The peripheral endocannabinoid system and its association with biomarkers of inflammation in untreated patients with multiple sclerosis.

BACKGROUND AND PURPOSE: The endocannabinoid system (ECS) has been found altered in patients with multiple sclerosis (MS). However, whether the ECS alteration is present in the early stage of MS remains unknown. First, we aimed to compare the ECS profile between newly diagnosed MS patients and healthy controls (HCs). Next, we explored the association of the ECS, biomarkers of inflammation, and clinical parameters in newly diagnosed MS patients. METHODS: Whole blood gene expression of ECS components and levels of endocannabinoids in plasma were measured by real-time quantitative polymerase chain reaction and ultra-high-pressure liquid chromatography-mass spectrometry, respectively, in 66 untreated MS patients and 46 HCs. RESULTS: No differences were found in the gene expression or plasma levels of the selected ECS components between newly diagnosed MS patients and HCs. Interferon-γ, encoded by the gene IFNG, correlated positively (ρ = 0.60) with the expression of G protein-coupled receptor 55 (GPR55), and interleukin1ß (IL1B) correlated negatively (ρ = -0.50) with cannabinoid receptor 2 (CNR2) in HCs. CONCLUSIONS: We found no alteration in the peripheral ECS between untreated patients with MS and HC. Furthermore, our results indicate that the ECS has a minor overall involvement in the early stage of MS on inflammatory markers and clinical parameters when compared with HCs.

Exposure to passive smoking during adolescence is associated with an increased risk of developing multiple sclerosis.

BACKGROUND: Environmental factors are associated with acquiring multiple sclerosis (MS) particularly in adolescence. OBJECTIVE: To test for association between MS and exposure to passive smoking at the age of 10-19. METHODS: A total of 919 patients from the Danish MS Registry and Biobank and 3419 healthy blood donors who had not smoked before the age of 19 were targeted. We analyzed separately for each sex and for those never-smokers (cohort 1) and active smokers above the age of 19 (cohort 2). All participants completed standardized questionnaires about smoking and lifestyle. We matched cases and controls in the ratio of 1:2 by propensity scores discarding unmatchable individuals and used logistic regression adjusted for all covariates and interactions. RESULTS: After matching, we included 110/213 male cases/controls and 232/377 female case/controls in cohort 1. In cohort 2, the numbers were 160/320 and 417/760, respectively. Among women in cohort 1, the odds ratio (OR) for MS by passive smoking at the age of 10-19 was 1.432 (p = 0.037) but in men it was 1.232 (p = 0.39). Among men in cohort 2, OR was 1.593 (p = 0.022) but among women it was only 1.102 (p = 0.44). CONCLUSION: Among never smokers, female MS cases were more often than female controls reported with passive smoking between the age of 10 and 19, and among smokers above the age of 19, male MS patients were more often than male controls reported with passive smoking.

Neutrophil-to-lymphocyte ratio and CRP as biomarkers in multiple sclerosis: A systematic review.

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, which causes demyelination and neuroaxonal damage. Low-grade systemic inflammation has been suggested to contribute to the pathogenesis due to amplification of pathogenic immune activation. However, there is a lack of reliable biomarkers of systemic inflammation predicting disease activity and progression in MS. The neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) have been identified as biomarkers of severity and disease activity in various disorders. In September 2020, we conducted a systematic literature search on multiple databases on studies reporting NLR values or CRP levels in MS. The aim of this systematic review was to highlight the current knowledge about the potential of NLR and CRP as biomarkers in MS. A total of nineteen articles qualified for inclusion. Data on CRP were included in fourteen studies and NLR in nine studies. The results regarding CRP were inconsistent, and present literature does not support the use of CRP as a diagnostic or prognostic biomarker in MS. In contrast, NLR values were increased in MS patients compared with healthy controls in all case-control studies. Furthermore, NLR was associated with disease activity in untreated patients. Our systematic review therefore indicates that NLR might serve as a potential biomarker of disease activity. Given that the results of NLR are mainly drawn from retrospective case-control or cross-sectional studies, future prospective studies with long-term follow-up are required to accurately determine optimal timing and cutoff values that may be used in the clinical setting.

Alcohol consumption in adolescence is associated with a lower risk of multiple sclerosis in a Danish cohort.

BACKGROUND AND OBJECTIVE: Due to the possible existence of a vulnerable period of multiple sclerosis (MS) susceptibility in adolescence and because Danish teenagers have a high alcohol consumption, we investigated the association between alcohol consumption at ages 15-19 and the risk of developing MS. METHODS: A total of 1717 patients with MS and 4685 healthy blood donors filled in a comprehensive environmental and lifestyle questionnaire. Data were analysed by logistic regression models and adjusted for selected confounders. RESULTS: We found an inverse association between alcohol consumption in adolescence and risk of developing MS in both women (p < 0.001) and men (p = 0.012). Women with low alcohol consumption had an odds ratio (OR) of 0.56 (95% confidence interval (CI): 0.47-0.66) compared with non-drinking women. The ORs were similar for women with moderate (OR = 0.49, 95% CI: 0.38-0.62) and high consumption (OR = 0.57, 95% CI: 0.38-0.84). Men with low alcohol consumption had an OR of 0.69 (95% CI: 0.53-0.89) compared with non-drinking men but no decreased risk was found for men with moderate and high consumption. CONCLUSION: Alcohol consumption in adolescence was associated with lower risk of developing MS among both sexes.

Pharmacokinetics and pharmacodynamics of cannabis-based medicine in a patient population included in a randomized, placebo-controlled, clinical trial.

Information on the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered cannabis-based medicine (CBM) in capsule formulation in patient populations is sparse. In this exploratory study, we aimed to evaluate the PK and PD in a probable steady state of CBM in neuropathic pain and spasticity in a population of patients with multiple sclerosis (MS). Of 134 patients participating in a randomized, double-blinded, placebo-controlled, trial, 23 patients with MS (17 female) mean age 52 years (range 21-67) were enrolled in this substudy. They received oral capsules containing Δ9 -tetrahydrocannabinol (THC, n = 4), cannabidiol (CBD, n = 6), a combination (THC&CBD, n = 4), or placebo (n = 9). Maximum doses were 22.5 mg (THC) and 45 mg (CBD) a day divided into three administrations. PD parameters were evaluated for pain and spasticity. Blood samples were analyzed using an ultra-high-performance liquid chromatography-tandem mass spectrometer after protein precipitation and phospholipid removal. PK parameters were estimated using computerized modeling. The variation in daily dose and PK between individuals was considerable in a steady state, yet comparable with previous reports from healthy controls. Based on a simulation of the best model, the estimated PK parameters (mean) for THC (5 mg) were Cmax 1.21 ng/mL, Tmax 2.68 h, and half-life 2.75 h, and for CBD (10 mg) were Cmax 2.67 ng/mL, Tmax 0.10 h, and half-life 4.95 h, respectively. No effect was found on the PD parameters, but the placebo response was considerable. More immediate adverse events were registered in the active treatment groups compared with the placebo group.

Unprescribed cannabinoids and multiple sclerosis: a multicenter, cross-sectional, epidemiological study in Lombardy, Italy.

INTRODUCTION: Cannabinoids are approved for spasticity and pain in multiple sclerosis (MS). In 2017 the prevalence of current users in the Italian general population was 10.2%, while data on Italian MS patients are limited. METHODS: From March 2022 to February 2023, we conducted a multicenter, cross-sectional study. Adult MS patients completed an anonymous online survey. The primary outcome was the estimated prevalence of unprescribed cannabis current use. Cannabis use patterns and associations with clinical and socio-demographical variables were investigated. The binomial method was used to estimate 95% confidence interval (95% CI) for primary outcome. RESULTS: 5620 patients were invited and 2024 (36.0%) were included (mean age 45.2 years, females 64.5%). Relapsing remitting form was the most frequent (77.3%). Median expanded disability status scale (EDSS) was 2.0. The proportion of current users was 15.5% (95% CI 13.9-17.1) and 36.4% of them disclosed to their physician their unprescribed cannabis use. 15.0% patients were former users while 69.5% never used cannabis. Current users more frequently reported a medical use (i.e., current medical users) compared to former users (p < 0.001). 41.1% of never users would use cannabis if it was legal. Young age, being male, and a free marital status were associated with current use. Current medical users had higher disability, spasticity and pain, reduced quality of life, concomitant neurological/psychiatric drugs and analgesics use. Unprescribed cannabis appeared relatively safe, with limited addiction risk, and reported clinical benefits, including concomitant medications reduction. CONCLUSION: Unprescribed cannabis use is common in patients with MS in Italy, with observed prevalence seemingly superior to the general population, often intended for medical use and without the disclosure to the treating physician, although with potential clinical benefits.

Acute disseminated encephalomyelitis following the COVID-19 vaccine Ad26.COV2.S, a case report.

Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has been leading to dramatic health, social and economic problems around the world. It was necessary to introduce worldwide vaccination program against SARS-CoV-2 virus. Vaccination of billions of people around the world leads to many questions about risk of vaccines and possible side effects. It is well known that acute disseminated encephalomyelitis (ADEM) is a rare, but possible complication of vaccines. Previously, cases of ADEM following various COVID-19 vaccines, including the vaccines from AstraZenica, Pfizer, Sputnik V, SinoVac, Moderna, Sinopharm, have been described. In this case report, we present the first documented case of ADEM following the COVID-19 vaccine Ad26.COV2.S from Johnson & Johnson. Case presentation: We present the case of a 31-year-old female with gradually progression of right-sided weakness and numbness during a three-week period. Four weeks prior to symptom onset, the patient received the single-dose SARS-CoV-2 vaccine Ad26.COV2.S. Neuroimaging revealed five large juxtacortical T2 FLAIR hyperintense lesions with incomplete contrast enhancement on post-contrast T1 images located supratentorial: one in the right cerebral hemisphere and four in left cerebral hemisphere. The patient was followed up for four months. Symptom debut, clinical picture and MRI were typical for ADEM and the patient completely recovered after high dose intravenous methylprednisolone treatment. Conclusions: This is, to the best of our knowledge, the first case report of ADEM following the COVID-19 vaccine Ad26.COV2.S. This case illustrates, although ADEM is a rare complication following SARS-CoV-2 vaccines, the necessity of maintaining a vaccine safety monitoring system to identify patients at high risk from developing severe complications from the vaccines.

Cannabis-Based Medicine for Neuropathic Pain and Spasticity-A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial.

Patients with multiple sclerosis (MS) and spinal cord injury (SCI) commonly sustain central neuropathic pain (NP) and spasticity. Despite a lack of consistent evidence, cannabis-based medicine (CBM) has been suggested as a supplement treatment. We aimed to investigate the effect of CBM on NP and spasticity in patients with MS or SCI. We performed a randomized, double-blinded, placebo-controlled trial in Denmark. Patients aged ≥18 years with NP (intensity >3, ≤9 on a numerical rating scale (NRS0-10) and/or spasticity (>3 on NRS0-10) were randomized to treatment consisting of either delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), a combination of THC&CBD in maximum doses of 22.5 mg, 45 mg and 22.5/45 mg per day, respectively, or placebo. A baseline registration was performed before randomization. Treatment duration was six weeks followed by a one-week phaseout. Primary endpoints were the intensity of patient-reported NP and/or spasticity. Between February 2019 and December 2021, 134 patients were randomized (MS n = 119, SCI n = 15), where 32 were assigned to THC, 31 to CBD, 31 to THC&CBD, and 40 to placebo. No significant difference was found for: mean pain intensity (THC 0.42 (-0.54-1.38), CBD 0.45 (-0.47-1.38) and THC&CBD 0.16 (-0.75-1.08)), mean spasticity intensity (THC 0.24 (-0.67-1.45), CBD 0.46 (-0.74-1.65), and THC&CBD 0.10 (-1.18-1.39), secondary outcomes (patient global impression of change and quality of life), or any tertiary outcomes. We aimed to include 448 patients in the trial; however, due to COVID-19 and recruitment challenges, fewer were included. Nevertheless, in this four-arm parallel trial, no effect was found between placebo and active treatment with THC or CBD alone or in combination on NP or spasticity in patients with either MS or SCI. The trial was registered with the EU Clinical Trials Register EudraCT (2018-002315-98).

MRI of the Entire Spinal Cord-Worth the While or Waste of Time? A Retrospective Study of 74 Patients with Multiple Sclerosis.

Spinal cord lesions are included in the diagnosis of multiple sclerosis (MS), yet spinal cord MRI is not mandatory for diagnosis according to the latest revisions of the McDonald Criteria. We investigated the distribution of spinal cord lesions in MS patients and examined how it influences the fulfillment of the 2017 McDonald Criteria. Seventy-four patients with relapsing-remitting MS were examined with brain and entire spinal cord MRI. Sixty-five patients received contrast. The number and anatomical location of MS lesions were assessed along with the Expanded Disability Status Scale (EDSS). A Chi-square test, Fischer's exact test, and one-sided McNemar's test were used to test distributions. MS lesions were distributed throughout the spinal cord. Diagnosis of dissemination in space (DIS) was increased from 58/74 (78.4%) to 67/74 (90.5%) when adding cervical spinal cord MRI to brain MRI alone (p = 0.004). Diagnosis of dissemination in time (DIT) was not significantly increased when adding entire spinal cord MRI to brain MRI alone (p = 0.04). There was no association between the number of spinal cord lesions and the EDSS score (p = 0.71). MS lesions are present throughout the spinal cord, and spinal cord MRI may play an important role in the diagnosis and follow-up of MS patients.

The Effect of Cannabis-Based Medicine on Neuropathic Pain and Spasticity in Patients with Multiple Sclerosis and Spinal Cord Injury: Study Protocol of a National Multicenter Double-Blinded, Placebo-Controlled Trial.

Disease or acquired damage to the central nervous system frequently causes disabling spasticity and central neuropathic pain (NP), both of which are frequent in multiple sclerosis (MS) and spinal cord injury (SCI). Patients with MS and SCI often request treatment with cannabis-based medicine (CBM). However, knowledge about effects, side effects, choice of active cannabinoids (Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) alone or in combination), and doses of CBM remains limited. Using a double-blind, parallel design in a national multicenter cohort, this study examines the effect of CBM on spasticity and NP. Patients are randomized to treatment with capsules containing either THC, CBD, THC and CBD, or placebo. Primary endpoints are patient-reported pain and spasticity on a numerical rating scale. Other endpoints include quality of life and sleep, depression and anxiety, and relief of pain and spasticity. Side-effects of CBM are described. In a sub-study, the pharmacodynamics (PD) and pharmacokinetics (PK) of oral capsule CBM are examined. We expect that the study will contribute to the literature by providing information on the effects and side-effects of CBD, THC, and the combination of the two for central neuropathic pain and spasticity. Furthermore, we will describe the PD/PK of THC and CBD in a patient population.

Serum Short-Chain Fatty Acids and Associations With Inflammation in Newly Diagnosed Patients With Multiple Sclerosis and Healthy Controls.

Multiple sclerosis (MS) is a chronic immune-mediated disease characterized by demyelination and neuroaxonal damage in the central nervous system. The etiology is complex and is still not fully understood. Accumulating evidence suggests that our gut microbiota and its metabolites influence the MS pathogenesis. Short-chain fatty acids (SCFAs), such as acetate, propionate and butyrate, are metabolites produced by gut microbiota through fermentation of indigestible carbohydrates. SCFAs and kynurenine metabolites have been shown to have important immunomodulatory properties, and propionate supplementation in MS patients has been associated with long-term clinical improvement. However, the underlying mechanisms of action and its importance in MS remain incompletely understood. We analyzed serum levels of SCFAs and performed targeted metabolomics in relation to biomarkers of inflammation, and clinical and MRI measures in newly diagnosed patients with relapsing-remitting MS before their first disease modifying therapy and healthy controls (HCs). We demonstrated that serum acetate levels were nominally reduced in MS patients compared with HCs. The ratios of acetate/butyrate and acetate/(propionate + butyrate) were significantly lower in MS patients in a multivariate analysis (orthogonal partial least squares discriminant analysis; OPLS-DA). The mentioned ratios and acetate levels correlated negatively with the pro-inflammatory biomarker IFNG, indicating an inverse relation between acetate and inflammation. In contrast, the proportion of butyrate was found higher in MS patients in the multivariate analysis, and both butyrate and valerate correlated positively with proinflammatory cytokines (IFNG and TNF), suggesting complex bidirectional regulatory properties of SCFAs. Branched SCFAs were inversely correlated with clinical disability, at a nominal significance level. Otherwise SCFAs did not correlate with clinical variables or MRI measures. There were signs of an alteration of the kynurenine pathway in MS, and butyrate was positively correlated with the immunomodulatory metabolite 3-hydroxyanthranilic acid. Other variables that influenced the separation between MS and HCs were NfL, ARG1 and IL1R1, D-ribose 5-phosphate, pantothenic acid and D-glucuronic acid. In conclusion, we provide novel results in this rapidly evolving field, emphasizing the complexity of the interactions between SCFAs and inflammation; therefore, further studies are required to clarify these issues before supplementation of SCFAs can be widely recommended.