Identification of prognostic factors predicting the long-term clinical outcome in Multiple Sclerosis

Multiple Sclerosis (MS) evolution varies from benign to aggressive forms, and its prognosis remains largely unpredictable, especially in individual cases. Relapse frequency is commonly used as indicator of disease activity and as primary endpoint in randomized clinical trials (RCTs). However, the role of inflammatory attacks on the disease progression is still largely debated. The lack of reliable predictors of the long-term evolution prevents from applying a rational and individualized therapeutic approach. In addition, RCTs methodology is still not sufficiently rigorous for protecting against the bias due to the large variability of the clinical outcome. The project was carried out by analysing the London Ontario (LO) database, one of the largest collections of natural history data from untreated patients, followed up for 28 years. We analysed factors affecting prognosis and predicting disease evolution up to its latest stages. We first investigated in details the relationship between relapses and long-term outcome. The analysis demonstrated poor correlation between number of attacks and the attainment of severe disability, invalidating relapse frequency as surrogate marker for late outcome. In addition, it evidenced the onset of the secondary progressive (SP) phase as the key determinant of prognosis, differentiating patients’ outcome and accounting for the variability of disease course. We therefore analysed in details factors affecting the rate of conversion to SP MS, in order to calculate how the risk of becoming progressive varies with disease duration. This information can be used for designing RCTs using SP onset as primary outcome. We then extensively investigated the effect of age on the disease evolution, before and after the onset of progression. The analysis highlighted age as the strongest determinant of MS prognosis, exerting its predictive effect primarily by affecting the evolution of the relapsing remitting (RR) phase and by increasing the probability of experiencing a progressive courseOpen Acces

A novel prognostic score to assess the risk of progression in relapsing-remitting multiple sclerosis patients

BACKGROUND: At patient-level, the prognostic value of several features that are known to be associated with an increased risk of converting from relapsing remitting (RR) to secondary phase (SP) multiple sclerosis (MS), remain limited.METHODS: Among 262 RRMS patients followed up for ten years, we assessed the probability of developing the SP course based on clinical and conventional and non-conventional magnetic resonance imaging (MRI) parameters at diagnosis and after two years. We used a machine learning method, the Random Survival Forests, to identify, according to their minimal depth (MD), the most predictive factors associated with the risk of SP conversion, which were then combined to compute the Secondary Progressive Risk Score (SP-RiSc).RESULTS: During the observation period, 69 (26%) patients converted to SPMS. The number of cortical lesions (MD=2.47) and age (MD=3.30) at diagnosis, the global cortical thinning (MD = 1.65), the cerebellar cortical volume loss (MD = 2.15) and the cortical lesion load increase (MD=3.15) over the first two years, exerted the greatest predictive effect. Three patients' risk-groups were identified; in the high-risk group, 85% (46 out of 55) of patients entered the SP phase in 7 median years. The SP-RiSc optimal cut-off estimated was 17.7 showing specificity and sensitivity of 87% and 92% respectively, and overall accuracy of 88%.CONCLUSIONS: The SP-RiSc yielded a high performance in identifying MS patients with high probability to develop SPMS, which can help improve management strategies. These findings are the premise of further larger prospective studies to assess its use in clinical settings

Dyspnea (breathlessness) in amyotrophic lateral sclerosis/motor neuron disease: prevalence, progression, severity, and correlates

Objective: Dyspnea, or breathlessness, is an important symptom in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). We examined the measurement properties of the Dyspnea-12. Methods: Rasch analysis enabled conversion of raw Dyspnea-12 scores to interval level metric equivalents. Converted data were used to perform trajectory modeling; those following different trajectories were compared for demographic, clinical, symptom, and functioning characteristics. Logistic regression examined differences between distinct trajectories. Results: In 1022 people, at baseline, mean metric Dyspnea-12 was 7.6 (SD 9.3). 49.8% had dyspnea, severe in 12.6%. Trajectory analysis over 28 months revealed three breathlessness trajectories: group 1 reported none at baseline/follow-up (42.7%); group 2 significantly increased over time (9.4%); group 3 had a much higher level at baseline which rose over follow-up (47.9%). Group 3 had worse outcomes on all symptoms, functioning and quality of life; compared to group 1, their odds of: respiratory onset sixfold greater; King’s stage ≥3 2.9 greater; increased odds of being bothered by choking, head drop, fasciculations, and muscle cramps; fatigue and anxiety also elevated (p < .01). Conclusion: Dyspnea is a cardinal symptom in ALS/MND and can be quickly measured using the Dyspnea-12. Raw scores can easily be converted to interval level measurement, for valid change scores and trajectory modeling. Dyspnea trajectories reveal different patterns, showing that clinical services must provide monitoring which is customized to individual patient need. Almost half of this large population had worsening dyspnea, confirming the importance of respiratory monitoring and interventions being integrated into routine ALS care

Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving "chronic" worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion-independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024

Acute Inflammatory Diseases of the Central Nervous System After SARS-CoV-2 Vaccination

BACKGROUND AND OBJECTIVES: Acute inflammatory CNS diseases include neuromyelitis optica spectrum disorders (NMOSDs) and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD). Both MOGAD and acute disseminated encephalomyelitis (ADEM) have been reported after vaccination. Consequently, the mass SARS-CoV-2 vaccination program could result in increased rates of these conditions. We described the features of patients presenting with new acute CNS demyelination resembling NMOSDs or MOGAD within 8 weeks of SARS-CoV-2 vaccination. METHODS: The study included a prospective case series of patients referred to highly specialized NMOSD services in the UK from the introduction of SARS-CoV-2 vaccination program up to May 2022. Twenty-five patients presented with new optic neuritis (ON) and/or transverse myelitis (TM) ± other CNS inflammation within 8 weeks of vaccination with either AstraZeneca (ChAdOx1S) or Pfizer (BNT162b2) vaccines. Their clinical records and paraclinical investigations including MRI scans were reviewed. Serologic testing for antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin 4 (AQP4) was performed using live cell–based assays. Patients' outcomes were graded good, moderate, or poor based on the last clinical assessment. RESULTS: Of 25 patients identified (median age 38 years, 14 female), 12 (48%) had MOG antibodies (MOGIgG+), 2 (8%) had aquaporin 4 antibodies (AQP4IgG+), and 11 (44%) had neither. Twelve of 14 (86%) antibody-positive patients received the ChAdOx1S vaccine. MOGIgG+ patients presented most commonly with TM (10/12, 83%), frequently in combination with ADEM-like brain/brainstem lesions (6/12, 50%). Transverse myelitis was longitudinally extensive in 7 of the 10 patients. A peak in new MOGAD cases in Spring 2021 was attributable to postvaccine cases. Both AQP4IgG+ patients presented with brain lesions and TM. Four of 6 (67%) seronegative ChAdOx1S recipients experienced longitudinally extensive TM (LETM) compared with 1 of 5 (20%) of the BNT162b2 group, and facial nerve inflammation was reported only in ChAdOx1S recipients (2/5, 40%). Guillain-Barre syndrome was confirmed in 1 seronegative ChAdOx1S recipient and suspected in another. DISCUSSION: ChAdOx1S was associated with 12/14 antibody-positive cases, the majority MOGAD. MOGAD patients presented atypically, only 2 with isolated ON (1 after BNT162b2 vaccine) but with frequent ADEM-like brain lesions and LETM. Within the seronegative group, phenotypic differences were observed between ChAdOx1S and BNT162b2 recipients. These observations might support a causative role of the ChAdOx1S vaccine in inflammatory CNS disease and particularly MOGAD. Further study of this cohort could provide insights into vaccine-associated immunopathology

Smouldering multiple sclerosis: the 'real MS'

Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the 'real MS' is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of 'no evident inflammatory disease activity' (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes

ADAMS project: a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the UK

PURPOSE: Genetic studies of multiple sclerosis (MS) susceptibility and severity have focused on populations of European ancestry. Studying MS genetics in other ancestral groups is necessary to determine the generalisability of these findings. The genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis (ADAMS) project aims to gather genetic and phenotypic data on a large cohort of ancestrally-diverse individuals with MS living in the UK. PARTICIPANTS: Adults with self-reported MS from diverse ancestral backgrounds. Recruitment is via clinical sites, online (https://app.mantal.co.uk/adams) or the UK MS Register. We are collecting demographic and phenotypic data using a baseline questionnaire and subsequent healthcare record linkage. We are collecting DNA from participants using saliva kits (Oragene-600) and genotyping using the Illumina Global Screening Array V.3. FINDINGS TO DATE: As of 3 January 2023, we have recruited 682 participants (n=446 online, n=55 via sites, n=181 via the UK MS Register). Of this initial cohort, 71.2% of participants are female, with a median age of 44.9 years at recruitment. Over 60% of the cohort are non-white British, with 23.5% identifying as Asian or Asian British, 16.2% as Black, African, Caribbean or Black British and 20.9% identifying as having mixed or other backgrounds. The median age at first symptom is 28 years, and median age at diagnosis is 32 years. 76.8% have relapsing-remitting MS, and 13.5% have secondary progressive MS. FUTURE PLANS: Recruitment will continue over the next 10 years. Genotyping and genetic data quality control are ongoing. Within the next 3 years, we aim to perform initial genetic analyses of susceptibility and severity with a view to replicating the findings from European-ancestry studies. In the long term, genetic data will be combined with other datasets to further cross-ancestry genetic discoveries

The ADAMS project - a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the United Kingdom

Purpose Genetic studies of multiple sclerosis (MS) susceptibility and severity have focused on populations of European ancestry. Studying MS genetics in other ancestral groups is necessary to determine the generalisability of these findings. The genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis (ADAMS) project aims to gather genetic and phenotypic data on a large cohort of ancestrally-diverse individuals with MS living in the UK. Participants Adults with self-reported MS from diverse ancestral backgrounds. Recruitment is via clinical sites, online (https://app.mantal.co.uk/adams) or the UK MS Register. We are collecting demographic and phenotypic data using a baseline questionnaire and subsequent healthcare record linkage. We are collecting DNA from participants using saliva kits (Oragene-600) and genotyping using the Illumina Global Screening Array V.3. Findings to date As of 3 January 2023, we have recruited 682 participants (n=446 online, n=55 via sites, n=181 via the UK MS Register). Of this initial cohort, 71.2% of participants are female, with a median age of 44.9 years at recruitment. Over 60% of the cohort are non-white British, with 23.5% identifying as Asian or Asian British, 16.2% as Black, African, Caribbean or Black British and 20.9% identifying as having mixed or other backgrounds. The median age at first symptom is 28 years, and median age at diagnosis is 32 years. 76.8% have relapsing–remitting MS, and 13.5% have secondary progressive MS. Future plans Recruitment will continue over the next 10 years. Genotyping and genetic data quality control are ongoing. Within the next 3 years, we aim to perform initial genetic analyses of susceptibility and severity with a view to replicating the findings from European-ancestry studies. In the long term, genetic data will be combined with other datasets to further cross-ancestry genetic discoveries

La religione romana di VI secolo a.C.; dialettica interna ed interazioni con le culture greca e fenicia nelle tradizioni tarquinie e serviane.

Nel tentativo di assegnare un\u2019identit\ue0 alla statua di una divinit\ue0 femminile armata che coronava l'acroterio del santuario romano di Fortuna e Mater Matuta nella fase edilizia pertinente all'attivit\ue0 di Tarquinio il Superbo, l\u2019autore identifica lo schema compositivo dell\u2019intero gruppo acroteriale come presentazione del mito corinzio di Ino e Melicerte, cui si affianca l\u2019autorappresentazione dell\u2019ultimo sovrano di Roma e della divinit\ue0 femminile tutelare del suo potere personale e dell\u2019intera dinastia dei Tarquini, famiglia di origine corinzia. Viene pertanto rivisitata la documentazione archeologica e letteraria sulla natura di alcune divinit\ue0 femminili greche di tradizione esiodea e omerica in cui si riconoscono tratti arcaici dovuti alla contaminazione con la divinit\ue0 fenicia Astarte; tale interazione \ue8 particolarmente profonda per le figure di Astarte e della Afrodite di Corinto, che solo in et\ue0 classica perder\ue0 gli attributi courotrophici e bellici per essere destinata a diverse competenze, ma che nelle attestazioni d'et\ue0 arcaica \ue8 una divinit\ue0 militare che riveste un ruolo tutelare sulla citt\ue0 e sulle dinastie che vi sovrintendono. Gli aspetti orientali riconosciuti al culto della Fortuna-Afrodite romana potrebbero, dunque, derivare da una mediazione dovuta alla cultura religiosa greca piuttosto che da un diretto apporto di mercanti fenici presenti nell\u2019area emporica del Foro Boario. Intorno ai motivi cultuali che risiedono nel patrimonio mitopoietico romano a proposito degli ultimi sovrani di Roma e delle divinit\ue0 che li investono del potere regale, si ipotizza che essi derivino da una doppia tradizione costruita al principio del V secolo a.C. nel momento in cui il Senato di Roma e Aristodemo di Cuma sono avversari in un pubblico processo per l'assegnazione dell'eredit\ue0 di Tarquinio il Superbo; le parti in causa avrebbero, pertanto, utilizzato ricostruzioni genealogiche opposte tra loro perch\ue9 riferite a diversi personaggi mitici che legittimassero le rispettive richieste di assegnazione di tale eredit\ue0.In an attempt to assign an identity to the statue of a female deity armed the crowning acroterion of the Roman sanctuary of Fortuna and Mater Matuta in the building phase relevant to the activity of Tarquinius Superbus, the author identifies the compositional scheme of the entire group acroterial as presentation of the Corinthian myth of Ino and Melicertes, which is accompanied by the self-representation of the last ruler of Rome and the female deity of his personal power and protect the entire dynasty of Tarquini, family of Corinthian origin. It is therefore revisited the sources archaeological and literary about the nature of some Greek goddesses of Hesiod and the Homeric tradition in which we can recognize archaic features due to contamination with the Phoenician goddess Astarte, and this interaction is particularly profound for the figures of Astarte and Aphrodite in Corinth that only in the classical age of war and lose the attributes courotrophici to be allocated to different skills, but that in the proof of the Archaic period is a deity who plays a military role to protect the city and the dynasties that they oversee. Aspects eastern recognized to the cult of Aphrodite Fortuna-Roman might, therefore, result from a mediation due to the Greek religious culture rather than a direct contribution of Phoenician merchants in the area of the Forum Boarium. Around the grounds cult residing in the Roman heritage mitopoietico about the last sovereign of Rome and the gods who invest them with royal power, it is assumed that they stem from a double tradition built at the beginning of the fifth century BC when the Senate of Rome and Aristodemus of Cumae are opponents in a public process for the allocation of the legacy of Tarquinius Superbus, the parties would, therefore, used genealogical reconstructions opposed to each other because they refer to different mythical characters that legitimize their requests for allocation of this legacy

Prognostic information for people with MS: Impossible or inevitable?

Delivering prognostic information is a challenging issue in medicine and has been largely neglected in the past. A major reason has been a suspected nocebo effect of pessimistic estimates, although this is largely unproven. Among people with multiple sclerosis (MS), there is a strong unmet need to receive long-term prognostic information. This viewpoint discusses reasons for this blind spot in physicians' attitude, foremost among which is the uncertainty of prognostic estimates. Possible strategies to move forward include tools to identify matching patients from large well-defined databases, to deliver an evidence-based individualized estimate of long-term prognosis, and its confidence interval, in a clinical setting