Humoral and cellular immune response from first to fourth SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients-a longitudinal cohort study.

Background: This study examines the humoral and cellular response in multiple sclerosis (MS) patients on anti-CD20 therapy before and after the 1st to 4th BNT162b2 mRNA SARS-CoV-2 vaccination and the relationship with breakthrough infection. Methods: Participants with McDonald 2017 MS that were treated with ocrelizumab were included. The study duration was throughout the COVID-19 pandemic until four months after fourth mRNA SARS-CoV-2 vaccination (BNT162b2). Longitudinal blood samples were analysed for: IgG antibodies of SARS-CoV-2 spike anti-receptor binding domain (anti-RBD), nucleocapsid IgG antibodies (anti-N) and activation induced marker expressing CD4+, CD8+ T-cells and concentration of ocrelizumab and anti-drug antibodies. Incidences of breakthrough infection were confirmed with SARS-CoV-2 PCR tests. Results: The rate of anti-RBD positive participants increased substantially between the third and fourth vaccination from 22.2% to 55.9% (median 54.7 BAU/mL; IQR: 14.5 - 221.2 BAU/mL and 607.7 BAU/mL; IQR: 29.4 - 784.6 BAU/mL, respectively). Within the same period 75% of participants experienced breakthrough infection. The fourth vaccination resulted in an additional increase in seropositive individuals (64.3%) (median 541.8 BAU/mL (IQR: 19.1-1007 BAU/mL). Breakthrough infection did not influence the cellular response without a significant change after the fourth vaccination. During the study period two participants had detectable anti-N, both after the fourth vaccination. No correlation was found between serum concentration of ocrelizumab and the humoral and cellular response. Discussion: Low levels or absence of specific anti-RBD following vaccination, with a significant increase after breakthrough infections and boosted by the fourth vaccination. T-cell reactivity remained sustained and unaffected by breakthrough infections.

Exploring the peripheral mechanisms of lower limb immobilisation on muscle function using novel electrophysiological methods.

OBJECTIVE: To explore the effects of short-term immobilisation and subsequent retraining on peripheral nervous system (PNS) measures using two novel electrophysiological methods, muscle velocity recovery cycles (MVRC) and MScanFit motor unit number estimation (MUNE) alongside lower limb muscle strength, muscle imaging and walking capacity. METHODS: Twelve healthy participants underwent 1-week of ankle immobilisation and 2-weeks of retraining. Assessments before and after immobilisation, and after retraining, included MVRC [muscle membrane properties; muscle relative refractory period (MRRP), early and late supernormality], MScanFit, MRI-scans [muscle contractile cross-sectional area (cCSA)], isokinetic dynamometry [dorsal and plantar flexor muscle strength], and 2-minute maximal walk test [physical function]. RESULTS: After immobilisation, compound muscle action potential (CMAP) amplitude reduced (-1.35[-2.00;-0.69]mV); mean change [95%CI]) alongside reductions in plantar (but not dorsal) flexor muscle cCSA (-124[-246;3]mm2), dorsal flexor muscle strength (isometric -0.06[-0.10;-0.02]Nm/kg, dynamicslow -0.08[-0.11;-0.04]Nm/kg, dynamicfast no changes), plantar flexor muscle strength (isometric -0.20[-0.30;-0.10]Nm/kg, dynamicslow -0.19[-0.28;-0.09]Nm/kg, dynamicfast -0.12[-0.19;-0.05]Nm/kg) and walking capacity (-31[-39;-23]m). After retraining, all immobilisation-affected parameters returned to baseline levels. In contrast, neither MScanFit nor MVRC were affected apart from slightly prolonged MRRP in gastrocnemius. CONCLUSIONS: PNS do not contribute to the changes observed in muscle strength and walking capacity. SIGNIFICANCE: Further studies should include both corticospinal and peripheral mechanisms.

Persistently reduced humoral and sustained cellular immune response from first to third SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients.

OBJECTIVE: To examine humoral and cellular response in multiple sclerosis patients on anti-CD20 therapy after third BNT162b2 mRNA SARS-CoV-2 vaccination. METHODS: A prospective longitudinal study design from first throughout third vaccination in Danish and American MS centers. All participants were treated with ocrelizumab. Antibody (Ab) levels were assessed before and after third vaccination using SARS-CoV-2 IgG II Quant assay (Abbott Laboratories). B- and T-lymphocytes enumeration was done with BD Multitest™6-color TBNK reagent. Spike-specific T-cell responses were measured through PBMC stimulation with spike peptide pools (JPT Peptide Technologies). RESULTS: We found that 14.0%, 37.7%, and 33.3% were seropositive after first, second and third vaccination. The median Ab-levels were 74.2 BAU/mL (range: 8.5-2427) after second vaccination, as well as 43.7 BAU/ml (range: 7.8-366.1) and 31.3 BAU/mL (range: 7.9-507.0) before and after third vaccination, respectively. No difference was found in levels after second and third vaccination (p = 0.1475). Seropositivity dropped to 25.0% of participants before the third vaccination, a relative reduction of 33.3% (p = 0.0020). No difference was found between frequencies of spike reactive CD4+and CD8+ T-cells after second (0.65 ± 0.08% and 0.95 ± 0.20%, respectively) and third vaccination (0.99 ± 0.22% and 1.3 ± 0.34%, respectively). CONCLUSION: In this longitudinal cohort we found no significant increased humoral or cellular response with administration of a third SARS-CoV-2 mRNA vaccination. These findings suggest the need for clinical strategies to include allowance of B cell reconstitution before repeat vaccination and/or provision of pre-exposure prophylactic monoclonal antibodies.

The operational definition of epileptiform discharges significantly improves diagnostic accuracy and inter-rater agreement of trainees in EEG reading.

To assess whether trainees can learn and implement the operational definition of interictal epileptiform discharges (IEDs) of the International Federation of Clinical Neurophysiology (IFCN), based on six morphological criteria, and whether its implementation improves their diagnostic performance and inter-rater agreement (IRA). Seven trainees evaluated a balanced dataset of 70 EEG samples containing sharp transients (35 from patients with epilepsy and 35 from patients with non-epileptic paroxysmal events). The gold standard was derived from video-EEG recordings of the habitual clinical episodes. The trainees individually reviewed the EEGs, blinded to all other data, in two successive training sessions, three months apart. The second session was preceded by a teaching module about the IFCN criteria, and the trainees implemented them during the second reading session. By implementing the IFCN criteria, trainees significantly improved their specificity (94.29% vs. 77.14%; p=0.01) and overall accuracy (81.43% vs. 64.29%; p=0.01) for identifying IEDs. Sensitivity also improved but did not reach the level of statistical significance (77.14% vs. 60%; p=0.07). IRA improved significantly from fair (k=0.31; 95% CI: 0.22-0.40) to high-moderate (k=0.56; 95% CI:0.46-0.67) beyond-chance agreement. Implementing the IFCN criteria significantly improves the diagnostic performance and IRA of trainees in identifying IEDs. Teaching the IFCN criteria for IEDs will increase specificity in clinical EEG and avoid over-reading, the most common cause of misdiagnosing epilepsy.

Muscle Velocity Recovery Cycles to Examine Muscle Membrane Properties.

Although conventional nerve conduction studies (NCS) and electromyography (EMG) are suitable for the diagnosis of neuromuscular disorders, they provide limited information about muscle fiber membrane properties and underlying disease mechanisms. Muscle velocity recovery cycles (MVRCs) illustrate how the velocity of a muscle action potential depends on the time after a preceding action potential. MVRCs are closely related to changes in membrane potential that follow an action potential, thereby providing information about muscle fiber membrane properties. MVRCs may be recorded quickly and easily by direct stimulation and recording from multi-fiber bundles in vivo. MVRCs have been helpful in understanding disease mechanisms in several neuromuscular disorders. Studies in patients with channelopathies have demonstrated the different effects of specific ion channel mutations on muscle excitability. MVRCs have been previously tested in patients with neurogenic muscles. In this prior study, muscle relative refraction period (MRRP) was prolonged, and early supernormality (ESN) and late supernormality (LSN) were reduced in patients compared to healthy controls. Thereby, MVRCs can provide in vivo evidence of membrane depolarization in intact human muscle fibers that underlie their reduced excitability. The protocol presented here describes how to record MVRCs and analyze the recordings. MVRCs can serve as a fast, simple, and useful method for revealing disease mechanisms across a broad range of neuromuscular disorders.

Correction: Traumatic spinal cord injury due to human tower accident in Catalonia.

[This corrects the article DOI: 10.1038/s41394-018-0142-z.].

Traumatic spinal cord injury due to human tower accident in catolonia.

Study design: Retrospective case series. Objectives: The aim of this paper was to review the cases of SCI associated with human towers in the neurorehabilitation hospital Guttmann in Barcelona, clarify the mechanisms of these accidents and classify the injuries. Settings and methods: Data and history were retrospectively reviewed to detect SCI patients injured from human tower accidents admitted at the Guttmann Institute, Barcelona, in the period 1965-2017, from patient histories and interviews with patients and their relatives. Results: In total, five men with SCI acquired from "human tower" accidents were admitted between 1988 and 2017. All of them were at the base of the tower. They were all injured at cervical level, with very severe injury (AIS-A in two, AIS-B in one, and AIS-C in two). Two died due to pneumonia associated to mechanical ventilation at 4 and 10 years post injury. Conclusion: Human tower is a rare cause of traumatic tetraplegia in Catalonia. People forming the base of the tower are at greater risk for injury. Moreover, in our case series, all accidents causing SCI occurred when the human tower was greater than seven levels and had over three participants at each level.

Reducing delay of carotid endarterectomy in acute ischemic stroke patients: a nationwide initiative.

BACKGROUND AND PURPOSE: Guidelines recommend carotid endarterectomy (CEA) within 2 weeks from an ischemic event. However, previous studies have shown that only a minority of patients undergo CEA within this period. The aim of this study was to examine the effect of a multidisciplinary nationwide initiative aimed at reducing time to CEA after acute ischemic stroke. METHODS: We examined a historic population-based observational cohort based on individual patient-level records from the Danish Stroke Registry and the Danish Vascular Registry. The implementation of early ultrasound examination of the carotids (within 4 days from admission) in medical departments coupled with fast CEA after referral to a department of vascular surgery were monitored and audited systematically from 2008 and onward. RESULTS: A total of 813 acute ischemic stroke patients underwent CEA during 2007-2010. The percentage of patients undergoing CEA within 2 weeks increased from 13% in 2007 to 47% in 2010 (adjusted odds ratio, 5.8 [95% CI, 3.4-10.1]). The overall median time decreased from 31 days to 16 days. The percentage of relevant acute ischemic stroke patients receiving early ultrasound examination of the carotids increased from 41% in 2008 to 72% in 2010. The time from referral to operation at a vascular department was reduced by ≈40%. CONCLUSIONS: Establishing time limits of 4 days to ultrasound examination of the carotids and of 2 weeks to CEA from onset of stroke followed by a systematic multidisciplinary monitoring and auditing of processes was associated with a substantial increase in the proportion of acute ischemic stroke patients who undergo CEA within 2 weeks in Denmark.