The retirement rate due to multiple sclerosis has decreased since 1995- A retrospective study in a Finnish central hospital.

BACKGROUND: Multiple sclerosis (MS) is the most common cause of non-traumatic neurological disability affecting young adults during their best working years. Previous studies have shown that approximately two-thirds of patients with MS (PwMS) are unable to retain employment in the long term, and many retire soon after the diagnosis. However, it is not known, how the rate of retirement has changed over the decades, especially after the introduction of disease modifying therapies (DMTs). The year 1995 was selected as a division point because DMTs have been increasingly available ever since. OBJECTIVE: To evaluate the change in retirement rate due to MS and to present risk factors for early retirement. METHODS: A retrospective survey of all PwMS treated at the Department of Neurology, Kanta-Häme Central Hospital, Finland between 1978 and 2015, was conducted. The population was divided into two groups: those diagnosed before year 1995 and those diagnosed thereafter. A Kaplan-Meier analysis was performed to evaluate the time from diagnosis to beginning of a pension in both groups. Crude incidence rates, incidence rate differences as well as age and multivariable adjusted Cox proportional hazard regression analysis were calculated for all pension predictors collected. RESULTS: A total of 484 PwMS were identified, 140 of whom were diagnosed before the year 1995 and 344 after. Actual retirement rates were 88 (63%) before the year the year 1995 and 111 (32%) after, respectively. The hazard for disability pension diminished in PwMS diagnosed after the year 1995 compared to those diagnosed before, HR 0.41 (95% confidence interval 0.31-0.55). The median time from diagnosis to retirement was 8.3 years in the group diagnosed before year 1995 and 11.1 years in the group diagnosed later. Male sex and age were statistically significant risk factors in relapsing-remitting MS, HR for male sex 1.8 (95% confidence interval 1.18-2.75) and for age 1.1 (95% confidence interval 1.07-1.12). Only age was a risk factor in progressive MS with HR 1.09 (95% confidence interval 1.07-1.11). In subgroup of relapsing-remitting MS, not using disease modifying therapies was a statistically significant risk factor, HR 1.89 (95% confidence interval 1.19-3.01). CONCLUSION: The rate of retirement due to MS in Finland has decreased significantly since 1995 and the median time from diagnosis to retirement has become longer. Not using disease modifying therapies for relapsing remitting MS was identified as one risk factor for losing ability to work prematurely.

Risk of osteoporotic fractures in multiple sclerosis patients in southwest Finland.

OBJECTIVES: Increased risk of osteoporotic fractures in multiple sclerosis (MS) patients compared with general population has been reported. The purpose of this study was to assess the risk of osteoporotic and other low-energy fractures in an MS cohort from a large hospital district in southwest Finland. Age-adjusted total and gender-specific prevalence for definite MS per 100 000 in a population of 472 139 was calculated as a point prevalence in December 31, 2012. MATERIALS AND METHODS: Patients with MS and comorbid fractures were identified by searching for ICD-9 and ICD-10 codes during a period from 2004 to 2012 from hospital administrative data in Turku University Hospital (TYKS) in southwest Finland Case ascertainment was performed by review of medical records. Osteoporotic fracture was defined as a low-energy fracture of the pelvis, hip, femur, tibia, humerus, collar bone, ulna/radius, vertebrae, or rib. The control population was a 10-fold age- and gender-matched population. RESULTS: The point prevalence (N 1004) of MS was 212.6/105 (CI 199.5-225.8) in December 31, 2012. A total of 100 (9.9%) of 1004 confirmed MS cases experienced at least one fracture during the study period. Relative risks (RRs) for all fractures (1.33, 95% CI 1.10-1.60) and osteoporotic fractures (1.50, 95% CI 1.18-1.90) were significantly increased in patients with MS compared with controls. In particular, RRs for hip fractures (5.00, 95% CI 2.96-8.43) and fractures of humerus (2.36, 95% CI 1.32-4.42) were elevated in patients with MS vs controls. CONCLUSIONS: We observed high prevalence of MS in southwest Finland and confirmed increased age-adjusted comorbid risk for osteoporotic fractures and other low-energy fractures compared with individually matched controls.

Relationship between subjective and objective cognitive performance in multiple sclerosis.

OBJECTIVES: Self- and informant reports of patients' cognitive performance are an important source of information for clinicians to consider in neuropsychological evaluation. The aim of the study was to find out whether the relationship between subjective or informant observations of cognitive deterioration and objective cognitive performance differ in patients with relapsing and progressive multiple sclerosis (MS). MATERIALS & METHODS: One ninety-six MS patients (relapsing-remitting n = 138; progressive n = 58) underwent neuropsychological assessment with the Brief Repeatable Battery of Neuropsychological Tests. Subjective and informant-reported cognitive symptoms, mood, impact of the disease, and quality of life were evaluated with self-reports. According to consistency of evaluations, patients and informants were classified as accurate estimators (consistent subjective and objective cognitive performance), underestimators (subjectively but not objectively cognitively impaired), or overestimators (objectively but not subjectively cognitively impaired). RESULTS: Patients' and informants' reports on patients' cognitive performance were approximately equally appropriate, slightly over half being accurate. Mood was associated with patients' subjective cognitive complaints. The relapsing group reported more subjective cognitive symptoms than the progressive group, although the objective cognitive performance did not differ between the groups. Overestimation occurred especially among patients with more severe physical disability, progressive phenotype of the disease, more pronounced cognitive impairment, and less education. CONCLUSIONS: Slightly over half of patient and informant observations of cognitive deterioration were appropriate. Patients with progressive phenotype were more prone to overestimation than patients with relapsing phenotype.

The effects of heat stress on cognition in persons with multiple sclerosis.

BACKGROUND: Heat sensitivity and cognitive deficits are typical manifestations of multiple sclerosis (MS). Although cognitive deficits are quite well characterized, practically no data exist on the effects of heat on cognitive performances in MS. OBJECTIVE: To assess the effects of short-term heat stress on cognitive functioning in subjects with MS. METHODS: A total of 23 heat-sensitive MS and 19 healthy control (HC) subjects participated. Moderate heat exposure took place in a Finnish sauna. Cognitive functioning was measured with tests of sustained attention and processing speed, the Paced Auditory Serial Addition Test (PASAT 3" and 2") and the computerized visual vigilance test, before, during and after heat exposure. RESULTS: During the heat exposure, the core body temperature of the MS group rose significantly more (p = 0.002) than that of the HC group. The heat stress worsened the performance of the MS group in the PASAT 3" (p = 0.025) but not in the other cognitive measures. The performance in the PASAT 3" was reversed almost to the baseline level only 1- h after the heat exposure. CONCLUSIONS: A significant increase in core body temperature during heat stress is associated with a mild and reversible worsening of the PASAT 3" performance, while visual vigilance performance seems to remain almost unaffected.

The effects of rivastigmine on processing speed and brain activation in patients with multiple sclerosis and subjective cognitive fatigue.

BACKGROUND: Cognitive decline and fatigue are typical in multiple sclerosis (MS). However, there is no official medication for either of these symptoms. OBJECTIVE: The purpose of this study was to estimate the effects of a single dose of rivastigmine on processing speed and associated brain activity in patients with MS and subjective cognitive fatigue. METHODS: Fifteen patients with MS and subjective cognitive fatigue and 13 healthy controls (HCs) matched for age, gender and education performed a neuropsychological assessment and functional (f)MRI. A modified version of the Paced Visual Serial Addition Test (mPVSAT) was used as the behavioural task during fMRIs. After the first scanning session, both groups were randomly divided into two subgroups receiving either rivastigmine or placebo. A single dose of rivastigmine or placebo was administrated double-blindly and 2.5 hours later the scanning was repeated. RESULTS: At baseline, the patients with MS showed slower processing speed in mPVSAT compared with the HCs. They also demonstrated stronger bilateral frontal activation after sustained cognitive effort than the HCs. Performance improvement and a further activation increase in the left anterior frontal cortex and additional activation in the right cerebellum were observed in patients who received rivastigmine but not in patients on placebo, or in HCs with placebo or rivastigmine. CONCLUSION: These preliminary findings suggest that rivastigmine may improve cognitive processing speed by enhancing compensatory brain activation in patients with MS.

Fatigue in multiple sclerosis patients during inpatient rehabilitation.

PURPOSE: This study was designed to evaluate symptomatic fatigue in patients with mild to moderate multiple sclerosis (MS) during inpatient rehabilitation. We examined fatigue at the beginning and at the end of a 3-week rehabilitation period as well as its daily variation. METHOD: Ninety-one patients participated. Fatigue severity was measured using the Fatigue Severity Scale (FSS). On the basis of the FSS scores, patients were divided into a fatigue (n = 66) and non-fatigue (n = 25) group. General fatigue was self-evaluated using a Visual Analogue Scale (FVAS). Depression was measured using The Centre for Epidemiologic Studies Depression scale (CES-D). RESULTS: In the fatigue group the mean FSS score decreased by 0.34 points, whereas in the non-fatigue group it increased by 0.23 points. The difference for change between groups was significant (p = 0.003), but a covariate analysis showed that this was strongly affected by a decrease in depression. Fatigue varied greatly from day-to-day. The lowest FVAS coefficient of variation per patient was 9% and the highest 131%. CONCLUSION: Inpatient rehabilitation decreases MS patients' fatigue. This effect seems to be modified by an improvement in mood.

Effects of a 6-month exercise program on patients with multiple sclerosis: a randomized study.

OBJECTIVE: To improve walking and other aspects of physical function with a progressive 6-month exercise program in patients with multiple sclerosis (MS). METHODS: MS patients with mild to moderate disability (Expanded Disability Status Scale scores 1.0 to 5.5) were randomly assigned to an exercise or control group. The intervention consisted of strength and aerobic training initiated during 3-week inpatient rehabilitation and continued for 23 weeks at home. The groups were evaluated at baseline and at 6 months. The primary outcome was walking speed, measured by 7.62 m and 500 m walk tests. Secondary outcomes included lower extremity strength, upper extremity endurance and dexterity, peak oxygen uptake, and static balance. An intention-to-treat analysis was used. RESULTS: Ninety-one (96%) of the 95 patients entering the study completed it. Change between groups was significant in the 7.62 m (p = 0.04) and 500 m walk tests (p = 0.01). In the 7.62 m walk test, 22% of the exercising patients showed clinically meaningful improvements. The exercise group also showed increased upper extremity endurance as compared to controls. No other noteworthy exercise-induced changes were observed. Exercise adherence varied considerably among the exercisers. CONCLUSIONS: Walking speed improved in this randomized study. The results confirm that exercise is safe for multiple sclerosis patients and should be recommended for those with mild to moderate disability.

Exercise capacity, disability and leisure physical activity of subjects with multiple sclerosis.

The purpose of the present study was to examine exercise capacity and its relationship to neurological disability as measured using the Expanded Disability Status Scale (EDSS) and to leisure physical activity in subjects with multiple sclerosis (MS). Thirty-four men and 61 women (mean age 44 +/- 6.7 years, mean disease duration 5.7 +/- 6.4 years) with mild to moderate disability (EDSS range 1.0-5.5) participated. They underwent an incremental exercise test on a leg cycling ergometer. Leisure physical activity was measured using a questionnaire. Peak oxygen uptake (VO2peak) in men was 27.0 +/- 5.2 mL/kg/min, and in women 21.7 +/- 5.5 mL/kg/min. The disability correlated inversely with the VO2peak both in men (r = - 0.50, P = 0.004) and in women (r = - 0.25, P = 0.05). No correlation between disease duration and VO2peak was found. In a multivariate regression analysis, neurological disability was confirmed as a predictor of VO2peak. No evidence of a relationship between leisure physical activity and VO2peak was found. A main finding was that disability and exercise capacity are inter-related, even in subjects who are not severely handicapped (84% had an EDSS of < 4.0). The level of disability should be taken into account in the planning of aerobic exercise programs for fully ambulatory MS subjects.

A whole genome association study in Finnish multiple sclerosis patients with 3669 markers.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with complex genetic background. In the present study, based in the Finnish population, we typed a large number of microsatellite markers in separately pooled DNA samples from 195 MS patients and 205 controls. A total of 108 markers showed evidence of association. Five genomic regions containing two or more of these markers within a 1-Mb interval were identified, 1q43, 2p16, 4p15, 4q34 and 6p21 (the MHC region). Substantial overlap with previously published linkage genome screens is also seen.

Linkage disequilibrium between the MBP tetranucleotide repeat and multiple sclerosis is restricted to a geographically defined subpopulation in Finland.

We have previously found evidence for linkage as well as allelic and haplotype association between the myelin basic protein (MBP) gene and multiple sclerosis (MS). These findings have, however, not been reproduced in other populations. Here, we have analyzed association between MBP and MS in a new set of 349 Finnish triad families. Families with a parent born in the Southern Ostrobothnian region in western Finland (Bothnia families, n=98) were analyzed as a separate group since our previous studies included a high proportion of patients and families from this high-incidence region. Other families (n=251) were collected at five hospitals in southern, eastern, and northern Finland. The MBP short tandem repeat was genotyped, and haplotype patterns were verified by sequencing. In the Bothnia families, the previously detected associations with the 1.27 kb allele and haplotype 1.27-B10 were confirmed (P=0.01 and 0.02, respectively), whereas in the other families there was not even a trend toward association. These results demonstrate a geographic/genealogical restriction in the association between MS and the MBP short tandem repeat, highlight the importance of genealogical information in genetic studies of complex traits, and may provide an explanation why the association has not been found in many other populations.

Chromosome 19q13 and multiple sclerosis susceptibility in Finland: a linkage and two-stage association study.

Several studies have previously provided some albeit weak evidence for linkage or association between chromosome 19q13 and multiple sclerosis (MS) susceptibility. We performed a two-stage association analysis with 19 markers spanning 7 Mb/5.5 cM of 19q13. In stage 1 analysis (135 MS families) allelic and haplotypic associations were found with markers within or close to the ApoE-ApoC subregion. These observations were taken as a hypothesis, which was tested in stage 2 in 125 families. However, none of the initial associations were replicated suggesting that they were most likely due to chance. Linkage analysis was performed in 27 Finnish multiplex families using 10 microsatellites spanning 23 Mb/24 cM of 19q13. DNA was available from 72 MS patients and 150 unaffected relatives. Parametric and non-parametric linkage analyses did not provide evidence for linkage when all families were tested. After stratifying the families according to HLA-DR15 there was weak evidence for linkage to the 19q13.1 subregion in DR15 negative families (LOD(max)=1.8). Taken together these results do not support a major role of chromosome 19q13.2-q13.3 in MS susceptibility among Finnish MS patients, whereas conclusions on the 19q13.1 subregion are less clear and this region requires further study.

Assistive technology to improve PC interaction for people with intention tremor.

Many patients with upper limb intention tremor encounter difficulties in mouse-driven interaction with the personal computer (PC). An assistive technology system ("the Tremor Control System"), consisting of a motion-filtering software program that supports multiple interfaces, was developed and validated with 36 persons with Multiple Sclerosis in a multi-center trial. PC-tests, requiring basic functions such as cursor placement and click and drag function, were able to differentiate between patients and control subjects (ANOVA: p<0.05). A significant time improvement on the PC-tests was found when using an optimal alternative interface instead of the standard PC-mouse (paired t-tests: p<0.01 for Point & Click test, p<0.05 for Drag & Drop test and p<0.1 for Double Click test). A significant time improvement was found for the Double Click test (paired t-tests: p<0.05) when the motion-filtering program was implemented. The number of patients able to perform fully the PC-tests increased with the Tremor Control System. Patients with marked intention tremor seemed to profit especially from this assistive technology. These users reported that working with the Tremor Control System was less fatiguing and more comfortable compared to the use of the standard PC-mouse.

Visual object recognition in multiple sclerosis.

Deficits in tasks measuring visual processing have been earlier reported in studies of MS. Yet, the nature and severity of visual-processing deficits in MS remains unclear. We used a new method in order to measure the different stages of visual processing in object recognition: shape recognition, familiarity recognition, semantic categorization, and identification with naming. Six two-choice reaction-time tasks were presented to 30 MS patients and 15 healthy controls. The patients were divided into cognitively preserved and cognitively deteriorated study groups according to their cognitive status. The purpose was to find out whether deficits at specific stages of visual processing can be found in cognitively deteriorated MS patients. Cognitively deteriorated MS patients did not perform as well as cognitively preserved MS patients or healthy controls. They were slower already at the early stage of visual processing where discrimination of whole objects from scrambled ones was required. They also had higher error rates in tasks requiring object familiarity detection and object identification with naming. Thus, cognitively deteriorated MS patients had difficulties in visual shape recognition and semantic-lexical processing. However, variation of performances was large within both of the patient groups indicating that even patients without a generalized cognitive decline may have deficits in some stages of the visual processing. We suggest that because of the heterogeneity of the patients, every single case needs to be examined separately in order to identify the possible deficits in visual processing.

Sematic memory deficit in multiple sclerosis; impaired understanding of conceptual meanings.

The aim of the present study was to determine whether a cognitive decline, related to multiple sclerosis (MS), also involves deficits in semantic memory. Semantic memory function was evaluated by studying the conscious understanding of conceptual meanings. A group of MS patients with cognitive decline was presented with four tasks concerning concepts, their attributes and relationships to other concepts. The tasks were designed to measure spontaneous, cued and recognition performance separately. The patients had difficulties in understanding conceptual meanings. Easing the retrieval demands of the tasks did not help them to improve their performance which was poorer than the control group's on every task used. The results indicate a retrieval deficit combined with an underlying storage deficit in the semantic memory of MS patients with cognitive decline.

Pelvic floor rehabilitation is effective in patients with multiple sclerosis.

OBJECTIVE: To determine the effect of pelvic floor muscle exercises combined with electrical stimulation of pelvic floor on lower urinary tract dysfunction in multiple sclerosis (MS) patients with near normal (< 100 ml) postvoid residual volumes. DESIGN: Open, controlled, randomized study in two parallel groups. SETTING: Rehabilitation centre for MS patients. SUBJECTS: Fifty women and 30 men with definite MS and current symptoms of lower urinary tract dysfunction. OUTCOME: The muscle activity of the pelvic floor muscles was tested using surface EMG. Subjective urinary symptoms were assessed using a questionnaire. INTERVENTIONS: Pelvic floor muscles were stimulated using electrical stimulation at six sessions. During and after the final session the patients were taught to exercise their pelvic floor muscles and advised to continue these exercises regularly for at least six months. The control group was not treated. RESULTS: The maximal contraction power and endurance of the pelvic floor muscles increased after six sessions of electrical stimulation with interferential currents. Symptoms of urinary urgency, frequency and incontinence were significantly less frequent in the treated group than in the untreated subjects. Male patients appeared to respond better to the treatment than female patients. Compliance with the pelvic floor exercises was over 60% at the end of a follow-up for six months. Most drop-outs were due to the disappearance of urinary tract symptoms or to severe relapses in MS. CONCLUSIONS: The present study indicates that pelvic floor muscle exercises combined with electrical stimulation of the pelvic floor constitute an effective treatment for lower urinary tract dysfunction at least in male patients with MS.

The progress of cognitive decline in multiple sclerosis. A controlled 3-year follow-up.

The purpose of this study was to illustrate how cognitive functioning evolves over time in patients with multiple sclerosis. We followed the evolution of cognitive performances in two clinically and demographically similar multiple sclerosis groups, the 'cognitively preserved' (n = 20) and the 'cognitively mildly deteriorated' (n = 22), and in healthy controls (n = 34). We conducted the follow-up examination using the Mild Deterioration Battery, the Mini-Mental State Examination, and a set of additional neuropsychological measures after an interval of 3 years. The drop-out rate in our study was only 5%. The 'cognitively preserved' multiple sclerosis group showed substantial neuropsychological stability by performing as well as the controls both at baseline and at follow-up. By contrast, the initially 'cognitively mildly deteriorated' group demonstrated progressive cognitive decline on many neuropsychological tests. The intermediate-length screening battery, the Mild Deterioration Battery, was sensitive to this decline, whereas the briefer Mini-Mental State Examination was not. The progressive cognitive decline could not be predicted from other disease variables. The study demonstrated that intact cognitive functioning in multiple sclerosis may remain stable, whereas incipient cognitive decline seems to be widespread and progressive in nature. Thus, progressive cognitive deterioration should be considered as one of the characteristics of multiple sclerosis.

Language functions in incipient cognitive decline in multiple sclerosis.

Although the mechanisms of cognitive impairment in multiple sclerosis (MS) have been extensively studied, evaluation of language functions has been given little attention. In the present study, we evaluated whether impairment of language functions is associated with cognitive decline in MS. We studied naming, reading, and writing performance of two carefully matched patient groups differing only with respect to cognitive status. In language tasks, the patients with incipient cognitive decline not only demonstrated performance slowness but also made more errors than the patients with preserved cognitive capacity and the healthy controls. The comprehensive naming error analysis revealed that the cognitively deteriorated patients produced error types not present in the other two study groups. Contrary to previous suggestions, the present study indicates that impaired language performances in MS are attributable to mild cognitive deterioration rather than to sensory or motor factors. Thus, assessment of language functions should be included in neuropsychological evaluations of MS patients.

Memory deficits and early cognitive deterioration in MS.

INTRODUCTION: In the present study, the pattern of memory and learning deficits in two cognitively different, but clinically and demographically similar, multiple sclerosis (MS) groups was compared. MATERIAL & METHODS: 23 patients represented the cognitively preserved MS group and 22 patients the MS group with early cognitive decline. A control group of 35 healthy controls was also included. The cognitive status of the subjects was defined using the Mild Deterioration Battery (MDB). Furthermore, all subjects were given a set of memory and learning tests and were instructed to evaluate the frequency of their memory and learning difficulties. The Mini-Mental State Examination (MMSE) was also administered to all subjects. RESULTS: The cognitively deteriorated patients, even those with normal MMSE performance, showed widespread memory and learning deficits, but adequate self-evaluation of their everyday memory and learning difficulties. The preserved group, in turn, performed similarly to the controls. CONCLUSION: Widespread memory and learning deficits are associated with relatively mild cognitive decline in MS. These deficits were observable in the intermediate-length screening battery, the MDB, but not in the MMSE. The present study suggests that the accuracy of patients' own evaluations of their memory and other cognitive problems is superior to the results of very brief screening batteries, like the MMSE. Therefore, brief screening in neuropsychological assessment of MS patients is not recommendable.

Attention related performance in two cognitively different subgroups of patients with multiple sclerosis.

To evaluate the underlying mechanisms of cognitive decline in multiple sclerosis, two clinically and demographically matched multiple sclerosis groups differing in cognitive status were assessed with attention related tasks. In addition to the attention tests recommended by the Cognitive Function Study Group of the American National Multiple Sclerosis Society, a test of sustained attention was used to evaluate the role of possible fatigue on cognitive performance. The cognitively mildly deteriorated group was slower than the cognitively preserved group and the controls on all tests of attention. The mildly deteriorated group did not, however, consistently differ from the other groups in the error scores of the attention tests. The preserved group exhibited slowness at the end of the visual vigilance test, but no deficits were found on the other attention related tests in this group. It is suggested that dissociable kinds of processing slowness are the origin of the deficits found on the attention tests in the two multiple sclerosis groups. Our preserved group exhibited signs of motor and fatigue related slowness, whereas the mildly deteriorated group also had extensive cognitive slowness. As sensitive indicators of cognitive slowness, attentional tests should be included in evaluation of the cognitive status of patients with multiple sclerosis.