Consensus on early detection of disease progression in patients with multiple sclerosis.

Background: Early identification of the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) can be challenging for clinicians, as diagnostic criteria for SPMS are primarily based on physical disability and a holistic interpretation. Objective: To establish a consensus on patient monitoring to identify promptly disease progression and the most useful clinical and paraclinical variables for early identification of disease progression in MS. Methods: A RAND/UCLA Appropriateness Method was used to establish the level of agreement among a panel of 15 medical experts in MS. Eighty-three items were circulated to the experts for confidential rating of the grade of agreement and recommendation. Consensus was defined when ≥66% agreement or disagreement was achieved. Results: Consensus was reached in 72 out of 83 items (86.7%). The items addressed frequency of follow-up visits, definition of progression, identification of clinical, cognitive, and radiological assessments as variables of suspected or confirmed SPMS diagnosis, the need for more accurate assessment tools, and the use of promising molecular and imaging biomarkers to predict disease progression and/or diagnose SPMS. Conclusion: Consensus achieved on these topics could guide neurologists to identify earlier disease progression and to plan targeted clinical and therapeutic interventions during the earliest stages of SPMS.

Disease modifying therapy switching in relapsing multiple sclerosis: A Delphi consensus of the demyelinating expert group of the Spanish society of neurology.

BACKGROUND: The increase in available disease modifying therapies (DMTs) for multiple sclerosis has led to greater emphasis on improving treatment sequencing paradigms. This article summarises the opinions from a panel of 25 experts on treatment switching approaches in relapsing multiple sclerosis (RMS). METHODS: A modified Delphi consensus process was carried out to develop clinically relevant statements for aiding treatment decisions in patients with RMS between the 16th January and the 9th October 2019. A sub-group of two experts (core group) carried out an extensive review of the literature and formulated 106 statements for the expert panel to evaluate. RESULTS: From a total number of 106 statements that were submitted to the expert panel for critical evaluation, consensus (at least 80% of the panelists agreed) was reached on 99 of them. These statements cover treatment objectives, reasons for DMT switching, suboptimal response criteria, strategies for treatment change and washout periods. CONCLUSION: The agreed statements provide up-to-date guidance on DMT sequencing for optimal patient management.

Short-term data on disease activity, cognition, mood, stigma and employment outcomes in a cohort of patients with primary progressive multiple sclerosis (UPPMS study).

BACKGROUND: Primary progressive multiple sclerosis (PPMS) has long been defined by progressive disability accrual in the absence of initial relapses. However, its underlying neurodegenerative process seems to be accompanied by central nervous system inflammation. A new classification defined multiple sclerosis courses according to clinical/radiological activity and progression. We provide further insight into PPMS activity according to this classification and other daily living aspects. METHODS: This was a multicentre, prospective, cohort study including 55 adult patients with PPMS according to 2010 McDonald criteria, within ten years from neurologic symptom onset and not receiving disease-modifying therapies during the past six months, who were followed up for 12 months. The primary study endpoint was the percentage of patients with active disease based on clinical relapses and/or magnetic resonance activity. Disability progression, cognitive function, physical/psychological impact, depression symptoms, stigma and employment were secondary endpoints. RESULTS: Eleven (25.6%) patients exhibited multiple sclerosis activity throughout the 12-month study follow-up. Fourteen showed non-active multiple sclerosis without progression, 11 non-active multiple sclerosis with progression, 6 active multiple sclerosis without progression and 4 active multiple sclerosis with progression; one patient with disease activity was not assessable for progression. Cognitive function scores remained unchanged or increased, disease physical impact was maintained and disease psychological impact significantly decreased. The proportion of patients with depression symptoms or stigma remained without significant changes as well as employment outcomes. CONCLUSION: This study shows that one-fourth of PPMS patients may exhibit disease activity over one year, with disability progression in approximately one-third but without worsening of cognitive function, disease impact, depression, stigma or employment outcomes.

Brain region volumes and their relationship with disability progression and cognitive function in primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Evidence on regional changes resulting from neurodegenerative processes underlying primary progressive multiple sclerosis (PPMS) is still limited. We assessed brain region volumes and their relationship with disability progression and cognitive function in PPMS patients. METHODS: This was an MRI analysis of 43 patients from the prospective Understanding Primary Progressive Multiple Sclerosis (UPPMS) cohort study. MRI scans were performed within 3 months before enrollment and at month 12. RESULTS: Gray matter volume of declive and white matter volumes adjacent to left straight gyrus, right calcarine sulcus, and right inferior occipital gyrus significantly decreased from baseline to month 12. Baseline white matter volumes adjacent to right amygdala and left cuneus significantly differed between patients with and without disability progression, as well as baseline gray matter volumes of left cuneus, right parahippocampal gyrus, right insula, left superior frontal gyrus, declive, right inferior temporal gyrus, right superior temporal gyrus (pole), and right calcarine sulcus. Baseline gray matter volumes of right cuneus and right superior temporal gyrus positively correlated with 12-month Selective Reminding Test and Word List Generation performance, respectively. Gray matter changes in right superior semilunar lobe and white matter adjacent to left declive and right cerebellar tonsil also positively correlated with Word List Generation scores, while white matter change in left inferior semilunar lobe positively correlated with Symbol Digit Modalities Test performance after 12 months. CONCLUSIONS: White and gray matter volumes of specific brain regions could predict disability progression and cognitive performance of PPMS patients after one year.

Safety and Tolerability of More than Six Days of Tedizolid Treatment.

Tedizolid has demonstrated its efficacy and safety in clinical trials; however, data concerning its tolerability in long-term treatments are scarce. The aim of the study was to assess the indications and to describe the long-term safety profile of tedizolid. A multicentric retrospective study of patients who received tedizolid for more than 6 days was conducted. Adverse events (AEs) were identified from patients' medical records and laboratory data. The World Health Organization causality categories were used to discern AEs that were probably associated with tedizolid. Eighty-one patients, treated with tedizolid 200 mg once daily for a median (interquartile range [IQR]) duration of 28 (14 to 59) days, were included; 36 (44.4%) had previously received linezolid. The most common reasons for selecting tedizolid were to avoid linezolid potential toxicities or interactions (53.1%) or due to previous linezolid-related toxicities (27.2%). The most common indications were off-label, including prosthetic joint infections, osteomyelitis, and respiratory infections (77.8%). Overall, 9/81 patients (11.1%) experienced a probably associated AE. Two patients (2.5%) developed gastrointestinal disorders, 1 (1.2%) developed anemia, and 6 developed thrombocytopenia (7.4%) after a median (IQR) duration of treatment of 26.5 (17 to 58.5) days. Four (5%) patients discontinued tedizolid due to AEs. Among 23 patients with chronic renal failure (CRF), the rate of myelotoxicity was 17.4%, and only 8.7% had to stop tedizolid; 20 out of 22 with previous linezolid-associated toxicity had no AE. Long-term tedizolid treatments had good tolerance with rates of gastrointestinal AE and hematological toxicity lower than those reported with linezolid, particularly in patients with CRF and in those with a history of linezolid-associated toxicity.

Spanish real-world experience with fingolimod in relapsing-remitting multiple sclerosis patients: MS NEXT study.

PURPOSE: The objective of this study was to characterize the demographic and clinical profile of RRMS patients receiving fingolimod in Spain, and to evaluate drug effectiveness and safety in clinical practice. METHODS: This observational, retrospective, multicentre, nationwide study was performed at 56 Spanish hospitals and involved 804 RRMS patients who received oral fingolimod (0.5 mg) since November 2011, with a minimum follow-up of 12 months. RESULTS: The mean annualized relapse rate (ARR) in the year before fingolimod was 1.08 and the median EDSS was 3; patients were exposed to fingolimod for 2.2 years as average; regarding magnetic resonance imaging (MRI) activity, more than half of the patients had >20 lesions at baseline. Patients were previously treated with first-line injectable DMTs (60.3%), or natalizumab (31.3%), and 8.3% were naïve patients. Overall, the ARR significantly decreased to 0.28, 0.22 and 0.17 (74.1%, 79.7% and 83.5% of relative reduction, respectively) after 12, 24 and 36 months of treatment, P<0.001. The ARR of patients who switched from natalizumab to fingolimod was stable over the study. Most of the patients (88.7%) were free from confirmed disability and MRI activity (67.3%) after 24 months. The persistence after 12 months on fingolimod was 93.9%. CONCLUSIONS: The subgroups of patients analysed showed differential baseline demographic and clinical characteristics. The analysis of patients who received fingolimod in routine clinical practice confirmed adequate efficacy and safety, even for long-term treatment. The present data also confirmed the positive benefit/risk balance with fingolimod in real-world clinical practice setting.

Ability of Swept-Source Optical Coherence Tomography to Detect Retinal and Choroidal Changes in Patients with Multiple Sclerosis.

PURPOSE: To evaluate the ability of new swept-source (SS) optical coherence tomography (OCT) technology to detect changes in retinal and choroidal thickness in patients with multiple sclerosis (MS). METHODS: A total of 101 healthy and 97 MS eyes underwent retinal and choroidal assessment using SS Triton OCT (Topcon). Macular thickness and peripapillary data (retinal, ganglion cell layer (GCL+, GCL++) and retinal nerve fiber layer (RNFL) thickness) were analyzed, including choroidal thickness evaluation. RESULTS: Significant macular thinning was observed in all ETDRS areas (p < 0.001) in MS patients. Peripapillary retinal, RNFL, and GCL ++ thickness showed a significant reduction in patients in all sectors (p < 0.001) except in the nasal quadrant/sector (p > 0.05). GCL+ measurements were found to be reduced in the nasal (p=0.003), inferonasal (p=0.045), and temporal (p=0.001) sectors and total thickness (p < 0.001). Choroidal thickness was reduced in the outer macular ring in MS patients compared with controls (p=0.038). CONCLUSION: New swept-source technology for OCT devices detects retinal thinning in MS patients, providing increased depth analysis of the choroid in these patients. MS patients present reduced retinal and choroidal thickness in the macular area and reduced peripapillary retinal, RNFL, and GCL thickness.

Relationship between Visual Dysfunction and Retinal Changes in Patients with Multiple Sclerosis.

AIM: To evaluate structural changes in the retina and their correlation with visual dysfunction in patients with multiple sclerosis. METHODS: Patients with multiple sclerosis (n = 84) and healthy controls (n = 84) underwent structural evaluation of the retinal nerve fiber layer, and macular and ganglion cell layer thicknesses using Spectral domain optical coherence tomography (SD-OCT). All subjects underwent high and low contrast visual acuity, color vision (using the Farnsworth and L´Anthony desaturated D15 color tests), and contrast sensitivity vision using the Pelli Robson chart and CSV 1000E test. RESULTS: Macular, retinal nerve fiber layer, and ganglion cell layer thinning was observed in multiple sclerosis patients compared to healthy controls (p<0.05). High- and low-contrast visual acuity and contrast sensitivity vision at four different spatial frequencies were significantly reduced in comparison with healthy subjects (p<0.05). Macular, retinal nerve fiber layer and ganglion cell layer measurements correlated with high and low contrast visual acuity, and contrast sensitivity vision. Contrast sensitivity vision was the functional parameter that most strongly correlated with the structural measurements in multiple sclerosis and was associated with ganglion cell layer measurements. The L´Anthony color vision score (age-corrected color confusion index) was associated with macular measurements. CONCLUSIONS: Patients with multiple sclerosis had visual dysfunction that correlated with structural changes evaluated by SD-OCT. Macular and ganglion cell layer measurements may be good indicators of visual impairment in multiple sclerosis patients.

Uso del QuantiFERON-TB Gold en la consulta de Medicina del Trabajo en un medio hospitalario. 8 años de experiencia / Utility of QuantiFERON-TB Gold in screening of health care workers. 8 years of experience

Objetivo: Valorar la eficiencia del uso del QuantiFERON-TB Gold (QTFGIT) en el diagnóstico de infección tuberculosa latente. Material y métodos: En la consulta de Medicina del Trabajo de un medio hospitalario, se comparan los resultados del QTF-GIT en trabajadores con prueba de la tuberculina (PT) positiva entre los años 2007-2014. Además, se realiza un estudio de validación diagnóstica para la PT en los puntos de corte de 10 y 5mm. Resultados: Se estudiaron 2.085 pacientes y se realizaron 2.679PT 182 (+), 2435 (-). Se realizaron 1.623 QTF-GIT; 132 (+), 1.486 (-). Tras una PT positiva el 61,4% QTF-GIT presentaron un resultado negativos (p<0.001). La PT, con puntos de corte en 10 y 5mm, muestra una sensibilidad del 88% y 100% (p<0.001) una especificidad del 35% y 3% (p<0.001) respectivamente. Conclusiones: La PT en la consulta de Medicina del Trabajo está justificada al tratarse de una prueba diagnóstica con alta sensibilidad, pero al generar un gran número de falsos positivos, precisa posteriormente de una prueba con una alta especificidad como el QTF-+GIT para evitar la quimioprofilaxis innecesaria (AU)

Objective: To evaluate the efficiency of QuantiFERON-TB Gold (QFT-GIT) to diagnose latent tuberculosis infection. Methods: In an Occupational Medicine consultation, we analysed the results of QFT-GIT in hospital workers with positive tuberculin skin test (TST) between years 2007-2014. Also a validation study was performed for the TST in the cut offs considered as 10 and 5 mm. Results: 2,085 patients were studied. We performed 2,679 TST 182 (+), 2,435 (-). 1,623 QTF-GIT were done; 132 (+), 1,486 (-). After a positive TST 61.4% QFTGIT showed a negative result (p<0.001). The TST, with 10 or 5 mm considered as cut-off, showed a sensitivity of 88% and 100% (p<0.001) and a specificity of 35% and 3% (p<0.001) respectively. Conclusions: The use of TST in Occupational Medicine is justified as it is a diagnostic test with high sensitivity, but as it generates a large number of false positive, confirmation with a higher specificity test, such as the QFT-GIT is required to avoid unnecessary chemoprophylaxis (AU)

Natalizumab-related anaphylactoid reactions in MS patients are associated with HLA class II alleles.

OBJECTIVES: We aimed to investigate potential associations between human leukocyte antigen (HLA) class I and class II alleles and the development of anaphylactic/anaphylactoid reactions in patients with multiple sclerosis (MS) treated with natalizumab. METHODS: HLA class I and II genotyping was performed in patients with MS who experienced anaphylactic/anaphylactoid reactions and in patients who did not develop infusion-related allergic reactions following natalizumab administration. RESULTS: A total of 119 patients with MS from 3 different cohorts were included in the study: 54 with natalizumab-related anaphylactic/anaphylactoid reactions and 65 without allergic reactions. HLA-DRB1*13 and HLA-DRB1*14 alleles were significantly increased in patients who developed anaphylactic/anaphylactoid reactions (p M-H = 3 × 10(-7); odds ratio [OR]M-H = 8.96, 95% confidence interval [CI] = 3.40-23.64), with a positive predictive value (PPV) of 82%. In contrast, the HLA-DRB1*15 allele was significantly more represented in patients who did not develop anaphylactic/anaphylactoid reactions to natalizumab (p M-H = 6 × 10(-4); ORM-H = 0.2, 95% CI = 0.08-0.50), with a PPV of 81%. CONCLUSIONS: HLA-DRB1 genotyping before natalizumab treatment may help neurologists to identify patients with MS at risk for developing serious systemic hypersensitivity reactions associated with natalizumab administration.

Stressed cybrids model demyelinated axons in multiple sclerosis.

Multiple sclerosis is likely caused by a complex interaction of multiple genes and environmental factors. The contribution of mitochondrial DNA genetic backgrounds has been frequently reported. To evaluate the effect of mitochondrial DNA haplogroups in the same genetic and environmental circumstances, we have built human transmitochondrial cell lines and simulated the effect of axon demyelination, one of the hallmarks of multiple sclerosis pathology, by altering the ionic gradients through the plasmalemma and increasing ATP consumption. In this model, mitochondrial biogenesis is observed. This process is larger in Uk cybrids, which mirrors their lower oxidative phosphorylation capacity in basal conditions. This model replicates a process occurring in both patients suffering from multiple sclerosis and several animal models of axon demyelination. Therefore, it can be used to analyze the contribution of various mitochondrial DNA genotypes to multiple sclerosis. In this sense, a longer or stronger energy stress, such as that associated with demyelinated axons in multiple sclerosis, could make Uk individuals more susceptible to this pathology. Finally, pharmacologic compounds targeted to mitochondrial biogenesis could be a potential therapy for multiple sclerosis.

Fourier-domain OCT in multiple sclerosis patients: reproducibility and ability to detect retinal nerve fiber layer atrophy.

PURPOSE: To evaluate the ability of Fourier-domain (FD) optical coherence tomography (OCT) to detect retinal nerve fiber layer (RNFL) atrophy in multiple sclerosis (MS) patients. To test the intrasession reproducibility of RNFL thickness measurements in MS and healthy subjects using Cirrus (Carl Zeiss Meditec, Dublin, CA) and Spectralis (Heidelberg Engineering, Heidelberg, Germany) OCT. METHODS: Two hundred twenty-two eyes of 111 subjects (50 MS patients and 61 healthy subjects) underwent three 360° circular scans centered on the optic disc by the same experienced examiner using the Cirrus and Spectralis OCT instruments. Differences between healthy and MS eyes were compared. The relationship between average thicknesses with each OCT was evaluated. Repeatability was studied by intraclass correlation coefficients and coefficients of variation (COV). RESULTS: RNFL atrophy was detected in the MS eyes for all OCT parameters (P < 0.05). Cirrus and Spectralis showed an RNFL average thickness of 99.4 and 102.5 µm, respectively, in healthy subjects, and 86.0 and 90.4 µm in the MS eyes. RNFL average thickness in the MS eyes determined by both OCTs correlated (r = 0.812; P < 0.001), but were significantly different (P < 0.001). Reproducibility was good. In the MS eyes, Cirrus measurements showed a mean COV of 5.85%, Spectralis 6.80%, and Spectralis with a progression feature 4.16%. Intraclass correlation coefficients were higher than 0.840. RNFL average thickness correlated with disease duration and an optic neuritis antecedent. CONCLUSIONS: There are significant differences in RNFL thickness measurements between Cirrus and Spectralis despite a high correlation of measurement between the two instruments. Fourier-domain OCT can be considered a valid device for detecting RNFL atrophy in MS patients.

Sub-clinical atrophy of the retinal nerve fibre layer in multiple sclerosis.

PURPOSE: This study aimed to evaluate the presence of abnormalities in the retinal nerve fibre layer (RNFL) in multiple sclerosis (MS) patients with normal ophthalmic examination, and to compare the ability of optical coherence tomography (OCT) and scanning laser polarimetry (GDx) to detect axonal loss. METHODS: Patients with MS and disease-free controls were invited to enrol in the study from 1 February 2007 to 30 June 2008. Ophthalmic examination, including evaluation of visual acuity (VA) and visual field (VF), showed normal results in all subjects. Retinal nerve fibre layer properties were measured by means of OCT and GDx. Visual evoked potentials (VEPs) were also recorded. RESULTS: Forty eyes of 40 MS patients and 20 eyes of age- and sex-matched controls were included in the study. Despite normal VA and VF results, significant differences between the two groups were observed in VF mean deviation (MD), most of the RNFL measurements provided by OCT and GDx, and VEP P100 latency and amplitude. There was a significant correlation between OCT and GDx parameters, and between these parameters and VEP results. Nineteen MS eyes (35.7%) showed RNFL abnormalities detected either by OCT or GDx. DISCUSSION: Sub-clinical ganglion cell loss can be detected in MS patients with normal visual function. Both OCT and GDx are useful complementary tools with which to identify this damage.

Estudio de la degeneración axonal a nivel de la capa de fibras nerviosas de la retina en pacientes con esclerosis múltiple / No disponible

No disponible

Degeneración axonal de la capa de fibras nerviosas de la retina en función del tratamiento recibido para la esclerosis múltiple / No disponible

No disponible

Spontaneous subdural hematoma of the thoracolumbar region with massive recurrent bleed.

Spinal subdural hematoma is a rare disorder and can be caused by abnormalities of coagulation, blood dyscrasias, lumbar puncture, trauma, underlying neoplasm, and arteriovenous malformation. We discuss an unusual case of an elderly woman who presented with spontaneous spinal subdural hematoma and developed massive rebleeding on the third day following initial evacuation of hematoma. This case illustrates that a patient with routine normal coagulation profile and adequate hemostasis can still harbor platelet dysfunction (in present case due to polycythemia) and later on can manifest as rebleeding and neurological deterioration.

[Do not resuscitate orders in patients with acute stroke. What circumstances decide their use?]. / Factores determinantes en la aplicación de las órdenes de no reanimación en el ictus.

BACKGROUND: Patients with acute stroke are known to have a poor prognosis after cardiopulmonary resuscitation manoeuvres (CPR), and their application should be revisited in these patients. Although clinical criteria for a 'do not resuscitate order' (DNR) are available in some countries, studies about DNR in stroke are lacking in Spain. The purpose of this study was to evaluate the frequency of DNR orders in patients with acute stroke and to identify factors influencing decision-making in them. PATIENTS AND METHOD: All patients with acute stroke who had cardiac and pulmonary arrest were prospectively included in the study during one year. Clinical and demographic data of patients and data related to doctors were recorded and analysed. RESULTS: 165 patients had a cardiac and pulmonary arrest and 17 (10%) of them had had a DNR order. No factor was significantly associated with DNR decision-making. CONCLUSIONS: DNR orders were scarcely applied and explicit clinical criteria for their application were lacking. It is necessary to implement DNR policies in Spain in order to improve the use of CPR manoeuvres in patients with acute stroke.