E.U. paediatric MOG consortium consensus: Part 4 - Outcome of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders

There is increasing knowledge on the role of antibodies against myelin oligodendrocyte glycoprotein (MOG-abs) in acquired demyelinating syndromes and autoimmune encephalitis in children. Better understanding and prediction of outcome is essential to guide treatment protocol decisions. Therefore, this part of the Paediatric European Collaborative Consensus provides an oversight of existing knowledge of clinical outcome assessment in paediatric MOG-ab-associated disorders (MOGAD). The large heterogeneity in disease phenotype, disease course, treatment and follow-up protocols is a major obstacle for reliable prediction of outcome. However, the clinical phenotype of MOGAD appears to be the main determinant of outcome. Patients with a transverse myelitis phenotype in particular are at high risk of accruing neurological disability (motor and autonomic), which is frequently severe. In contrast, having a single episode of optic neuritis any time during disease course is broadly associated with a lower risk of persistent disability. Furthermore, MOG-ab-associated optic neuritis often results in good functional visual recovery, although retinal axonal loss may be severe. The field of cognitive and behavioural outcome and epilepsy following demyelinating episodes has not been extensively explored, but in recent studies acute disseminated encephalomyelitis (-like) phenotype in the young children was associated with cognitive problems and epilepsy in long-term follow-up. In conclusion, main domains of importance in determining clinical outcome in paediatric MOGAD are visual, motor, autonomic and cognitive function. A standardised evaluation of these outcome domains in all children is of importance to allow adequate rehabilitation and follow-up

Current international trends in the treatment of multiple sclerosis in children:impact of the COVID-19 pandemic

Background: Only recently has the first disease-modifying therapy been approved for children with multiple sclerosis (MS) and practice patterns including substantial off-label use have evolved. Understanding attitudes towards treatment of paediatric MS and whether this has changed due to the ongoing COVID-19 pandemic is vital to guide future therapeutic trials and for developing guidelines that reflect practice. Methods: We performed an online survey within the International Paediatric Multiple Sclerosis Study Group between July and September 2020. The survey was sent to 130 members from 25 countries and consisted of five sections: demographic data, treatment, disease modifying therapies and COVID-19, outcome and three patient cases. Results: The survey was completed by 66 members (51%), both paediatric neurologists and adult neurologists. Fingolimod and β-interferons were the most frequently used disease-modifying therapies, especially among paediatric neurologists. Almost a third (31%) of respondents had altered their prescribing practice due to COVID-19, in particular at the beginning of the pandemic. Conclusions: The survey results indicate a tendency of moving from the traditional escalation therapy starting with injectables towards an early start with newer, highly effective disease modifying therapies. The COVID-19 pandemic only slightly affected prescribing patterns and treatment choices in paediatric MS

International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis

To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE).After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ?75% agreement).Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3-12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided.These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients.Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

Respiratory control in the newborn : Central chemosensitivity, neuropeptides and nicotinic effects

Breathing is regulated by a complex network of neurons located mainly in the brainstem. For the newborn, it is critical for survival that a continuous respiration is established after birth. However, the regulation of respiration also undergoes maturation in the postnatal period. This thesis focuses on some of the systems modulating respiration that may be of great importance for the newborn: central (C02) chemosensitivity and the neuropeptides substance P (SP) and galanin (GAL). We have also examined how perinatal nicotine exposure interferes with these systems. Areas in the brainstem that contain putative C02 chemoreceptors expressed high levels of c-fos and c-jun mRNA following birth, indicating activation of these areas at this time. Exposure to hypercapnia also evoked expression of c-fos mRNA in several, but not all, of the areas described as chemosensitive in the adult. This may represent a maturational difference in the CO2-sensitivity. Indeed, using flow plethysmography to study the in vivo response to moderate hypercapnia, we found that although a response was present already on postnatal day 1 (P1) this developed during the first 10 postnatal days. We propose that the ventilatory response to hypercapnia develops in a biphasic manner, with a decreasing response until P7 and thereafter an increase, mainly due to increased tidal volumes. Using osmotic minipumps to administer nicotine during gestation we also show that the ventilatory response to moderate hypercapnia was attenuated on P1, possibly reflecting a premature neuronal differentiation. We further demonstrate that GAL is expressed in the prenatal brainstem and that expression then increases postnatally. Also, we found expression of galanin receptor 1 (GALR- 1) in the brainstem already on embryological day 16, and in increasing amounts during later gestation. Postnatally, GALR-1 expression decreased dramatically in the locus coeruleus. The presence of GAL and GALR-1, and the maturational differences, in respiration-related areas of the brainstem present a theoretical involvement of GAL in respiratory control. We could further demonstrate that mortality increased in P1 mice, perinatally exposed to nicotine, during severe hypoxia. These nicotine-treated mice displayed no increased expression of tyrosine hydroxylase (TH) or GAL mRNA in the locus coeruleus following hypoxia, as was seen in control animals. Furthermore, the basal levels of TH mRNA in the adrenals were decreased following perinatal nicotine, also representing a possible deficiency in the defence against hypoxia. Levels of SP mRNA increased immediately following birth in the nucleus of the solitary tract, indicating a role for this neuropeptide in the newborn. Using the neurokinin-1 receptor antagonist RP67580 we could demonstrate that intracerebroventricular injection on P5 altered the hypoxic ventilatory response, without affecting basal respiration. This indicates a role for endogenous SP release when increased demands are put on respiration. It also demonstrates that frequency and volume are regulated separately and that volume is affected also by other neurotransmitters and/or other neurokinin receptors. Using c-fos as a marker of neuronal activation, we found that neurons in the rostral ventrolateral medulla may be responsible for the altered response. Perinatal administration of nicotine (3 mg/kg*day) reduced levels of SP in the brainstem and cerebellum, without affecting SP levels in the forebrain or adrenals. Similar increases are seen after intrauterine hypoxia and in human infants that have succumbed to sudden infant death syndrome. In conclusion, we have demonstrated maturational changes in both the C02-chemosensitive system and the expression patterns of SP and GAL. All these systems were also altered in different ways by perinatal nicotine exposure in the rat and mouse. This supports the idea that perinatal nicotine leads to multiple alterations at a neuronal level, and adds new possible mechanisms underlying the detrimental effect seen following perinatal nicotine exposure

Arterial Stiffness and Carotid Intima‐Media Thickness in Children Exposed to Smokeless Tobacco in Fetal Life

Background Arterial stiffening and increased intima‐media thickness can be seen as early as childhood and are associated with increased risk of cardiovascular events in adult life. The authors hypothesized that exposure to prenatal smokeless tobacco (Swedish snus) without additional nicotine exposure after the breastfeeding period would be associated with increased arterial stiffness and intima‐media thickening in preschool children. Methods and Results This was a longitudinal follow‐up cohort study of children aged 5 to 6 years exposed to high doses of nicotine in utero. Women exclusively using snus and unexposed controls were enrolled in early pregnancy (gestational age range, 6–12 weeks). Exposure data were collected during and after pregnancy with questionnaires from both groups. For this study, only children of women using >48 mg nicotine per day during their entire pregnancy were included in the exposure group. Outcomes were determined in 40 healthy children (21 exposed to snus in utero). Ultrasonography of the common carotid artery was used to determine carotid intima‐media thickness and calculate arterial stiffness index from the relationship between pulsatile changes in arterial diameter and arterial pressure. Children exposed to snus in fetal life had higher carotid stiffness (median 4.1 [interquartile range (IQR), 2.4–5] versus 2.9 [IQR, 2.1–3.5]; P=0.014) than tobacco‐free controls. Carotid strain (relative diameter change) was lower in children exposed to snus (mean 16% [SD, 5.7%] versus 21% [SD, 6.6%]) than in controls (P=0.015). Carotid intima‐media thickness did not differ significantly between children exposed to snus and controls. Conclusions Exposure to snus during fetal life was associated with a stiffer carotid artery in preschool children

Editorial: Advances in diagnosing and treating new-onset refractory status epilepticus (NORSE).

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