfunction that contribute to a total score (23). It is filled out by the patient (“self-report form”) and additionally by a designated significant other or family member (“family form”), retrospectively with regard to the behavioral status before first symptoms of MS (called “before illness”) and with regard to the current status (called “after illness”). The FrSBe was shown to be a sensitive measure of behavioral changes and a predictor of neuropsychological deficits and poor adaptive function in patients with MS. It was validated using a healthy control group and normal values are available (6, 9).

The Beck Depression Inventory (BDI) test to evaluate depressive symptoms (24), the Wuerzburg Fatigue Inventory for Multiple Sclerosis (WEIMuS) test to evaluate fatigue (25), and the FrSBe (23) were performed.

Statistical analyses were exploratory and were performed using R (version 3.1.2, R Core Team) (26). Analyses were based on all evaluable patients, and missing values were not imputed. Normal values were available for all analyses. Unless otherwise stated, normalized T scores corrected for age, sex, and education were calculated. T scores have a mean of 50 and a SD of 10. With the exception of the FrSBe, T scores ≤35 are pathological, and T scores of 36–40 may be interpreted as borderline impairment. With respect to FrSBe, T scores ≥65 are pathological. T scores of 60–64 may be interpreted as borderline impairment.

The relationship of behavioral changes measured by the FrSBe and disease characteristics (age, gender, education, disease duration, MS type, and treatment) as well as disability (EDSS) was assessed by multivariable analysis of covariance. To analyze the relationship of behavioral changes to the neuropsychological and behavioral evaluations, Spearman rank correlation coefficients were calculated between the FrSBe self- and family-form postillness with all neuropsychological tests, the BDI, and the WEIMuS. The level of significance of two-sided statistical tests was set at p = 0.05, and no correction for multiple testing was applied.

To improve sensitivity to the different cognitive domains, additional mean scores of the respective tests for the domains “Verbal memory,” “Non-verbal memory,” “Executive function,” “Attention,” “Visuospatial Abilities/Visual perception,” and “Language” were calculated and correlated to the FrSBe as well (see above, Tables 2 and 4).

The differences in the assessment of behavioral changes by patients and by significant others, the “self-report form” of the FrSBe (filled out by the patient), and the “family form” of the FrSBe (filled out by a designated significant other or family member), with regard to the behavioral status before the first symptoms of MS (called “before illness”) and the current status (called “after illness”), were compared using the Wilcoxon signed-rank test.

66 consecutive patients were included. The characteristics of the study population regarding age, gender, education and disease duration, mean EDSS, EDSS distribution, MS type, and current immunomodulatory therapy are shown in Table 1. There were no relevant comorbidities. Non-steroidal anti-inflammatory drugs and antidepressants were the most common additional medical treatments. Patients with higher EDSS scores had more muscle relaxants.

The descriptive results of the cognitive and behavioral tests including the prevalence of pathological test results are outlined in Table 2.

With regard to cognitive functions, patients were largely unimpaired in memory, executive functions, visuospatial abilities/perception, neglect, apraxia, and language (pathological values most often in less than 10% of patients), with the exception of planning abilities. In different aspects of attention, we found deficits in up to 23% of patients (Table 2).

With regard to the FrSBe, the total score for behavioral self-ratings showed pathological values in 11.47% before and 24.59% after illness. With regard to the behavioral domains of the FrSBe, i.e., apathy, executive dysfunction, or disinhibition, up to 11.47% patients before and up to 27.9% patients after illness showed pathological values in at least one domain. There was a significant increase after illness compared to before illness in all FrSBe scales (all p < 0.0001) except for the domain “disinhibition” that showed a non-significant trend (p = 0.08) (Figure 1).

Behavioral family rating of the FrSBe showed a pathological total score in 12.12% before illness and 30% after illness and in up to 12.1% before illness and up to 33.3% after illness in one of the examined FrSBe domains (Table 2). There was a significant increase of all FrSBe scales after illness compared to before illness (all p < 0.0001) (Figure 1).

In the BDI, 36% of patients did not have depressive symptoms, 59.1% showed minimal to medium depressive symptoms, and 4.9% heavily depressive symptoms (Table 2).

The WEIMuS showed higher rates of cognitive than physical fatigue, with rates of up to 22.58% compared to healthy controls and up to 17.74% compared to MS patients (Table 2).

The TULIA showed three patients with mild apraxia (4.5% of study population) and none with moderate or severe apraxia (normal values taken from the studs by Vanbellingen et al.) (27).

Self-ratings and family ratings of the FrSBe did not show significant differences except for the domains “apathy after illness” and “disinhibition before illness” (p = 0.0407 and p = 0.0066, respectively), with higher values in the self-ratings (Figure 2).

The correlations of the FrSBe scales with disease-specific aspects are outlined in Table 3. The strongest correlation was found between the family ratings and PPMS, especially in the disinhibition scale. Higher FrSBe test values before illness were indicative for pathological test results after illness.

The correlations of the FrSBe with all cognitive and behavioral tests are outlined in Table 4. The strongest and most consistent correlation was found between the FrSBe (self- and family rating) and the WEIMuS and BDI. Otherwise, only single significant correlations were found as indicated in Table 4. In addition, the correlation of the FrSBe with a frontal lobe test battery resembling the cognitive domain “Executive function” (= mean values of “Word fluency task,” “Design fluency task,” “Stroop’s color-word test III (mistakes),” “Stroop’s color-word test III (time),” “Planning test (number of moves),” “Planning test (quality total),” and “Kramer’s card sorting test”) showed a significant correlation to Executive dysfunctions (self-rating) of the FrSBe. All other correlations were not significant.

We used multivariable linear models to investigate the contribution of measures of depressive symptoms and/or fatigue concurrently with frontal lobe tests (Kramer test correct ones, Word fluency, Design fluency, and Planning test moves) to the current self-rating FrSBe scores. Data indicate that fatigue and depressive symptoms were in most cases significant predictors for FrSBe test results (only for WEIMuS did not predict disinhibition), and frontal lobe tests were not.

The study was performed in a mildly affected MS patient cohort especially with regard to cognitive functioning, and therefore, conclusions for moderately to severely affected patients cannot be made. The tests used in this study are validated and existing normative values were compared to the results of our study population. However, we did not include an own control group and did therefore not account for differences, which might be population specific to our group. Validated subjectively reported outcome measurements, answered by patients and family members, were used in the study. Furthermore, the number of CIS and PPMS patients was low rendering any conclusions impossible.