We investigated the neural correlates underlying response inhibition and conflict detection processes using ERPs and source localization analyses simultaneously acquired during fMRI scanning. ERPs ...were elicited by a simple reaction time task (SRT), a Go/NoGo task, and a Stroop-like task (CST). The cognitive conflict was thus manipulated in order to probe the degree to which information processing is shared across cognitive systems. We proposed to dissociate inhibition and interference conflict effects on brain activity by using identical Stroop-like congruent/incongruent stimuli in all three task contexts and while varying the response required. NoGo-incongruent trials showed a larger N2 and enhanced activations of rostral anterior cingulate cortex (ACC) and pre-supplementary motor area, whereas Go-congruent trials showed a larger P3 and increased parietal activations. Congruent and incongruent conditions of the CST task also elicited similar N2, P3 and late negativity (LN) ERPs, though CST-incongruent trials revealed a larger LN and enhanced prefrontal and ACC activations. Considering the stimulus probability and experimental manipulation of our study, current findings suggest that NoGo N2 and frontal NoGo P3 appear to be more associated to response inhibition rather than a specific conflict monitoring, whereas occipito-parietal P3 of Go and CST conditions may be more linked to a planned response competition between the prepared and required response. LN, however, appears to be related to higher level conflict monitoring associated with response choice-discrimination but not when the presence of cognitive conflict is associated with response inhibition.
•We manipulate cognitive conflict responses by different choice-discrimination tasks.•ERP components and their cortical sources were recorded inside the MR scanner.•ICA after AAS-based correction improved the quality of EEG data.•Inhibition responses involved increased neural activity in cingulated and motor areas.•High conflict responses showed increased activations of prefrontal areas.
(Headache 2011;51:1267‐1273)
Objective.— The aim of this prospective study is to assess the time lapse between the onset of recurring headache and the correct diagnosis in a cohort of pediatric ...patients attending an Italian children's headache center for the first time.
Methods.— One hundred and one patients and parents, referred to the Pediatric Headache Centre of San Raffaele Hospital in Milan, Italy, underwent a semi‐structured interview to ascertain features of headache since onset (clinical and family history, presence of childhood periodic syndromes, previously undergone instrumental exams and specialists' examinations before the correct diagnosis, past and current treatment). All patients were evaluated by expert neurologists and their headache was classified according to the International Classification of Headache Disorders II (2004).
Results.— The median time delay from the onset of the first episode of recurrent headache to definite diagnosis was 20 months (interquartile range 12 to 36 months). A correlation with younger age and a more delayed headache diagnosis was found (r Spearman = 0.25; P = .039). An association between diagnostic delay and positive family history (median 24 months 12 to 48 vs 12 6 to 24; P = .014) or female gender (median 18 months 12 to 42 vs 12 5 to 30; P trend = .070) was also evident. Notably, 76 out of 101 patients referred to our Center received an appropriate diagnosis according to International Classification of Headache Disorders II at the time of our visit only. Of note, up to 21% of this group were previously misdiagnosed (for epilepsy 43%, sinusitis 38%, or other diseases 19%), a fact that contributed to a longer time of clinical assessment (median 39 months) before reaching a correct diagnosis. The other group of 80 patients (79%) did not receive a specific diagnosis and treatment, and were not studied until their symptom became chronic and disabling.
Conclusion.— Pediatric headache is still under‐diagnosed and not adequately considered as a health problem in the medical community as well as social settings. There is a need for educational programs regarding headache involving not only general practitioners, pediatricians, and neurologists, but also the general population. These are desirable in order to raise awareness of such a condition and, accordingly, treat children accurately.
Alemtuzumab is highly effective in the treatment of patients with relapsing multiple sclerosis (PwRMS) and selectively targets the CD52 antigen, with a consequent profound lymphopenia, particularly ...of CD4+ T lymphocytes. However, the immunological basis of its long-term efficacy has not been clearly elucidated.
We followed up 29 alemtuzumab-treated RMS patients over a period of 72 months and studied the immunological reconstitution of their CD4+ T cell subsets by means of phenotypic and functional analysis and through mRNA-related molecule expression, comparing them to healthy subject (HS) values (rate 2:1).
In patients receiving only two-course alemtuzumab, the percentage of CD4+ lymphocytes decreased and returned to basal levels only at month 48. Immune reconstitution of the CD4+ subsets was characterized by a significant increase (p < 0.001) in Treg cell percentage at month 24, when compared to baseline, and was accompanied by restoration of the Treg suppressor function that increased within a range from 2- to 6.5-fold compared to baseline and that persisted through to the end of the follow-up. Furthermore, a significant decrease in self-reactive myelin basic protein-specific Th17 (p < 0.0001) and Th1 (p < 0.05) cells reaching HS values was observed starting from month 12. There was a change in mRNA of cytokines, chemokines, and transcriptional factors related to Th17, Th1, and Treg cell subset changes, consequently suggesting a shift toward immunoregulation and a reduction of T cell recruitment to the central nervous system.
These data provide further insight into the mechanism that could contribute to the long-term 6-year persistence of the clinical effect of alemtuzumab on RMS disease activity.
Objective
This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID‐19) in people with multiple sclerosis ...(PwMS).
Methods
We retrospectively collected data of PwMS with suspected or confirmed COVID‐19. All the patients had complete follow‐up to death or recovery. Severe COVID‐19 was defined by a 3‐level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID‐19 by multivariate and propensity score (PS)‐weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.
Results
Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID‐19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty‐eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized.
After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti‐CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio OR = 2.37, 95% confidence interval CI = 1.18–4.74, p = 0.015) with increased risk of severe COVID‐19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20–12.53, p = 0.001). Results were confirmed by the PS‐weighted analysis and by all the sensitivity analyses.
Interpretation
This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID‐19 pandemic persists. ANN NEUROL 2021;89:780–789
The exclusion of other diseases that can mimic multiple sclerosis (MS) is the cornerstone of current diagnostic criteria. However, data on the frequency of MS mimics in real life are incomplete.
A ...total of 695 patients presenting with symptoms suggestive of MS in any of the 22 RIREMS centers underwent a detailed diagnostic workup, including a brain and spinal cord MRI scan, CSF and blood examinations, and a 3-year clinical and radiologic follow-up.
A total of 667 patients completed the study. Alternative diagnoses were formulated in 163 (24.4%) cases, the most frequent being nonspecific neurologic symptoms in association with atypical MRI lesions of suspected vascular origin (40 patients), migraine with atypical lesions (24 patients), and neuromyelitis optica (14 patients). MS was diagnosed in 401 (60.1%) patients according to the 2017 diagnostic criteria. The multivariate analysis revealed that the absence of CSF oligoclonal immunoglobulin G bands (IgG-OB) (odds ratio OR 18.113), the presence of atypical MRI lesions (OR 10.977), the absence of dissemination in space (DIS) of the lesions (OR 5.164), and normal visual evoked potentials (OR 3.550) were all independent predictors of an alternative diagnosis.
This observational, unsponsored, real-life study, based on clinical practice, showed that diseases that mimicked MS were many, but more than 45% were represented by nonspecific neurologic symptoms with atypical MRI lesions of suspected vascular origin, migraine, and neuromyelitis optica. The absence of IgG-OB and DIS, the presence of atypical MRI lesions, and normal visual evoked potentials should be considered suggestive of an alternative disease and red flags for the misdiagnosis of MS.
Background
The detection of antibodies to myelin oligodendrocyte glycoprotein (MOG) is fundamental for the identification of MOG antibody-associated disorders (MOGAD), and the differential diagnosis ...of acquired demyelinating syndromes of the CNS, among which multiple sclerosis (MS). We compared the diagnostic performance of four cell-based assays (CBAs) for their detection.
Methods
Consecutive sera from 204 patients with ‘possible MOGAD’ (55), MS (112), and other neurological disorders (OND, 37) were tested for MOG-IgG with a live-CBA with anti-heavy-and-light chain secondary-antibody (LCBA-IgG
H+L
), and a live-CBA for IgG
1
(LCBA-IgG
1
). A subgroup of 71 patients was additionally tested with a live-CBA with anti-Fcγ secondary-antibody (LCBA-IgG
Fcγ
), and a commercial fixed-CBA with anti-Fcγ secondary-antibody (FCBA-IgG
Fcγ
)
.
Results
Fifty-seven/204 patients (27.9%) were MOG-IgG-positive. Sensitivity was 89.1% (CI:77.8–95.9) and specificity 93.3% (CI:88.0–96.7) for LCBA-IgG
H+L
, and 74.6% (CI:61.0–85.3) and 100% (CI:97.6–100) for LCBA-IgG
1
. Eighteen of 57 (31%) samples showed discrepant results (all negative on LCBA-IgG
1
); of these, three with ‘possible MOGAD’ showed high-titer MOG-IgG (≥ 1:640), and positivity for MOG-IgG
2
, whereas 15/18 had low-titer MOG-IgG (1:160/1:320) and mixed diagnoses (5 ‘possible MOGAD’, 6 MS, 4 OND). In the subgroup analysis, sensitivity was 92.3% (CI:79.1–98.4) and specificity 97.0% (CI:83.8–99.9) for LCBA-IgG
Fcγ
, and 87.2% (CI:72.6–95.7) and 97.0% (CI:83.8–99.9) for FCBA-IgG
Fcγ
.
Conclusions
LCBA-IgG
1
showed the highest specificity but can miss MOG-IgG
2
reactivities, whose meaning warrants further investigations. Titration of samples tested with LCBA-IgG
H+L
/ IgG
Fcγ
is important for meaningful interpretation of the results. In the subgroup analysis, LCBA-IgG
Fcγ
yielded the highest accuracy, and FCBA-IgG
Fcγ
good specificity, but it was at risk of false-negative results.
To assess the risk of disease reactivation during pregnancy after natalizumab suspension in women with multiple sclerosis (MS).
Data of all pregnancies occurring between 2009 and 2015 in patients ...with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents through a 2-factor repeated measures analysis. Predictors of disease activity were assessed through stepwise multivariable logistic regression models.
A total of 92 pregnancies were tracked in 83 women receiving natalizumab. Among these pregnancies, 74 in 70 women resulted in live births, with a postpartum follow-up of at least 1 year, and were compared with 350 previously published pregnancies. Relapse rate during and after pregnancy was higher in women treated with natalizumab (
< 0.001). In multivariable analysis, longer natalizumab washout period was the only predictor of relapse occurrence during pregnancy (
= 0.001). Relapses in the postpartum year were related to relapses during pregnancy (
= 0.019) and early reintroduction of disease-modifying drugs (DMD;
= 0.021). Disability progression occurred in 16.2% of patients and was reduced by early reintroduction of DMD (
= 0.024).
Taken as a whole, our findings indicate that the combination of avoiding natalizumab washout and the early resumption of DMD after delivery could be the best option in the perspective of maternal risk. This approach must take into account possible fetal risks that need to be discussed with the mother and require further investigation.
This study provides Class IV evidence that in women with MS, the risk of relapses during pregnancy is higher in those who had been using natalizumab as compared to those who had been using interferon-β or no treatment.
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