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Objective: The most common genetic cause of amyotrophic lateral sclerosis (ALS) is the C9orf72 expansion. A high incidence of this expansion has been detected in Sweden and Finland. This Norwegian population-based study aimed to identify the prevalence, geographic distribution, ancestry, and relatedness of ALS patients with a C9orf72 expansion (C9 pos ). Further, we compared C9 pos and C9 neg patients' clinical presentation, family history of ALS and other neurodegenerative disorders, and sociodemographic status., Methods: We recruited ALS patients from all 17 Departments of neurology in Norway. Blood samples and questionnaires regarding clinical characteristics, sociodemographic status and family history of ALS, and other neurodegenerative disorders were collected. The C9orf72 expansion was examined for all patients., Results: The study enrolled 500 ALS patients, 8.8% of whom were C9 pos , with half being sporadic ALS cases. The proportion of C9 pos cases differed between regions, ranging from 17.9% in the Northern region to 1.9% in the Western region. The majority of C9 pos patients had non-Finnish European descent and were not closely related. C9 pos patients exhibited a significantly shorter mean survival time, had a higher frequency of relatives with ALS or dementia, and were more often unmarried/single and childless than C9 neg patients., Conclusion: C9 pos patients constitute a large portion of the Norwegian ALS population. Ancestry and relatedness do not adequately explain regional differences. Relying on clinical information to identify C9 pos patients has proven to be challenging. Half of C9 pos patients were reported as having sporadic ALS, underlining the importance of carefully assessing family history and the need for genetic testing.

Genetic repeat expansions cause neuronal degeneration in amyotrophic lateral sclerosis as well as other neurodegenerative disorders such as spinocerebellar ataxia, Huntington's disease and Kennedy's disease. Repeat expansions in the same gene can cause multiple clinical phenotypes. We aimed to characterize repeat expansions in a Norwegian amyotrophic lateral sclerosis cohort. Norwegian amyotrophic lateral sclerosis patients ( n = 414) and neurologically healthy controls adjusted for age and gender ( n = 713) were investigated for repeat expansions in AR , ATXN1 , ATXN2 and HTT using short read exome sequencing and the ExpansionHunter software. Five amyotrophic lateral sclerosis patients (1.2%) and two controls (0.3%) carried ≥36 repeats in HTT ( P = 0.032), and seven amyotrophic lateral sclerosis patients (1.7%) and three controls (0.4%) carried ≥29 repeats in ATXN2 ( P = 0.038). One male diagnosed with amyotrophic lateral sclerosis carried a pathogenic repeat expansion in AR , and his diagnosis was revised to Kennedy's disease. In ATXN1 , 50 amyotrophic lateral sclerosis patients (12.1%) and 96 controls (13.5%) carried ≥33 repeats ( P = 0.753). None of the patients with repeat expansions in ATXN2 or HTT had signs of Huntington's disease or spinocerebellar ataxia type 2, based on a re-evaluation of medical records. The diagnosis of amyotrophic lateral sclerosis was confirmed in all patients, with the exception of one patient who had primary lateral sclerosis. Our findings indicate that repeat expansions in HTT and ATXN2 are associated with increased likelihood of developing amyotrophic lateral sclerosis. Further studies are required to investigate the potential relationship between HTT repeat expansions and amyotrophic lateral sclerosis., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons. In Europe, disease-causing genetic variants have been identified in 40-70% of familial ALS patients and approximately 5% of sporadic ALS patients. In Norway, the contribution of genetic variants to ALS has not yet been studied. In light of the potential development of personalized medicine, knowledge of the genetic causes of ALS in a population is becoming increasingly important. The present study provides clinical and genetic data on familial and sporadic ALS patients in a Norwegian population-based cohort., Methods: Blood samples and clinical information from ALS patients were obtained at all 17 neurological departments throughout Norway during a 2-year period. Genetic analysis of the samples involved expansion analysis of C9orf72 and exome sequencing targeting 30 known ALS-linked genes. The variants were classified using genotype-phenotype correlations and bioinformatics tools., Results: A total of 279 ALS patients were included in the study. Of these, 11.5% had one or several family members affected by ALS, whereas 88.5% had no known family history of ALS. A genetic cause of ALS was identified in 31 individuals (11.1%), among which 18 (58.1%) were familial and 13 (41.9%) were sporadic. The most common genetic cause was the C9orf72 expansion (6.8%), which was identified in 8 familial and 11 sporadic ALS patients. Pathogenic or likely pathogenic variants of SOD1 and TBK1 were identified in 10 familial and 2 sporadic cases. C9orf72 expansions dominated in patients from the Northern and Central regions, whereas SOD1 variants dominated in patients from the South-Eastern region., Conclusion: In the present study, we identified several pathogenic gene variants in both familial and sporadic ALS patients. Restricting genetic analysis to only familial cases would miss more than 40 percent of those with a disease-causing genetic variant, indicating the need for genetic analysis in sporadic cases as well., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: Whether disease-modifying therapies (DMTs) influence cancer in multiple sclerosis (MS) is uncertain., Objectives: Assess incidence of cancer diagnosis among Norwegian MS patients compared to the general population in 1953 to 1995 and 1996 to 2017-reflecting era before and after introduction of DMTs., Methods: We performed a nationwide cohort study comprising 6949 MS patients and 37,922 controls, matched on age, sex and county. The cohort was linked to Norwegian Cancer Registry, Cause of Death Registry and National Educational database. We used Poisson regression to calculate incidence rate ratio (IRR) of cancer., Results: During 1953-1995 MS patients had similar cancer frequency compared to controls (IRR: 1.11 (95% Confidence Intervals (CI): 0.90-1.37)), although MS patients had increased frequency of cancer in endocrine glands (IRR: 2.51 (1.27-4.93). During 1996-2017 we identified significant increased frequency of cancer among MS patients compared to controls (IRR: 1.38 (95% CI: 1.28-1.52): in brain (IRR: 1.97 (1.41-2.78)), meninges (IRR: 2.44 (1.54-3.77)), respiratory organs (IRR: 1.96 (1.49-2.63)). The excess cancer diagnosis was most frequent among MS patients ≥ 60 years of age (HR 1.30 (1.15-1.47))., Conclusion: Incidence of cancer among MS patients compared to controls was higher in 1996 to 2017, corresponding in time to the introduction of DMT for MS. This was observed more frequently among MS patients older than 60 years of age., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: The effect of vitamin D supplementation on the disease course of multiple sclerosis (MS) is not established. Neurofilament light chain (NFL) is a sensitive marker of axonal degeneration. The aim of this study was to establish whether high-dose vitamin D supplementation reduces serum levels of NFL., Materials and Methods: We have performed a 96 weeks placebo-controlled randomized study of weekly supplementation with 20 000 IU vitamin D3 in 71 patients with relapsing remitting MS (RRMS). Serum levels of NFL were measured at baseline, week 48 and week 96 with a single molecule (Simoa) assay in 69 of these patients., Results: Serum levels of 25-hydroxyvitamin D more than doubled in the vitamin D group. Compared to placebo, vitamin D supplementation had no overall effect on the change in serum levels of NFL from baseline (P = 0.93 at week 48 and P = 0.56 at week 96). In the subgroup of patients not receiving disease-modifying therapy, NFL decreased by 30.9% to week 48% and 32.6% to week 96 from baseline in the vitamin D group as compared to the placebo group (P = 0.06 for both time points)., Conclusion: With a possible exception for patients not treated with disease-modifying drugs, weekly supplementation with 20 000 IU vitamin D3 did not affect NFL levels in these RRMS patients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Results from previous studies on a possible interaction between smoking and Epstein-Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting., Objectives: To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS., Methods: Within the case-control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale., Results: Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis ( p = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66-1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): -0.98, 95% CI: -2.05-0.15, p = 0.09)., Conclusion: Our findings indicate competing antagonism, where the two exposures compete to affect the outcome.

Background: People with multiple sclerosis have high risk of osteoporosis and fractures. A poor vitamin D status is a risk factor for MS, and vitamin D supplementation has been recommended both to prevent MS progression and to maintain bone health., Methods: We assessed the effect of 20,000 IU vitamin D 3 weekly compared to placebo on biochemical markers of bone metabolism in 68 persons with relapsing remitting multiple sclerosis., Results: Serum levels of 25-hydroxyvitamin D more than doubled in the vitamin D group, and parathyroid hormone decreased in the vitamin D group compared to the placebo group at week 48 and week 96. There was however no effect on bone formation as measured by procollagen type I N propeptide (PINP), or on bone resorption as measured by C-terminal cross-linking telopeptide of type I collagen (CTX1). Neither PINP nor CTX1 predicted bone loss from baseline to week 96., Conclusions: These findings corroborate the previously reported lack of effect of weekly high dose vitamin D supplementation on bone mass density in the same patients, and suggest that such vitamin D supplementation does not prevent bone loss in persons with MS who are not vitamin D deficient., Trial Registration: The trial was registered at ClinicalTrials.gov on April 4 2008, registration number NCT00785473 .

Background: Elevated antibody levels against Epstein-Barr virus (EBV) and a poor vitamin D status are environmental factors that may interact in relapsing-remitting multiple sclerosis (RRMS) aetiology., Objectives: To examine effects of high-dose oral vitamin D 3 supplementation on antibody levels against EBV nuclear antigen 1 (EBNA1) in RRMS., Methods: Serum 25-hydroxyvitamin D 3 (25(OH)D) and immunoglobulin G antibody levels against EBNA1 (whole protein and amino acid 385-420 fragment), EBV viral capsid antigen (VCA), cytomegalovirus (CMV) and varicella zoster virus (VZV) were measured in 68 RRMS patients enrolled in a 96-week randomised double-blinded placebo-controlled clinical trial of oral vitamin D 3 supplementation (20,000 IU/week) (NCT00785473)., Results: The mean 25(OH)D level more than doubled in the vitamin D group and was significantly higher than in the placebo group at study conclusion (123.2 versus 61.8 nmol/L, p < 0.001). Compared to the placebo group, both anti-EBNA1 protein and fragment antibody levels decreased in the vitamin D group from baseline to week 48 ( p = 0.038 and p = 0.004, respectively), but not from baseline to week 96. Vitamin D 3 supplementation did not affect antibodies against VCA, CMV or VZV., Conclusion: The results indicate that high-dose oral vitamin D 3 supplementation can affect humoral immune responses against the latent EBV antigen EBNA1 in RRMS.

Background: The conflicting results from studies on socioeconomic status (SES) and multiple sclerosis (MS) risk might be due to a change in the distribution of environmental exposures over time or to methodological limitations in previous research., Objective: To examine the association between SES and MS risk during 50 years., Methods: We included patients registered in Norwegian MS registries and prevalence studies born between 1930 and 1979, and identified their siblings and parents using the Norwegian Population Registry. Information on education was retrieved from the National Education Registry, categorized into four levels (primary, secondary, undergraduate and graduate) and compared in patients and siblings using conditional logistic regression., Results: A total of 4494 MS patients and 9193 of their siblings were included in the analyses. Level of education was inversely associated with MS risk ( p trend < 0.001) with an odds ratio (OR) of 0.73 (95% confidence interval (CI): 0.59-0.90) when comparing the highest and lowest levels. The effect estimates did not vary markedly between participants born before or after the median year of birth (1958), but we observed a significant effect modification by parental education ( p = 0.047)., Conclusion: Level of education was inversely associated with MS risk, and the estimates were similar in the earliest and latest birth cohorts., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EG Celius has received funding for travel, advice and speaker’s fees from Sanofi-Aventis, Merck-Serono, Genzyme, Biogen Idec, Roche, Teva, Almirall and Novartis, and received unrestricted research support from Biogen Idec and Novartis. KM Myhr has participated on scientific advisory boards for Novartis Norway, Biogen Idec, Genzyme and Roche; received funding for travel from Allergan, Bayer, Novartis, Merck-Serono and Biogen; received speaker honoraria from Allergan, Almirall, Bayer, Biogen, Genzyme, Novartis, Merck-Serono and Teva; and received unrestricted research support from Bayer, Genzyme, Novartis, Merck-Serono, Biogen, Pronova Biocare and Bergen and Norwegian MS Society. Ø Torkildsen has served on scientific advisory boards for Biogen Idec, Genzyme and Merck-Serono and received speaker honoraria and travel grants from Genzyme, Merck-Serono, Novartis and Biogen Idec.

Background: Several recent studies have found a higher risk of multiple sclerosis (MS) among people with a low level of education. This has been suggested to reflect an effect of smoking and lower vitamin D status in the social class associated with lower levels of education., Objective: The objective of this paper is to investigate the association between level of education and MS risk adjusting for the known risk factors smoking, infectious mononucleosis, indicators of vitamin D levels and body size., Methods: Within the case-control study on Environmental Factors In MS (EnvIMS), 953 MS patients and 1717 healthy controls from Norway reported educational level and history of exposure to putative environmental risk factors., Results: Higher level of education were associated with decreased MS risk (p trend = 0.001) with an OR of 0.53 (95% CI 0.41-0.68) when comparing those with the highest and lowest level of education. This association was only moderately reduced after adjusting for known risk factors (OR 0.61, 95% CI 0.44-0.83). The estimates remained similar when cases with disease onset before age 28 were excluded., Conclusion: These findings suggest that factors related to lower socioeconomic status other than established risk factors are associated with MS risk., (© The Author(s), 2015.)

Observational studies have suggested that vitamin D may reduce inflammation in relapsing-remitting multiple sclerosis (RRMS), but this has not been clearly confirmed in randomized controlled trials. To further explore the possible anti-inflammatory effects of vitamin D in RRMS, we examined the effect of high-dose oral vitamin D3 on eleven markers of systemic inflammation in 68 RRMS patients enrolled in a double-blinded randomized placebo-controlled trial of vitamin D3 supplementation (20,000 IU/week) (NCT00785473). Serum inflammation markers and 25-hydroxyvitamin D (25(OH)D) were measured at baseline and week 96, and no restrictions were set on additional standard immunomodulatory treatment for RRMS. The mean 25(OH)D level rose from 56 ± 29 to 123 ± 34 nmol/L among patients receiving vitamin D3 supplementation, whereas only a minor increase from 57 ± 22 to 63 ± 24 nmol/L was seen in the placebo group. However, no significant differences appeared between the vitamin D group and the placebo group for any of the inflammation markers. Patients on immunomodulatory therapy had significantly higher levels of interleukin-1 receptor antagonist and chemokine (C-X-C motif) ligand 16 than patients without immunomodulatory treatment, but there were no clear synergistic effects between immunomodulatory therapy and vitamin D3 supplementation on any of the inflammation markers. The rise in 25(OH)D levels after vitamin D3 supplementation was unaffected by immunomodulatory treatment. We conclude that in this study of RRMS patients, high-dose oral vitamin D3 supplementation prominently increased serum 25(OH)D levels without affecting markers of systemic inflammation, while a more anti-inflammatory phenotype was found among patients on immunomodulatory treatment.

Background: Low vitamin D levels have been associated with an increased risk of multiple sclerosis (MS), although it remains unknown whether this relationship varies by age., Objective: The objective of this paper is to investigate the association between vitamin D3 supplementation through cod liver oil at different postnatal ages and MS risk., Methods: In the Norwegian component of the multinational case-control study Environmental Factors In Multiple Sclerosis (EnvIMS), a total of 953 MS patients with maximum disease duration of 10 years and 1717 controls reported their cod liver oil use from childhood to adulthood., Results: Self-reported supplement use at ages 13-18 was associated with a reduced risk of MS (OR 0.67, 95% CI 0.52-0.86), whereas supplementation during childhood was not found to alter MS risk (OR 1.01, 95% CI 0.81-1.26), each compared to non-use during the respective period. An inverse association was found between MS risk and the dose of cod liver oil during adolescence, suggesting a dose-response relationship (p trend = 0.001) with the strongest effect for an estimated vitamin D3 intake of 600-800 IU/d (OR 0.46, 95% CI 0.31-0.70)., Conclusions: These findings not only support the hypothesis relating to low vitamin D as a risk factor for MS, but further point to adolescence as an important susceptibility period for adult-onset MS., (© The Author(s), 2015.)

Background and Purpose: In patients with acute stroke, undernutrition and aspiration pneumonia are associated with increased mortality and length of hospital stay. Formal screening for nutritional risk and dysphagia helps to ensure optimal nutritional management in all patients with stroke and to reduce the risk of aspiration in patients with dysphagia. We developed a national guideline for nutritional and dysphagia screening in acute stroke, which was introduced in our stroke unit on June 1, 2012. The primary objective was to audit adherence to the guideline and to achieve full implementation. Second, we assessed the prevalence of nutritional risk and dysphagia., Methods: We performed a chart review to assess performance of screening for nutritional risk and dysphagia in all patients with stroke hospitalized for ≥48 hours between June 1, 2012, and May 31, 2013. Next we applied a "clinical microsystems approach" with rapid improvement cycles and audits over a 6-month period to achieve full implementation., Results: The chart review showed that nutritional risk screening was performed in 65% and swallow testing in 91% of eligible patients (n = 185). Proactive implementation resulted in >95% patients screened (n = 79). The overall prevalence of nutritional risk was 29%, and 23% of the patients failed the initial swallow test., Conclusions: Proactive implementation is required to obtain high screening rates for nutritional risk and swallowing difficulties using validated screening tools. The proportion of patients at nutritional risk and the prevalence of dysphagia at initial swallow test were in the lower range of previous reports., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Obesity may be a risk factor for developing multiple sclerosis (MS)., Objective: We examined if body size influences the risk of MS in a population-based, case control study., Methods: A total of 953 cases and 1717 controls from Norway and 707 cases and 1333 controls from Italy reported their body size by choosing a silhouette 1 to 9 (largest) every fifth year from age 5 to 30 and at time of study. The body size-related MS risk was defined by odds ratios (ORs) in logistic regression analyses adjusting for age, smoking and outdoor activity., Results: In Norway a large body size (silhouettes 6-9) compared to silhouette 3 increased the risk of MS, especially at age 25 (OR 2.21; 95% CI 1.09-4.46 for men and OR 1.43; 95% CI 0.90-2.27 for women). When comparing silhouette 9 to 1, we found a significant dose-response from age 10 until age 30 peaking at age 25 (sex-adjusted OR 2.83; 95% CI 1.68-4.78). The association was present for at least 15 years prior to disease onset. No significant associations were found in Italy., Conclusions: Obesity from childhood until young adulthood is a likely risk factor for MS with a seemingly stronger effect in Norway than in Italy., (© The Author(s), 2014.)

Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system, often resulting in significant neurological disability. The causes of MS are not known; however, the incidence of MS is increasing, thereby suggesting that changes in lifestyle and/or environmental factors may be responsible. On this background, the Environmental Risk Factors in MS Study or EnvIMS study was designed to further explore the etiology of MS. The design and methodology are described, providing details to enable investigators to (i) use our experiences to design their own studies; (ii) take advantage of, and build on the methodological work completed for, the EnvIMS study; (iii) become aware of this data source that is available for use by the research community., Methods: EnvIMS is a multinational case-control study, enrolling 2,800 cases with MS and 5,012 population-based controls in Canada, Italy, Norway, Serbia and Sweden. The study was designed to investigate the most commonly implicated risk factors for MS etiology using a self-report questionnaire., Results/conclusions: The use of a common methodology to study MS etiology across several countries enhances the comparability of results in different geographic regions and research settings, reduces the resources required for study design and enhances the opportunity for data harmonization., (© 2015 S. Karger AG, Basel.)

Objectives: The objective of this paper is to estimate the association between multiple sclerosis (MS) and measures of sun exposure in specific age periods in Norway and Italy., Methods: A total of 1660 MS patients and 3050 controls from Italy and Norway who participated in a multinational case-control study (EnvIMS) reported sun habits during childhood and adolescence., Results: A significant association between infrequent summer outdoor activity and increased MS risk was found in Norway and in Italy. The association was strongest between the ages of 16 and 18 years in Norway (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.30-2.59), and between birth and age 5 years in Italy (OR 1.56, 95% CI 1.16-2.10). In Italy a significant association was also found during winter (OR 1.42, 95% CI 1.03-1.97). Frequent sunscreen use between birth and the age of 6 years was associated with MS in Norway (OR 1.44, 95% CI 1.08-1.93) after adjusting for outdoor activity during the same period. Red hair (OR 1.67, 95% CI 1.06-2.63) and blonde hair (OR 1.36, 95% CI 1.09-1.70) were associated with MS after adjusting for outdoor activity and sunscreen use., Conclusion: Converging evidence from different measures underlines the beneficial effect of sun exposure on MS risk., (© The Author(s) 2014.)

Background: Seasonal fluctuations in solar radiation and vitamin D levels could modulate the immune response against Epstein-Barr virus (EBV) infection and influence the subsequent risk of multiple sclerosis (MS)., Methods: Altogether 1660 MS patients and 3050 controls from Norway and Italy participating in the multinational case-control study of Environmental Factors In Multiple Sclerosis (EnvIMS) reported season of past infectious mononucleosis (IM)., Results: IM was generally reported more frequently in Norway (p=0.002), but was associated with MS to a similar degree in Norway (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.64-2.73) and Italy (OR 1.72, 95% CI 1.17-2.52). For all participants, there was a higher reported frequency of IM during spring compared to fall (p<0.0005). Stratified by season of IM, the ORs for MS were 1.58 in spring (95% CI 1.08-2.31), 2.26 in summer (95% CI 1.46-3.51), 2.86 in fall (95% CI 1.69-4.85) and 2.30 in winter (95% CI 1.45-3.66)., Conclusions: IM is associated with MS independently of season, and the association is not stronger for IM during spring, when vitamin D levels reach nadir. The distribution of IM may point towards a correlation with solar radiation or other factors with a similar latitudinal and seasonal variation.

A month of birth effect on multiple sclerosis (MS) risk has been reported from different countries. Recent critics have suggested that this finding is caused by confounding and that adequately adjusting for year and place of birth would markedly reduce this effect. All inhabitants in Norway are registered in the Norwegian Population Registry (Statistics Norway), making this an ideal area for performing adjusted analyses. Using the entire Norwegian population born between 1930 and 1979 (n = 2,899,260), we calculated the excess between observed and expected number of births for each month for 6649 Norwegian MS patients, 5711 mothers, 5247 fathers, and 8956 unaffected siblings. The analyses were adjusted for year of birth and place of birth according to the 19 counties in Norway. An unadjusted analysis revealed 13% fewer MS births than expected in February (P = 0.0015; Bonferroni corrected P = 0.018), 10% more in April (P = 0.0083; Bonferroni corrected P = 0.0996) and 15% more in December (P = 0.00058; Bonferroni corrected P = 0.007). Adjustments for both year and place of birth significantly altered our results for February and December, but even after these adjustments there were still 10% more MS births than expected in April (P = 0.00796; Bonferroni corrected P = 0.096). MS patients had a higher incidence of April births than their siblings (Fisher-exact test; P = 0.011), mothers (Fisher-exact test; P = 0.004), and fathers (Fisher-exact test; P = 0.011) without MS. Adjustments for confounding significantly affected our results. However, even after adjustments, there appears to be a persistent higher than expected frequency of April births in the MS population.

Objective: We aimed to determine if the risk of Multiple Sclerosis (MS) is associated with month of birth in Norway and to explore a possible latitudinal gradient., Methods: All patients with MS born between 1930 and 1979 registered in the Norwegian MS Registry or ascertained in Norwegian prevalence studies were included (n = 6649). The latitude gradient was divided in Southern, Middle and Northern Norway, according to the estimated regional yearly mean vitamin D effective UV dose., Results: Risk of MS was 11% higher for those born in April (p = 0.045), and 5% higher for those born in May (p = 0.229), 5% lower for those born in November (p = 0.302) and 12% lower for those born in February (p = 0.053) compared with the corresponding population, unaffected mothers and siblings. In Southern Norway the odds ratio of MS births in April and May was 1.05 (0.98-1.24), in Middle Norway 1.11 (0.97-1.27) and in Northern Norway 1.28 (1.0-1.63) compared with the other months., Conclusions: This study confirms previous reports of increased MS births in spring and decreased MS births in the winter months. This could support the role of decreased sunlight exposure during pregnancy and vitamin D deficiency in prenatal life in MS.

A remarkable increase in female to male ratio of multiple sclerosis (MS) is recognised in high incidence areas. Norway is a high-risk area for MS, spanning latitudes 58-71 °N. We studied whether the sex ratio has changed over time and whether it differs by clinical phenotype or by latitude. Population-based epidemiological data and data from the Norwegian MS Registry on patients born from 1930 to 1979 were combined in this study. Place of birth was retrieved from the Norwegian Population Registry and information on clinical subtypes was obtained from the Norwegian MS Registry. The female to male ratio ranged from 1.7 to 2.7 (median 2.0) in 5,469 patients born in Norway, and increased slightly by 5-year blocks of year of birth (p = 0.043). The sex ratio was 2.6:1 in 825 patients born 1970-1979, which is significantly higher than in those born 1930-1969 (p < 0.001). In patients with relapsing remitting onset, the sex ratio was 2.4:1, while it was 1.1:1 in those with primary progressive disease. The sex ratio did not differ between the south, the middle and the north of the country. The overall sex ratio of MS is strongly determined by cases with relapsing remitting onset. We did not observe the remarkable increase in sex ratios of MS reported from other high-risk areas. The high sex ratio in the youngest birth cohorts may change as an increasing proportion of cases in this age group is being diagnosed. Sex ratio was not associated with latitude.

Vitamin D sufficiency has been associated with lower risk of multiple sclerosis and may also have a favorable effect on the course of the disease. The aim of this work was to identify predictors of serum 25-hydroxy vitamin D (25[OH]D) levels in persons with multiple sclerosis (MS) and to assess the effect of high-dose vitamin D(3) supplementation on vitamin D status. A 96-week randomized controlled trial was performed to assess the effect of supplementation with 20,000 IU of vitamin D(3) weekly on bone mineral density in 68 patients. We collected data on vitamin D intake and UV-exposure and repeatedly measured serum 25(OH)D levels. Half of the participants had sufficient winter vitamin D levels at baseline (≥ 50 nmol/l). Vitamin D status was predicted by sun exposure during the last 3 months and by ingested vitamin D from diet and supplements. In the placebo group, the proportion of the participants with sufficient levels increased from 55 % in winter to 92 % during the summer. In the intervention group, all participants had winter 25(OH)D levels above 50 nmol/l at the end of the study. MS patients who have no sun exposure and low dietary vitamin D intake during the winter months should be recommended to take vitamin D supplements to achieve serum 25(OH)D levels of at least 50 nmol/l.

Epidemiological and experimental evidence suggest that a poor vitamin D status is associated with an increased risk of developing multiple sclerosis (MS), and also an unfavorable disease course. Vitamin D may exert relevant effects both on the immune system and on resident cells within the CNS. The data from clinical trials is, however, restricted, and does not allow any conclusion on the effect of high-dose vitamin D supplementation on disease course. The results from sufficiently powered studies will not be available for at least 2 years. MS patients are, however, prone to develop osteoporosis and have increased risk of fractures. Therefore, the authors advise that the serum concentration of 25-hydroxyvitamin D is monitored in order to prevent bone deficit, and that a serum level of 75-125 nmol/l is targeted. This level is sufficient for maintenance of bone health, is not known to be associated with adverse events, and is in the range that has been associated with low risk of developing MS and low disease activity.

Background: High vitamin D levels may reduce the risk of relapses and disease progression in multiple sclerosis., Methods: This 96-week randomised controlled trial was designed to assess the effect of vitamin D(3) supplementation on bone mineral density in persons with multiple sclerosis. Supplementation with 20,000 IU vitamin D(3) weekly raised median serum 25-hydroxy vitamin D (25[OH]D) to 121 nmol/L. The modified intention to treat analysis included 35 persons in the vitamin D(3) group and 33 in the placebo group. Participants were age 21 to 50 years and fully ambulatory (median Expanded Disability Status Scale (EDSS) 2.5). We studied the effect of supplementing vitamin D(3) on the exploratory outcomes annualised relapse rate (ARR), EDSS, multiple sclerosis functional composite (MSFC) components, grip strength, and fatigue., Results: After 96 weeks, there was no significant difference between groups in ARR (absolute difference 0.10, 95% CI -0.07 to 0.27; p = 0.25), EDSS (absolute difference -0.01, 95% CI -0.35 to 0.35; p = 0.97), MSFC components, grip strength, or fatigue., Conclusion: Supplementation with 20,000 IU vitamin D(3) weekly did not result in beneficial effects on the measured multiple sclerosis-related outcomes. This study was not powered to address clinical outcomes, but none of the results were suggestive of an effect in this unselected population of fully ambulatory persons with multiple sclerosis.

Background: Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG., Methodology/principal Findings: This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥ 60 years) (OR 2.38, p(c)7.4 × 10(-5)). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, p(c) 4.71 × 10(-4)), a finding not previously described. No significant association was found to the DRB1*07:01 allele (p(nc) = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies., Conclusion: The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG.

Objectives: The increasing incidence of multiple sclerosis (MS) worldwide, especially in women, points to the crucial role of environmental and lifestyle risk factors in determining the disease occurrence. An international multicentre case-control study of Environmental Risk Factors In Multiple Sclerosis (EnvIMS) has been launched in Norway, Sweden, Italy, Serbia and Canada, aimed to examine MS environmental risk factors in a large study population and disclose reciprocal interactions. To ensure equivalent methodology in detecting age-related past exposures in individuals with and without MS across the study sites, a new questionnaire (EnvIMS-Q) is presented., Materials and Methods: EnvIMS-Q builds on previously developed guidelines for epidemiological studies in MS and is a 6-page self-administered postal questionnaire. Participants are de-identified through the use of a numerical code. Its content is identical for cases and controls including 'core' and population-specific questions as proxies for vitamin D exposure (sun exposure, dietary habits and supplementation), childhood infections (including infectious mononucleosis) and cigarette smoking. Information on possible confounders or effect modifiers is also obtained. EnvIMS-Q was initially drafted in English and subsequently translated into Italian, Serbian, Norwegian, Swedish and French-Canadian. EnvIMS-Q has been tested for acceptability, feasibility and reliability., Results and Conclusions: EnvIMS-Q has shown cross-cultural feasibility, acceptability and reliability in both patients with MS and healthy subjects from all sites. EnvIMS-Q is an efficient tool to ensure proper assessment of age-specific exposure to environmental factors in large multinational population-based case-control studies of MS risk factors., (© 2012 John Wiley & Sons A/S.)

Background: Several studies have indicated month of birth as a risk factor for multiple sclerosis (MS) susceptibility and disease progression., Methods: We performed a systematic search on PubMed and Medline up to May 2012 using the search string 'multiple sclerosis' and 'month of birth' or 'season of birth'. In addition, congress abstracts and the reference lists of the publications identified were examined for further citations of relevance., Results: A total of fifteen published studies and two congress abstracts were found on the effect of month or season of birth on MS risk (sixteen in the northern and one in the southern hemisphere). Most studies in the northern hemisphere detected an excess of MS births in spring and a decrease in autumn. In the southern hemisphere, a reverse pattern was detected, with an excess in November and a decrease in April. Only three studies did not report any month of birth effect, all in low-risk areas for MS. Five studies have analysed a possible effect on disease course by month of birth. Of these, two studies reported an association between month of birth and age at onset of relapsing-remitting MS, with a younger disease onset for those born in the winter months. No consistent findings have been detected on the association between month of birth and disease progression., Discussion: The month of birth effect is consistently found to influence the risk of MS, and the effect seems to be most prominent in high-risk areas of the disease, especially in areas with low sunlight exposure. There seems to be little or no month of birth effects in areas with high sunlight exposure. These findings indicate a possible role for vitamin D concentrations during pregnancy or early life of the newborn. A possible effect of vitamin D supplementation needs to be further investigated., (© 2012 John Wiley & Sons A/S.)

Multiple sclerosis (MS) is a possible cause of secondary osteoporosis. In this phase II trial we assessed whether a weekly dose of 20,000 IU vitamin D(3) prevents bone loss in ambulatory persons with MS age 18-50 years. ClinicalTrials.gov ID NCT00785473. All patients managed at the University Hospital of North Norway who fulfilled the main inclusion criteria were invited to participate in this double-blinded trial. Participants were randomised to receive 20,000 IU vitamin D(3) or placebo once a week and 500 mg calcium daily for 96 weeks. The primary outcome was the effect of the intervention on percentage change in bone mineral density (BMD) at the hip, the spine, and the ultradistal radius over the study period. Of 71 participants randomised, 68 completed. Mean serum 25-hydroxyvitamin D [25(OH)D] levels in the intervention group increased from 55 nmol/L at baseline to 123 nmol/L at week 96. After 96 weeks, percentage change in BMD did not differ between groups at any site. BMD decreased at the hip, by 1.4% in the placebo group (95% CI -2.3 to -0.4, SD 2.7, p = 0.006) and by 0.7% in the treatment group (-1.6 to 0.2, 2.7, p = 0.118), difference 0.7% (-1.9 to 0.7, p = 0.332). Findings were not altered by adjustment for sex or serum 25(OH)D. Supplementation with 20,000 IU vitamin D(3) a week did not prevent bone loss in this small population. Larger studies are warranted to assess the effect of vitamin D on bone health in persons with MS.

Background: Both women and men with multiple sclerosis (MS) are at increased risk of developing osteoporosis., Methods: A non-systematic review of the prevalence,pathogenesis and treatment of osteoporosis in patients with multiple sclerosis., Results: MS and osteoporosis share aetiological risk factors such as smoking and hypovitaminosis D, as well as pathogenetic players such as osteopontin and osteoprotegerin. Recently, low bone mineral density (BMD) values have been measured shortly after diagnosis of clinically isolated syndrome and MS and in fully ambulatory persons with MS below 50 years of age. Studies consistently show that BMD at the femoral neck decreases with increasing MS-related disability. Osteoporosis-related fractures cause increased morbidity and mortality and add to the burden of having MS., Conclusion: We argue that MS, like a number of other chronic diseases, is a cause of secondary osteoporosis. Therefore, bone health assessment should be a part of the integral management of persons with MS. We suggest that BMD be measured shortly after diagnosis, that BMD measurements be repeated depending on BMD values and individual osteoporosis risk profile, and that serum 25-hydroxyvitamin D be monitored. All persons with MS should receive bone health advice., (© 2011 John Wiley & Sons A/S.)

Multiple sclerosis (MS) risk is determined by environmental influences acting on the individual genetic background. Recent epidemiologic and experimental evidence supports a role of low environmental supplies of vitamin D in mediating an increased susceptibility to MS. We review available evidence suggesting that vitamin D status may influence MS risk and even modulate clinical disease activity. The level of serum 25-hydroxyvitamin D providing these effects remains to be determined., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The implications of having multiple sclerosis (MS) for bone health are incompletely understood. The aim of this population-based study is to identify past and current exposures that are associated with bone mass in fully ambulatory persons with MS up to age 50 years and to determine the prevalence of low bone mineral density (BMD) in this group. We measured BMD (hips, lumbar spine, forearms), physical function, BMI, and serum 25(OH) vitamin D in 55 women and 25 men with MS. Patients provided information on demographic variables and medical history, as well as past and current vitamin D and calcium intake, physical activity, and lifestyle habits. In regression analyses, BMD levels were adjusted for age, sex, and BMI. At the femoral neck, strong associations were found for walking distance (beta = 0.152; P < 0.001) and age (beta = -0.004; P = 0.003), and less certain associations for male sex (beta = 0.055; P = 0.014) and 10-foot timed tandem walk (-0.008; P = 0.013). At the lumbar spine, walking distance (beta = 0.013; P = 0.006) and possibly physical activity growing up (beta = 0.035; P = 0.028) and male sex (beta = -0.057; P = 0.042), were associated with BMD. At the ultradistal radius, strength of grip (beta = 0.001; P = 0.002), and, less certainly, summer outdoor activities age 16-20 (beta = 0.021; P = 0.009), and age at MS onset (beta = 0.002; P = 0.036) were associated with BMD. Low BMD (z score < or = -2) was present in 19 out of 80 patients. This study shows that MS-related variables as well as past exposures differentially affect BMD at three clinically important skeletal sites. Low BMD is prevalent in these young patients. Bone health should receive attention in care for persons with MS.

Multiple sclerosis (MS) is a chronic disease of the central nervous system, pathologically characterized by inflammation, demyelination, and axonal damage, presumably auto-immune in nature. Complex interactions between genetic susceptibility and environmental factors, such as vitamin D status and primary Epstein-Barr virus infection in adolescence or later in life, probably determine the MS risk. Norway at a latitude 58-71 degrees N is a discrete exception to the hypothesis that solar UV radiation exposure, mediated by vitamin D, coheres with the latitude gradient seen for MS prevalence. Where UV radiation exposure is low in Norway,vitamin D sufficiency is maintained through a traditional diet providing vitamin D as well as marine omega-3 polyunsaturated fatty acids. This observation supports an environmental interaction between diet and latitude, with vitamin D as the common mediator. The potential roles of vitamin D, other environmental exposures, and genes in the complex aetiology of MS are discussed in this review., ((c) 2008 S. Karger AG, Basel)

Objectives: Multiple sclerosis (MS) likely results from an interaction between genetic and exogenous factors. While genetics shapes the overall population MS susceptibility, observed epidemiological patterns strongly suggest a role for the environment in disease initiation and modulation., Results: Findings from studies on seasonality in MS patients' birth, disease onset and exacerbations, as well as apparent temporal trends in incidence and gender ratio support an influential effect of viruses, metabolic and lifestyle factors on MS risk. Epstein-Barr virus, vitamin D status, and smoking are factors that may explain such epidemiological patterns., Conclusions: Further epidemiological investigations are encouraged and opportunities to use data from existing cohort studies as well as the design of new studies should be pursued. In particular, the development of new large multicentre population-based case-control studies which incorporate the study of the role of environment and genetics, including epigenetic mechanisms, in determining MS risk is proposed.

Treatment with cytochrome P450 enzyme-inducing antiepileptic drugs (P450-inducing AEDs) is known to interfere with folate metabolism. Low folate status is of special concern in women with epilepsy who might become pregnant. Therefore, folate status was assessed in women age 16-42 treated for epilepsy. Staple food is not folic acid fortified in Norway. Only 1/94 women was folate-deficient by the laboratory reference value for serum folate of > 4 nM. Fourteen (15%) patients with serum folate values from 5 to 9 nM may be considered folate-insufficient. Plasma homocysteine was elevated > 13 microM in 2/65 women. These findings compare favorably with previous reports. A questionnaire addressing factors interfering with folate metabolism was answered by 58 of the women. In women who did not use a supplement containing > or =0.2 mg of folic acid regularly (n=33), the median serum folate value was lower in those using P450-inducing AEDs than in those using other AEDs (p=0.023). The interaction between P450-inducing AEDs and folate metabolism may be clinically relevant and can be balanced by supplementation of small doses of folic acid. The results of this survey support the recommendation that women of childbearing age treated with AEDs receive folic acid supplementation, particularly those taking P450-inducing AEDs.

Background: A relationship between the latitude related distribution of multiple sclerosis (MS) and exposure to sunlight has long been considered. Higher sun exposure during early life has been associated with decreased risk of MS., Objective: Since Norway is an exception to the latitude gradient of MS prevalence, we tested here whether sunlight exposure or vitamin D-related dietary factors in childhood and adolescence are associated with the risk of MS., Methods: Retrospective recall questionnaire data from 152 MS patients and 402 population controls born at and living at latitudes 66-71 degrees N were analysed by means of conditional logistic regression analysis accounting for the matching variables age, sex, and place of birth., Results: Increased outdoor activities during summer in early life were associated with a decreased risk of MS, most pronounced at ages 16-20 years (odds ratio (OR) 0.55, 95% CI 0.39-0.78, p = 0.001, adjusted for intake of fish and cod-liver oil). A protective effect of supplementation with cod-liver oil was suggested in the subgroup that reported low summer outdoor activities (OR 0.57, 95% CI 0.31-1.05, p = 0.072). Consumption of fish three or more times a week was also associated with reduced risk of MS (OR 0.55, 95% CI 0.33-0.93, p = 0.024)., Conclusion: Summer outdoor activities in childhood and adolescence are associated with a reduced risk of MS even north of the Arctic Circle. Supplemental cod-liver oil may be protective when sun exposure is less, suggesting that both climate and diet may interact to influence MS risk at a population level.

This study confirms a low frequency of multiple sclerosis (MS) among Sami. Only 12 Sami with a diagnosis of MS were identified in the Norwegian Sami population, which represents a significantly lower prevalence of MS in Sami (30/10(5)) compared with other Norwegians (73-164/10(5)). The clinical characteristics as well as the results of human leukocyte antigen (HLA)-DRB1 and -DQB1 typing of the Sami MS patients are reported, showing that three (27%) of the Sami MS patients carried the MS-associated HLA-DRB1*15-DQB1*06 haplotype. Interestingly, the DRB1*15-DQB1*06 haplotype had a significantly reduced frequency among Sami controls (0.086) compared with non-Sami Norwegian controls (0.163) (P(corrected) = 0.015). The low frequency of the disease-associated DRB1*15-DQB1*06 haplotype in the Sami population may contribute to the low prevalence of MS in Sami, in addition to other yet unidentified genetic and environmental factors.

Purpose: Several international guidelines for the management of women with epilepsy (WWE) have been developed since 1989. We aimed to determine whether guidelines for the management of WWE are followed and whether active implementation of such guidelines makes a difference to clinical practice., Methods: The study covered a 2-year period of "passive dissemination" of guidelines followed by a 2-year period of "active implementation." Documentation reflecting adherence to the guidelines was abstracted retrospectively from electronic medical records on 215 WWE aged 16-42 years. Data abstracted from case notes included counselling on contraception and pregnancy-related issues; follow-up during pregnancy; advice on supplementation of folic acid, calcium, and vitamin D; and serum folate measurements. A questionnaire assessing the knowledge of WWE issues was completed by 112 (71%) of 157 patients., Results: Documentation that WWE issues had been addressed was found in approximately one third of medical case records with no measurable effect of active implementation. Only the follow-up during pregnancy seemed to have improved. Serum folate measurements in 51 women treated with enzyme-inducing antiepileptic drugs (AEDs) revealed folate deficiency in 11 (22%). Respondents to the questionnaire recalled having received information from their neurologists on the interaction between AEDs and oral contraceptives (46%), need to plan pregnancy (63%), and folic acid requirement (56%)., Conclusions: Judged by a review of documentation in case notes, active implementation of guidelines had no measurable effect on clinical practice. However, the follow-up during pregnancy seemed to have improved. Patients' knowledge of WWE issues compared favorably with published studies. Better strategies are needed to secure successful implementation of guidelines.

We studied the effect of denervation on the spontaneous inflammatory myopathy that occurs in SJL mice. Cryosections from innervated and denervated calf muscles were assessed for severity of inflammation, relative proportions of mononuclear cell subsets, and major histocompatibility complex (MHC) class I expression. A significant increase in mononuclear cell infiltrates occurred in the denervated muscle. Denervation also changed the composition of mononuclear cell infiltrates towards a higher percentage of CD8(+) T cells (19% versus 11%). MHC class I expression was enhanced in denervated muscle compared with innervated muscle. Our findings indicate that inflammation in muscle may be enhanced by denervation., (Copyright 1999 John Wiley & Sons, Inc.)

In polymyositis (PM), T-cell mediated myocytotoxicity is directed against strongly human leukocyte antigen class I positive (HLA-I+) muscle fibers. Fiber regeneration probably is partly responsible for this HLA-I up-regulation. We have evaluated regeneration, denervation/impulse blockade, and focal leukocyte infiltrates as possible HLA-I inducing factors in PM. Distinctive patterns of HLA-I, nerve cell adhesion molecule (NCAM), and vimentin expression accompany denervation and regeneration. Regenerating fibers also have centralized nuclei. Using semiquantitative methods, we examined strongly HLA-I+ fibers in PM muscle biopsies for these markers. Sarcoplasmic HLA-I levels were related to the presence of leukocyte infiltrates and invasion of fibers. Strongly HLA-I+ fibers were frequently invaded, and regeneration-associated changes were usually observed at sites of fiber damage. Sarcoplasmic HLA-I levels were stable along intact fibers, also adjacent to leukocyte infiltrates. A majority of the strongly HLA-I+ fibers were nonregenerating (NCAM+ only). Though other mechanisms cannot be excluded, this suggests that impulse blockade or denervation may contribute to extra HLA-I up-regulation in these fibers.

Hyperammonemia has been suggested to induce enhanced cerebral cortex ammonia uptake, subsequent glutamine synthesis and accumulation, and finally net glutamine release into the blood stream, but this has never been confirmed in liver insufficiency models. Therefore, cerebral cortex ammonia- and glutamine-related metabolism was studied during liver insufficiency-induced hyperammonemia by measuring plasma flow and venous-arterial concentration differences of ammonia and amino acids across the cerebral cortex (enabling estimation of net metabolite exchange), 1 day after portacaval shunting and 2, 4, and 6 h after hepatic artery ligation (or in controls). The intra-organ effects were investigated by measuring cerebral cortex tissue ammonia and amino acids 6 h after liver ischemia induction or in controls. Arterial ammonia and glutamine increased in portacaval-shunted rats versus controls, and further increased during liver ischemia. Cerebral cortex net ammonia uptake, observed in portacaval-shunted rats, increased progressively during liver ischemia, but net glutamine release was only observed after 6 h of liver ischemia. Cerebral cortex tissue glutamine, gamma-aminobutyric acid, most other amino acids, and ammonia levels were increased during liver ischemia. Glutamate was equally decreased in portacaval-shunted and liver-ischemia rats. The observed net cerebral cortex ammonia uptake, cerebral cortex tissue ammonia and glutamine accumulation, and finally glutamine release into the blood suggest that the rat cerebral cortex initially contributes to net ammonia removal from the blood during liver insufficiency-induced hyperammonemia by augmenting tissue glutamine and ammonia pools, and later by net glutamine release into the blood. The changes in cerebral cortex glutamate and gamma-aminobutyric acid could be related to altered ammonia metabolism.

In normal rats, muscle is the major glutamine releasing organ and gut is the major glutamine consuming organ. It has been suggested that enhanced muscle ammonia detoxification and gut ammonia production occurs during liver insufficiency-induced hyperammonemia. Therefore, ammonia and amino acid fluxes across portal-drained viscera and hindquarter, and muscle concentrations were measured in portacaval shunted and acute liver ischemia rats. Arterial ammonia and most amino acids were increased after portacaval shunting and increased progressively during liver ischemia, but net hindquarter ammonia uptake was not observed. Net hindquarter glutamine efflux was increased during portacaval shunting, but it decreased during liver ischemia, while muscle glutamine concentrations increased. The comparable net portal drained viscera glutamine uptake in normal and portacaval shunted rats changed during liver ischemia from net uptake to release, coinciding with release of most other amino acids. These results cast doubt on the ammonia detoxifying role of muscle during acute liver ischemia-induced hyperammonemia in the rat. The portal drained viscera glutamine release during severe hyperammonemia could be due to intestinal damage.