Serology results after COVID vaccine in multiple sclerosis patients treated with fingolimod.

INTRODUCTION: While it is recommended that patients with multiple sclerosis (MS) be vaccinated against COVID-19, it is unknown what the vaccine response is in MS patients treated with fingolimod, an agent which modulates the humoral response. We aimed to characterize the immune response to the COVID-19 vaccine in MS patients treated with fingolimod and to explore which factors influenced response. METHOD: We collected the following data from 59 MS patients treated with fingolimod and vaccinated against COVID-19: age, sex, duration of treatment, number of vaccine doses, date of last vaccination, type of vaccine, lymphocyte count, history of COVID-19, and serology to measure the vaccine response. We used Student's t-test and Chi2 test to see whether there was a relationship between these variables and seropositivity. A multivariate logistic regression model was used to identify factors influencing the serology result. A multivariate linear regression model was used to identify factors influencing the antibody titer. RESULTS: Twenty-eight participants (47%) developed a positive serology. Age (P<0.001) and the duration of treatment (P=0.002) were significantly related to seropositivity. Gender (P=0.73), number of vaccinations (P=0.78), lymphocyte count (P=0.46), and the time between the last vaccine dose and blood sampling (P=0.84) were not significant variables. Multivariate analysis using logistic regression (n=59) showed that age (P=0.003, RR = 2.28, 95%CI = 1.28, 4.07) and duration of treatment (P=0.04, RR=1.91, 95%CI=1.04, 3.50) were significantly and independently correlated with COVID serology. Multivariate linear regression analysis of the antibody titer (n=59) found the duration of treatment to be significant (P = 0.015), but not age (P = 0.53). After removing three outliers, age (P = 0.005, RR=6.82, 95%CI=1.66, 27.98) and duration of treatment (P = 0.008, RR=5.12, 95%CI=1.24, 21.03) were significantly correlated with the antibody titer. CONCLUSION: COVID-19 seropositivity was present in 47% of our sample of 59 MS patients on fingolimod. A strong relationship was found between antibody development, age, and duration of treatment, as well as between antibody titer and age and duration of treatment.

An algorithm to determine the date when the McDonald criteria are met for the diagnosis of relapsing-remitting multiple sclerosis.

BACKGROUND: A patient is diagnosed with multiple sclerosis once they meet the McDonald criteria of dissemination in space and time. Studies of cohorts of patients with multiple sclerosis need a reproducible way to determine an accurate date of diagnosis. We developed an automatic data-driven algorithm to determine the date when the MacDonald criteria are met, which we validated with the Registre Lorrain des Scleroses en Plaques (ReLSEP), a regional French registry of patients with multiple sclerosis. METHODS: We developed an algorithm to determine the date of diagnosis based on clinical and paraclinical data adapted from the four versions of the McDonald criteria. For validation, the dates of diagnosis generated by the algorithm were compared with those determined by an expert physician using the patients' files as the gold standard. We calculated the sensitivity and specificity of the algorithm to provide a date, then we tested the equivalence between the dates of the gold standard and the algorithm (two-one-sided-t-test). RESULTS: The algorithm used every possibility of determining dissemination in space and time according to the four sets. The sensitivity of the algorithm was 100% for the four sets, and specificity ranged between 95 and 100%. The difference between the dates of diagnosis found by the physician and the algorithm was usually less than 2 weeks (equivalence test P<0.0001). CONCLUSION: The algorithm appears to be an efficient surrogate to accurately determine dates of diagnosis of multiple sclerosis in datasets of patients.

Multidisciplinary management of patients presenting with Lyme disease suspicion.

OBJECTIVE: The teaching hospital of Nancy, France, implemented a specific multidisciplinary care pathway (French acronym AMDPL) to improve the management of patients presenting with Lyme borreliosis (LB) suspicion. We aimed to assess the first year of activity of this care pathway. PATIENTS AND METHODS: We included all patients managed in the AMDPL pathway from November 1, 2016 to October 31, 2017. The first step was a dedicated Lyme disease consultation with an infectious disease specialist. Following this consultation, the LB diagnosis was either confirmed and adequate treatment was prescribed, or a differential diagnosis was established and patients received adequate management, or further investigations were required and patients were offered multidisciplinary management as part of a day hospitalization. RESULTS: A total of 468 patients were included. LB diagnosis was confirmed in 15% of patients (69/468), 49% of patients received a differential diagnosis, and 26% (122/468) of patients had the LB diagnosis ruled out without receiving any other diagnosis. CONCLUSIONS: This is to our knowledge the first multidisciplinary center implemented in France for the management of patients presenting with LB suspicion related to polymorphous signs and symptoms. Several diagnoses could be confirmed or corrected, although some symptoms and complaints could not be explained. This cohort could improve our knowledge of LB and its differential diagnoses.

Clinical follow-up of 411 patients with relapsing and progressive multiple sclerosis 10 years after discontinuing mitoxantrone treatment: a real-life cohort study.

BACKGROUND AND PURPOSE: Mitoxantrone (MITOX) has been used to treat patients with aggressive multiple sclerosis (MS) for decades. We aimed to describe the effectiveness and adverse events over 10 years post-MITOX in patients with relapsing and progressive MS from an exhaustive real-life database. METHODS: Data from patients who received MITOX before 1 January 2006 were collected from the MS Lorraine registry. Expanded Disability Status Scale (EDSS) scores and annual relapse rates (ARRs) year by year during follow-up and the year prior to MITOX were compared. Time to the first relapse and a 1-point increase in EDSS score were used in Cox multivariate models to find associations with potential predictive factors. RESULTS: A total of 411 patients were included. The ARR for the 155 relapsing patients had decreased from 2.0 (SD 1.20) the year before treatment to 0.3 (SD 0.31) by year 10 (P < 0.0001). The EDSS score increased from 2.8 (SD 1.44) to 4.8 (SD 1.90) by year 10 (P < 0.0001). A high ARR at MITOX initiation was associated with a longer time to a 1-point increase in EDSS score (hazard ratio, 0.81; 95% confidence interval, 0.67-0.99; P = 0.04). The EDSS score in 256 progressive patients increased from 5.0 (SD 1.33) to 6.5 (SD 1.26) by year 10 (P < 0.0001). We identified four cases of acute myeloid leukemias. CONCLUSIONS: Patients with the most active forms of MS are the most likely to benefit from MITOX in the long term.

Classification and diagnostic criteria for demyelinating diseases of the central nervous system: Where do we stand today?

The diagnosis of multiple sclerosis (MS) and other demyelinating diseases of the central nervous system is challenging, and although the currently available biological and imaging tools offer considerable support to physicians, these tools often fail to provide a simple and final answer at the time of a first event. Thus, sets of diagnostic criteria have been published and tested on patient cohorts, and are now used in clinical trials and in daily clinical practice. These criteria have evolved over time to take into account physicians' and patients' needs, along with emerging paraclinical tests. The different presentations of MS have given rise to the use of a common classification system to identify patient profiles and adapt care protocols accordingly. This article reviews the various classifications of the forms and diagnostic criteria of MS and related syndromes, including neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSDs), acute disseminated (demyelinating) encephalomyelitis (ADEM) and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Also discussed is their validity in the light of the currently available literature.

One-year outcome after a first clinically possible epileptic seizure: predictive value of clinical classification and early EEG.

OBJECTIVE: To assess the one-year outcome of patients referred to the emergency room for a first paroxysmal event of clinically certain or uncertain epileptic origin. METHODS: This prospective observational cohort study included 175 adult patients who were consecutively referred for a first paroxysmal event and excluding clinically certain syncope faints. Simple descriptive clinical criteria were used by emergency room physicians for epileptic assessment. Follow-up and final diagnosis were made by neurologists specialized in epilepsy. The risk of recurrence and epilepsy over time was described using Kaplan-Meier estimates. The effect of risk factors (including EEG results) was assessed using univariate log-rank tests and a Cox regression multivariate model. Negative and positive predictive values (NPV and PPV) at 1 year of significant factors were calculated. RESULTS: Clinical criteria were positive in 67 patients and negative in 108. At 1 year, the rate of recurrence was respectively 8% in the negative clinical criteria group (NCC) and 30% in the positive clinical criteria group (PCC) (RR=9.3; 95% CI=[1.22; 71.4]). The risk of subsequent epilepsy was respectively 16% in the NCC group and 57% in PCC group (RR=5.6; 95% CI=[2.0; 15.6]). Positive predictive value (PPV) of clinical criteria was 28.8% for recurrence and 57.6% for definite epilepsy. Negative predictive value (NPV) of clinical criteria was 93.2% for recurrence and 83.5% for definite epilepsy. The presence of significant abnormalities on early EEG (paroxysms or focal abnormalities) supported an epileptic origin in 17% of clinically uncertain seizures. It was associated with a higher risk of subsequent epilepsy (RR=2.50; 95% CI [1.37; 4.41]; P=0.007), but did not significantly improve the PPV of clinical criteria alone. CONCLUSION: These results may help provide a prognosis at 1 year after a first paroxysmal event of certain or uncertain epileptic origin. Future studies focusing on the outcome after a first epileptic seizure should take into consideration the degree of certainty of the clinical diagnosis and integrate the group of patients with uncertain epileptic seizure.

Paroxysmal hypothermia in two patients with multiple sclerosis.

BACKGROUND: Hypothermia is a rare condition in patients with multiple sclerosis (MS). Only 17 patients have been reported so far. CASE REPORT: We report 2 patients with a long history of MS who presented with severe acute hypothermia associated with thrombocytopenia and hepatic cytolysis. Both patients presented with an aggravation of their neurological status, psychomotor slowing and confusion. There was no clinical or biological sign of infection. Magnetic resonance imaging (1.5 T) revealed bilateral preoptic T(2)-weighted lesions for 1 patient. The neurological status of one patient was worse after the episode of hypothermia than before, which suggests that hypothermia could be a factor of poor prognosis concerning disease progression.

[Hypothalamic involvement in multiple sclerosis]. / Atteintes hypothalamiques dans la sclérose en plaques.

Hypothalamic involvement is a rare condition in patients with multiple sclerosis (MS). We report two patients with a long history of MS who presented with severe acute hypothermia with associated thrombocytopenia and elevated transaminase levels. Several cases of hypothermia or hyperthermia in patients with MS have been reported in the literature. They could be linked with hypothalamic lesions, in particular in the pre-optic area. However, other anatomical locations seem to be involved in thermoregulation and can be affected by MS. Besides, some cases of syndrome of inappropriate antidiuretic hormone secretion have been reported in patients with MS. Finally, some sleep disorders, particularly hypersomnia or narcolepsy, could be related to hypothalamic lesions, through the fall in hypocretin-1 in the cerebrospinal fluid. Hypocretin-1 is a neuropeptide that is secreted by some hypothalamic cells. It plays a role in the sleep-awake rhythm. We report one patient with narcolepsy and cataplexy before the first symptoms of MS appeared. Hypothalamic signs are rare in MS. However, several series of autopsies have shown a high frequency of demyelinating lesions in the hypothalamic area. Among these lesions, the proportion of active lesions seems elevated. Yet only few of them have a clinical or biological translation such as thermoregulation dysfunction, sleep disorders or natremia abnormalities. Thus, it seems unlikely that inflammatory hypothalamic lesions alone, even when bilateral, could be the explanation of these signs. A sufficient number of inflammatory demyelinating lesions, which we can observe in patients with a long history of MS and an already severe disability, is probably necessary to develop such a rare symptomatology. Hypothalamic signs might be a factor of poor prognosis for the disease course and progression of the disability.

Chromosomal aberrations in hepatocellular carcinomas: relationship with pathological features.

Fluorescence in situ hybridization performed on tissue sections can reveal chromosomal abnormalities related to histopathological features. This technique was performed on serial frozen sections from seven normal livers and 29 hepatocellular carcinomas (HCCs) using pericentromeric repeat-specific probes for chromosomes 1, 4, 6, 7, 8, 16, and 17. For each HCC and each probe, the percentage of cells showing one, two, or more than two signals was counted and compared with the distribution in the normal liver. According to these results, HCCs were categorized as monosomic, disomic, or polysomic (more than two signals) for the chromosome tested. These data were compared with the main histopathological characteristics of HCC. Chromosome gains were very common, preferentially affecting chromosome 1 (23 of 27 cases, 85%), chromosome 16 (16 of 27 cases, 59%), chromosome 7 (16 of 29 cases, 55%), chromosome 6 (15 of 29 cases, 52%) and chromosome 8 (14 of 29 cases, 48%). Monosomy was seen more rarely, affecting preferentially chromosome 16 (19%), chromosome 17 (14%), and chromosome 4 (10%). A significant correlation was observed between aneusomy of chromosome 4 and tumor size (P < .05) or the presence of vascular embolism (P < .05). In conclusion, chromosomal gains are frequent genetic events in human HCC. A significant association between a gain in chromosome 4 and large tumor size or vascular embolism suggests that this genetic abnormality is a late event in liver carcinogenesis.

Scintigraphic evidence that the right ventricular myocardium tolerates ischaemia better than the left ventricular myocardium.

To study the incidence of right ventricular infarction and the effect of intracoronary thrombolysis on the ischaemic right ventricular myocardium, we performed intracoronary myocardial thallium scintigraphy in 18 patients with complete occlusion of the right coronary artery who underwent intracoronary thrombolysis. In 15 of these patients, intracoronary thallium-201 and technetium-99 m pyrophosphate scintigrams were performed simultaneously. All 18 patients had a right ventricular thallium defect before thrombolysis, and all had new thallium uptake after thrombolysis. 17 out of 18 patients had a left ventricular thallium defect before thrombolysis, but only 10 of them showed new thallium uptake after thrombolysis. 14 out of 15 patients had a left ventricular technetium-99 m pyrophosphate spot after thrombolysis and some diffuse pyrophosphate accumulation in the area of the right ventricle. In one patient pyrophosphate accumulation was found only in the area of the right ventricle. Thus, right ventricular thallium defects were detected by intracoronary thallium scintigraphy in the majority of patients with inferior acute myocardial infarction due to right coronary artery occlusion. Right ventricular thallium defects were always reversible in contrast to left ventricular thallium defects in the same patients, suggesting that right ventricular myocardium tolerates ischaemia better than left ventricular myocardium.