Radiological Disease Activity in Secondary Progressive Multiple Sclerosis.

INTRODUCTION: MRI activity is less frequent among secondary progressive multiple sclerosis (SPMS) patients. In the current study, we aimed to identify SPMS patients with higher radiological disease activity (RDA) and determine their clinical characteristics. METHODS: We evaluated the occurrence of RDA in SPMS patients followed at the Sheba Multiple Sclerosis Center between January 1, 2015, and December 31, 2020. All patients underwent brain and spinal cord MRI examinations as a routine follow-up unrelated to clinical disease activity. Patients were subdivided into RDA and non-RDA MRI groups based on the presence of active gadolinium-enhancing T1 lesions and/or new/enlarging T2 lesions. Demographic variables and disease-related data were compared. RESULTS: One hundred consecutive SPMS patients, 74 females, median age of 50 years, disease duration of 19.5 years, and neurological disability by the Expanded Disability Status Scale (EDSS) score of 6.0, were included in the study. The RDA group comprised 35 patients (35%), of them 65.7% (n = 23) exhibited only brain MRI activity, 22.8% (n = 8) only spinal cord MRI activity, and 11.4% (n = 4) had both. Patients in the RDA group were diagnosed at a younger mean (SD) age of 28.2 (8.9) versus 33.7 (10.1) years and were younger with a mean (SD) age of 47.8 (9.9) versus 53.4 (10.1) years, as compared with the non-RDA group. No significant differences were found in relation to disease duration, EDSS, exposure to immunomodulatory treatments, and duration of immunomodulatory treatments. CONCLUSIONS: RDA unrelated to clinical symptomatology was more frequent in a subgroup of young SPMS patients.

Thrombin Activity in Rodent and Human Skin: Modified by Inflammation and Correlates with Innervation.

Thrombin is present in peripheral nerves and is involved in the pathogenesis of neuropathy. We evaluated thrombin activity in skin punch biopsies taken from the paws of male mice and rats and from the legs of patients with suspected small-fiber neuropathy (SFN). In mice, inflammation was induced focally by subcutaneous adjuvant injection to one paw and systemically by intraperitoneal lipopolysaccharides (LPS) administration. One day following injection, thrombin activity increased in the skin of the injected compared with the contralateral and non-injected control paws (p = 0.0009). One week following injection, thrombin increased in both injected and contralateral paws compared with the controls (p = 0.026), coupled with increased heat-sensitivity (p = 0.009). Thrombin activity in the footpad skin was significantly increased one week after systemic administration of LPS compared with the controls (p = 0.023). This was not accompanied by increased heat sensitivity. In human skin, a correlation was found between nerve fiber density and thrombin activity. In addition, a lower thrombin activity was measured in patients with evidence of systemic inflammation compared with the controls (p = 0.0035). These results support the modification of skin thrombin activity by regional and systemic inflammation as well as a correlation with nerve fiber density. Skin thrombin activity measurments may aid in the diagnosis and treatment of SFN.

COVID-19 vaccination in patients with multiple sclerosis: What we have learnt by February 2021.

BACKGROUND: Since vaccination against coronavirus disease 2019 (COVID-19) became available, risks related to vaccinating patients with multiple sclerosis (MS) need to be carefully assessed. OBJECTIVE: Characterize safety and occurrence of immediate relapses following COVID-19 vaccination in a large cohort of MS patients. METHODS: We assessed the safety of BNT162b2 COVID-19 vaccination in adult MS patients. RESULTS: Between 20 December 2020 and 25 January 2021, 555 MS patients received the first dose of BNT162b2 vaccine and 435 received the second dose. There were three cases of COVID-19 infection encountered after the first dose. Safety profile of COVID-19 vaccine was characterized by pain at the injection site, fatigue, and headache. No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively. The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, similar to the rate in non-vaccinating patients during the corresponding period. Mild increase in the rate of adverse events was noted in younger patients (18-55 years), among patients with lower disability (Expanded Disability Status Scale (EDSS) ⩽3.0), and in patients treated with immunomodulatory drugs. CONCLUSION: COVID-19 BNT162b2 vaccine proved safe for MS patients. No increased risk of relapse activity was noted.

Markers for neural degeneration and regeneration: novel highly sensitive methods for the measurement of thrombin and activated protein C in human cerebrospinal fluid.

Inflammation and coagulation are tightly interconnected in the pathophysiology of neuronal diseases. Thrombin, a pro-coagulant serine protease is associated with neurodegeneration and its indirect inhibitor, activated protein C (aPC), is considered neuroprotective. While levels of thrombin and aPC activity are readily measured in the blood, similar assays in the cerebrospinal fluid (CSF) have not been described. The aim of this study was to establish a specific and sensitive enzymatic assay to measure both thrombin and aPC activity in the CSF. CSF was collected from 14 patients with suspected normal pressure hydrocephalus served as a control group, while seven patients with central nervous system infections served as an acute neuro-inflammatory study group and one sample of CSF following traumatic lumbar puncture served as a positive control. Thrombin and aPC activities were measured by fluorescence released by specific proteolytic cleavage in the presence of endopeptidase and amino-peptidase inhibitors to ensure specificity. Specificity of the method was verified by thrombin and serine-protease inhibitors N-alpha-((2-naphthylsulfinyl)glycyl)-DL-p-amidinophenylalanylpiperidine and phenylmethanesulfonyl fluoride. Inhibition of thrombin activity by CSF samples and levels of specific thrombin inhibitors were also assessed. Thrombin and aPC activities were reliably measured and were significantly higher in the CSF of patients with central nervous system infections compared to normal pressure hydrocephalus controls, suggesting the involvement of these factors in neuro-inflammation. CSF thrombin activity levels in the presence of known thrombin concentration were high in patients with central nervous system infections, and low in normal pressure hydrocephalus patients. Quantification of endogenous thrombin inhibitors protease nexin 1, amyloid precursor protein and anti-thrombin III in CSF by western blot indicated a significant elevation of amyloid precursor protein in infectious CSF. In conclusion, this study describes a novel and sensitive assay aimed at the detection of thrombin and aPC activity in CSF. This method may be useful for measuring these factors that reflect degenerative and protective influences of coagulation on neurological disorders. The study procedure was approved by the Ethics Committee of the Chaim Sheba Medical Center (approval No. 4245-17-SMC) on October 18, 2018.

Anti-MDA5 Positive Dermatomyositis Associated with Rapidly Progressive Interstitial Lung Disease and Correlation between Serum Ferritin Level and Treatment Response.

Clinically amyopathic dermatomyositis is an uncommon autoimmune disorder in the Middle East. The clinical picture of clinically amyopathic dermatomyositis is characterized mainly by pulmonary and dermatological manifestations. Occasionally muscle symptoms are observed as well. Serum anti-MDA5 autoantibody positivity is associated with rapidly progressive interstitial lung disease among clinically amyopathic dermatomyositis patients. Moreover, high serum ferritin level is correlated with poor prognosis and high mortality. Herein we describe the case of an Israeli patient with rapidly progressive interstitial lung disease and without pathognomonic dermatological features who was diagnosed with anti-MDA5 positive clinically amyopathic dermatomyositis and did not survive despite immunomodulatory therapy followed by reduction in serum ferritin levels.