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María Dolores Edo Solsona,1 Emilio Monte Boquet,1 Bonaventura Casanova Estruch,2 José Luis Poveda Andrés1 1Department of Pharmacy, 2Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain Background: Adherence to disease-modifying drugs (DMDs) is one of the key factors for achieving optimal clinical outcomes. Rebismart® is an injection device for subcutaneous administration of interferon beta-1a (INF β-1a) that is also able to monitor adherence objectively. The aim of this study was to describe adherence to INF β-1a using the said electronic autoinjection device and to explore the relationship between adherence and relapses in a Spanish cohort. Methods: This is a retrospective observational study in which 110 Spanish patients self-administered INF β-1a subcutaneously using an electronic autoinjection device between June 2010 and June 2015. The primary end point was the percentage of adherence measured by Rebismart® to subcutaneous INF β-1a injections calculated as number of injections received in time period versus number of injections scheduled in time period. Other variables recorded were demographic and clinical data. Statistical analysis was performed using SPSS 19.0 software. Results: Median adherence for the total study period was 96.5% (interquartile range [IQR]: 91.1–99.1). Similar values were observed during the first 6 months: 98.7% (IQR: 91.3–100), and the last 6 months: 97.6% (IQR: 91.1–99.8). Median duration of treatment was 979 days (IQR: 613.8–1,266.8). During the entire treatment period, 77.3% of patients were relapse free and mean annualized relapse rate was 0.14 (standard deviation: 0.33). Increased adherence was associated with better clinical outcomes, leading to lower relapse risk (odds ratio: 0.953; 95% confidence interval: 0.912–0.995). Specifically, every percentage unit increase in adherence resulted in a 4.7% decrease in relapse. Conclusion: Patients with multiple sclerosis who self-injected INF β-1a with Rebismart® had excellent adherence, correlating with a high proportion of relapse-free patients and very low annualized relapse rate. Keywords: adherence, multiple sclerosis, interferon beta-1a, autoinjector

Abstract Background Multiple sclerosis (MS) is a complex, inflammatory and neurodegenerative disease of the central nervous system leading to long-term disability. Recent studies indicate a close association between inflammation and neurodegeneration in all lesions and disease stages of MS. Prolyl oligopeptidase (POP) is a proline-specific serine protease that cleaves several neuroactive peptides. This peptidase has been implicated in neurodegeneration, as well as in the modulation of the inflammatory response. Methods We examined plasma POP and the levels of an endogenous POP inhibitor from relapsing remitting MS patients and compared these with healthy controls, by monitoring the fluorescent changes due to standard fluorescently labelled substrate cleavage. We analysed the data in relationship to patient age and disease disability status. Results We observed a significant decrease in POP activity in plasma of relapsing remitting MS patients relative to healthy controls, coupled with an increase of POP endogenous inhibitor. The POP activity was also correlated with patient age and disability status. The lowered POP activity from plasma of MS patients could be rescued by reductants Conclusions The decrease in circulating POP activity measured in MS is reverted by reductants. This suggests that POP inactivation in MS might be a result of the oxidative conditions prevailing in the plasma of the diseased patients. Plasma levels of POP activity as well as those of their endogenous inhibitor are suggested as biomarkers of inflammation and oxidative stress in MS.

Immune checkpoint inhibitors (ICIs) are a pharmacological group increasingly used in Oncology and Hematology. These treatments can lead to autoimmune complications, with neurological conditions, especially central nervous system (CNS) involvement, being rare. We describe a case of seropositive neuromyelitis optica in a patient with locally advanced lung adenocarcinoma treated with Atezolizumab., (© 2023. Fondazione Società Italiana di Neurologia.)

Alzheimer's disease (AD) is the most prevalent dementia, but it shows similar initial symptoms to other neurocognitive diseases (Lewy body disease (LBD) and frontotemporal dementia (FTD)). Thus, the identification of reliable AD plasma biomarkers is required. The aim of this work is to evaluate the use of a few plasma biomarkers to develop an early and specific AD screening method. Plasma p-Tau181, neurofilament light (NfL), and glial fibrillary acid protein (GFAP) were determined by Single Molecule Assay (SIMOA ® Quanterix, Billerica, MA, USA) in patients with mild cognitive impairment due to AD (MCI-AD, n = 50), AD dementia ( n = 10), FTD ( n = 20), LBD ( n = 5), and subjective cognitive impairment (SCI ( n = 21)). Plasma p-Tau181 and GFAP showed the highest levels in AD dementia, and significant correlations with clinical AD characteristics; meanwhile, NfL showed the highest levels in FTD, but no significant correlations with AD. The partial least squares (PLS) diagnosis model developed between the AD and SCI groups showed good accuracy with a receiver operating characteristic (ROC) area under curve (AUC) of 0.935 (CI 95% 0.87-0.98), sensitivity of 86%, and specificity of 88%. In a first screen, NfL plasma levels could identify FTD patients among subjects with cognitive impairment. Then, the developed PLS model including p-Tau181 and GFAP levels could identify AD patients, constituting a simple, early, and specific diagnosis approach.

Alzheimer's disease (AD) is the primary type of dementia, followed by frontotemporal lobar degeneration (FTLD). They share some clinical characteristics, mainly at the early stages. So, the identification of early, specific, and minimally invasive biomarkers is required. In this study, some plasma biomarkers (Amyloid β42, p-Tau181, t-Tau, neurofilament light (NfL), TAR DNA-binding protein 43 (TDP-43)) were determined by single molecule array technology (SIMOA ® ) in control subjects ( n = 22), mild cognitive impairment due to AD (MCI-AD, n = 33), mild dementia due to AD ( n = 12), and FTLD ( n = 11) patients. The correlations between plasma and cerebrospinal fluid (CSF) levels and the accuracy of plasma biomarkers for AD early diagnosis and discriminating from FTLD were analyzed. As result, plasma p-Tau181 and NfL levels correlated with the corresponding CSF levels. Additionally, plasma p-Tau181 showed good accuracy for distinguishing between the controls and AD, as well as discriminating between AD and FTLD. Moreover, plasma NfL could discriminate dementia-AD vs. controls, FTLD vs. controls, and MCI-AD vs. dementia-AD. Therefore, the determination of these biomarkers in plasma is potentially helpful in AD spectrum diagnosis, but also discriminating from FTLD. In addition, the accessibility of these potential early and specific biomarkers may be useful for AD screening protocols in the future.

IgM oligoclonal bands (OCMBs) against myelin-specific lipids have been identified as a marker for poor prognosis in multiple sclerosis (MS). The aim is to examine the relation between lipid-specific OCMBs (LS-OCMBs) and the evolution of MS. An analytical, ambispective and individual-based study was conducted. We selected 116 patients, out of whom 95 had LS-OCMBs. The predominant lipid recognized was phosphatidylcholine. The positive gangliosides OCMB group reached better scores in the 9HPT, and the phosphatidylcholine, sphingolipids and phosphatidylethanolamine OCMB groups showed statistical differences in the magnetic resonance parameters. In conclusion: some LS-OCMBs showed statistically significant differences with functional or imaging tests., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and objective: Chronic relapsing inflammatory optic neuritis (CRION) is one of the more common phenotypes related to myelin oligodendrocyte glycoprotein antibodies (MOG-Abs). The absence of specific biomarkers makes distinguishing between CRION and relapsing inflammatory ON (RION) difficult. A recent work has suggested a widespread affectation of the central nervous system in CRION patients. In order to search for a potential CRION marker we have measured brain atrophy in a cohort of patients, stratified by phenotypes: CRION, RION, multiple sclerosis with a history of optic neuritis (MS-ON), and MOG-Abs status. Methods: A cross-sectional study was conducted in 31 patients (seven CRION, 11 RION, and 13 MS-ON). All patients were tested for MOG and aquaporin-4 antibodies (AQ4-Abs). Clinical data were collected. Brain atrophy was calculated by measuring the brain parenchyma fraction (BPF) with Neuroquant® software. Results: Four of seven CRION patients and one of 11 RION patients were positive for MOG-Abs ( p = 0.046) and no MS-ON patients tested positive to MOG-Abs. All patients were negative to AQ4-Abs. The BPF was lower in patients with CRION than patients with RION (70.6 vs. 75.3%, p = 0.019) and similar to that in MS-ON patients. Conclusions: Brain atrophy in idiopathic inflammatory relapsing ON is present in patients with the CRION phenotype. Data from this study reflect that the optic nerve is a main target involved in these patients but not the only one. Our results should be further investigated in comprehensive and prospective studies., (Copyright © 2019 Cantó, Boscá, Vicente, Gil-Perontín, Pérez-Miralles, Villalba, Nuñez and Casanova Estruch.)

Stigma associated with neurological disorders may contribute to a poor health-related quality of life. However, limited information is available in primary progressive multiple sclerosis. We investigated the presence and impact of stigma in patients with primary progressive multiple sclerosis. A non-interventional, cross-sectional study was conducted. A total of 55 primary progressive multiple sclerosis patients were studied (mean age 55.8±9.5 years, 56.4% male). The median Expanded Disability Status Scale score was 5.5 (4.0-6.5). Stigma prevalence was 78.2% ( n =43). Twenty-four patients (43.6%) were classified as depressed. Scores on the eight-item Stigma Scale for Chronic Illness correlated with physical (rho=0.464, p <0.001) and psychological (rho=0.358, p =0.007) 29-item Multiple Sclerosis Impact Scale subscores. Stigma predicted concurrent depression (odds ratio=1.13; p =0.046). Stigma was highly prevalent with a detrimental effect on quality of life and mood in primary progressive multiple sclerosis.

Introduction: Gait impairment, a frequent sign in multiple sclerosis (MS), places a major burden on patients since it results in progressive loss of personal and social autonomy, along with work productivity. This guide aims to provide recommendations on how to evaluate gait impairment and use prolonged-release fampridine (PR-fampridine) as treatment for MS patients with gait impairment in Spain., Development: PR-fampridine dosed at 10mg every 12hours is currently the only drug approved to treat gait impairment in adults with MS. Additionally, PR-fampridine has been shown in clinical practice to significantly improve quality of life (QoL) in patients who respond to treatment. Treatment response can be assessed with the Timed 25-Foot Walk (T25FW) or the 12-item MS Walking Scale (MSWS-12); tests should be completed before and after starting treatment. The minimum time recommended for evaluating treatment response is 2 weeks after treatment onset. Patients are considered responders and permitted to continue the treatment when they demonstrate a decrease in their T25FW time or an increase in MSWS-12 scores. A re-evaluation is recommended at least every 6 months. The SF-36 (Short Form-36) and the MSIS-29 (MS Impact Scale-29) tests are recommended for clinicians interested in performing a detailed QoL assessment. This drug is generally well-tolerated and has a good safety profile. It should be taken on an empty stomach and renal function must be monitored regularly., Conclusions: These recommendations will help ensure safer and more efficient prescription practices and easier management of PR-fampridine as treatment for gait impairment in Spanish adults with MS., (Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Acquired periodic alternating nystagmus (PAN) is a rare but well-defined syndrome that consists of a horizontal nystagmus that cyclically reverses its direction. PAN can be caused by degenerative, neoplastic, or toxic diseases of the cerebellum and, in a few cases, by subacute cerebellar ataxia of immune origin., Case Presentation: A 44-year-old man came to our attention because of rapidly progressive gait instability and blurred vision. Clinical examination showed PAN and a mild pancerebellar syndrome. Eye movement recordings disclosed a short cycle PAN with significant slow-phase velocity only in darkness. Under the effect of a γ-aminobutyric acid type B (GABA B ) agonist, PAN was not modified. Right after treatment with intravenous immunoglobulin (IVIg) was started, PAN was essentially eliminated. Three months after last dose of IVIg, this nystagmus reappeared., Conclusions: IVIg resolved PAN in this patient. This finding may point to an autoimmune mechanism underlying this patient's nystagmus. This case suggests that the usefulness of IVIg at treating PAN might be worth a consideration in similar clinical settings.

Background: Adherence to disease-modifying drugs (DMDs) is one of the key factors for achieving optimal clinical outcomes. Rebismart ® is an injection device for subcutaneous administration of interferon beta-1a (INF β-1a) that is also able to monitor adherence objectively. The aim of this study was to describe adherence to INF β-1a using the said electronic autoinjection device and to explore the relationship between adherence and relapses in a Spanish cohort., Methods: This is a retrospective observational study in which 110 Spanish patients self-administered INF β-1a subcutaneously using an electronic autoinjection device between June 2010 and June 2015. The primary end point was the percentage of adherence measured by Rebismart ® to subcutaneous INF β-1a injections calculated as number of injections received in time period versus number of injections scheduled in time period. Other variables recorded were demographic and clinical data. Statistical analysis was performed using SPSS 19.0 software., Results: Median adherence for the total study period was 96.5% (interquartile range [IQR]: 91.1-99.1). Similar values were observed during the first 6 months: 98.7% (IQR: 91.3-100), and the last 6 months: 97.6% (IQR: 91.1-99.8). Median duration of treatment was 979 days (IQR: 613.8-1,266.8). During the entire treatment period, 77.3% of patients were relapse free and mean annualized relapse rate was 0.14 (standard deviation: 0.33). Increased adherence was associated with better clinical outcomes, leading to lower relapse risk (odds ratio: 0.953; 95% confidence interval: 0.912-0.995). Specifically, every percentage unit increase in adherence resulted in a 4.7% decrease in relapse., Conclusion: Patients with multiple sclerosis who self-injected INF β-1a with Rebismart ® had excellent adherence, correlating with a high proportion of relapse-free patients and very low annualized relapse rate., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: More than 3,000 multiple sclerosis (MS) patients were treated with disease-modifying drugs (DMDs) in the Region of Valencia during 2005-2014. We aimed at describing the demographic and clinical characteristics of MS patients who requested treatment with DMDs, variations in their use, and the factors associated with change to second-line therapies during this decade., Methods: A retrospective cohort study with information from Subcomité Especializado de Medicamentos de Alto Impacto Sanitario y/o Económico registers. A statistical analysis was run in 2 phases: descriptive analysis of the sample using classical statistical methods, and of DMD trend by a chi-square test for linear trends; analytic analysis to examine the factors associated with change to second-line treatment (logistic regression model)., Results: We selected 2,205 patients (mean age 32.12, SD 9.64; 70% females, and 86.6% remising-remitting MS (RRMS)); 1,012 patients were attended to in highly specialized MS units (45.8%); 525 in monographic units (23.8%); and 668 in general units (30.2%). DMD prescriptions increased, and glatiramer acetate was more widespread at the end of the period (35.4%)., Conclusion: Variability in access to different treatments was slight. The younger the patient, the higher the risk of first-line RRMS treatment failing in female gender and first treatment with interferon., (© 2016 S. Karger AG, Basel.)

Introduction: Neuromyelitis optica is an inflammatory and usually relapsing demyelinating autoimmune disease of the central nervous system that targets the optic nerves and spinal cord. Rituximab has been used for different neurological diseases that are probably immune-mediated or involving humoural immunity. The objective of this study is to evaluate the efficacy and safety of rituximab as treatment for neuromyelitis optica in a tertiary hospital., Methods: Retrospective study of patients with neuromyelitis optica treated with rituximab 1000mg on days 1 and 15, repeated every 6 to 8 months. We recorded EDSS score, relapse rate, overall condition, CD19+ count, presence of anti-NMO antibodies, and possible adverse reactions., Results: Six patients were treated; all were women with a median age of 46 years (range, 38-58). Anti-NMO antibodies were detected in 3 patients (50%). Baseline EDSS was 4 (range 2.0-5.5). Two patients had previously been treated with an immunomodulatory drug. Median time from the first rituximab infusion to first relapse was 3.7 years (range 1.7-6.9). Two patients had infusion reactions after the first dose of rituximab. Four patients remained relapse-free and their EDSS score did not progress during rituximab treatment, one patient showed no clinical improvement, and one patient could not be evaluated., Conclusion: Rituximab can be considered an attractive therapeutic alternative for patients with neuromyelitis optica as there are no approved treatments for this disease. Further studies with rituximab are needed to establish the role of this drug in treating neuromyelitis optica., (Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Multiple sclerosis is a chronic, demyelinating and inflammatory disease of the central nervous system that mainly affects young adults. It is characterised by processes involving inflammation, demyelination and axonal destruction, and as a result the pathogenic aspects and response to treatment of the disease vary widely. It is therefore difficult to establish a prognosis for these patients or to determine the effectiveness of the different drugs that are employed. Current clinical research into the development of new biomarkers has advanced a great deal in recent years, especially in the early stages of the disease. Yet, it is essential to further our knowledge about novel markers of the disease, and not only in the more advanced stages, so as to be able to stop disability from progressing and to establish new therapy regimens in these patients. This review presents an update on the information available about the biomarkers that are currently validated and used in multiple sclerosis, together with the possible candidates for utilisation in routine clinical practice.

Introduction: Spasticity is a common symptom among patients with multiple sclerosis (MS). This study aims to assess the effectiveness and safety of the combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in clinical practice for the treatment of spasticity in MS., Methods: Retrospective observational study with patients treated with inhaled THC/CBD between April 2008 and March 2012. Descriptive patient and treatment variables were collected. Therapeutic response was evaluated based on the doctor's analysis and overall impression., Results: Of the 56 patients who started treatment with THC/CBD, 6 were excluded because of missing data. We evaluated 50 patients (42% male) with a median age 47.8 years (25.6-76.8); 38% were diagnosed with primary progressive MS, 44% with secondary progressive MS, and 18% with relapsing-remitting MS. The reason for prescribing the drug was spasticity (44%), pain (10%), or both (46%). Treatment was discontinued in 16 patients because of ineffectiveness (7 patients), withdrawal (4), and adverse effects (5). The median exposure time in patients whose treatment was discontinued was 30 days vs 174 days in those whose treatment continued at the end of the study. THC/CBD was effective in 80% of patients at a median dose of 5 (2-10) inhalations/day. The adverse event profile consisted of dizziness (11 patients), somnolence (6), muscle weakness (7), oral discomfort (2), diarrhoea (3), dry mouth (2), blurred vision (2), agitation (1), nausea (1), and paranoid ideation (1)., Conclusions: THC/CBD appears to be a good alternative to standard treatment as it improves refractory spasticity in MS and has an acceptable toxicity profile., (Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

Introduction: Monoclonal antibodies are immunoglobulins specially designed to act against specific targets, in such a way that their administration stops a specific pathogenic process, stimulates a particular cellular action, or changes a cell mechanism to another pathway of interest. Their production is based on the establishment of modified immortal B lymphocytes to produce a specific immunoglobulin. Depending on the level of purity, this immunoglobulin may be murine complement (ending in "o", for example muromonab); chimeric, in which all the immunoglobulin is human, except in the variable region which is murine (ending in "xi", for example, rituximab); humanised, in which all the immunoglobulin is human, except in the variable complement region which remains murine (ending in "zu", for example, natalizumab); and human complement (ending in "u", for example, adalimumab). Therefore, there will be two types of secondary effects: those arising from the action of the antibody, such as opportunistic infections due to immunosuppression, and those arising from the administration of a protein, such as anaphylactic reactions. The sources used for the present articles were articles published in PubMed, located by searching for "Monoclonal antibodies and Secondary effects", and the web pages of the European Medicines Agency (EMEA) and the US Food and Drus Administration (FDA)., Development: The secondary effects arising from the mechanisms of action were opportunistic infections, common infections, development of tumours and autoimmune phenomena, and those arising from the administration of proteins: anaphylactic reaction, cytokine release syndrome, and the development of neutralising antibodies. Finally, the management of monoclonal antibodies in clinical practice and in special situations is discussed, including administering vaccines, pregnancy and paediatric use. Reference will be made to immune recovery syndrome., Conclusions: Monoclonal antibodies are highly effective drugs when specifically indicated, but they also may incur serious secondary effects, which although incidence is low, require close monitoring of the patients receiving these treatments., (Copyright © 2010 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

The new insights presented at the 5th Joint Triennial Congress of the European and Americas Committees on Treatment and Research in Multiple Sclerosis (ECTRIMS and ACTRIMS) held in Amsterdam, the Netherlands, 19-22 October 2011, have been summarized at the fourth edition of Post-ECTRIMS meeting held in Madrid in November 2011. Regional grey-matter atrophy is more sensitive to cognitive impairment than global grey-matter atrophy measures. In patients with clinically isolated syndrome cognitive impairment does not predict conversion to multiple sclerosis (MS) after 5-years of follow-up. Focusing on central nervous system plasticity and functional reorganization in MS, an early intervention can improve clinical aspects and enhances brain plasticity. Preservation of a potential for plasticity provides a rationale for rehabilitation interventions even in later stages of disease. Therapeutical strategies have focused on stem cell-mediated remyelination and immunomodulation functions, on cellular infiltration into the brain, and on new ways for immuno-modulation for the development of future therapies in MS. Encouraging findings from clinical trials with current and emerging disease-modifying therapy being developed was also a key theme at this edition. Positive results have been reported for rituximab, ocrelizumab, ofatumumab, daclizumab, alemtuzumab, teriflunomide, BG-12, and laquinimod, including a favorable safety profile. Since armamentarium for the treatment of MS is fast increasing, concerns exist about the risk of severe adverse events with their use. This aspect reinforces the importance of disease registries as a proactive tool for monitoring drug safety in the post-approval setting.

Background: Multiple sclerosis (MS) is a complex, inflammatory and neurodegenerative disease of the central nervous system leading to long-term disability. Recent studies indicate a close association between inflammation and neurodegeneration in all lesions and disease stages of MS. Prolyl oligopeptidase (POP) is a proline-specific serine protease that cleaves several neuroactive peptides. This peptidase has been implicated in neurodegeneration, as well as in the modulation of the inflammatory response., Methods: We examined plasma POP and the levels of an endogenous POP inhibitor from relapsing remitting MS patients and compared these with healthy controls, by monitoring the fluorescent changes due to standard fluorescently labelled substrate cleavage. We analysed the data in relationship to patient age and disease disability status., Results: We observed a significant decrease in POP activity in plasma of relapsing remitting MS patients relative to healthy controls, coupled with an increase of POP endogenous inhibitor. The POP activity was also correlated with patient age and disability status. The lowered POP activity from plasma of MS patients could be rescued by reductants, Conclusions: The decrease in circulating POP activity measured in MS is reverted by reductants. This suggests that POP inactivation in MS might be a result of the oxidative conditions prevailing in the plasma of the diseased patients. Plasma levels of POP activity as well as those of their endogenous inhibitor are suggested as biomarkers of inflammation and oxidative stress in MS.

Between 1989 and 1992 we had two cases of mucormycosis. The first patient presented with left hemiplegia: radiologic studies showed a right sphenoidal sinus mass, cerebral ischaemic infarction and occlusion of the right carotid artery. The second patient was seen with an abscess of the hard palate after long term steroid therapy. CT scan showed a soft-tissue mass occupying the maxillary sinus, which had eroded its walls and spread to palate, orbit and ethmoidal cells. We have emphasised the presence of hyperglycemia in both cases, the marked tendency of this lesion to invade blood vessels, and the good results obtained by combining liposomal amphotericin B with radical surgical debridement.