A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).
To describe the ...epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes.
Retrospective multicenter study.
The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80 % (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40 % (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36 %) and markedly impaired ambulation due to paresis or ataxia (25 %) as the most common long-term sequelae. Functional blindess in one or both eyes was noted during at least one ON attack in around 70 %. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70 %). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44 %. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50 %; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70 %, oligoclonal bands in only 13 %, and blood-CSF-barrier dysfunction in 32 %. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9 %). Wingerchuk's 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28 %, 32 %, 15 %, 33 %, respectively; MS had been suspected in 36 %. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases.
Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.
Multiple sclerosis (MS) is a multifactorial autoimmune disease of the central nervous system with a heterogeneous and unpredictable course. To date there are no prognostic biomarkers even if they ...would be extremely useful for early patient intervention with personalized therapies. In this context, the analysis of inter-individual differences in cerebrospinal fluid (CSF) proteome may lead to the discovery of biological markers that are able to distinguish the various clinical forms at diagnosis.
To this aim, a two dimensional electrophoresis (2-DE) study was carried out on individual CSF samples from 24 untreated women who underwent lumbar puncture (LP) for suspected MS. The patients were clinically monitored for 5 years and then classified according to the degree of disease aggressiveness and the disease-modifying therapies prescribed during follow up.
The hierarchical cluster analysis of 2-DE dataset revealed three protein spots which were identified by means of mass spectrometry as Apolipoprotein E (ApoE) and two isoforms of vitamin D binding protein (DBP). These three protein spots enabled us to subdivide the patients into subgroups correlated with clinical classification (MS aggressive forms identification: 80%). In particular, we observed an opposite trend of values for the two protein spots corresponding to different DBP isoforms suggesting a role of a post-translational modification rather than the total protein content in patient categorization.
These findings proved to be very interesting and innovative and may be developed as new candidate prognostic biomarkers of MS aggressiveness, if confirmed.
Background: The availability of high-efficacy disease-modifying therapy (DMT), including natalizumab, improved treatment efficacy in adults with highly-active relapsing-remitting multiple sclerosis ...(RRMS). Natalizumab patent protection has expired, and the natalizumab biosimilar (Tyruko®) has been recently reimbursed by AIFA. As the price of natalizumab biosimilar is expected to be lower as compared with natalizumab originator’s price, a budget impact analysis was conducted to assess the economic impact associated to the introduction of natalizumab biosimilar for patients with highly-active RRMS. Methods: A budget impact model was developed, considering the INHS perspective and a 5-years time horizon. The number of patients treated with natalizumab was estimated based on historical natalizumab consumption data, disease prevalence rates and natalizumab market share. The budget impact population was divided into prevalent and incident patients. The model assumes that some patients in treatment with natalizumab originator will switch to natalizumab biosimilar and that some naïve patients will directly start treatment with natalizumab biosimilar. The ex-factory price of natalizumab originator (intravenous and subcutaneous) and biosimilar (intravenous) and the corresponding administration costs were included. All assumptions were validated by expert opinion. Results: Eligible population was estimated at 7,552, 7,779, 8,090, 8,494 and 8,834 in years 1, 2, 3, 4 and 5 respectively. The introduction of natalizumab biosimilar, considering a progressive increase in market share from 9.6% (year 1) to 40.5% (year 5), would provide an overall savings (5-years time horizon) over € 47 million to the INHS. The scenario analysis highlights that the lower treatment cost of biosimilar natalizumab compared to originator natalizumab would offset the higher cost associated with intravenous versus subcutaneous administration. Conclusion: Considering the results of this budget impact analysis, it is realistic to expect that the presence of biosimilar natalizumab will contribute to the sustainability of public pharmaceutical expenditure.
We evaluated the effect of DMTs on Covid‐19 severity in patients with MS, with a pooled‐analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with ...Covid‐19 severity was assessed by multivariate ordinal‐logistic models and pooled by a fixed‐effect meta‐analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti‐CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid‐19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled‐analysis confirms an increased risk of severe Covid‐19 in patients on anti‐CD20 therapies and supports the protective role of interferon.
The transcription factor NURR1 is essential to the generation and maintenance of midbrain dopaminergic (mDA) neurons and its deregulation is involved in the development of dopamine (DA)‐associated ...brain disorders, such as Parkinson's disease (PD). The old male NURR1 heterozygous knockout (NURR1‐KO) mouse has been proposed as a model of PD due to its altered motor performance that was, however, not confirmed in a subsequent study. Based on these controversial results, we explored the effects of the NURR1 deficiency on locomotor activity, motor coordination, brain and plasma DA levels, blood pressure and heart rate of old mice, also focusing on the potential effect of sex. As a probable consequence of the role of NURR1 in DA pathway, we observed that the old NURR1‐KO mouse is characterized by motor impairment, and increased brain DA level and heart rate, independently from sex. However, we also observed an alteration in spontaneous locomotor activity that only affects males. In conclusion, NURR1 deficiency triggers sex‐ and age‐specific alterations of behavioral responses, of DA levels and cardiovascular abnormalities. Further studies in simplified systems will be necessary to dissect the mechanism underlying these observations.
NURR1 regulates the production of dopamine. Dopamine is present in dopaminergic neurons to regulate movement and emotion and in blood to control cardiac functions. Here, we demonstrated motor impairment, increased brain DA level and heart rate in old NURR1‐deficient mice independently from sex, although sex affects their spontaneous locomotion.
Autologous hematopoietic stem cell transplantation (AHSCT) has been used in the treatment of highly active multiple sclerosis (MS) for over two decades. It has been demonstrated to be highly ...efficacious in relapsing–remitting (RR) MS patients failing to respond to disease-modifying drugs (DMDs). AHSCT guarantees higher rates of no evidence of disease activity (NEDA) than those achieved with any other DMDs, but it is also associated with greater short-term risks which have limited its use. In the 2019 updated EBMT and ASBMT guidelines, which review the clinical evidence of AHSCT in MS, AHSCT indication for highly active RRMS has changed from “clinical option” to “standard of care”. On this basis, AHSCT must be proposed on equal footing with second-line DMDs to patients with highly active RRMS, instead of being considered as a last resort after failure of all available treatments. The decision-making process requires a close collaboration between transplant hematologists and neurologists and a full discussion of risk–benefit of AHSCT and alternative treatments. In this context, we propose a standardized protocol for decision-making and informed consent process.
Previous exposure to Epstein–Barr virus (EBV) is strongly associated with the development of multiple sclerosis (MS). By contrast, past cytomegalovirus (CMV) infection may have no association, or be ...negatively associated with MS. This study aimed to investigate the associations of herpesvirus infections with MS in an Italian population. Serum samples (n = 200) from Italian people with multiple sclerosis (PwMS) classified as the relapsing-and-remitting clinical phenotype and (n = 137) healthy controls (HCs) were obtained from the CRESM Biobank, Orbassano, Italy. Both PwMS and HCs samples were selected according to age group (20–39 years, and 40 or more years) and sex. EBV virus capsid antigen (VCA) IgG, EBV nucleic acid-1 antigen (EBNA-1) IgG, CMV IgG, herpes simplex virus (HSV) IgG, and varicella zoster virus (VZV) IgG testing was undertaken using commercial ELISAs. EBV VCA IgG and EBNA-1 IgG seroprevalences were 100% in PwMS and 93.4% and 92.4%, respectively, in HCs. EBV VCA IgG and EBNA-1 IgG levels were higher (p < 0.001) in PwMS compared with HCs. For PwMS, the EBNA-1 IgG levels decreased with age, particularly in females. The CMV IgG seroprevalence was 58.7% in PwMS and 62.9% in HCs. CMV IgG seroprevalence increased with age. The HSV IgG seroprevalence was 71.2% in PwMS and 70.8% in HCs. HSV IgG levels were lower (p = 0.0005) in PwMS compared with HCs. VZV IgG seroprevalence was 97.5% in PwMS and 98.5% in HCs. In the population studied, several herpesvirus infections markers may have been influenced by the age and sex of the groups studied. The lack of a negative association of MS with CMV infection, and the observation of lower levels of HSV IgG in PwMS compared with HCs are findings worthy of further investigation.
Intertrial variability (ITV) of motor responses to peripheral (CMAP) and transcranial (MEP) stimulation prevents their use in follow-up studies. Our purpose was to develop strategies to reduce and ...measure CMAP and MEP ITV to guide long-term monitoring of conduction slowing and conduction failure of peripheral and central motor pathway in the individual patient.
Maximal compound muscle action potentials to High Voltage Electrical Stimulation (HVES) of lumbo-sacral nerve roots (r-CMAP) and activated, averaged motor evoked potentials (MEPs) to Transcranial Magnetic Stimulation (TMS) using double cone coil were recorded from 10 proximal and distal muscle districts of lower limbs. The procedure was repeated twice, 1-2 days apart, in 30 subjects, including healthy volunteers and clinically stable multiple sclerosis patients, using constant stimulating and recording sites and adopting a standardized procedure of voluntary activation. ITV for latency and area indexes and for the ratio between MEP and r-CMAP areas (a-Ratio) was expressed as Relative Intertrial Variation (RIV, 5th-95th percentile). As an inverse correlation between the size of area and ITV was found, raw ITV values were normalized as a function of area to make them comparable with one another.
All RIV values for latencies were significantly below the optimum threshold of ± 10%, with the exception of r-CMAP latencies recorded from Vastus Lateralis muscle. RIVs for a-Ratio, the most important index of central conduction failure, ranged from a maximum of -25.3% to +32.2% (Vastus Medialis) to a minimum of -15.0% to + 17.4% (Flexor Hallucis Brevis).
The described procedure represents an effort to lower as much as possible variability of motor responses in serial recording; the reported ITV normative values are the necessary premise to detect significant changes of motor conduction slowing and failure in the individual patient in follow-up studies.
Introduction
We sought insights into neuromyelitis optica spectrum disorder (NMOSD) treatment practices worldwide.
Methods
Neurologists from the USA, Germany, Italy, Brazil, South Korea, and China ...completed an online survey, contributing clinical records for aquaporin-4 (AQP4) immunoglobulin G (IgG)-seropositive adults with NMOSD, which included patient demographics, diagnosis, maintenance treatment history, relapse occurrence, and severity. Interviewed patients receiving NMOSD maintenance therapy provided information about their diagnosis, treatment, perceptions about relapse severity or disease stability, and treatment switches.
Results
A total of 389 neurologists submitted clinical records for 1185 patients with AQP4-IgG-seropositive NMOSD; 33 patients with NMOSD were interviewed. Approximately 25% (228/910) of patients from the clinical record review (CRR) were initially misdiagnosed; 24% (8/33) of patients interviewed reported formal misdiagnosis. Misdiagnosis was associated with treatment delay and more relapses compared with correct diagnosis (mean 3.3 vs 2.8). Maintenance therapy was not initiated within 2 months for 47% (221/472) of patients from the CRR and 24% (8/33) of interviewed patients. Oral corticosteroids/immunosuppressive therapies were typically the first maintenance treatment initiated, except for the USA, where monoclonal antibodies were equally likely to be prescribed. Relapse severity influenced the decision to initiate/change therapy and use monoclonal antibodies. Of interviewed patients, 76% (25/33) did not recall having a choice of treatment and many did not know the rationale for treatment choice.
Conclusion
Misdiagnosis of NMOSD appears to be common and is associated with a delay in initiation of maintenance therapy, with decisions influenced by relapse severity. Further real-world studies assessing relapse severity in treatment initiation/switch are required to revise NMOSD treatment recommendations.
Introduction
We sought insights into the classification of and factors associated with relapse severity and disease stability in neuromyelitis optica spectrum disorder (NMOSD) clinical practice ...worldwide.
Methods
Neurologists recruited from six countries (the USA, Germany, Italy, Brazil, South Korea, and China) participated in a 30–60 minute online survey and submitted two to four clinical records for aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive adults with NMOSD, which included patient demographics, diagnosis, maintenance treatment history, relapse occurrence, and severity. Separately, patients with NMOSD receiving maintenance therapy were interviewed over the telephone about their treatment journey, as well as perceptions of relapse severity and disease stability, and their potential influence on treatment decisions.
Results
Clinical records for 1185 patients with AQP4-IgG-seropositive NMOSD were provided by 389 neurologists (July–August 2020); 33 patients were interviewed (October–November 2020). There was no clear consensus on how relapse severity was defined in clinical practice, with geographical variations in relapse classification also found. Neurologists tended to rely on clinical assessments when determining severity, viewing each relapse in isolation, whereas patients had a more subjective view based on the changes in their daily lives and comparisons with prior relapses. Similarly, there was a disconnect in the definition of disease stability: the complete absence of relapses was more important for patients than for neurologists.
Conclusion
A clear consensus on how to assess relapse severity and disease stability is needed to ensure that patients receive appropriate and timely treatment. In the future, clinical measures should be combined with patient-focused assessments.
PDF
