Trygve Holmøy

• Kleftogiannis, Dimitrios; Gavasso, Sonia; Eidem, Live Egeland; Haugsøen, Jonas Bull; Holmøy, Trygve & Steffensen, Linn Hofsøy [Show all 20 contributors for this article] (2026). Intrathecal mesenchymal stem cell therapy in progressive multiple sclerosis: integrated blood and CSF profiling in the SMART-MS randomized trial. Fluids and Barriers of the CNS. doi: 10.1186/s12987-026-00886-3. Full text in Research Archive Show summary

  Therapeutic options for progressive multiple sclerosis (MS) remain limited, and the mechanisms engaged by intrathecal mesenchymal stem cell (MSC) therapy are incompletely understood. MSCs are proposed to exert immunomodulatory and trophic effects, yet most studies rely on targeted biomarkers and lack systems-level analysis across immune compartments. Here, we applied an integrated blood–cerebrospinal fluid (CSF) multi-omics framework to characterize responses after intrathecal MSC exposure in patients with progressive MS enrolled in the SMART-MS trial, a randomized, placebo-controlled crossover study of a single intrathecal MSC injection. Although the trial did not demonstrate a neuro-regenerative signal for the primary endpoint, exploratory MRI findings and adverse events, including fever and back pain, suggested localized responses after intrathecal administration. Within the 18-participant SMART-MS cohort, peripheral blood mass cytometry was analysed longitudinally across baseline, six months, and 12 months, whereas matched CSF proteomics was analysed using paired baseline and six-month samples from the first treatment period. Immune phenotypes and marker-derived functional program scores were quantified using mixed-effects modelling. To summarize CSF proteomic changes, we generated exploratory composite scores reflecting extracellular matrix/interface-associated, innate/vascular inflammatory, metabolic/cytoskeletal, and reactivity-associated proteins. These scores enabled exploratory integration with circulating immune programs. MSC exposure was not associated with broad remodelling of peripheral immune-cell composition or marker-derived functional programs across circulating lymphocyte, monocyte, B-cell, and NK-cell populations. Instead, the most consistent treatment-associated changes were observed within the CSF proteome, where MSC exposure was associated with coordinated extracellular-matrix-associated protein changes, including fibrillar collagens and matrix-regulatory proteins, together with changes in innate, vascular, metabolic, and cytoskeletal pathways. Inflammatory, metabolic, and reactivity-associated CSF protein signatures tended to show greater changes in exploratory analyses of patients with adverse events or spinal MRI reactivity, consistent with heterogeneous local responsiveness rather than a uniform response. Cross-compartment analyses showed weak and heterogeneous coupling between circulating immune programs and CSF proteomic changes. Together, these findings suggest that intrathecal MSC exposure in progressive MS is associated with compartmentalized CSF proteomic changes rather than broad systemic immune alterations. This study demonstrates the value of integrated blood–CSF profiling for dissecting treatment-associated biology in CNS-targeted interventional trials.

• Kvistad, Christopher Elnan; Kråkenes, Torbjørn; Holmøy, Trygve; Eidem, Live Egeland; Steffensen, Linn Hofsøy & Wesnes, Kristin [Show all 25 contributors for this article] (2026). Intrathecal Mesenchymal Stem Cells in Progressive Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial (SMART-MS). Neurology. ISSN 0028-3878. 106(10). doi: 10.1212/WNL.0000000000214915. Full text in Research Archive Show summary

  Background and Objectives: There is an unmet need for neuroregenerative therapies in multiple sclerosis (MS). Mesenchymal stem cells (MSCs) have shown immunomodulatory and regenerative effects in preclinical models and early clinical studies. Intrathecal administration may enhance therapeutic potential by direct delivery to the CNS. However, randomized, placebo-controlled trials are needed to establish safety and efficacy. The objective of this trial was to assess whether a single intrathecal administration of autologous MSCs could provide evidence of a neuroregenerative effect in progressive MS. Methods: In this randomized, double-blind, placebo-controlled phase I/II trial (NCT04749667), patients with progressive MS enrolled at 4 Norwegian tertiary hospitals received a single intrathecal injection of autologous bone marrow–derived MSCs (1 × 106 cells/kg) in a crossover design. The primary end point was the change in latency of combined evoked potentials at 6 months. Secondary end points included safety, brain MRI measures, functional and ophthalmologic assessments, and serum biomarkers at 6 and 12 months. Exploratory analyses comprised proteomic profiling of CSF. Outcomes were analyzed using baseline-adjusted regression models. Results: A total of 18 patients were included (mean age 46.7 years; 55.6% female). No significant between-group difference was observed for the primary end point (β = −0.31, 95% CI –1.84 to 1.22, p = 0.668). At 6 months, patients in the MSC group showed reduced cerebral atrophy on MRI (β = 9.37, 95% CI 0.29 to 18.45, p = 0.044) and lower serum glial fibrillary acidic protein levels (β = −16.3 pg/mL, 95% CI –33.0 to 0.3, p = 0.054), but neither were sustained at 12 months. Exploratory CSF proteomics revealed reductions in multiple inflammation-related proteins at 6 months. One serious adverse event was deemed probably related to MSC treatment. Common adverse events included fever (n = 9) and low back pain (n = 10) after MSC administration, and spinal MRI abnormalities with fluid loculations and nerve root clumping (n = 7) at 6 months. One patient developed chronic coccygeal pain attributed to arachnoiditis. Discussion: A neuroregenerative effect was not detected, although interpretation may be limited by the small sample size. Adverse events suggest an acute localized inflammatory reaction after MSC administration. Our findings suggest that intrathecal administration of MSCs in progressive MS should be approached with caution in future studies.

• Rasmussen, Tilde Harridsleff; Schikora-Rustad, Stine; Lorentzen, Åslaug Rudjord; Tran, Trung; Øverås, Mathias Herstad & Myhr, Kjell-Morten [Show all 22 contributors for this article] (2026). Low risk of severe COVID-19 in vaccinated people with multiple sclerosis: a nationwide Norwegian study. BMJ Neurology Open. 8(1). doi: 10.1136/bmjno-2026-001556. Full text in Research Archive Show summary

  Background: We aimed to assess antibody responses and COVID-19 outcomes after vaccination in people with multiple sclerosis (pwMS) receiving disease-modifying therapies. Methods: NevroVAX is a Norwegian multicentre cohort study including 3559 pwMS and 449 healthy controls (HCs) who received at least one dose of BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna) or ChAdOx1 (AstraZeneca/Oxford) between January 2021 and December 2022. Data from records, registries, questionnaires and blood samples collected June 2021–November 2023 were analysed. Primary outcomes were humoral immune responses assessed by seroconversion (anti-spike and anti-receptor-binding domain (RBD) IgG ≥5 binding antibody units/mL). Secondary outcomes included quantitative anti-RBD IgG levels, breakthrough SARS-CoV-2 infection, COVID-19-related hospitalisation and death. Associations with breakthrough infection were evaluated using multivariable logistic regression. Results: Among 3559 pwMS, 1201 received anti-CD20 monoclonal antibodies and 324 sphingosine-1-phosphate receptor (S1PR) modulators. After three vaccine doses, seroconversion was observed in 43.0% of anti-CD20-treated patients and 48.4% of S1PR-treated patients. In multivariable analysis, seroconversion was associated with lower risk of breakthrough infection (OR 0.67, 95% CI 0.58 to 0.78). During follow-up, 58 pwMS (1.6%) were hospitalised for COVID-19; 4 (0.1%) required non-invasive ventilatory support, no patients required invasive ventilation and no deaths occurred. Conclusions: Humoral vaccine responses were impaired in pwMS receiving anti-CD20 or S1PR therapies, but severe COVID-19 was rare. These findings support continued vaccination programmes and tailored protective measures for immunomodulated populations.

• Ytterdal, Marie; Sandvik, Casper Eugen; Holmøy, Trygve; Bø, Lars; Kvistad, Christopher Elnan & Kråkenes, Torbjørn (2026). The neural transdifferentiation potential of bone marrow mesenchymal stem cells. PLOS ONE. 21(4). doi: 10.1371/journal.pone.0347119. Full text in Research Archive Show summary

  Background Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by demyelination and neuronal degeneration. Currently, there is no treatment that can promote remyelination or axonal repair and thus improve patient outcomes. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach in multiple sclerosis due to their regenerative and immunomodulatory properties. Priming MSCs toward neural- or glial-like cells may enhance their therapeutic potential. Methods Bone marrow MSCs from multiple sclerosis patients were cultured in differentiation medium containing growth factors for induction of glial and neural transdifferentiating process. Functional assays were used to characterize the proliferation and migration rates of undifferentiated and transdifferentiating MSCs. In addition, immunostaining with five different markers was performed as well as mass spectrometry to investigate and compare protein expressions among the cell types. Results Proliferation and migration rates of MSCs decreased in glial and neural transdifferentiating cells. The immunostaining showed expression of neuro-glial markers, and the mass spectrometry data demonstrated substantial variance in protein expression in transdifferentiating MSCs compared to undifferentiated MSCs. Glial and neural markers were upregulated in the transdifferentiating MSCs, while MSC markers were downregulated. Conclusion The results demonstrate that MSCs can be guided toward a neuro-glial lineage in vitro and that the transdifferentiating process continues over several weeks. Future research should investigate the in vitro and in vivo therapeutic differences between different transdifferentiating lengths.

• Johansen, Henriette; Nakken, Ola; Holmøy, Trygve & Fredheim, Olav Magnus Søndenå (2026). Disease trajectories and end of life care in a Norwegian ALS cohort. BMC Neurology. 26(1). doi: 10.1186/s12883-026-04698-8. Full text in Research Archive
• Huygens, Simone; Versteegh, Matthijs; Berg-Hansen, Pål; Bjelland, Stein Henry; Holmøy, Trygve & Torkildsen, Øivind (2026). Cost-effectiveness of treatment sequences following first-line rituximab in relapsing-remitting multiple sclerosis: a Norwegian microsimulation study. Frontiers in Neurology. 17. doi: 10.3389/fneur.2026.1783506. Full text in Research Archive Show summary

  Background The Norwegian guideline recommends highly effective disease-modifying therapies (DMTs) as the first line treatment for multiple sclerosis (MS), with rituximab preferred in clinical practice. While rituximab is effective, patients may discontinue due to side-effects or develop disease activity. Limited guidance exists on optimal switches following first line rituximab. Objectives To estimate the costs and effects of different treatment sequences following first line rituximab in relapsing remitting MS patients in Norway. Design A microsimulation model adapted to the Norwegian setting estimated outcomes for different treatment sequences following first line rituximab. Four neurologists were interviewed using a structured expert elicitation tool to inform switching behavior. The model allowed for three treatment lines after rituximab, with switches possible to fingolimod, ponesimod, cladribine tablets, or natalizumab. Methods The model simulated all 32 possible treatment sequences and calculated costs per quality adjusted life year (QALY) according to Norwegian pharmacoeconomic guidelines. Results Neurologists were more likely to switch patients with >1 relapse (78%) or relapse and disability progression (66%) versus one relapse (54%). The most cost-effective sequence after rituximab is cladribine tablets (line 2), ponesimod (line 3), and natalizumab (line 4). The probability that second line cladribine tablets are most cost-effective is >75%. Mean time on first line rituximab was 15.2 years. The model predicts that over lifetime 21% of patients would require a fourth line of treatment due to the cumulative effects of discontinuation and recurring disease activity triggering treatment switches. Conclusion Patients on first line rituximab may require a treatment switch due to side-effect induced discontinuation or new disease activity. If a switch from rituximab to another DMT is the preferred clinical course of action, this study showed that it is most cost-effective to switch to cladribine tablets followed by ponesimod and natalizumab.

• Nakken, Ola; Vaage, Anders Myhre; Stigum, Hein; Bjørnevik, Kjetil Lauvland; Holmøy, Trygve & Meyer, Haakon Eduard (2025). Duration of Current Statin Use and Amyotrophic Lateral Sclerosis Risk: A Norwegian Population-Based Cohort Study. Neurology. ISSN 0028-3878. 105(8). doi: 10.1212/WNL.0000000000214221. Full text in Research Archive
• Vaage, Anders Myhre; Holmøy, Trygve; Dahl, Jesper; Stigum, Hein; Meyer, Haakon Eduard & Nakken, Ola (2025). Statin Use and Amyotrophic Lateral Sclerosis Survival: A Population-Based Cohort Study. European Journal of Neurology. ISSN 1351-5101. 32(3). doi: 10.1111/ene.70095. Full text in Research Archive Show summary

  Background Dyslipidemia is common in amyotrophic lateral sclerosis (ALS). Statin use has been associated with both favorable and poor prognoses. We assessed whether statin use affects ALS survival. Methods We linked four Norwegian health surveys (1972–2003) with mandatory national registries to obtain information on premorbid health, ALS diagnosis, and death. Using the Norwegian Prescribed Drug Registry, we identified participants who had dispensed statins pre- and post-diagnosis. We first compared pre-diagnosis statin discontinuation rates between ALS patients and matched controls. Flexible parametric models were then fitted to estimate the relationship between statin use and survival time in ALS, using restricted mean survival time and hazard ratio (HR) as effect measures. Results A total of 524 patients (43% female) with ALS were included. Mean time from ALS diagnosis to death or end of study was 2.0 (SD 2.1) years. A substantial proportion of statin users (21%) discontinued statins during the year leading up to diagnosis. This group was characterized by poorer ALS prognosis compared to those adhering to statins and were included as statin users in our analysis. After adjusting for sex, age, birth year, riluzole use and premorbid smoking status, body mass index, and total cholesterol levels, statin use was not associated with ALS survival. The estimated mean survival difference comparing statin users to non-users was 0.74 (95% CI −5.98 to 7.47) months, corresponding to a HR of 0.97 (95% CI 0.77–1.23). Conclusion Statin use was not associated with ALS survival, suggesting that statins should not routinely be discontinued in ALS.

• Olsen, Cathrine Goberg; Malmberg, Vetle Nilsen; Fahlström, Maria; Alstadhaug, Karl Bjørnar; Bjørnå, Ingrid Kristine & Braathen, Geir Julius [Show all 24 contributors for this article] (2024). Amyotrophic lateral sclerosis caused by the C9orf72 expansion in Norway–prevalence, ancestry, clinical characteristics and sociodemographic status. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. ISSN 2167-8421. 26(1-2), p. 132–140. doi: 10.1080/21678421.2024.2405118. Full text in Research Archive Show summary

  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 (C9pos). Further, we compared C9pos and C9neg 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 C9pos, with half being sporadic ALS cases. The proportion of C9pos cases differed between regions, ranging from 17.9% in the Northern

• Nakken, Ola; Aarseth, Jan Harald; Wergeland, Stig; Stigum, Hein; Meyer, Haakon E. & Holmøy, Trygve (2024). BCG vaccination and multiple sclerosis risk: A Norwegian cohort study. Multiple Sclerosis. ISSN 1352-4585. 30(6), p. 646–653. doi: 10.1177/13524585241230440. Full text in Research Archive Show summary

  Introduction: Bacillus Calmette–Guérin (BCG) vaccination induces long-lasting effects on the adaptive and innate immune systems and prevents development of experimental autoimmune encephalomyelitis and possibly also inflammatory disease activity in multiple sclerosis (MS). Objective: The objective is to examine if BCG given in early adulthood decreases MS risk. Methods: From 791,369 (52% females) Norwegians participating in a national tuberculosis screening program from 1963 to 1975, we collected information on BCG vaccination and tuberculosis disease status. Later, MS disease was ascertained through both the Norwegian MS Registry and Biobank and the Norwegian Death Registry. We used logistic regression models to assess the relationship between BCG vaccination and MS risk. Results: In those BCG vaccinated, mean age at vaccination was 15.6 (standard deviation (SD) = 5.5) years. A total of 2862 (65% females) MS cases were retrieved. Overall, we found no association between MS risk and BCG vaccination. Compared to non-BCG-vaccinated individuals with no signs of tuberculosis infection, odds ratio (OR) for MS was 1.00 (95% confidence interval (CI) = 0.80–1.25) in the BCG-vaccinated group. In those not BCG vaccinated because of latent tuberculosis infection, the corresponding OR was 0.86 (95% CI = 0.66–1.13). Conclusion: We found no evidence of BCG vaccination or latent tuberculosis infection in young adulthood being linked to MS risk.

• Eid, Karine; Torkildsen, Øivind; Aarseth, Jan Harald; Cortese, Marianna; Holmøy, Trygve & Myhr, Kjell-Morten [Show all 10 contributors for this article] (2024). Migraine in the multiple sclerosis prodrome: a prospective nationwide cohort study in pregnant women. The Journal of Headache and Pain. ISSN 1129-2369. 25(1). doi: 10.1186/s10194-024-01941-w. Full text in Research Archive Show summary

  Background People with multiple sclerosis (MS) have an increased risk of migraine. However, little is known about migraine and other headaches during the prodromal phase (before MS symptom onset). Our objective was to study the risk of migraine in women with MS before MS onset. Methods A nationwide, prospective cohort study of women participating in the Norwegian Mother, Father, and Child cohort study 1999–2008. The women reported the occurrence of migraine and other headaches prior to or during pregnancy. We identified women who later developed MS through data linkage with national health registries in 2018. We excluded women with an established MS diagnosis (n = 125) and women who had experienced their first clinical symptom of MS, but not yet received an MS diagnosis (n = 91). The reference group comprised all other women in the cohort (n = 85,292). We used logistic regression to estimate adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs). Results Two hundred and forty-six women developed MS during follow-up. Of these, 116 women had MS symptom onset after 1–5 years, 92 after 6–10 years, and 38 after 10 years. Migraine was more common among women who developed MS compared to the reference group, 18% vs 11%, aOR 1.6 (1.2–2.3), adjusted for age, smoking, socioeconomic status and overweight. The risk of other headaches was similar for women who developed MS compared to the reference group, 29% vs 27%, aOR 1.1 (0.8–1.4). Migraine was reported by 21 of 116 (18%) women with 5 years until MS symptom onset (aOR 1.7 [1.1–2.8]) and 19 of 92 (21%) women with 6–10 years until MS symptom onset (aOR 1.9 [1.1–2.8]. Only three of 38 (8%) women with > 10 years until MS symptom onset reported migraine, aOR 0.7 (0.2–2.2). Conclusions Women with MS have increased risk of migraine, but not other headaches, up to a decade before the onset of classical MS symptoms. This supports that migraine can be a symptom of the MS prodrome. Special attention in people with migraine may lead to earlier recognition of MS.

• Hartung, Hans-Peter; Berger, Thomas; Bermel, Robert A.; Brochet, Bruno; Carroll, William M. & Holmøy, Trygve [Show all 19 contributors for this article] (2024). ENSEMBLE PLUS: final results of shorter ocrelizumab infusion from a randomized controlled trial. Journal of Neurology. ISSN 0340-5354. 271(7), p. 4348–4360. doi: 10.1007/s00415-024-12326-z. Full text in Research Archive Show summary

  Introduction Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study. Methods ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing–remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs. Results At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [− 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion. Conclusion ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions.

• Havdal, Lise Beier; Selvakumar, Joel Pradeepkumar; Lund-Berven, Lise; Stiansen-Sonerud, Tonje; Zetterberg, Henrik & Blennow, Kaj [Show all 8 contributors for this article] (2024). Neurological involvement among non-hospitalized adolescents and young adults 6 months after acute COVID-19. Frontiers in Neurology. 15. doi: 10.3389/fneur.2024.1345787. Full text in Research Archive Show summary

  Introduction: The post-COVID-19 condition (PCC) is characterized by debilitating persistent symptoms, including symptoms suggesting neurological aberrations such as concentration difficulties, impaired memory, pain, and sleep disturbances. The underlying mechanisms remain elusive. This study aimed to investigate brain injury biomarkers, neurocognitive test performance, and self-reported neurological and neuropsychological symptoms in young people with PCC. Methods: A total of 404 non-hospitalized adolescents and young adults aged 12–25 years who tested positive for SARS-CoV-2, along with 105 matched SARS-CoV-2 negative individuals, were prospectively enrolled and followed-up for 6 months (Clinical Trials ID: NCT04686734). All participants underwent comprehensive assessment encompassing clinical examinations, questionnaires, neurocognitive testing and blood sampling. Serum samples were immunoassayed for the brain injury biomarkers neurofilament light chain (Nfl) and glial fibrillary acidic protein (GFAp). At 6 months, cross-sectional analyses of serum Nfl/GFAp, neurocognitive test results and symptom scores were performed across groups based on adherence to PCC criteria as well as initial SARS-CoV-2 test results. Also, associations between Nfl/GFAp, neurocognitive test results, and symptom scores were explored. Results: A total of 381 SARS-CoV-2 positive and 85 SARS-CoV-2 negative were included in the final analysis at 6 months, of whom 48% and 47%, respectively, adhered to the PCC criteria. Serum levels of Nfl and GFAp were almost equal across groups and did not differ from reference values in healthy populations. Also, neurocognitive test results were not different across groups, whereas symptom scores were significantly higher in patients fulfilling PCC criteria (independent of initial SARS-CoV-2 status). No significant associations between Nfl/GFAp, neurocognitive test results, and symptom scores were found. Conclusion: Normal brain injury biomarkers and neurocognitive performance 6 months after mild COVID-19 implies that the persistent symptoms associated with PCC are not concurrent with ongoing central nervous system damage or permanent disruption of cognitive functions. This finding contradicts the notion of neuroinflammation as a likely explanation for the persistent symptoms.

• Vaage, Anders Myhre; Meyer, Haakon Eduard; Landgraff, Ida Kalstad; Myrstad, Marius; Holmøy, Trygve & Nakken, Ola (2024). Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study. Neurology. ISSN 0028-3878. 103(2). doi: 10.1212/WNL.0000000000209575. Full text in Research Archive Show summary

  Background and Objectives Observational studies have demonstrated an increased amyotrophic lateral sclerosis (ALS) risk among professional athletes in various sports. For moderately increased levels of physical activity and fitness, the results are diverging. Through a cohort study, we aimed to assess the relationship between indicators of physical activity and fitness (self-reported physical activity and resting heart rate) and long-term ALS risk. Methods From a large Norwegian cardiovascular health survey (1985–1999), we collected information on self-reported physical activity in leisure time, resting heart rate, and other cardiovascular risk factors. Patients with ALS were identified through health registries covering the whole population. We fitted Cox proportional hazard models to assess the risk of ALS according to levels of self-reported physical activity in 3 categories (1: sedentary; 2: minimum 4 hours per week of walking or cycling; 3: minimum 4 hours per week of recreational sports or hard training), and resting heart rate modeled both on the continuous scale and as quartiles of distribution. Results Out of 373,696 study participants (mean 40.9 [SD 1.1] years at inclusion), 504 (41.2% women) developed ALS during a mean follow-up time of 27.2 (SD 5.0) years. Compared with participants with the lowest level of physical activity, the hazard ratio was 0.71 (95% CI 0.53–0.95) for those with the highest level. There were no clear associations between resting heart rate and ALS in the total sample. In men, the hazard ratio of ALS was 0.71 (95% CI 0.53–0.95) for those reporting moderate levels of physical activity and 0.59 (95% CI 0.42–0.84) for those reporting high levels, compared with those reporting low levels. Men with resting heart rate in the lowest quartile had 32% reduced risk of ALS (hazard ratio 0.68, 95% CI 0.49–0.94) compared with those in the second highest quartile. In women, no association was detected between neither self-reported levels of physical activity nor resting heart rate and ALS risk. Discussion Indicators of high levels of physical activity and fitness are associated with a reduced risk of ALS more than 30 years later in men, but not in women.

• Kvistad, Christopher Elnan; Lehmann, Anne Kristine; Stokke, Silje Agnethe; Holmøy, Trygve; Lorentzen, Åslaug Rudjord & Trovik, Linn [Show all 9 contributors for this article] (2024). Autologous hematopoietic stem cell transplantation for multiple sclerosis: Long-term follow-up data from Norway. Multiple Sclerosis. ISSN 1352-4585. 30(6), p. 751–754. doi: 10.1177/13524585241231665. Full text in Research Archive Show summary

  Background: Autologous hematopoietic stem cell transplantation (HSCT) is a potent treatment option for patients with aggressive relapsing-remitting multiple sclerosis (RRMS). Objective: To evaluate long-term outcomes of HSCT in MS. Methods: National retrospective single-center observational study of patients with aggressive RRMS that underwent HSCT in Norway from January 2015 to January 2018. Criteria for receiving HSCT included at least two clinical relapses the last year while on disease modifying treatment (DMT). Results: In total, 29 patients, with a mean follow-up time of 70 months (standard deviation:14.3), were evaluated. Twenty patients (69%) had sustained no evidence of disease activity (NEDA-3) status, 24 (83%) were relapse-free, 23 (79%) free of magnetic resonance imaging (MRI) activity, and 26 (90%) free of progression. Number of patients working full-time increased from 1 (3%), before HSCT, to 10 (33%) after 2 years and 15 (52%) after 5 years. Conclusion: HSCT offers long-term disease-free survival with successively increasing work participation in patients with aggressive MS resistant to DMTs.

• Hartung, Hans-Peter; Benedict, Ralph H.B.; Berger, Thomas; Bermel, Robert A.; Brochet, Bruno & Carroll, William M. [Show all 22 contributors for this article] (2024). Ocrelizumab in Early-Stage Relapsing-Remitting Multiple Sclerosis: The Phase IIIb ENSEMBLE 4-Year, Single-Arm, Open-Label Trial. Neurology. ISSN 0028-3878. 103(12). doi: 10.1212/WNL.0000000000210049. Full text in Research Archive Show summary

  Background and Objectives Early treatment of multiple sclerosis (MS) reduces disease activity and the risk of long-term disease progression. Effectiveness of ocrelizumab is established in relapsing MS (RMS); however, data in early RMS are lacking. We evaluated the 4-year effectiveness and safety of ocrelizumab as a first-line therapy in treatment-naive patients with recently diagnosed relapsing-remitting MS (RRMS). Methods ENSEMBLE was a prospective, 4-year, international, multicenter, single-arm, open-label, phase IIIb study. Patients were treatment naive, aged 18–55 years, had early-stage RRMS with a disease duration ≤3 years, Expanded Disability Status Scale (EDSS) score ≤3.5, and ≥1 clinically reported relapse(s) or ≥1 signs of brain inflammatory activity on MRI in the prior 12 months. Patients received IV ocrelizumab 600 mg every 24 weeks. Effectiveness endpoints over 192 weeks were proportion of patients with no evidence of disease activity (NEDA-3; defined as absence of relapses, 24-week confirmed disability progression [CDP], and MRI measures, with prespecified MRI rebaselining at week 8), 24-week/48-week CDP and 24-week confirmed disability improvement, annualized relapse rate (ARR), mean change in EDSS score from baseline, and safety. Cognitive status, patient-reported outcomes, and serum neurofilament light chain (NfL) were assessed. Descriptive analysis was performed on the intention-to-treat population. Results Baseline characteristics (N = 678) were consistent with early-stage RRMS (n = 539 patients, 64.6% female, age 40 years and younger; median age: 31.0 years; duration since: MS symptom onset 0.78 years, RRMS diagnosis 0.24 years; mean baseline EDSS score [SD] 1.71 [0.95]). At week 192, most of the patients had NEDA-3 (n = 394/593, 66.4%), 85.0% had no MRI activity, 90.9% had no relapses, and 81.8% had no 24-week CDP over the study duration. Adjusted ARR at week 192 was low (0.020, 95% CI 0.015–0.027). NfL levels were reduced to and remained within the healthy donor range, by week 48 and week 192, respectively. No new or unexpected safety signals were observed. Discussion Disease activity based on clinical and MRI measures was absent in most of the patients treated with ocrelizumab over 4 years in the ENSEMBLE study. Safety was consistent with the known profile of ocrelizumab. Although this single-arm study was limited by lack of a parallel group for comparison of outcome measures, the positive benefit–risk profile observed may provide confidence to adopt ocrelizumab as a first-line treatment in newly diagnosed patients with early RMS. Classification of Evidence This study provides Class IV evidence that adult patients with early-stage MS who were treatment naive maintained low disease activity (NEDA-3) over 4 years with ocrelizumab treatment; no new safety signals were detected.

• Novy, Camilla; Busk, Øyvind; Tysnes, Ole-Bjørn; Landa, Sigve Strand; Aanjesen, Tori Navestad & Alstadhaug, Karl Bjørnar [Show all 29 contributors for this article] (2024). Repeat expansions in AR, ATXN1, ATXN2 and HTT in Norwegian patients diagnosed with amyotrophic lateral sclerosis. Brain Communications. 6(2), p. 1–10. doi: 10.1093/braincomms/fcae087. Full text in Research Archive Show summary

  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 Kenne

• Novy, Camilla; Tysnes, Ole-Bjørn; Busk, Øyvind; Jaioun, Keson; Holmøy, Trygve & Holla, Øystein Lunde [Show all 7 contributors for this article] (2024). Association of UNC13A with increased amyotrophic lateral sclerosis risk, bulbar onset, and lower motor neuron involvement in a Norwegian ALS cohort. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. ISSN 2167-8421. doi: 10.1080/21678421.2024.2447922. Full text in Research Archive Show summary

  Objective: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by the loss of motor neurons, has limited treatment options available. Treatments targeting specific ALS genes, including UNC13A, have attracted considerable attention. The UNC13A rs12608932 variant has been associated with an increased risk of ALS, shorter survival, and more frequent bulbar onset. Methods: In this study, we investigated the allele frequency of rs12608932 among 500 Norwegian ALS patients, divided into three groups: patients with a genetic cause, patients without a genetic cause, and the entire ALS population.The three groups were compared to two independent control groups.The patients carrying UNC13A genotypes AA, AC, and CC were further clinically characterized and compared using additive, recessive, and dominant models. Results: The frequency of the rs12608932 C allele was higher in the patients with ALS (0.438) than in the controls (0.365; p<0.001). Among ALS patients without a known genetic cause, individuals with the CC genotype exhibited higher frequencies of bulbar onset (p¼0.015) and prominent lower motor neuron involvement (p¼0.007) than those with the AA and AC genotypes. Conclusions: The CC genotype of rs12608932 is associated with an increased risk of ALS. Additionally, it acts as a modifier of the ALS phenotype, increasing the risk of bulbar onset and dominant lower motor neuron involvement, specifically in patients without a genetic cause in known ALS genes.

• Olsen, Cathrine Goberg; Busk, Øyvind; Holla, Øystein Lunde; Tveten, Kristian; Holmøy, Trygve & Tysnes, Ole-Bjørn [Show all 7 contributors for this article] (2023). Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. ISSN 2167-8421. doi: 10.1080/21678421.2023.2270705. Full text in Research Archive Show summary

  Objective: In Norway, 89% of patients with Amyotrophic lateral sclerosis (ALS) lacks a genetic diagnose. ALS genes and genes that cause other neuromuscular or neurodegenerative disorders extensively overlap. This population-based study examined whether patients with ALS have a family history of neurological disorders and explored the occurrence of rare genetic variants associated with other neurodegenerative or neuromuscular disorders. Methods: During a two-year period, blood samples and clinical data from patients with ALS were collected from all 17 neurological departments in Norway. Our genetic analysis involved exome sequencing and bioinformatics filtering of 510 genes associated with neurodegenerative and neuromuscular disorders. The variants were interpreted using genotype-phenotype correlations and bioinformatics tools. Results: A total of 279 patients from a Norwegian population-based ALS cohort participated in this study. Thirty-one percent of the patients had first- or second-degree relatives with other neurodegenerative disorders, most commonly dementia and Parkinson's disease. The genetic analysis identified 20 possible pathogenic variants, in ATL3, AFG3L2, ATP7A, BICD2, HARS1, KIF1A, LRRK2, MSTO1, NEK1, NEFH, and SORL1, in 25 patients. NEK1 risk variants were present in 2.5% of this ALS cohort. Only four of the 25 patients reported relatives with other neurodegenerative or neuromuscular disorders. Conclusion: Gene variants known to cause other neurodegenerative or neuromuscular disorders, most frequently in NEK1, were identified in 9% of the patients with ALS. Most of these patients had no family history of other neurodegenerative or neuromuscular disorders. Our findings indicated that AFG3L2, ATP7A, BICD2, KIF1A, and MSTO1 should be further explored as potential ALS-causing genes.

• Selvakumar, Joel Pradeepkumar; Havdal, Lise Beier; Drevvatne, Martin Solstrand; Brodwall, Elias Myrstad; Lund-Berven, Lise & Stiansen-Sonerud, Tonje [Show all 19 contributors for this article] (2023). Prevalence and Characteristics Associated With Post-COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults. JAMA Network Open. 6(3). doi: 10.1001/jamanetworkopen.2023.5763. Full text in Research Archive Show summary

  Importance The prevalence and baseline risk factors of post–COVID-19 condition (PCC) remain unresolved among the large number of young people who experienced mild COVID-19. Objectives To determine the point prevalence of PCC 6 months after the acute infection, to determine the risk of development of PCC adjusted for possible confounders, and to explore a broad range of potential risk factors. Design, Setting, and Participants This cohort study included nonhospitalized individuals from 2 counties in Norway between ages 12 and 25 years who underwent reverse transcription–polymerase chain reaction (RT-PCR) testing. At the early convalescent stage and at 6-month follow-up, participants underwent a clinical examination; pulmonary, cardiac, and cognitive functional testing; immunological and organ injury biomarker analyses; and completion of a questionnaire. Participants were classified according to the World Health Organization case definition of PCC at follow-up. Association analyses of 78 potential risk factors were performed. Exposures SARS-CoV-2 infection. Main Outcomes and Measures The point prevalence of PCC 6 months after RT-PCR testing in the SARS-CoV-2–positive and SARS-CoV-2–negative groups, and the risk difference with corresponding 95% CIs. Results A total of 404 individuals testing positive for SARS-CoV-2 and 105 individuals testing negative were enrolled (194 male [38.1%]; 102 non-European [20.0%] ethnicity). A total of 22 of the SARS-CoV-2–positive and 4 of the SARS-CoV-2–negative individuals were lost to follow-up, and 16 SARS-CoV-2–negative individuals were excluded due to SARS-CoV-2 infection in the observational period. Hence, 382 SARS-CoV-2–positive participants (mean [SD] age, 18.0 [3.7] years; 152 male [39.8%]) and 85 SARS-CoV-2–negative participants (mean [SD] age, 17.7 [3.2] years; 31 male [36.5%]) could be evaluated. The point prevalence of PCC at 6 months was 48.5% in the SARS-CoV-2–positive group and 47.1% in the control group (risk difference, 1.5%; 95% CI, −10.2% to 13.1%). SARS-CoV-2 positivity was not associated with the development of PCC (relative risk [RR], 1.06; 95% CI, 0.83 to 1.37; final multivariable model utilizing modified Poisson regression). The main risk factor for PCC was symptom severity at baseline (RR, 1.41; 95% CI, 1.27-1.56). Low physical activity (RR, 0.96; 95% CI, 0.92-1.00) and loneliness (RR, 1.01; 95% CI, 1.00-1.02) were also associated, while biological markers were not. Symptom severity correlated with personality traits. Conclusions and Relevance The persistent symptoms and disability that characterize PCC are associated with factors other than SARS-CoV-2 infection, including psychosocial factors. This finding raises questions about the utility of the World Health Organization case definition and has implications for the planning of health care services as well as for further research on PCC.

• Wolf, Asia-Sophia Fumika Michaela; Ravussin, Anthony; König, Marton; Øverås, Mathias Herstad; Solum, Guri & Kjønstad, Ingrid Fadum [Show all 18 contributors for this article] (2023). T cell responses to SARS-CoV-2 vaccination differ by disease-modifying therapy for multiple sclerosis. JCI Insight. 8(12), p. 1–14. doi: 10.1172/jci.insight.165111. Full text in Research Archive Show summary

  Immune responses in people with multiple sclerosis (pwMS) receiving disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies, including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators, attenuate Ab responses after vaccination. Evaluation of cellular responses after vaccination, therefore, is of particular importance in these populations. In this study, we used flow cytometry to analyze CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy control study participants and pwMS receiving 5 different DMTs. Although pwMS receiving rituximab and fingolimod therapies had low Ab responses after both 2 and 3 vaccine doses, T cell responses in pwMS taking rituximab were preserved after a third vaccination, even when an additional dose of rituximab was administered between vaccine doses 2 and 3. PwMS taking fingolimod had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that, even in the absence of robust Ab responses, vaccination can generate immune responses in pwMS.

• Vaage, Anders Myhre; Benth, Jurate Saltyte; Meyer, Haakon Eduard; Holmøy, Trygve & Nakken, Ola (2023). Premorbid lipid levels and long-term risk of ALS—a population-based cohort study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. ISSN 2167-8421. doi: 10.1080/21678421.2023.2295455. Full text in Research Archive Show summary

  Objective To assess the temporal relationship between premorbid lipid levels and long-term amyotrophic lateral sclerosis (ALS) risk. Methods From Norwegian cardiovascular health surveys (1974–2003), we collected information on total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose, and other cardiovascular risk factors. ALS incidence and mortality were identified through validated Norwegian health registries. The relation between premorbid lipid levels and ALS risk was assessed by Cox regression models. Results Out of 640,066 study participants (51.5% females), 974 individuals (43.5% females) developed ALS. Mean follow-up time was 23.7 (SD 7.1) years among ALS cases. One mmol/l increase in LDL-C was associated with 6% increase in risk for ALS (hazard ratio 1.06 [95% CI: 1.01–1.09]). Higher levels of TC and TG were also associated with increased ALS risk, but only within the last 6–7 years prior to ALS diagnosis or death. No association between HDL-C and ALS risk was found. Adjusting for body mass index, birth cohort, smoking, and physical activity did not alter the results. Conclusions Higher levels of LDL-C are associated with increased ALS risk over 40 years later, compatible with a causal relationship. The temporal relationship between TG, TC, and ALS risk suggests that increased levels of these lipid biomarkers represent consequences of ALS.

• Rød, Brit Ellen; Wergeland, Stig; Bjørnevik, Kjetil Lauvland; Holmøy, Trygve; Ulvestad, Elling & Njølstad, Gro [Show all 8 contributors for this article] (2023). Humoral response to Epstein-Barr virus in patients with multiple sclerosis treated with B cell depletion therapy. Multiple Sclerosis and Related Disorders. ISSN 2211-0348. 79. doi: 10.1016/j.msard.2023.105037. Full text in Research Archive Show summary

  Background: B cell depletion therapy is highly effective in relapsing-remitting multiple sclerosis (RRMS). However, the precise underlying mechanisms of action for its biological effects in MS have still not been clarified. Epstein-Barr virus (EBV) is a known risk factor for MS and seems to be a prerequisite for disease development. EBV resides latently in the memory B cells, and may not only increase the risk of developing MS, but also contribute to disease activity and disability progression. Therefore, the effects of B cell depletion in MS could be associated with the depletion of EBV-infected cells and the altered immune response to the virus. In this study, we investigate the impact of B cell depletion on the humoral immune response specific to EBV in patients with MS. Methods: Newly diagnosed, treatment-naïve patients with RRMS were followed up to 18 months after initiation of B-cell depletion therapy in the Overlord-MS study, a phase III trial (NCT04578639). We analyzed serum sampled before treatment and after 3, 6, 12 and 18 months for immunoglobulin γ (IgG) against Epstein-Barr nuclear antigen 1 (EBNA1) and Epstein-Barr viral capsid antigen (VCA). We analyzed antibodies to cytomegalovirus (CMV) and total IgG in serum, as controls for viral and overall humoral immunity. The risk allele, HLA-DRB1*15:01, and the protective allele, HLA-A*02:01, were determined in all participants. In addition, polymerase chain reaction (PCR) for circulating EBV-DNA was performed in the first 156 samples drawn. The associations between time on B cell-depletion therapy and serum anti-EBV antibody levels were estimated using linear mixed-effects models. Results: A total of 290 serum samples from 99 patients were available for analysis. After 6, 12 and 18 months, the EBNA1 IgG levels decreased by 12.7 % (95 % CI -18.8 to -6.60, p < 0.001), 12.1 % (95 % CI -19.8 to -3.7, p = 0.006) and 14.6 % (95 % CI to -25.3 to -2.4, p = 0.02) respectively, compared to baseline level. Carriers of the HLA-DRB1*15:01 allele had higher EBNA1 IgG levels at baseline (p = 0.02). The VCA IgG levels significantly increased by 13.7 % (95 % CI 9.4 to 18.1, p < 0.001) after 3 months, compared to baseline, and persisted at this level throughout the follow-up. CMV IgG levels decreased, but to a lesser extent than the decrease of EBNA1 IgG, and total IgG levels decreased during therapy. Circulating EBV-DNA was found in only three of 156 samples from 64 patients. Conclusions: EBNA1 IgG levels decreased, while VCA IgG levels increased, during B cell depletion therapy. This supports the hypothesis that the mechanism of action for B cell depletion therapy might be mediated by effects on EBV infection, which, in turn, mitigate immune cross-reactivity and disease perpetuation.

• Ueland, Grethe Åstrøm; Ueland, Hans Olav; Stokland, Ann-Elin Meling; Bhan, Alok; Schønberg, Anne & Sollid, Stina Therese [Show all 13 contributors for this article] (2023). Prevalence, Risk Factors, and Clinical and Biochemical Characteristics of Alemtuzumab-Induced Graves Disease. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 109(2), p. 344–350. doi: 10.1210/clinem/dgad540. Full text in Research Archive Show summary

  Objective Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical characteristics of alemtuzumab-induced GD. Methods Retrospective follow-up study of MS patients treated with alemtuzumab from 2014 to 2020, including clinical course of GD, pregnancy outcome, and thyroid eye disease (TED). Results We enrolled 183 of 203 patients (90%, 68% women) treated with alemtuzumab at 4 hospitals in Norway. Seventy-five (41%) developed thyroid dysfunction, of whom 58 (77%) had GD. Median time from the first dose of alemtuzumab to GD diagnosis was 25 months (range, 0-64). Twenty-four of 58 GD patients (41%) had alternating phases of hyper- and hypothyroidism. Thyrotropin receptor antibodies became undetectable in 23 of 58 (40%) and they could discontinue antithyroid drug treatment after a median of 22 (range, 2-58) months. Conversely, 26 (44%) had active disease during a median follow-up of 39 months (range, 11-72). Two patients (3%) received definitive treatment with radioiodine, 6 (10%) with thyroidectomy. Nine developed TED (16%), 7 had mild and 2 moderate to severe disease. Four patients completed pregnancy, all without maternal or fetal complications. Patients who developed GD had a lower frequency of new MS relapses and MRI lesions than those without. Conclusion GD is a very common complication of alemtuzumab treatment and is characterized by alternating hyper- and hypothyroidism. Both remission rates and the prevalence of TED were lower than those reported for conventional GD. Pregnancies were uncomplicated and GD was associated with a lower risk of subsequent MS activity.

• Nakken, Ola; Vaage, Anders Myhre; Stigum, Hein; Heldal, Einar; Meyer, Haakon E. & Holmøy, Trygve (2023). Tuberculin responses after BCG vaccination predict amyotrophic lateral sclerosis risk. Brain, Behavior, and Immunity - Health (BBI - Health). 34, p. 1–6. doi: 10.1016/j.bbih.2023.100704. Full text in Research Archive Show summary

  Background T cell infiltration around dying motor neurons is a hallmark of amyotrophic lateral sclerosis (ALS). It is not known if this immune response represents a cause or a consequence of the disease. We aimed to establish whether individual variation in regulation of a T cell driven immune response is associated with long-term ALS risk. Methods Tuberculin skin test (TST) following BCG vaccination represents a standardized measure of a secondary T cell driven immune response. During a Norwegian tuberculosis screening program (1963–1975) Norwegian citizens born from 1910 to 1955 underwent TST. In those previously BCG vaccinated (median 7 years prior to TST), we related tuberculin skin tests to later ALS disease identified through validated Norwegian health registers. We fitted Cox proportional hazard models to investigate the association between tuberculin reactivity and ALS risk. Results Among 324,629 participants (52 % women) with median age 22 (IQR 10) years at tuberculosis screening, 496 (50 % women) later developed ALS. Hazard ratio for ALS was 0.74 (95% CI 0.57–0.95) for those who remained TST negative compared to those who mounted a positive TST. The association was strongest when time between BCG immunization and TST was short. The associations observed persisted for more than four decades after TST measurement. Conclusions Negative TST responses after BCG vaccination is associated with decreased long-term risk for ALS development, supporting a primary role for adaptive immunity in ALS development.

• Høyer, Helle; Nakken, Ola & Holmøy, Trygve (2023). A Novel SPAST Variant Associated with Isolated Spastic Paraplegia. Case Reports in Genetics. ISSN 2090-6552. doi: 10.1155/2023/4553365. Full text in Research Archive Show summary

  Genetic variants in SPAST are the most common cause of hereditary spastic paraplegia (HSP), entitled spastic paraplegia type 4 (SPG4). Inheritance is autosomal dominant, and age of onset can vary from childhood to adulthood. Pathogenic SPAST variants are often observed in isolated cases, likely due to reduced penetrance and clinical variability. We report an isolated case of SPG4 associated with a novel likely pathogenic variant in SPAST. A 38-year-old woman presented with an eight-year history of progressive difficulty walking. Neurological examination revealed spastic paraparesis in the absence of upper motor neuron dysfunction, sensory deficits, or intellectual disability. Magnetic resonance imaging (MRI) of the brain and spinal cord was normal. No family members had similar complaints. Genetic analysis revealed a novel heterozygous sequence variant in SPAST, c.1751A > G p.(Asp584Gly) (NM_014946.4). The affected amino acid is highly conserved among orthologue and paralogue species. Four other nucleotide substitutions predicted to affect the same amino acid, a "hot spot", have been reported previously in adult-onset HSP. This report describes a novel SPAST variant in a female with HSP without a known family history of the disorder.

• Aspli, Klaus Thanke; Aaseth, Jan; Holmøy, Trygve; Blennow, Kaj; Zetterberg, Henrik & Kirsebom, Bjørn-Eivind Seljelid [Show all 8 contributors for this article] (2023). CSF, Blood, and MRI Biomarkers in Skogholt’s Disease—A Rare Neurodegenerative Disease in a Norwegian Kindred. Brain Sciences. 13(11). doi: 10.3390/brainsci13111511. Full text in Research Archive Show summary

  Skogholt’s disease is a rare neurological disorder that is only observed in a small Norwegian kindred. It typically manifests in adulthood with uncharacteristic neurological symptoms from both the peripheral and central nervous systems. The etiology of the observed cerebral white matter lesions and peripheral myelin pathology is unclear. Increased cerebrospinal fluid (CSF) concentrations of protein have been confirmed, and recently, very high concentrations of CSF total and phosphorylated tau have been detected in Skogholt patients. The symptoms and observed biomarker changes in Skogholt’s disease are largely nonspecific, and further studies are necessary to elucidate the disease mechanisms. Here, we report the results of neurochemical analyses of plasma and CSF, as well as results from the morphometric segmentation of cerebral magnetic resonance imaging. We analyzed the biomarkers Aβ_1––42, Aβ_1–40, Aβ_x–38, Aβ_x–40, Aβ_x–42, total and phosphorylated tau, glial fibrillary acidic protein, neurofilament light chain, platelet-derived growth factor receptor beta, and beta-trace protein. All analyzed CSF biomarkers, except neurofilament light chain and Aβ1/_x–42, were increased several-fold. In blood, none of these biomarkers were significantly different between the Skogholt and control groups. MRI volumetric segmentation revealed decreases in the ventricular, white matter, and choroid plexus volumes in the Skogholt group, with an accompanying increase in white matter lesions. The cortical thickness and subcortical gray matter volumes were increased in the Skogholt group. Pathophysiological changes resulting from choroidal dysfunction and/or abnormal CSF turnover, which may cause the increases in CSF protein and brain biomarker levels, are discussed.

• Lindeman, Ida; Polak, Justyna; Qiao, Shuo-Wang; Holmøy, Trygve; Høglund, Rune Alexander & Vartdal, Frode [Show all 9 contributors for this article] (2022). Stereotyped B-cell responses are linked to IgG constant region polymorphisms in multiple sclerosis. European Journal of Immunology. ISSN 0014-2980. 52(4), p. 550–565. doi: 10.1002/eji.202149576. Full text in Research Archive Show summary

  Clonally related B cells infiltrate the brain, meninges, and cerebrospinal fluid of MS patients, but the mechanisms driving the B-cell response and shaping the immunoglobulin repertoires remain unclear. Here, we used single-cell full-length RNA-seq and BCR reconstruction to simultaneously assess the phenotypes, isotypes, constant region polymorphisms, and the paired heavy- and light-chain repertoires in intrathecal B cells. We detected extensive clonal connections between the memory B cell and antibody-secreting cell (ASC) compartments and observed clonally related cells of different isotypes including IgM/IgG1, IgG1/IgA1, IgG1/IgG2, and IgM/IgA1. There was a strong dominance of the G1m1 allotype constant region polymorphisms in ASCs, but not in memory B cells. Tightly linked to the G1m1 allotype, we found a preferential pairing of the immunoglobulin heavy-chain variable (IGHV)4 gene family with the κ variable (IGKV)1 gene family. The IGHV4-39 gene was most used and showed the highest frequency of pairing with IGKV1-5 and IGKV1(D)-33. These results link IgG constant region polymorphisms to stereotyped B-cell responses in MS and indicate that the intrathecal B-cell response in these patients could be directed against structurally similar epitopes

• Eid, Karine; Torkildsen, Øivind; Aarseth, Jan Harald; Aalstad, Mari; Bhan, Alok & Celius, Elisabeth Gulowsen [Show all 16 contributors for this article] (2022). Association of adverse childhood experiences with the development of multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry. ISSN 0022-3050. 93(6), p. 645–650. doi: 10.1136/jnnp-2021-328700. Full text in Research Archive Show summary

  Objective: To study whether exposure to childhood emotional, sexual or physical abuse is associated with subsequent multiple sclerosis (MS) development. Methods: A nationwide, prospective cohort study based on participants in the Norwegian Mother, Father and Child cohort study. Enrolment took place 1999-2008, with follow-up until 31 December 2018. Childhood abuse before age 18 years was obtained from self-completed questionnaires. We identified MS diagnoses through data-linkage with national health registries and hospital records. The Cox model was used to estimate HRs for MS with 95% CIs, adjusting for confounders and mediators. Results: In this prospective cohort study, 14 477 women were exposed to childhood abuse and 63 520 were unexposed. 300 women developed MS during the follow-up period. 71 of these (24%) reported a history of childhood abuse, compared with 14 406 of 77 697 (19%) women that did not develop MS. Sexual abuse (HR 1.65, 95% CI 1.13 to 2.39) and emotional abuse (HR 1.40, 95% CI 1.03 to 1.90) in childhood were both associated with an increased risk of developing MS. The HR of MS after exposure to physical abuse was 1.31 (95% CI 0.83 to 2.06). The risk of MS was further increased if exposed to two (HR 1.66, 95% CI 1.04 to 2.67) or all three abuse categories (HR 1.93, 95% CI 1.02 to 3.67). Interpretation: Childhood sexual and emotional abuse were associated with an increased risk of developing MS. The risk was higher when exposed to several abuse categories, indicating a dose-response relationship. Further studies are needed to identify underlying mechanisms. Keywords: multiple sclerosis; trauma, psychol seque. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

• Eid, Karine; Torkildsen, Øivind; Aarseth, Jan Harald; Celius, Elisabeth Gulowsen; Cortese, Marianna & Holmøy, Trygve [Show all 12 contributors for this article] (2022). Abuse and revictimization in adulthood in multiple sclerosis: a cross-sectional study during pregnancy. Journal of Neurology. ISSN 0340-5354. 269, p. 5901–5909. doi: 10.1007/s00415-022-11249-x. Full text in Research Archive Show summary

  Background: Knowledge concerning exposure to abuse in adulthood and in pregnancy in people with multiple sclerosis (MS) is sparse. Objective: To determine the occurrence of adult abuse and abuse in relation to pregnancy in women with MS and their risk of revictimization (repeated abuse as adults after childhood abuse). Methods: This cross-sectional study comprised pregnant women from the Norwegian Mother, Father and Child Cohort study. Information on abuse was acquired through self-completed questionnaires. We used logistic regression to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Results: We identified 106 women with MS at enrollment through linkage with national health registries. The reference group consisted of 77,278 women without MS. Twenty-seven women (26%) with MS reported any adult abuse compared to 15,491 women (20%) without MS, aOR 1.33 (0.85–2.09). Twenty-two (21%) women with MS reported systematic emotional abuse compared to 13% without MS, aOR 1.75 (1.08–2.83). Ten women (10%) with MS reported sexual abuse, compared to 6% without MS, aOR 1.72 (0.89–3.33). More women with MS reported rape as an adult, aOR 2.37 (1.02–5.49). Women with MS had higher risk of revictimization as adults, after childhood abuse, aOR 2.23 (1.22–4.10). The risk of abuse during pregnancy or 6 months preceding pregnancy was similar between the groups. Conclusions: Women with MS had increased occurrence of systematic emotional abuse, rape, and revictimization as adults, compared to women without MS.

• Nordfalk, Jenny Maria; Holmøy, Trygve; Thomas, Owen Matthew Truscott; Nylenna, Magne & Gulbrandsen, Pål (2022). Training physicians in providing complex information to patients with multiple sclerosis: a randomised controlled trial. BMJ Open. 12(3). doi: 10.1136/bmjopen-2021-049817. Full text in Research Archive Show summary

  Objective To evaluate the effect of a specific communication training for neurologists on how to provide complex information about treatment options to patients with multiple sclerosis (MS). Design Single-centre, single-blind, randomised controlled trial. Setting One university hospital in Norway. Participants Thirty-four patients with early-stage MS. Intervention A 3-hour training for neurologists on how to provide complex information about MS escalation therapy. Main outcome measures Patient recall rate, measured with a reliable counting system of provided and recalled information about drugs. Secondary outcome measures Number of information units provided by the physicians. Effects on patient involvement through questionnaires. Methods Patients with MS were instructed to imagine a disease development and were randomised and blinded to meet a physician to receive information on escalation therapy, before or after the physician had participated in a 3-hour training on how to provide complex information. Consultations and immediate patient recall interviews were video-recorded and transcribed verbatim. Results Patient recall rate was 0.37 (SD=0.10) pre-intervention and 0.39 (SD=0.10) post-intervention. The effect of the intervention on recall rate predicted with a general linear model covariate was not significant (coefficient parameter 0.07 (SE 0.04, 95% CI (−0.01 to 0.15)), p=0.099). The physicians tended to provide significantly fewer information units after the training, with an average of 91.0 (SD=30.3) pre-intervention and 76.5 (SD=17.4) post-intervention; coefficient parameter −0.09 (SE 0.02, 95% CI (−0.13 to −0.05)), p<0.001. There was a significant negative association between the amount of provided information and the recall rate (coefficient parameter −0.29 (SE 0.05, 95% CI (−0.39 to −0.18)), p<0.001). We found no significant effects on patient involvement using the Control Preference Scale, Collaborate or Four Habits Patient Questionnaire. Conclusion A brief course for physicians on providing complex information reduced the amount of information provided, but did not improve patient recall rate. Trial registration number ISRCTN42739508.

• König, Marton; Torgauten, Hilde Marie; Tran, Trung; Holmøy, Trygve; Vaage, John T. & Lund-Johansen, Fridtjof [Show all 7 contributors for this article] (2022). Immunogenicity and Safety of a Third SARS-CoV-2 Vaccine Dose in Patients with Multiple Sclerosis and Weak Immune Response after COVID-19 Vaccination. JAMA Neurology. ISSN 2168-6149. 79(3), p. 307–309. doi: 10.1001/jamaneurol.2021.5109. Full text in Research Archive
• Olsen, Cathrine Goberg; Busk, Øyvind Løvold; Aanjesen, Tori Navestad; Alstadhaug, Karl Bjørnar; Bjørnå, Ingrid Kristine & Braathen, Geir Julius [Show all 28 contributors for this article] (2022). Genetic Epidemiology of Amyotrophic lateral Sclerosis in Norway: A 2-Year Population-Based Study. Neuroepidemiology. ISSN 0251-5350. 56(4), p. 271–282. doi: 10.1159/000525091. Full text in Research Archive Show summary

  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 in 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 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 with 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.

• Lie, Ingrid Anne; Wesnes, Kristin; Kvistad, Silje Agnethe Stokke; Brouwer, Iman; Wergeland, Stig & Holmøy, Trygve [Show all 20 contributors for this article] (2022). The Effect of Smoking on Long-term Gray Matter Atrophy and Clinical Disability in Patients with Relapsing-Remitting Multiple Sclerosis. Neurology: Neuroimmunology and neuroinflammation. 9(5), p. 1–10. doi: 10.1212/NXI.0000000000200008. Full text in Research Archive Show summary

  Background and Objectives - The relationship between smoking, long-term brain atrophy, and clinical disability in patients with multiple sclerosis (MS) is unclear. Here, we assessed long-term effects of smoking by evaluating MRI and clinical outcome measures after 10 years in smoking and nonsmoking patients with relapsing-remitting MS (RRMS). Methods - We included 85 treatment-naive patients with RRMS with recent inflammatory disease activity who participated in a 10-year follow-up visit after a multicenter clinical trial of 24 months. Smoking status was decided for each patient by 2 separate definitions: by serum cotinine levels measured regularly for the first 2 years of the follow-up (during the clinical trial) and by retrospective patient self-reporting. At the 10-year follow-up visit, clinical tests were repeated, and brain atrophy measures were obtained from MRI using FreeSurfer. Differences in clinical and MRI measurements at the 10-year follow-up between smokers and nonsmokers were investigated by 2-sample t tests or Mann-Whitney tests and linear mixed-effect regression models. All analyses were conducted separately for each definition of smoking status. Results - After 10 years, smoking (defined by serum cotinine levels) was associated with lower total white matter volume (β = −21.74, p = 0.039) and higher logT2 lesion volume (β = 0.22, p = 0.011). When defining smoking status by patient self-reporting, the repeated analyses found an additional association with lower deep gray matter volume (β = −2.35, p = 0.049), and smoking was also associated with a higher score (higher walking impairment) on the log timed 25-foot walk test (β = 0.050, p = 0.039) after 10 years and a larger decrease in paced auditory serial addition test (attention) scores (β = −3.58, p = 0.029). Discussion - Smoking was associated with brain atrophy and disability progression 10 years later in patients with RRMS. The findings imply that patients should be advised and offered aid in smoking cessation shortly after diagnosis, to prevent long-term disability progression.

• Kliest, Tessa; Eijk, Ruben P. A. van; Al-Chalabi, Ammar; Albanese, Alberto; Andersen, Peter M. & Amador, Maria Del Mar [Show all 57 contributors for this article] (2022). Clinical trials in pediatric ALS: a TRICALS feasibility study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. ISSN 2167-8421. 23(7-8), p. 481–488. doi: 10.1080/21678421.2021.2024856. Full text in Research Archive Show summary

  Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA). Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe. Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS. Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS. Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

• Nakken, Ola; Holmøy, Trygve; Stigum, Hein; Myhr, Kjell-Morten; Dahl, Jesper & Heldal, Einar [Show all 7 contributors for this article] (2022). Strong tuberculin response after BCG vaccination is associated with low multiple sclerosis risk: a population-based cohort study. International Journal of Epidemiology. ISSN 0300-5771. 51(5), p. 1637–1644. doi: 10.1093/ije/dyac039. Full text in Research Archive Show summary

  Background: Multiple sclerosis (MS) is characterized by inflammatory lesions in the central nervous system involving pro-inflammatory T-cells. Immune dysregulation is well described in prevalent disease, but it is not known whether this precedes disease development. Bacillus Calmette–Guerin (BCG) vaccination ameliorates MS-like disease in mice. In people vaccinated with BCG, the tuberculin skin test (TST) offers a standardized measure of a T-cell-mediated immune response. We therefore hypothesized that the strength of the TST response after BCG vaccination is associated with subsequent MS risk. Methods: Using data from a Norwegian tuberculosis screening programme (1963–1975), we designed a population-based cohort study and related the size of TST reactions in individuals previously vaccinated with BCG to later MS disease identified through the Norwegian MS registry. We fitted Cox proportional hazard models and flexible parametric survival models to investigate the association between TST reactivity, MS risk and its temporal relationship. Results: Among 279 891 participants (52% females), 679 (69% females) later developed MS. Larger TST reactivity was associated with decreased MS risk. The hazard ratio for MS per every 4-mm increase in skin induration size was 0.86 (95% confidence interval 0.76–0.96) and similar between sexes. The strength of the association persisted for >30 years after the TST. Conclusion: A strong in vivo vaccine response to BCG is associated with reduced MS risk >30 years later. The immunological mechanisms determining TST reactivity suggest that skewed T-cell-mediated immunity precedes MS onset by many decades.

• Lie, Ingrid Anne; Kacar, Sezgi; Wesnes, Kristin; Brouwer, Iman; Kvistad, Silje Agnethe Stokke & Wergeland, Stig [Show all 24 contributors for this article] (2022). Serum neurofilament as a predictor of 10-year grey matter atrophy and clinical disability in multiple sclerosis: a longitudinal study. Journal of Neurology, Neurosurgery and Psychiatry. ISSN 0022-3050. 93(8), p. 849–857. doi: 10.1136/jnnp-2021-328568. Full text in Research Archive Show summary

  Background The predictive value of serum neurofilament light chain (sNfL) on long-term prognosis in multiple sclerosis (MS) is still unclear. Objective Investigate the relation between sNfL levels over a 2-year period in patients with relapsing-remitting MS, and clinical disability and grey matter (GM) atrophy after 10 years. Methods 85 patients, originally enrolled in a multicentre, randomised trial of ω−3 fatty acids, participated in a 10-year follow-up visit. sNfL levels were measured by Simoa quarterly until month 12, and then at month 24. The appearance of new gadolinium-enhancing (Gd+) lesions was assessed monthly between baseline and month 9, and then at months 12 and 24. At the 10-year follow-up visit, brain atrophy measures were obtained using FreeSurfer. Results Higher mean sNfL levels during early periods of active inflammation (Gd+ lesions present or recently present) predicted lower total (β=−0.399, p=0.040) and deep (β=−0.556, p=0.010) GM volume, lower mean cortical thickness (β=−0.581, p=0.010) and higher T2 lesion count (β=0.498, p=0.018). Of the clinical outcomes, higher inflammatory sNfL levels were associated with higher disability measured by the dominant hand Nine-Hole Peg Test (β=0.593, p=0.004). Mean sNfL levels during periods of remission (no Gd+ lesions present or recently present) did not predict GM atrophy or disability progression. Conclusion Higher sNfL levels during periods of active inflammation predicted more GM atrophy and specific aspects of clinical disability 10 years later. The findings suggest that subsequent long-term GM atrophy is mainly due to neuroaxonal degradation within new lesions.

• Holmøy, Trygve & Jørstad, Øystein Kalsnes (2021). Den første norske doktorgraden om multippel sklerose. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 141(5), p. 1–9. doi: 10.4045/tidsskr.20.0993. Full text in Research Archive
• Wesnes, Kristin; Myhr, Kjell-Morten; Riise, Trond; Kvistad, Silje Agnethe Stokke; Torkildsen, Øivind & Wergeland, Stig [Show all 17 contributors for this article] (2021). Low vitamin D, but not tobacco use or high BMI, is associated with long-term disability progression in multiple sclerosis. Multiple Sclerosis and Related Disorders. ISSN 2211-0348. 50:102801, p. 1–7. doi: 10.1016/j.msard.2021.102801. Full text in Research Archive Show summary

  Background: Low vitamin D levels, tobacco use and high body mass index (BMI) have been linked to adverse disease outcomes in multiple sclerosis (MS), but their influence on long-term disability progression remains unclear. Therefore, we explored whether these modifiable lifestyle factors were associated with 10-year clinical disability progression in patients with MS. Methods: In this prospective study, a cohort of 88 patients with relapsing-remitting MS completed a randomized controlled study on ω-3 fatty acids between 2004 and 2008. During 24 months, serum 25-hydroxyvitamin D (25 (OH)D), serum cotinine (nicotine metabolite), and BMI were repeatedly measured. In 2017, a follow-up study was conducted among 80 of the participants, including disability assessment by the Expanded Disability Status Scale (EDSS). Linear regression was used to explore associations between the lifestyle factors and the EDSS change over 10 years. Results: Higher seasonally adjusted 25(OH)D levels were associated with lower 10-year EDSS progression (change in EDSS per 1 SD increase in 25(OH)D in a model adjusted for sex, age and baseline EDSS: -0.45 point, 95% CI: -0.75 to -0.16, p=0.003). Further adjustments for potential confounders related to lifestyle and disease status gave similar results. The association was mainly driven by low 25(OH)D levels during spring, as well as seasonally adjusted levels below 80 nmol/L. No clear association was found for BMI and cotinine. Conclusion: Lower 25(OH)D levels, but apparently not tobacco use or higher BMI, were significantly associated with worse long-term disability progression in MS.

• Eid, Karine; Torkildsen, Øivind Fredvik Grytten; Aarseth, Jan Harald; Flemmen, Heidi Øyen; Holmøy, Trygve & Lorentzen, Åslaug Rudjord [Show all 15 contributors for this article] (2021). Perinatal Depression and Anxiety in Women with Multiple Sclerosis: A Population-Based Cohort Study. Neurology. ISSN 0028-3878. 96(23), p. e2789–e2800. doi: 10.1212/WNL.0000000000012062. Full text in Research Archive Show summary

  Objective: To assess the occurrence of perinatal depression and anxiety in women before and after diagnosis of multiple sclerosis (MS). Methods: 114,629 pregnant women were included in the Norwegian Mother, Father and Child Cohort study 1999-2008. We assessed depression and anxiety by questionnaires during and after pregnancy. Women with MS were identified from national health registries and hospital records and grouped into 1) MS diagnosed before pregnancy (n = 140), MS diagnosed after pregnancy with 2) symptom onset before pregnancy (n = 98) and 3) symptom onset after pregnancy (n = 308). Thirty-five women were diagnosed with MS in the postpartum period. The reference group (n = 111,627) consisted of women without MS. Results: Women with MS diagnosed before pregnancy had an adjusted odds ratio of 2.0 (95% confidence interval 1.2-3.1) for depression in the third trimester. Risk factors were adverse socioeconomic factors, history of psychiatric disease and physical/sexual abuse. The risk of anxiety was not increased. Women diagnosed with MS in the postpartum period had especially high risk of postpartum depression. Women with MS symptom onset within 5 years after pregnancy had increased risk of both depression and anxiety during pregnancy, whereas women with more than 5 years until symptom onset did not. Conclusion: Women diagnosed with MS have increased risk of perinatal depression. Women with MS symptom onset within 5 years after pregnancy have increased risk of both depression and anxiety during pregnancy.

• Pihl-Jensen, Gorm; Meling, Eva Ødegaard; Skogen, Karoline; Jørstad, Øystein Kalsnes & Holmøy, Trygve (2021). En kvinne i 40-årene med ensidig tåkesyn og smerter ved øyebevegelse. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 141(9), p. 1–7. doi: 10.4045/tidsskr.20.0932. Full text in Research Archive
• Høglund, Rune Alexander; Meyer, Haakon Eduard; Stigum, Hein; Torkildsen, Øivind; Grytten, Nina & Holmøy, Trygve [Show all 7 contributors for this article] (2021). Association of body mass index in Adolescence and young Adulthood and long-term risk of multiple Sclerosis: A Population-Based Study. Neurology. ISSN 0028-3878. 97(23), p. E2253–E2261. doi: 10.1212/WNL.0000000000012957. Full text in Research Archive Show summary

  Background and Objectives To prospectively investigate the long-term relationship between body mass index (BMI) in adolescents and young adults and risk for multiple sclerosis (MS) at the population level. Methods We used data from the population-based compulsory Norwegian tuberculosis screening program during 1963 to 1975, including objectively measured height and weight from ≈85% of all eligible citizens. This was combined with data from the Norwegian MS registry and biobank up to November 2020. BMI was standardized according to age and sex, and risk for MS was calculated with Cox proportional hazard models. Results During 30,829,506 years of follow-up, we found 1,409 cases of MS among 648,734 participants in eligible age groups (14–34 years). Overall, obesity was associated with increased MS risk (hazard ratio [HR] 1.53 [95% confidence interval (CI) 1.25–1.88]), and the risk was similar in men (HR 1.4 [95% CI 0.95–2.06] and women (HR 1.59 [95% CI 1.25–2.02]). Risk was highest for the youngest age groups (age 14–16: HR 1.73 [95% CI 1.19–2.53]; 17–19: HR 1.61 [95% CI 1.08–2.39]; 20–24: HR 1.56 [95% CI 1.04–2.36]) and was no longer present for those &gt;30 years of age. Discussion High BMI in individuals 14 to 24 years of age was associated with increased MS risk later in life in both male and female individuals.

• König, Marton; Lorentzen, Åslaug Rudjord; Torgauten, Hilde Marie; Tran, Trung; Schikora-Rustad, Stine & Vaage, Eline Benno [Show all 22 contributors for this article] (2021). Humoral immunity to SARS-CoV-2 mRNA vaccination in multiple sclerosis: the relevance of time since last rituximab infusion and first experience from sporadic revaccinations. Journal of Neurology, Neurosurgery and Psychiatry. ISSN 0022-3050. doi: 10.1136/jnnp-2021-327612. Full text in Research Archive Show summary

  Introduction The effect of disease-modifying therapies (DMT) on vaccine responses is largely unknown. Understanding the development of protective immunity is of paramount importance to fight the COVID-19 pandemic. Objective To characterise humoral immunity after mRNA-COVID-19 vaccination of people with multiple sclerosis (pwMS). Methods All pwMS in Norway fully vaccinated against SARS-CoV-2 were invited to a national screening study. Humoral immunity was assessed by measuring anti-SARS-CoV-2 SPIKE RBD IgG response 3–12 weeks after full vaccination, and compared with healthy subjects. Results 528 pwMS and 627 healthy subjects were included. Reduced humoral immunity (anti-SARS-CoV-2 IgG <70 arbitrary units) was present in 82% and 80% of all pwMS treated with fingolimod and rituximab, respectively, while patients treated with other DMT showed similar rates as healthy subjects and untreated pwMS. We found a significant correlation between time since the last rituximab dose and the development of humoral immunity. Revaccination in two seronegative patients induced a weak antibody response. Conclusions Patients treated with fingolimod or rituximab should be informed about the risk of reduced humoral immunity and vaccinations should be timed carefully in rituximab patients. Our results identify the need for studies regarding the durability of vaccine responses, the role of cellular immunity and revaccinations. This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

• Aspli, Klaus Thanke; Holmøy, Trygve; Flaten, Trond Peder; Whist, Jon Elling & Aaseth, Jan (2021). Skogholt’s disease—A tauopathy precipitated by iron and copper? Journal of Trace Elements in Medicine and Biology. ISSN 0946-672X. 70. doi: 10.1016/j.jtemb.2021.126915. Full text in Research Archive Show summary

  Background It has been suggested that Skogholt’s disease is a new neurological disease entity. The disease, confined to a family line in Hedmark county, Norway, usually affects both the brain and peripheral nerves. Typical findings are white matter lesions in the brain, myelin damage in peripheral nerves, and discolored cerebrospinal fluid with high concentrations of protein, copper, and iron. Little is known about the natural progression of the disease and its underlying cause, but the high level of copper and iron in the cerebrospinal fluid may cause or exacerbate inflammation in the central nervous system. Methods The present clinical study further explores the disease progression with clinical chemistry analyses and mass spectrometry of blood and cerebrospinal fluid (CSF) from patients and controls. Findings are corroborated with cognitive assessments. Results Pathological changes in CSF with low amyloid-β42 and high levels of tau proteins, total protein, copper, and iron, were discovered among Skogholt patients. The Montreal Cognitive Assessment identified 36 % of the patients as below normal range, while most patients performed slower than the norm mean time on the Trail Making Test. Mini-Mental Status Examination disclosed only minor deviations. Conclusion The findings in the present study strengthen our initial suggestion that Skogholt’s disease most likely is a new neurological disorder and provide new clues to its cause: The disease may belong to the family of neurodegenerative disorders termed tauopathies. The increased level of copper and iron may contribute to neuroinflammation as these metals also have been associated with other neurodegenerative disorders. Although the causes of neurodegenerative disorders are currently largely unknown, studies on rare disease entities, such as the present one, may increase the understanding of neurodegeneration in general.

• Hartung, HP; Berger, T.; Bermel, RA; Brochet, B; Carroll, WM & Holmøy, Trygve [Show all 19 contributors for this article] (2020). Shorter infusion time of ocrelizumab: Results from the randomized, doubleblind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis. Multiple Sclerosis and Related Disorders. ISSN 2211-0348. doi: 10.1016/j.msard.2020.102492. Full text in Research Archive Show summary

  Background: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5–6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocrelizumab infusions was investigated using results from ENSEMBLE PLUS. Methods: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early-stage relapsing-remitting MS received ocrelizumab 600 mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, ocrelizumab 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration); the durations of the initial infusions (2×300 mg, 14 days apart) were unaffected. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first Randomized Dose. Results: From November 1, 2018, to December 13, 2019, 745 patients were randomized 1:1 to the conventional or shorter infusion group. At the first Randomized Dose, 99/373 patients (26.5%) in the conventional and 107/372 patients (28.8%) in the shorter infusion group experienced IRRs. The majority of IRRs were mild or moderate; >99% of all IRRs resolved without sequelae in both groups (conventional infusion group, 99/99; shorter infusion group, 106/107). No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuations occurred. During the first Randomized Dose, 22/373 (5.9%) and 39/372 (10.5%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. Adverse events were consistent with the known safety profile of ocrelizumab. Conclusion: The rates and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shortening the infusion time to 2 hours reduces the total site stay time (including mandatory pre-medication/infusion/observation) from 5.5–6 hours to 4 hours, and may reduce patient and site staff burden. A short video summarizing the key results is provided in supplemental material.

• Røsjø, Egil Rørvik; Lindstrøm, Jonas Christoffer; Holmøy, Trygve; Myhr, Kjell-Morten; Varhaug, Kristin Nielsen & Torkildsen, Øivind Fredvik (2020). Natural Variation of Vitamin D and Neurofilament Light Chain in Relapsing-Remitting Multiple Sclerosis. Frontiers in Neurology. 11. doi: 10.3389/fneur.2020.00329. Full text in Research Archive Show summary

  Background: High serum levels of 25-hydroxyvitamin D (25(OH)D) have been found among patients with a favorable disease course in relapsing-remitting MS (RRMS), indicating that this may limit clinical deterioration. Clinical deterioration in RRMS correlates with increasing serum levels of neurofilament light chain (NfL). Objectives: To examine the association between physiological variations in serum 25(OH)D and NfL levels in RRMS patients before and during disease modifying therapy (DMT). Material and Methods: Serum 25(OH)D and NfL concentrations were measured in 85 newly diagnosed RRMS patients enrolled in a 24-month randomized double-blinded placebo-controlled trial of ω-3 fatty acid supplementation without vitamin D. Patients were without DMT until interferon β-1a (IFN-β) initiation at study month 6. Longitudinal serum measurements and brain magnetic resonance imaging (MRI) were obtained. Associations between 25(OH)D and NfL levels were analyzed with linear regression models for the whole study period and the periods before and during IFN-β treatment. Analyses with adjustment for inflammatory MRI disease activity were also performed. Results: No significant associations were found between variations in 25(OH)D and NfL levels during the whole study period (p = 0.95), or the periods without (p = 0.78) or with (p = 0.33) IFN-β therapy. Patients with inflammatory MRI disease activity had significantly higher serum NfL levels than patients without inflammatory MRI disease activity [mean (SD) difference 12.6 (2.0) pg/mL, p < 0.01]. Adjustment for this did not change the relationship between 25(OH)D and NfL concentrations. Conclusion: Natural variations in serum 25(OH)D values do not seem to be associated with alterations in serum NfL concentrations in RRMS patients.

• Holmøy, Trygve; Høglund, Rune Alexander; Illes, Zsolt; Myhr, Kjell-Morten & Torkildsen, Øivind (2020). Recent progress in maintenance treatment of neuromyelitis optica spectrum disorder. Journal of Neurology. ISSN 0340-5354. doi: 10.1007/s00415-020-10235-5. Full text in Research Archive Show summary

  Background Treatment of neuromyelitis optica spectrum disorder (NMOSD) has so far been based on retrospective case series. The results of six randomized clinical trials including five different monoclonal antibodies targeting four molecules and three distinct pathophysiological pathways have recently been published. Methods Literature search on clinical trials and case studies in NMOSD up to July 10. 2020. Results We review mechanism of action, efficacy and side effects, and consequences for reproductive health from traditional immunosuppressants and monoclonal antibodies including rituximab, inebilizumab, eculizumab, tocilizumab and satralizumab. Conclusion In NMOSD patients with antibodies against aquaporin 4, monoclonal antibodies that deplete B cells (rituximab and inebilizumab) or interfere with interleukin 6 signaling (tocilizumab and satralizumab) or complement activation (eculizumab) have superior efficacy compared to placebo. Tocilizumab and rituximab were also superior to azathioprine in head-to-head studies. Rituximab, tocilizumab and to some extent eculizumab have well-known safety profiles for other inflammatory diseases, and rituximab and azathioprine may be safe during pregnancy.

• Høglund, Rune Alexander; Bremel, Robert; Homan, E. Jane; Torsetnes, Silje Bøen; Lossius, Andreas & Holmøy, Trygve (2020). CD4+ T Cells in the Blood of MS Patients Respond to Predicted Epitopes From B cell Receptors Found in Spinal Fluid. Frontiers in Immunology. 11, p. 1–12. doi: 10.3389/fimmu.2020.00598. Full text in Research Archive Show summary

  B cells are important pathogenic players in multiple sclerosis (MS), but their exact role is not known. We have previously demonstrated that B cells from cerebrospinal fluid (CSF) of MS patients can activate T cells that specifically recognize antigenic determinants (idiotopes) from their B cell receptors (BCRs). The aim of this study was to evaluate whether in silico prediction models could identify antigenic idiotopes of immunoglobulin heavy-chain variable (IGHV) transcriptomes in MS patients. We utilized a previously assembled dataset of CSF IGHV repertoires from MS patients. To guide selection of potential antigenic idiotopes, we used in silico predicted HLA-DR affinity, endosomal processing, as well as transcript frequency from nine MS patients. Idiotopes with predicted low affinity and low likelihood of cathepsins cleavage were inert controls. Peripheral blood mononuclear cells from these patients were stimulated with the selected idiotope peptides in presence of anti-CD40 for 12 h. T cells were then labeled for activation status with anti-CD154 antibodies and CD3+CD4+ T cells phenotyped as memory (CD45RO+) or naïve (CD45RO−), with potential for brain migration (CXCR3 and/or CCR6 expression). Anti-CD14 and -CD8 were utilized to exclude monocytes and CD8+ T cells. Unstimulated cells or insulin peptides were negative controls, and EBNA-1 peptides or CD3/CD28 beads were positive controls. The mean proportion of responding memory CD4+ T cells from all nine MS patients was significantly higher for idiotope peptides with predicted high HLA-DR affinity and high likelihood of cathepsin cleavage, than toward predicted inert peptides. Responses were mainly observed toward peptides affiliated with the CDR3 region. Activated memory CD4+ T cells expressed the chemokine receptor CCR6, affiliated with a Th17 phenotype and allowing passage into the central nervous system (CNS). This in vitro study suggests that that antigenic properties of BCR idiotopes can be identified in silico using HLA affinity and endosomal processing predictions. It further indicates that MS patients have a memory T cell repertoire capable of recognizing frequent BCR idiotopes found in endogenous CSF, and that these T cells express chemokine receptors allowing them to reach the CSF B cells expressing these idiotopes.

• Gilmour, Brian Christopher; Gudmundsrud, Ruben; Frank, Johannes; Hov, Amund; Lautrup, Sofie Hindkjær & Aman, Yahyah [Show all 18 contributors for this article] (2020). Targeting NAD+ in translational research to relieve diseases and conditions of metabolic stress and ageing. Mechanisms of Ageing and Development. ISSN 0047-6374. 186, p. 1–6. doi: 10.1016/j.mad.2020.111208. Full text in Research Archive Show summary

  Nicotinamide adenine dinucleotide (NAD+) plays a fundamental role in life and health through the regulation of energy biogenesis, redox homeostasis, cell metabolism, and the arbitration of cell survival via linkages to apoptosis and autophagic pathways. The importance of NAD+ in ageing and healthy longevity has been revealed from laboratory animal studies and early-stage clinical testing. While basic researchers and clinicians have investigated the molecular mechanisms and translation potential of NAD+, there are still major gaps in applying laboratory science to design the most effective trials. This mini-review was based on the programme and discussions of the 3rd NO-Age Symposium held at the Akershus University Hospital, Norway on the 28th October 2019. This symposium brought together leading basic researchers on NAD+ and clinicians who are leading or are going to perform NAD+ augmentation-related clinical studies. This meeting covered talks about NAD+ synthetic pathways, subcellular homeostasis of NAD+, the benefits of NAD+ augmentation from maternal milk to offspring, current clinical trials of the NAD+ precursor nicotinamide riboside (NR) on Ataxia-Telangiectasia (A-T), Parkinson’s disease (PD), post-sepsis fatigue, as well as other potential NR-based clinical trials. Importantly, a consensus is emerging with respect to the design of clinical trials in order to measure meaningful parameters and ensure safety.

• Nakken, Ola; Meyer, Haakon E; Stigum, Hein & Holmøy, Trygve (2019). High BMI is associated with low ALS risk: A population-based study. Neurology. ISSN 0028-3878. 93(5), p. e424–e432. doi: 10.1212/WNL.0000000000007861. Full text in Research Archive Show summary

  This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased. Abstract Objective To investigate the temporal relationship among prediagnostic body mass index (BMI), weight change, and risk of amyotrophic lateral sclerosis (ALS). Methods From the compulsory Norwegian tuberculosis screening program, we collected objectively measured BMI from 85% of all citizens (near 1.5 million) between 20 and 70 years of age living in 18 of 19 Norwegian counties between 1963 and 1975. For those who participated in later health surveys, we collected further information on weight change, lifestyle, and health. We identified ALS cases until September 2017 through national registries of diagnoses at death and at encounters with the specialist health service. Both Cox hazard models and flexible parametric survival models were fitted to address our research question. Results We identified 2,968 ALS cases during a mean of 33 (maximum 54) years follow-up. High prediagnostic BMI was associated with low subsequent ALS risk across the typical ALS ages in both sexes. Overall, hazard ratio (HR) for ALS per 5-unit increase in prediagnostic BMI was 0.83 (95% confidence interval [CI] 0.79–0.88). After an initial increase during the first 10 years, it decreased almost linearly throughout the observation period and was 0.69 (95% CI 0.62–0.77) after 50 years. Those in the quartile with highest weight gain had lower ALS risk than those in the lowest quartile (HR 0.63, 95% CI 0.44–0.89). Conclusion High BMI and weight gain are associated with low ALS risk several decades later. The strength of the association between BMI and ALS risk increases up to 50 years after BMI measurement.

• Høglund, Rune Alexander; Torsetnes, Silje Bøen; Lossius, Peter Andreas Vold; Bogen, Bjarne; Homan, E. Jane & Bremel, Robert [Show all 7 contributors for this article] (2019). Human cysteine cathepsins degrade immunoglobulin G in vitro in a predictable manner. International Journal of Molecular Sciences. ISSN 1661-6596. 20:4843(19), p. 1–19. doi: 10.3390/ijms20194843. Full text in Research Archive Show summary

  Cysteine cathepsins are critical components of the adaptive immune system involved in the generation of epitopes for presentation on human leukocyte antigen (HLA) molecules and have been implicated in degradation of autoantigens. Immunoglobulin variable regions with somatic mutations and random complementarity region 3 amino acid composition are inherently immunogenic. T cell reactivity towards immunoglobulin variable regions has been investigated in relation to specific diseases, as well as reactivity to therapeutic monoclonal antibodies. Yet, how the immunoglobulins, or the B cell receptors, are processed in endolysosomal compartments of professional antigen presenting cells has not been described in detail. Here we present in silico and in vitro experimental evidence suggesting that cysteine cathepsins S, L and B may have important roles in generating peptides fitting HLA class II molecules, capable of being presented to T cells, from monoclonal antibodies as well as from central nervous system proteins including a well described autoantigen. By combining neural net models with in vitro proteomics experiments, we further suggest how such degradation can be predicted, how it fits with available cellular models, and that it is immunoglobulin heavy chain variable family dependent. These findings are relevant for biotherapeutic drug design as well as to understand disease development. We also suggest how these tools can be improved, including improved machine learning methodology.

• Larsen, Christopher Storm; Myhr, Kjell-Morten; Farbu, Elisabeth; Midgard, Rune; Nyquist, Kaja Beate & Broch, Line [Show all 14 contributors for this article] (2019). Gut microbiota composition during a 12-week intervention with delayed-release dimethyl fumarate in multiple sclerosis – a pilot trial. Multiple Sclerosis Journal, Experimental, Translational and Clinical. 5(4), p. 1–13. doi: 10.1177/2055217319888767. Full text in Research Archive Show summary

  Introduction Patients with multiple sclerosis may have a distinct gut microbiota profile. Delayed-release dimethyl fumarate is an orally administered drug for relapsing–remitting multiple sclerosis, which has been associated with gastrointestinal side-effects in some patients. Objectives The purpose of this study was to determine if dimethyl fumarate alters the abundance and diversity of commensal gut bacteria, and if these changes are associated with gastrointestinal side-effects. Methods Thirty-six patients with relapsing–remitting multiple sclerosis received either dimethyl fumarate (n = 27) or an injectable multiple sclerosis disease-modifying therapy (glatiramer acetate or interferons, n = 9) for 12 weeks. Stool samples were collected at baseline, two and 12 weeks. We included 165 healthy individuals as controls. Results At baseline, 16 microbial genera were altered in multiple sclerosis patients compared with healthy controls. In the dimethyl fumarate-treated patients (n = 21) we observed a trend of reduced Actinobacteria (p = 0.03, QFDR = 0.24) at two weeks, mainly driven by Bifidobacterium (p = 0.06, QFDR = 0.69). At 12 weeks, we observed an increased abundance of Firmicutes (p = 0.02, QFDR = 0.09), mostly driven by Faecalibacterium (p = 0.01, QFDR = 0.48). Conclusions This pilot study did not detect a major effect of dimethyl fumarate on the gut microbiota composition, but we observed a trend towards normalization of the low abundance of butyrate-producing Faecalibacterium after 12 weeks treatment. The study was underpowered to link microbiota to gastrointestinal symptoms.

• Myhr, Kjell-Morten; Torkildsen, Øivind; Lossius, Peter Andreas Vold; Bø, Lars & Holmøy, Trygve (2019). B cell depletion in the treatment of multiple sclerosis. Expert Opinion on Biological Therapy. ISSN 1471-2598. 19(3), p. 261–271. doi: 10.1080/14712598.2019.1568407. Full text in Research Archive
• Holmøy, Trygve; Fevang, Børre; Olsen, David Benee; Spigset, Olav & Bø, Lars (2019). Adverse events with fatal outcome associated with alemtuzumab treatment in multiple sclerosis. BMC Research Notes. 12(1), p. 1–5. doi: 10.1186/s13104-019-4507-6. Full text in Research Archive Show summary

  Objective Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality. Results We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment. Introduction Alemtuzumab is a humanized monoclonal antibody directed against CD52, and is regarded as one of the most efficacious drugs for treatment of relapsing–remitting multiple sclerosis (MS) [1]. Alemtuzumab induces a profound decrease of T and B lymphocytes, with a gradual recovery starting one month after administration [2, 3]. Even though alemtuzumab is generally considered safe, serious adverse reactions have been identified, including infections, immune-mediated thrombocytopenia and thyroiditis [3]. Following regulatory approval of alemtuzumab for relapsing remitting MS in 2013 by the European Medicines Agency (EMA) and in 2014 by the U.S. Food and Drug Administration (FDA), there have been reports of severe and even fatal suspected adverse effects. These include listeriosis [4, 5], alveolar hemorrhage [6], neutropenia with staphylococcus infection [7], autoimmune hemolytic anemia with necrotizing leukoencephalopathy [8], and hemophagocytic lymphohistiocytosis [9]. These concerns led us to perform a systematic search for information on fatal cases following treatment with alemtuzumab in MS, retrieving data from the European database of suspected adverse drug reaction reports (EudraVigilance).

• Tomescu-Baciu, Alina; Johansen, Jorunn; Holmøy, Trygve; Greiff, Victor; Stensland, Maria & Souza, Gustavo Antonio De [Show all 8 contributors for this article] (2019). Persistence of intrathecal oligoclonal B cells and IgG in multiple sclerosis. Journal of Neuroimmunology. ISSN 0165-5728. 333:576966, p. 1–7. doi: 10.1016/j.jneuroim.2019.576966. Full text in Research Archive Show summary

  In multiple sclerosis (MS), B cells are trafficking across the blood-brain barrier, but it is not known how this relates to the synthesis of oligoclonal IgG. We used quantitative mass spectrometry of oligoclonal bands and high-throughput sequencing of immunoglobulin heavy-chain variable transcripts to study the longitudinal B cell response in the cerebrospinal fluid (CSF) and blood of two MS patients. Twenty of 22 (91%) and 25 of 28 (89%) of oligoclonal band peptides persisted in samples collected 18 months apart, in spite of a dynamic exchange across the blood-CSF barrier of B lineage cells connecting to oligoclonal IgG.

• Smolders, Joost; Torkildsen, Øivind; Camu, William & Holmøy, Trygve (2019). An Update on Vitamin D and Disease Activity in Multiple Sclerosis. CNS Drugs. ISSN 1172-7047. 33(12), p. 1187–1199. doi: 10.1007/s40263-019-00674-8. Full text in Research Archive Show summary

  Vitamin D and its main active metabolite 1,25-dihydroxyvitamin D serve a crucial role in maintenance of a healthy calcium metabolism, yet have additional roles in immune and central nervous system cell homeostasis. Serum levels of 25-hydroxyvitamin D are a biomarker of future disease activity in patients with early relapsing–remitting multiple sclerosis (RRMS), and vitamin D supplementation in patients with low circulating 25-dihydroxyvitamin D levels has been anticipated as a potential efficacious treatment strategy. The results of the first large randomized clinical trials (RCTs), the SOLAR and CHOLINE studies, have now been published. The SOLAR study compared 14,000 IU of vitamin D3 (cholecalciferol) per day with placebo for 48 weeks in 232 randomized patients, whereas CHOLINE compared vitamin D3 100,000 IU every other week with placebo for 96 weeks in 129 randomized patients. All patients in both studies also used interferon-β-1a. None of the studies met their primary endpoints, which were no evidence of disease activity (NEDA-3) at 48 weeks in SOLAR and annualized relapse rate at 96 weeks in CHOLINE. Both studies did, however, suggest modest effects on secondary endpoints. Thus, vitamin D reduced the number of new or enlarging lesions and new T2 lesions in SOLAR, and the annualized relapse rate and number of new T1 lesions, volume of hypointense T1 lesions, and disability progression in the 90 patients who completed 96 weeks’ follow-up in CHOLINE. We conclude that none of the RCTs on vitamin supplementation in MS have met their primary clinical endpoint in the intention to treat cohorts. This contrasts the observation studies, where each 25 nmol/l increase in 25-hydroxyvitamin D levels were associated with 14–34% reduced relapse risk and 15–50% reduced risk of new lesions on magnetic resonnance imaging. This discrepancy may have several explanations, including confounding and reverse causality in the observational studies. The power calculations of the RCTs have been based on the observational studies, and the RCTs may have been underpowered to detect less prominent yet important effects of vitamin D supplementation. Although the effect of vitamin D supplementation is uncertain and less pronounced than suggested by observational studies, current evidence still support that people with MS should avoid vitamin D insufficiency, and preferentially aim for vitamin D levels around 100 nmol/L or somewhat higher.

• Hupperts, Raymond; Smolders, Joost; Vieth, Reinhold; Holmøy, Trygve; Marhardt, Kurt & Schluep, Myriam [Show all 10 contributors for this article] (2019). Randomized trial daily high-dose vitamin D3 in patients with RRMS receiving subcutaneous interferon β-1a. Neurology. ISSN 0028-3878. 93(20), p. E1906–E1916. doi: 10.1212/WNL.0000000000008445. Full text in Research Archive Show summary

  Objective: In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D3 in patients with RRMS. Methods: Eligible patients with RRMS treated with SC interferon-β-1a (IFN-β-1a) 44 μg 3 times weekly and serum 25(OH)D levels <150 nmol/L were included. From February 15, 2011, to May 11, 2015, 229 patients were included and randomized 1:1 to receive SC IFN-β-1a plus placebo (n = 116) or SC IFN-β-1a plus oral high-dose vitamin D3 14,007 IU/d (n = 113). The revised primary outcome was the proportion of patients with no evidence of disease activity (NEDA-3) at week 48. Results: At 48 weeks, 36.3% of patients who received high-dose vitamin D3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53–1.63; p = 0.80). Compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52–0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: −0.074; p = 0.035). Conclusions: SOLAR did not establish a benefit for high-dose vitamin D3 as add-on to IFN-β-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS.

• Holmøy, Trygve; Fogdell-Hahn, Anna & Svenningsson, Anders (2019). Serum sickness following rituximab therapy in multiple sclerosis. Neurology: Clinical Practice. ISSN 2163-0402. 9(6), p. 519–521. doi: 10.1212/CPJ.0000000000000685. Full text in Research Archive
• Høglund, Rune Alexander; Myro, Aija Zuleron; Zarnovicky, Svetozar & Holmøy, Trygve (2019). En ung kvinne med krampeanfall, synsforstyrrelser og lammelser. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 139(11). doi: 10.4045/tidsskr.19.0122. Full text in Research Archive
• Nakken, Ola; Lindstrøm, Jonas Christoffer & Holmøy, Trygve (2018). Sex ratio in multiple sclerosis mortality over 65 years; an age-period-cohort analysis in Norway. Journal of Neurology. ISSN 0340-5354. 265(6), p. 1295–1302. doi: 10.1007/s00415-018-8832-9. Full text in Research Archive Show summary

  Increasing female: male ratio in multiple sclerosis (MS) has been assigned to cohort effects, with females in more recent birth cohorts possibly being more exposed or vulnerable to environmental risk factors than males. We collected MS mortality data in Norway from 1951 to 2015 from The Norwegian Cause of Death registry. Age-Period-Cohort analysis was conducted using log-linear Poisson models, including sex interaction terms. MS was registered as the underlying, contributing or direct cause in 6060 deaths. MS associated mortality remained stable with a slight preponderance among males until after 1980, and have since increased preferentially among females. Throughout the study period the mean annual increase was 1.25% for females and 0.3% for males (p < 0.0001). Age-period-cohort analysis revealed limited evidence of cohort effects for the gender differences; the best fitting model only included gender-age and gender-period interaction terms. The period effect evened out for males in the last three decades but increased for females, especially among the oldest age-groups. In conclusion, the increased female: male mortality ratio in MS associated mortality is driven mainly by increased mortality among females in the three last decades, particularly in the older age groups. It is best explained by disproportional period effects, providing evidence of time-varying external factors including improved access to diagnosis among females.

• Høglund, Rune Alexander; Polak, Justyna; Vartdal, Frode; Holmøy, Trygve & Lossius, Peter Andreas Vold (2018). B-cell composition in the blood and cerebrospinal fluid of multiple sclerosis patients treated with dimethyl fumarate. Multiple Sclerosis and Related Disorders. ISSN 2211-0348. 26, p. 90–95. doi: 10.1016/j.msard.2018.08.032. Full text in Research Archive Show summary

  Background:B cells may contribute to the immunopathogenesis of multiple sclerosis (MS). Dimethyl fumarate(DMF) has recently been shown to reduce the frequency of memory B cells in blood, but it is not known whetherthe drug influences the cellular composition in the cerebrospinalfluid (CSF).Methods:A cross-sectional study examining the cellular composition in blood and cerebrospinalfluid (CSF) from10 patients treated with DMF and 18 patients receiving other disease modifying drugs or no treatment.Results:Patients treated with DMF had reduced proportions of memory B cells in blood compared to other MSpatients (p=0.0007), and the reduction correlated with treatment duration (rs=−0.75,p=0.021). In theCSF, the absolute number of mononuclear cells were significantly lower in DMF-treated patients compared to theother patients (p= 0.023), and there was a disproportionate decrease of plasmablasts (p=0.031).Conclusion:The results of this exploratory study support a B-cell mediated mechanism of action for DMF in bothblood and CSF.

• Stokke, Silje Agnethe; Myhr, Kjell-Morten; Holmøy, Trygve; Benth, Jurate Saltyte; Wergeland, Stig & Beiske, Antonie Giæver [Show all 11 contributors for this article] (2018). Serum levels of leptin and adiponectin are not associated with disease activity or treatment response in multiple sclerosis. Journal of Neuroimmunology. ISSN 0165-5728. 323, p. 73–77. doi: 10.1016/j.jneuroim.2018.07.011. Full text in Research Archive
• Nakken, Ola; Sørum, Lillian & Holmøy, Trygve (2018). Genetisk utredning ved amyotrofisk lateral sklerose. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 138(13). doi: 10.4045/tidsskr.18.0193. Full text in Research Archive
• Nakken, Ola; Lindstrøm, Jonas Christoffer; Tysnes, Ole-Bjørn & Holmøy, Trygve (2018). Assessing amyotrophic lateral sclerosis prevalence in Norway from 2009 to 2015 from compulsory nationwide health registers. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. ISSN 2167-8421. 19(3-4), p. 303–310. doi: 10.1080/21678421.2017.1418004. Full text in Research Archive Show summary

  Objective: In Norway, diagnoses from specialist health care visits, drug prescriptions, and causes of deaths are registered in compulsory health registers. We aimed to determine amyotrophic lateral sclerosis (ALS) prevalence from 2009 to 2015 by combining these registers. Methods:We validated the Norwegian Patient Registry (NPR) through hospital files, and linked it with the Norwegian Cause of Death Registry and the Norwegian Prescription Database. Poisson regression models were fitted for estimating gender ratios, time trends and possible interactions. Similar models were used for mortality data subtracted from the dataset. Results: Eleven percent of patients with at least one ALS-related entry in NPR did not have ALS. ALS prevalence could nevertheless be reliably estimated through ascertaining cases identified in two separate registers, or with at least two entries in NPR with first entry within four years prior to prevalence date. ALS prevalence remained stable, and was 7.6/100,000 (95% CI 6.9–8.4) at 31st December 2015. Mean male:female ratio was higher for prevalence (1.8; 95% CI 1.6–2.0) than for mortality (1.5; 95% CI 1.2–1.8) (p¼0.04). There were also significant regional differences in prevalence (p50.01) but not in mortality. Conclusions: Norwegian compulsory health registers provide reliable tools for ALS surveillance, and suggest gender and regional differences in survival after diagnosis.

• Myro, Aija Zuleron; Bjerke, Gisle; Zarnovicky, Svetozar & Holmøy, Trygve (2018). Diffuse alveolar hemorrhage during alemtuzumab infusion in a patient with multiple sclerosis: a case report. BMC Pharmacology and Toxicology. 19(75), p. 1–4. doi: 10.1186/s40360-018-0267-5. Full text in Research Archive Show summary

  Background Diffuse alveolar bleeding is a potentially life-threatening condition that can be induced by several drugs. Whereas fatal cases have been reported in patients treated for other indications, no report have so far been published in a patient with multiple sclerosis treated with alemtuzumab. Case presentation We report a case of alemtuzumab-induced diffuse alveolar bleeding in a 29 year old woman with relapsing remitting multiple sclerosis. The patient developed acute shortness of breath, chest pain on inspiration and haemoptysis following the second infusion of alemtuzumab during the first treatment cycle. Computed tomography showed bilateral alveolar opacities. Bronchoscopy and broncho-alveolar lavage showed persistently bloody return with no evidence of infection. The symptoms resolved completely without treatment and control computed tomography performed one week later showed total resolution of pulmonary infiltrates. Conclusion This is the first published report of diffuse alveolar bleeding in a patient with multiple sclerosis treated with alemtuzumab. Four similar cases in patients treated for multiple sclerosis and several fatal cases in patients treated for other conditions are registered at the World Health Organization database of suspected adverse events (VIgiBase©), underscoring that this is a serious and possibly under-recognized complication of alemtuzumab which can also occur in the treatment of multiple sclerosis. The clinician should consider the possibility of diffuse pulmonary haemorrhage in patients with sudden onset of respiratory distress and haemoptysis following administration of alemtuzumab for multiple sclerosis.

• Bjørnevik, Kjetil Lauvland; Myhr, Kjell-Morten; Beiske, Antonie Giæver; Bjerve, Kristian S; Holmøy, Trygve & Hovdal, Harald Olav [Show all 10 contributors for this article] (2018). α-Linolenic acid is associated with MRI activity in a prospective cohort of multiple sclerosis patients. Multiple Sclerosis. ISSN 1352-4585. 25(7), p. 987–993. doi: 10.1177/1352458518779925. Full text in Research Archive
• Holmøy, Trygve; Røsjø, Egil Rørvik; Zetterberg, Henrik; Blennow, Kaj; Lindstrøm, Jonas Christoffer & Steffensen, Linn Hofsøy [Show all 7 contributors for this article] (2018). Vitamin D supplementation and neurofilament light chain in multiple sclerosis. Acta Neurologica Scandinavica. ISSN 0001-6314. p. 1–5. doi: 10.1111/ane.13037. Full text in Research Archive
• Tomescu-Baciu, Alina; Vartdal, Frode; Holmøy, Trygve; Vedeler, Christian A. & Lossius, Peter Andreas Vold (2018). G1m1 predominance of intrathecal virus-specific antibodies in multiple sclerosis. Annals of clinical and translational neurology. 5(10), p. 1303–1309. doi: 10.1002/acn3.642. Full text in Research Archive Show summary

  We have previously shown that plasmablasts of the G1m1 allotype of IgG1 are selectively enriched in the cerebrospinal fluid of G1m1/G1m3 heterozygous patients with multiple sclerosis, whereas both allotypes are equally used in neuroborreliosis. Here, we demonstrate a strong preference for the G1m1 allotype in the intrathecal humoral immune responses against measles, rubella, and varicella zoster virus in G1m1/G1m3 heterozygous multiple sclerosis patients. Conversely, intrathecally synthesized varicella zoster virus‐specific IgG1 in varicella zoster virus meningoencephalitis comprised both allotypes. This implies that G1m1 B cells are selected to the central nervous system of multiple sclerosis patients regardless of specificity and suggests that an antigen‐independent mechanism could drive the intrathecal humoral immune response.

• Magelssen, Morten; Holmøy, Trygve; Horn, Morten Andreas; Fondenes, Ove; Dybwik, Knut Gustav & Førde, Reidun (2018). Ethical challenges in tracheostomy-assisted ventilation in amyotrophic lateral sclerosis. Journal of Neurology. ISSN 0340-5354. 265(11), p. 2730–2736. doi: 10.1007/s00415-018-9054-x. Full text in Research Archive Show summary

  The special nature of amyotrophic lateral sclerosis (ALS) and tracheostomy with invasive ventilation (TIV) leads to challenges that can be difficult in two senses: not only to handle well, but also to discuss with patients and other involved stakeholders. Because of the delicate nature of interpersonal relations and communication in ALS, some of the downsides to TIV may almost take on a nature of taboo, making them difficult to raise for open discussion. Yet these ethical challenges are important to be aware of, not only for health professionals and managers but, arguably, also for patients and next of kin. They are important also for a wider professional and societal debate about whether and to whom TIV should be offered. In this paper we highlight and examine ethical challenges in TIV for ALS, with a special emphasis on those that are hard to discuss openly and that therefore might fail to be addressed. The analysis is structured by the four core principles of healthcare ethics: beneficence, nonmaleficence, respect for patient autonomy, and justice.

• Holmøy, Trygve; Gythfeldt, Hedda & Leegaard, Truls Michael (2017). Listeria monocytogenes infection associated with alemtuzumab - - a case for better preventive strategies. BMC Neurology. 17(65). doi: 10.1186/s12883-017-0848-8. Full text in Research Archive
• Al-Chalabi, Ammar; Andersen, Peter M.; Chandran, Siddharthan; Chio, Adriano; Corcia, Philippe & Couratier, Philippe [Show all 41 contributors for this article] (2017). July 2017 ENCALS statement on edaravone. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. ISSN 2167-8421. 18(7-8), p. 471–474. doi: 10.1080/21678421.2017.1369125. Full text in Research Archive
• Høglund, Rune Alexander; Lossius, Peter Andreas Vold; Johansen, Jorunn; Homan, Jane; Benth, Jurate Saltyte & Robins, Harlan [Show all 9 contributors for this article] (2017). In silico prediction analysis of idiotope-driven T-B cell collaboration in multiple sclerosis. Frontiers in Immunology. 8. doi: 10.3389/fimmu.2017.01255. Full text in Research Archive Show summary

  Memory B cells acting as antigen-presenting cells are believed to be important in multiple sclerosis (MS), but the antigen they present remains unknown. We hypothesized that B cells may activate CD4+ T cells in the central nervous system of MS patients by presenting idiotopes from their own immunoglobulin variable regions on human leukocyte antigen (HLA) class II molecules. Here, we use bioinformatics prediction analysis of B cell immunoglobulin variable regions from 11 MS patients and 6 controls with other inflammatory neurological disorders (OINDs), to assess whether the prerequisites for such idiotope-driven T–B cell collaboration are present. Our findings indicate that idiotopes from the complementarity determining region (CDR) 3 of MS patients on average have high predicted affinities for disease associated HLA-DRB1*15:01 molecules and are predicted to be endosomally processed by cathepsin S and L in positions that allows such HLA binding to occur. Additionally, complementarity determining region 3 sequences from cerebrospinal fluid (CSF) B cells from MS patients contain on average more rare T cell-exposed motifs that could potentially escape tolerance and stimulate CD4+ T cells than CSF B cells from OIND patients. Many of these features were associated with preferential use of the IGHV4 gene family by CSF B cells from MS patients. This is the first study to combine high-throughput sequencing of patient immune repertoires with large-scale prediction analysis and provides key indicators for future in vitro and in vivo analyses.

• Røsjø, Egil Rørvik; Lossius, Peter Andreas Vold; Abdelmagid, Nada; Lindstrøm, Jonas Christoffer; Kampman, Margitta Theodora & Jørgensen, Lone [Show all 11 contributors for this article] (2017). Effect of high-dose vitamin D3 supplementation on antibody responses against Epstein-Barr virus in relapsing-remitting multiple sclerosis. Multiple Sclerosis. ISSN 1352-4585. 23(3), p. 395–402. doi: 10.1177/1352458516654310. Full text in Research Archive
• Holmøy, Trygve; Lindstrøm, Jonas Christoffer; Eriksen, Erik Fink; Steffensen, Linn Hofsøy & Kampman, Margitta Theodora (2017). High dose vitamin D supplementation does not affect biochemical bone markers in multiple sclerosis - a randomized controlled trial. BMC Neurology. 17:67, p. 1–6. doi: 10.1186/s12883-017-0851-0. Full text in Research Archive Show summary

  Background: <br> 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. <br> Methods: <br> We assessed the effect of 20,000 IU vitamin D3 weekly compared to placebo on biochemical markers of bone metabolism in 68 persons with relapsing remitting multiple sclerosis. <br> Results: <br> 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. <br> Conclusions: <br> 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. <br> Trial registration: <br> The trial was registered at ClinicalTrials.gov on April 4 2008, registration number NCT00785473.

• Lossius, Peter Andreas Vold; Tomescu-Baciu, Alina; Holmøy, Trygve; Vedeler, Christian A.; Røsjø, Egil Rørvik & Lorentzen, Åslaug Rudjord [Show all 8 contributors for this article] (2017). Selective intrathecal enrichment of G1m1-positive B cells in multiple sclerosis. Annals of clinical and translational neurology. 4(10), p. 756–761. doi: 10.1002/acn3.451. Full text in Research Archive Show summary

  Immunoglobulin gamma (IgG) heavy chain genes are associated with susceptibility to multiple sclerosis (MS) and IgG levels in the cerebrospinal fluid (CSF). However, how these variants are implicated in disease mechanisms remains unknown. Here, we show that proliferating plasmablasts expressing the G1m1 allotype of IgG1 are selectively enriched in CSF of G1m1/G1m3 heterozygous MS patients, whereas plasmablasts expressing either G1m1 or G1m3 are evenly distributed in blood. Moreover, there was a preferential intrathecal synthesis of oligoclonal IgG1 of the G1m1 allotype in heterozygous patients, whereas controls with Lyme neuroborreliosis displayed oligoclonal IgG1 of both allotypes. This points to a disease‐specific mechanism involved in B‐cell establishment within the central nervous system in MS.

• Holmøy, Trygve; Torkildsen, Øivind & Myhr, Kjell-Morten (2017). An update on cladribine for relapsing-remitting multiple sclerosis. Expert Opinion on Pharmacotherapy. ISSN 1465-6566. 18(15), p. 1627–1635. doi: 10.1080/14656566.2017.1372747. Full text in Research Archive Show summary

  INTRODUCTION: Despite recent progress, currently available therapies for relapsing remitting multiple sclerosis (MS) are only partly effective, and their use is limited by tolerability and safety issues, as well as high cost. Cladribine was originally rejected by the regulatory authorities in both the European Union and USA in 2011, but in June 2017 the European Medical Agency recommended marketing authorization for treatment of aggressive relapsing MS. Areas covered: We provide an update on chemistry, mechanism of action, efficacy and safety of cladribine for the treatment of MS. Expert opinion: Cladribine is well tolerated, it is dosed orally in cycles of one year, the need for regular blood testing during treatment is likely limited, and the two-year efficacy data for treatment of relapsing MS are at least in the same range as the most efficient licensed treatments. The increased risk of malignancies reported in the pivotal trial seems to be caused by unexpectedly low numbers of malignancies in the placebo group. Cladribine could therefore be an alternative for many patients with relapsing remitting MS. The main caveat is the lack of long term efficacy and safety data. Currently there are insufficient data to guide further treatment of patients who have completed two treatment cycles of cladribine.

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• König, Marton; Holmøy, Trygve; Nygaard, Gro Owren; Riise, Jon; Midtvedt, Karsten & Goll, Guro Løvik [Show all 11 contributors for this article] (2026). Vaccination of immunosuppressed patients. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. doi: 10.4045/tidsskr.25.0555. Full text in Research Archive
• Høgestøl, Einar August; Sowa, Piotr; Holmøy, Trygve; Bø, Lars; Nygaard, Gro Owren & Wergeland, Stig (2025). Oppdaterte diagnosekriterier for multippel sklerose. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 145(15). doi: 10.4045/tidsskr.25.0592. Full text in Research Archive
• Holmøy, Trygve; Hardang, Ingrid Marie; Fladby, Tormod; Kirsebom, Bjørn-Eivind & Røysland, Ragnhild (2025). Nevrofilament lettkjede – en markør for nevronskade. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 145(8). doi: 10.4045/tidsskr.25.0245. Full text in Research Archive
• Holmøy, Trygve & Nakken, Karl Otto (2025). Trollelgen og epilepsien. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 145(13). doi: 10.4045/tidsskr.25.0397. Full text in Research Archive
• Holmøy, Trygve & Nakken, Karl Otto (2024). Internasjonalt langrenns første offer. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 144(15). doi: 10.4045/tidsskr.24.0444. Full text in Research Archive
• Holmøy, Trygve (2024). «At komme deres værdige og trængende Efterladte til Hjælp». Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 144(4). doi: 10.4045/tidsskr.24.0066. Full text in Research Archive
• Nygaard, Gro Owren & Holmøy, Trygve (2024). Norsk helsevesen børtilby stamcellebehandling mot multippel sklerose. 144(2). doi: 10.4045/tidsskr.23.0770. Full text in Research Archive
• Ali, Amanuel Hassen; Benterud, Anna; Holmøy, Trygve & Myro, Aija Zuleron (2023). Progressive encephalomyelitis with rigidity and myoclonus (PERM) associated with anti-glycine receptor antibodies and urothelial carcinoma: a case report. Journal of Medical Case Reports. 17(1). doi: 10.1186/s13256-023-04059-w. Full text in Research Archive Show summary

  Background Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare neurological condition with paraneoplastic etiology in about 20% of cases, usually presenting before or shortly after the oncological diagnosis is established. PERM associated with anti-glycine receptor antibodies is not previously reported in a patient with bladder cancer. Case presentation A 72-years-old Caucasian male was admitted with acute onset of dysarthria, dysphagia and trismus three years after initial surgical treatment for bladder cancer. The condition was initially diagnosed as tetanus and treated accordingly, but the diagnosis was reconsidered because of progression despite adequate treatment. Diagnostic workup on readmission revealed lung and paraaortal metastases from bladder cancer and anti-glycine receptor (anti-GlyR) antibodies both in the cerebrospinal fluid and in serum, which supplemented with the clinical presentation led to the diagnosis of PERM, presumably related to bladder cancer. The patient showed improvement and stabilization after treatment with intravenous immunoglobulin and chemotherapy against metastatic bladder cancer. Conclusion To the best of our knowledge, this is the first reported case of anti-GlyR antibody positive PERM related to urothelial carcinoma. The symptoms mimicked tetanus, and responded to chemotherapy and immunotherapy.

• Nilsen, Henning Yu; Jørstad, Anna-Katharina; Ryan, Stephen James; Moe, Morten Carsten; Grimstad, Kristoffer & Aamodt, Anne Hege [Show all 8 contributors for this article] (2023). En kvinne i 60-årene som ikke lenger gjenkjente det hun så. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(16), p. 1419–1423. doi: 10.4045/tidsskr.23.0198. Full text in Research Archive
• Lie, Ingrid Anne; Rød, Brit Ellen; Stokke, Silje Agnethe; Holmøy, Trygve; Myhr, Kjell-Morten & Torkildsen, Øivind [Show all 7 contributors for this article] (2023). Interferon β1a treatment does not influence serum Epstein-Barr virus antibodies in patients with multiple sclerosis. Multiple Sclerosis and Related Disorders. ISSN 2211-0348. 70. doi: 10.1016/j.msard.2023.104530. Full text in Research Archive
• Ali, Amanuel Hassen; Høyer, Helle; Rugland, Eyvind & Holmøy, Trygve (2022). A. H. Ali og medarbeidere svarer. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 142(13). doi: 10.4045/tidsskr.22.0560. Full text in Research Archive
• Torkildsen, Øivind; Rød, Brit Ellen; Bø, Lars; Wergeland, Stig; Holmøy, Trygve & Myhr, Kjell-Morten (2022). Amming og behandling av multippel sklerose. 142(15), p. 1–5. doi: 10.4045/tidsskr.22.0529. Full text in Research Archive
• Rasmussen, Tilde; König, Marton; Lorentzen, Åslaug Rudjord; Schikora-Rustad, Stine; Berge, Tone & Holmøy, Trygve [Show all 17 contributors for this article] (2022). Safety of a third SARS CoV 2 mRNA vaccine dose in people with multiple sclerosis. Full text in Research Archive
• König, Marton; Wolf, Asia-Sophia Fumika Michaela; Ravussin, Anthony; Chopra, Adity; Tran, Trung & Torgauten, Hilde Marie [Show all 28 contributors for this article] (2022). Immunogenicity and efficacy of mRNA-COVID-19 vaccines in people with multiple sclerosis. Full text in Research Archive
• Ali, Amanuel Hassen; Høyer, Helle; Rugland, Eyvind & Holmøy, Trygve (2022). En kvinne i 50-årene med økende gangvansker. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 142(11), p. 984–987. doi: 10.4045/tidsskr.21.0522. Full text in Research Archive
• König, Marton; Lorentzen, Åslaug Rudjord; Torgauten, Hilde Marie; Tran, The Trung; Schikora-Rustad, Stine & Vaage, Eline Benno [Show all 22 contributors for this article] (2021). Humoral Immunity to SARS-CoV-2 mRNA Vaccination in People with Multiple Sclerosis using High-Efficacy Disease Modifying Therapies. Full text in Research Archive
• Holmøy, Trygve & Bø, Lars (2020). MS-behandlingen blir stadig bedre. Full text in Research Archive
• Holmøy, Trygve; Torkildsen, Øivind & Bø, Lars (2020). Treatment of multiple sclerosis under the COVID-19 pandemic. Full text in Research Archive
• Glover, Joel; Tysnes, Ole-Bjørn; Myhr, Kjell-Morten; Bråthen, Geir; Sandvig, Ioanna & Høyer, Helle [Show all 9 contributors for this article] (2019). Hvor står ALS-forskningen i Norge? Full text in Research Archive
• Nakken, Ola & Holmøy, Trygve (2018). Rett til ikke å vite og amyotrofisk lateral sklerose. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 138(16), p. 1502–1502. doi: 10.4045/tidsskr.18.0734. Full text in Research Archive
• Torkildsen, Øivind; Holmøy, Trygve & Myhr, Kjell-Morten (2018). Severe multiple sclerosis reactivation after gonadotropin treatment. Multiple Sclerosis and Related Disorders. ISSN 2211-0348. 22, p. 38–40. doi: 10.1016/j.msard.2018.02.031. Full text in Research Archive
• Holmøy, Trygve & Torkildsen, Øivind (2017). Re: Familieplanlegging, graviditet og amming ved multippel sklerose. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 137(4), p. 259–259. doi: 10.4045/tidsskr.17.0054. Full text in Research Archive
• Røsjø, Egil Rørvik; Lossius, Andreass; Abelmagid, Nada; Lindstrøm, Jonas Christoffer; Kampman, Margitta Theodora & Jørgensen, Lone [Show all 11 contributors for this article] (2017). Selective and transient effect of vitamin D3 supplementation on antibody responses against Epstein-Barr virus nuclear antigen 1 in relapsing-remitting multiple sclerosis. Full text in Research Archive
• Røsjø, Egil Rørvik & Holmøy, Trygve (2017). Vitamin A, D and E and inflammation in multiple scerosis. Universitetet i Oslo. ISSN 9788283333664. Full text in Research Archive

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