Organic solvent exposure as a risk factor for multiple sclerosis: An updated review.

Organic solvents exposure has for a long time been suspected as a risk factor for developing multiple sclerosis. The evidence, containing case reports, case-control studies and cohort studies has been contradictory. An early meta-analysis, however, pointed to a doubled risk for MS. Recent major case-control studies confirm this, but also have elucidated the risk pattern, being dependent on another risk factor, i.e. smoking.

Rapidly increasing off-label use of rituximab in multiple sclerosis in Sweden - Outlier or predecessor?

OBJECTIVES: Off-label use of rituximab to treat MS patients in Sweden is high, and the need for long-term safety data may not be met. Our objectives were to assess the rate of rituximab prescription in patients with multiple sclerosis in Sweden and, in addition, to evaluate the safety of rituximab in a single centre for patients with multiple sclerosis. MATERIAL AND METHODS: Review of the Swedish MS register was performed to study the number of MS patients treated with rituximab during the last 6 years. Investigation also included a retrospective review of medical files in search for possible side effects/adverse events in all adult patients with MS treated with rituximab at Uppsala University Hospital. RESULTS: Presently, in Sweden the rate of rituximab prescriptions in relation to other annually started of disease- modifying drugs in MS is 53.5%. CONCLUSIONS: The share of MS patients in Sweden who are treated with rituximab is very high, and also rapidly increasing. Taken into account the off-label use, cases with adverse medical conditions that could possibly be related to rituximab use should be reported thoroughly.

Patterns of antiepileptic drug prescription in Sweden: A register-based approach.

OBJECTIVES: To determine drug utilization pathways from the incident healthcare visit due to epilepsy and three years onward. MATERIAL AND METHODS: Anti-epileptic drug utilization was calculated using individual information on inpatient- and outpatient care utilization and drug sales. Throughout, we used national register information pertaining to pharmaceutical sales linked to diagnosis-related healthcare utilization. Information on pharmaceutical sales was collected for the 2007-2013 period. RESULTS: For the entire studied period, a majority of new patients with epilepsy were initiated on anti-epileptic drug treatment with a monotherapy (98%); most of these patients remained on that first treatment (64%). The three most frequently prescribed drugs accounted for 72% of the initiated AED treatments. Patients with epilepsy (ICD-10: G40/41) were most commonly prescribed carbamazepine, lamotrigine and valproate. The most common second-line monotherapy was levetiracetam. About 12% of new patients with epilepsy who were initiated on AED treatment during the period eventually switched to an add-on therapy. The proportion of patients who were initiated on treatment with carbamazepine or valproate decreased, and the proportion of patients who remained on their initial monotherapy increased between 2007 and 2013. CONCLUSIONS: A limited number of anti-epileptic drugs accounted for the treatment of a majority of new patients with epilepsy (carbamazepine, lamotrigine and valproate accounted for more than 70%). Add-on therapies showed the same pattern, as the most frequently prescribed add-on regimens were the same ones that accounted for most of the monotherapies. There was a tendency towards fewer patients being initiated on AED treatment with either carbamazepine or valproate.

Does the changing sex ratio of multiple sclerosis give opportunities for intervention?

In several international studies, an increasing women-to-men (w/m) ratio in patients with multiple sclerosis (MS) has been reported. Such sex ratios have been analysed by year of onset or by year of birth. In a Swedish study, data from the Swedish MS register (SMSreg) were used to analyse the w/m ratio in Sweden. The sex ratio was analysed both by year of birth (8834 patients) and by year of onset (9098 patients). No increased w/m ratio was seen in this study. The age-specific sex ratio did not demonstrate any significant changes. However, a new investigation of the sex ratio in Sweden, based on data from all available data sources (19,510 patients), showed a significantly increased w/m ratio of MS in Sweden from 1.70 to 2.67. Environmental factors such as cigarette smoking, hormonal factors and nutrition are of interest in this context, but the cause of the increasing w/m ratio in MS is yet not possible to explain.

Prevalence and cost of epilepsy in Sweden--a register-based approach.

OBJECTIVES: To estimate the prevalence of epilepsy, costs associated with in- and outpatient care, drug utilization and productivity losses due to epilepsy in Sweden for the years 2005 and 2011. METHODS: Cost components were calculated using registry data on inpatient- and outpatient-care utilization, drug sales and early pensions granted due to permanent disability and mortality. Moreover, by cross-identification of information in healthcare and pharmaceutical registries, we were able to distinguish between pharmaceuticals prescribed for epilepsy and non-epilepsy indications. RESULTS: The prevalence of epilepsy was estimated at 0.62% in 2005 and 0.88% in 2011. The total cost of epilepsy increased during the same period, while the per-patient cost decreased from €2929 to €1729. Direct medical costs accounted for about 36% of the estimated total cost in 2005 and 60% in 2011. The estimated healthcare cost due to epilepsy as a share of total healthcare costs for all illnesses was about the same in 2005 as in 2011 (0.2%), while the corresponding pharmaceutical cost increased from about 0.5% in 2005 to almost 1% in 2011. CONCLUSIONS: The per-patient cost of epilepsy is substantial, implying a significant aggregated cost incurred on society (despite a prevalence < 1%). Our results suggest that the per-patient pharmaceutical utilization increased, while the per-patient physician visits and hospitalizations decreased, between 2005 and 2011. Moreover, we demonstrate that the 2005 prevalence measure was underestimated the true prevalence in 2005.

Regional variation in prevalence and healthcare utilization due to epilepsy in Sweden.

OBJECTIVE: To estimate the regional differences in the prevalence of epilepsy and the associated costs due to inpatient and outpatient care and anti-epileptic drug (AED) utilization for the years 2005 and 2011 in Sweden. METHODS: Region-specific estimates of the prevalence of epilepsy were obtained using a method based on a linkage of the healthcare and pharmaceutical registries and the cause of death registry. Regional cost components were estimated using registry data by region on inpatient and outpatient care utilization, AED sales, and mortality. Per-patient utilization and monetary costs were calculated. RESULTS: Estimated prevalence of epilepsy varied substantially across the regions in 2011, from 0.76% in Jämtland to 1.08% in Gotland. The national prevalence was 0.88%. The average number of hospitalizations per patient and year decreased at the national level between 2005 and 2011. At the national level, the per-patient specialized care (outpatient) utilization also decreased between 2005 and 2011. However, at the regional level, the decrease was not uniform, and in some counties, the per-patient utilization increased during the period studied. The per-patient utilization of AEDs increased in all counties, except Kronoberg, between 2005 and 2011. Moreover, between-region differences in healthcare and AED utilization, and significant differences between regions and national averages were revealed. Similarly, regional per-patient costs were shown to deviate from the national average in 13 of 21 regions. CONCLUSIONS: There is significant variation in the prevalence of epilepsy and the provision of health care for patients with epilepsy across the different regions of Sweden.

Developing education in environmental health and medicine focusing on neurology: Initiatives in Sweden (the UPRISE model), France, and Turkey.

BACKGROUND: The role of environmental factors in neurological disorders constitutes a topic of increasing importance. Teaching in European universities should expand and update this field gaining future health professionals including adjacent disciplines. AIM: To describe recent efforts to create courses that cover crucial interdisciplinary content that we believe should be included in modern education, and to adapt modern pedagogic strategies. METHODS: In collaboration with RISE (Rencontres Internationales Santé Environnement), elective courses focused on Environmental Health and Medicine (EHM) were developed, in France, Sweden, and Turkey. The courses combined classic teaching methods and new pedagogic and digital solutions to create environment-related health awareness and facilitate future interprofessional collaboration in this field. RESULTS: UPRISE is an innovative elective course introduced in 2020 in Sweden's Uppsala University with the participation of lecturers from several countries and aim to recruit students from different universities. A total of 45, mainly female students (68%), participated in the course. In Strasbourg, France, a novel course on environmental medicine was held in 2019-2023 and examined 90 students, of which more than half were female. Nine graduate nurse students in Turkey attended ten seminar series focused on EHM. Overall, students expressed satisfaction with the courses. CONCLUSIONS: This European project for courses in higher education arising from RISE was met with appreciation and challenges from academic institutions. However, due to considerable efforts to introduce the EHM concept, a unique compulsory course for all medical students in the second year of training started in 2023 in all French medical faculties. In 2023, UPRISE was integrated into ENLIGHT, the European University Network to promote equitable quality of Life, sustainability, and Global engagement through Higher education Transformation.

Time to secondary progression in patients with multiple sclerosis who were treated with first generation immunomodulating drugs.

BACKGROUND: It is currently unknown whether early immunomodulatory treatment in relapsing-remitting MS (RRMS) can delay the transition to secondary progression (SP). OBJECTIVE: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort. METHODS: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995-2004, n = 730) and a historical population-based incidence cohort (onset 1950-64, n = 186). We retrospectively analyzed the difference in time to SP, termed the "period effect" within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis. RESULTS: We found that the "period" affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53). CONCLUSION: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given.

Cytokine mapping in cerebrospinal fluid and blood in multiple sclerosis patients without oligoclonal bands.

OBJECTIVE: Since there are clinical and genetic differences between MS patients with intrathecal oligoclonal bands (OCB+) in the cerebrospinal fluid (CSF) compared with those without (OCB-), the aim was to find out if OCB- patients showed a different pattern of cytokine immune activation compared with OCB+ patients. METHODS: The study included 25 MS patients (10 OCB- and 15 OCB+) and 13 controls. A panel of cytokines was measured; IL-1ß, IL-6, IL-8/CXCL8, IL-10, TNF and GM-CSF in serum, CSF and in supernatants from polyclonally stimulated blood mononuclear cells, where also levels of IL-12p40, IL-13, IL-15, IL-17 and IFN-γ were measured. The concentrations of soluble (s) VCAM-1 and sCD14 were measured in serum and CSF. RESULTS: In general, there were no extensive differences in cytokine concentrations between the OCB- and OCB+ groups. CONCLUSION: OCB- MS patients do not seem to constitute a separate entity concerning inflammatory parameters measured as cytokine concentrations in CSF and blood.

Synthetic MRI of the brain in a clinical setting.

BACKGROUND: Conventional magnetic resonance imaging (MRI) has relatively long scan times for routine examinations, and the signal intensity of the images is related to the specific MR scanner settings. Due to scanner imperfections and automatic optimizations, it is impossible to compare images in terms of absolute image intensity. Synthetic MRI, a method to generate conventional images based on MR quantification, potentially both decreases examination time and enables quantitative measurements. PURPOSE: To evaluate synthetic MRI of the brain in a clinical setting by assessment of the contrast, the contrast-to-noise ratio (CNR), and the diagnostic quality compared with conventional MR images. MATERIAL AND METHODS: Twenty-two patients had synthetic imaging added to their clinical MR examination. In each patient, 12 regions of interest were placed in the brain images to measure contrast and CNR. Furthermore, general image quality, probable diagnosis, and lesion conspicuity were investigated. RESULTS: Synthetic T1-weighted turbo spin echo and T2-weighted turbo spin echo images had higher contrast but also a higher level of noise, resulting in a similar CNR compared with conventional images. Synthetic T2-weighted FLAIR images had lower contrast and a higher level of noise, which led to a lower CNR. Synthetic images were generally assessed to be of inferior image quality, but agreed with the clinical diagnosis to the same extent as the conventional images. Lesion conspicuity was higher in the synthetic T1-weighted images, which also had a better agreement with the clinical diagnoses than the conventional T1-weighted images. CONCLUSION: Synthetic MR can potentially shorten the MR examination time. Even though the image quality is perceived to be inferior, synthetic images agreed with the clinical diagnosis to the same extent as the conventional images in this study.

Insular cortex activation in a patient with "sensed presence"/ecstatic seizures.

OBJECTIVE: Seizures with an aura of a "sensed presence," a religious emotion, or feelings of euphoria (ecstatic seizures) are characterized by heightened self-awareness. A previous case report on a patient with epilepsy and "sensed presence" as an aura described hypoperfusion in both temporal lobes and a local ictal increase in the left frontoparietal area. A reexamination of the data was suggested by a recent study of patients with ecstatic seizures, which proposed that hyperactivation of the left anterior insula might be a potential cause. METHODS: We reanalyzed the laboratory data on the case with "sensed presence" aura using a fusion of SPECT and MR images of the brain, which had not previously been available, and a close examination of the subdural ictal EEG registrations. RESULTS: Examination of the ictal EEG recordings from subdural strip electrodes implanted subtemporally and temporally on both sides showed that seizure activity occurred first at the most medial subtemporal electrode on the left side. From an anatomical point of view, this electrode position is close to the ventral aspect of the left anterior insula, and it is possible that the seizure activity was initiated there. Reexamination of the SPECT data after fusion with contemporary MR images clearly indicated that the region of strong hyperactivation overlies the left anterior insula. Hyperactive regions also appear on the midinsula bilaterally. Together with the neurophysiological ictal EEG, this evidence supports a reinterpretation that this aura of "sensed presence" can be attributed to hyperactivation of the left anterior insula. CONCLUSION: The present findings support the proposal that ecstatic seizures or "sensed presence" auras can originate from the left anterior insula, a region that has been suggested to engender self-awareness associated with positive feelings.

Right-hemispheric brain activation correlates to language performance.

Language function in the right-hemispheric homologues of Broca's and Wernicke's areas does not only correlate with left-handedness or pathology, but occurs naturally in right-handed healthy subjects as well. In the current study, two non-invasive methods of assessing language lateralization are correlated with behavioral results in order to link hemispheric dominance to language ability in healthy subjects. Functional magnetic resonance imaging (fMRI) together with a sentence-completion paradigm was used to determine region-specific lateralization indices in the left- and right-sided Broca's and Wernicke's areas, the frontal temporal lobe, the anterior cingulate cortex and the parietal lobe. In addition, dichotic listening results were used to determine overall language lateralization and to strengthen conclusions by correlating with fMRI indices. Results showed that fMRI lateralization in the superior parietal, the posterior temporal, and the anterior cingulate cortices correlated to dichotic listening. A decreased right ear advantage (REA), which indicates less left-hemispheric dominance in language, correlated with higher performance in most administered language tasks, including reading, language ability, fluency, and non-word discrimination. Furthermore, right hemispheric involvement in the posterior temporal lobe and the homologue of Broca's area suggests better performance in behavioral language tasks. This strongly indicates a supportive role of the right-hemispheric counterparts of Broca's and Wernicke's areas in language performance.

Application of a vagal nerve stimulator in an epilepsy patient with cardiac pacemaker after post-ictal cardiac arrest.

In this case report we present a patient with temporal lobe epilepsy (TLE) showing partial complex seizures and secondary generalization, and treated with several antiepileptic drugs. After two consecutive seizures she had an episode of cardiac arrest followed by AV-block III which led to the implantation of a cardiac pacemaker. She subsequently received a vagal nerve stimulator because of poor response to epilepsy treatment. Combined treatment with two different electromagnetic stimulators raises the question of safety during surgery which is discussed.

Symptoms of multiple sclerosis in women in relation to cyclical hormone changes.

OBJECTIVES: To prospectively investigate if women with multiple sclerosis (MS) experience changes in MS-symptoms in relation to cyclical hormonal changes. METHODS: Sixty-three women with MS, either with regular, spontaneous menstrual cycles or taking combined oral contraceptives (COCs), were asked to score their MS symptoms every day during three cycles. Symptom scores were analysed in relation to different phases of the spontaneous menstrual- or pill-driven cycle. RESULTS: Twenty-three women completed the score record. Among the 16 women who were not using a COC there were no significant differences in symptom scores between the phases of the menstrual cycle. The seven women taking a COC reported significantly higher symptom score points for weakness, numbness and tiredness during the pill-free interval compared with the phase during which they took the COC daily. CONCLUSIONS: This prospective study appears to contradict earlier retrospective studies regarding variations in MS symptoms in relation to the menstrual cycle in women who are not using a COC. The lower symptom scores during the three weeks of pill taking suggest a positive effect of the steroids on the manifestations of MS. Further studies concerning both short- and long-term effects of OC-use on MS symptoms are needed.

Low choline concentrations in normal-appearing white matter of patients with multiple sclerosis and normal MR imaging brain scans.

BACKGROUND AND PURPOSE: Spectroscopic studies (1H-MR spectroscopy) of normal-appearing white matter (NAWM) in patients with multiple sclerosis (MS) with MR imaging brain lesions have already been performed, but our intention was to investigate NAWM in MS patients who lack brain lesions to elucidate whether the same pathologic changes could be identified. MATERIALS AND METHODS: We checked 350 medical files of patients with MS who are registered in our institution. Fourteen patients (11 women and 3 men; mean age, 48.6 years; handicap score, Expanded Disability Status Scale [EDSS] 2.9; range, 1-6.5) with clinically definite MS and a normal MR imaging of the brain were included. 1H-MR spectroscopy was performed in 4 voxels (size approximately 17x17x17 mm3) using absolute quantification of metabolite concentrations. Fourteen healthy control subjects (11 women and 3 men; mean age, 43.3 years) were analyzed in the same way. RESULTS: Significant differences in absolute metabolite concentrations were observed, with the patients with MS showing a lower total concentration of N-acetyl compounds (tNA), including N-acetylaspartate and N-acetyl aspartylglutamate (13.5 mmol/L versus 14.6 mmol/L; P=.002) compared with the healthy control subjects. Unexpectedly, patients with MS presented significantly lower choline-containing compounds (Cho) compared with healthy control subjects (2.2 mmol/L versus 2.4 mmol/L; P<.001). The EDSS showed a positive correlation to myo-inositol concentrations (0.14 mmol/L per EDSS; r2=0.06) and a negative correlation to tNA concentrations (-0.41 mmol/L per EDSS; r2=0.22). CONCLUSION: The unexpected finding of lower Cho concentrations has not been reported previously. We suggest that patients with MS who lack lesions in the brain constitute a separate entity and may have increased protective or healing abilities.

Symptoms of multiple sclerosis in women in relation to sex steroid exposure.

OBJECTIVE: To investigate if women with multiple sclerosis (MS) experience changes in MS symptoms related to pregnancy, the postpartum period, menopause or use of oral contraception (OC) or postmenopausal hormone therapy (HT). METHODS: Women with diagnosed MS were recruited from registers of all MS patients known in two counties of Sweden, respectively. Ninety-four women were recruited in Linköping and 52 in Sundsvall. The women answered a questionnaire with categorized alternatives regarding their MS symptoms related to menstruation, pregnancy, delivery, menopause and use of OC or HT. RESULTS: Forty percent of the women reported worsening of MS symptoms related to menopause, whereas 56% reported no change of symptoms and 5% reported decreased symptoms. More than a fourth of the women reported decreased symptoms during pregnancy, 64% reported unchanged symptoms and 10% reported increased symptoms. Every third woman reported increased symptoms after delivery, 59% reported no change and 5% reported decreased symptoms. Few women reported changes in MS symptoms in relation to use of HT or OC. CONCLUSION: The presented data indicate a relationship between high-oestrogen states and ameliorated symptoms whereas low-oestrogen states seem to relate to a worsening of the disease. A majority of women, however, reported no changes in MS symptoms in relation to the different oestrogen states.

The risk for multiple sclerosis in female nurse anaesthetists: a register based study.

BACKGROUND: Previous studies have suggested that exposure to organic solvents, including volatile anaesthetic agents, may be a risk factor for multiple sclerosis (MS), possibly in combination with genetic and other environmental factors. AIMS: To further investigate the role of volatile anaesthetic agents having similar acute toxic effects to other organic solvents. METHODS: Female nurse anaesthetists, other female nurses, and female teachers from middle and upper compulsory school levels were identified and retrieved from the 1985 census, Statistics Sweden. By means of the unique personal identity number in Sweden, these individuals were linked with the disability pension registers at The National Social Insurance Board and also with data on hospital care 1985-2000 at The National Board of Health and Welfare. RESULTS: The cumulative incidence rate ratio of MS was found to be increased in female nurse anaesthetists in relation to other nurses (statistically not significant) and teachers (statistically significant), respectively. CONCLUSIONS: These findings give some support to previous findings of an increased risk for MS in nurse anaesthetists. This is interesting in the context of previous observations of organic solvents in general as a potential risk factor in MS.

Linkage and association analysis of genes encoding cytokines and myelin proteins in multiple sclerosis.

Several genetic factors are likely to play a role in the etiology of multiple sclerosis (MS). We used a candidate gene strategy in a study of polymorphic markers within or close to genes encoding cytokines (interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-4, IL-4 receptor (IL-4R), IL-10, transforming growth factor-beta1 and -beta2) and myelin proteins (2',3'-cyclic-nucleotide 3'-phosphohydrolase (CNP:ase), myelin associated glycoprotein, oligodendrocyte myelin glycoprotein, proteolipid protein) in 34 Swedish multiplex MS families and in 147 sporadic MS patients and 95 healthy controls. No evidence for linkage was observed in two-point linkage analysis. However, a slightly positive LOD score of 0.88 (theta = 0.01) for IFN-gamma was found. Affected pedigree member (APM) analysis indicated a possible linkage with TGF-beta2 (p = 0.008) and IL-4R (p = 0.043). None of the cytokine markers were associated with MS in case-control analysis. Our results suggest a possible importance of the TGF-beta2, IL-4R and IFN-gamma genes in MS.

Multiple sclerosis and exposure to solvents, ionizing radiation and animals.

Earlier studies have indicated an association between multiple sclerosis and environmental factors, especially occupational exposure to solvents. The present study examined such relationships further. From medical files of hospitals in Kalmar and Jönköping, 91 cases of multiple sclerosis, diagnosed in 1983-1988, were identified from population registers corresponding to the catchment areas of the hospitals, and 348 referents were randomly drawn. The cases and referents answered a questionnaire concerning occupational exposure and animal contacts. The men had significantly elevated risks, determined from logistic odds ratios, for solvent exposure, occupational contact with dogs or cats, and leisure-time contact with caged birds. X-ray treatment and previous diseases were risk indicators among the women. For the men and women together, solvent exposure, radiological work, and previous diseases were associated with clearly elevated risks. Although the study concerned rather few subjects, the findings indicate that several exogenous factors might contribute to the development of multiple sclerosis.

Effects of gadolinium contrast agent administration on automatic brain tissue classification of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: The administration of gadolinium contrast agent is a common part of MR imaging examinations in patients with MS. The presence of gadolinium may affect the outcome of automated tissue classification. The purpose of this study was to investigate the effects of the presence of gadolinium on the automatic segmentation in patients with MS by using the synthetic tissue-mapping method. MATERIALS AND METHODS: A cohort of 20 patients with clinically definite multiple sclerosis were recruited, and the T1 and T2 relaxation times and proton density were simultaneously quantified before and after the administration of gadolinium. Synthetic tissue-mapping was used to measure white matter, gray matter, CSF, brain parenchymal, and intracranial volumes. For comparison, 20 matched controls were measured twice, without gadolinium. RESULTS: No differences were observed for the control group between the 2 measurements. For the MS group, significant changes were observed pre- and post-gadolinium in intracranial volume (-13 mL, P < .005) and cerebrospinal fluid volume (-16 mL, P < .005) and the remaining, unclassified non-WM/GM/CSF tissue volume within the intracranial volume (+8 mL, P < .05). The changes in the patient group were much smaller than the differences, compared with the controls, which were -129 mL for WM volume, -22 mL for GM volume, +91 mL for CSF volume, 24 mL for the remaining, unclassified non-WM/GM/CSF tissue volume within the intracranial volume, and -126 mL for brain parenchymal volume. No significant differences were observed for linear regression values against age and Expanded Disability Status Scale. CONCLUSIONS: The administration of gadolinium contrast agent had a significant effect on automatic brain-tissue classification in patients with MS by using synthetic tissue-mapping. The observed differences, however, were much smaller than the group differences between MS and controls.