Cerebral Palsy and Epilepsy

The frequency of epilepsy in children with cerebral palsy is 40 times higher than the common population rate. The presence of epilepsy aggravates the clinical course of cerebral palsy, complicates the rehabilitation, affects the prognosis of motor and intellectual functions, and could be life-threatening. Another problem is the possibility of aggravation of epileptic seizures and their appearance de novo due to application of some neurorehabilitation methods (electrophoresis, acupuncture, nootropic drugs, brain stimulators, etc.). Children with cerebral palsy have a broad spectrum of epilepsies—varying from favorable combinations with benign idiopathic forms to extremely severe epileptic encephalopathies. Frequent combination of epileptic and non-epileptic paroxysms causes difficulty in their interpretation and differential diagnosis. Video-EEG monitoring is the “golden standard” for differential diagnostic of epileptic and non-epileptic events, and it is very useful for investigation of patients with cerebral palsy. Treatment of epilepsy in combination with cerebral palsy strictly requires an individual approach due to the form of epilepsy, seizure types, age of the patient, comorbidity, and somatic and mental condition of the patient

Malignant Migrating Partial Seizures of Infancy (Coppola-Dulac Syndrome)

Malignant migrating partial seizures of infancy (MMPSI) is a rare and usually an unrecognized epileptic syndrome of infancy. The first publication was presented by Coppola and colleagues in 1995, and Dulac in 2005 summarized 24 patients’ follow-up in the Saint Vincent de Paul Hospital in Paris. Clinical cases have demonstrated a new epileptic syndrome, different from previously described forms of epileptic encephalopathies of infancy for the whole world of epileptology. Seizure onset before the age of 6 months but commonly start within a few weeks of birth. In the age of 1 to 10 months seizures become very frequent, polymorphic and usually get clustered nature; mental and motor retardation is clear observed. Clinical manifestation of seizures may include head and eyes version, lateralized clonic eyelid twitchings, fixed gaze, tonic tension or clonias of one limb or hemispasms, axial tonic spasms, chewing or sucking movements, episodes of apnea, flushing, hypersalivation, and secondary generalized seizures. MMPSI could be also considered as a special type of infantile status epilepticus. Video-EEG monitoring plays the most important role in the MMPSI diagnosis. Ictal EEG patterns involve different areas of the cerebral cortex of both hemispheres; initial zone of ictal patterns shifts from one region to another. MMPSI is a drug-resistant epilepsy with serious prognosis

Neurobehavioral, Cognitive, and Paroxysmal Disorders in the Long-Term Period of Pediatric Traumatic Brain Injury

The consequences of the traumatic brain injury (TBI) in children and adolescents represent a major medical and social problem, as TBI interferes in the normal processes of neuroontogenesis. Brain damage in TBI in children and adolescents occurs during the ongoing processes of its growth and maturation, and therefore the clinical course and outcomes may differ significantly from those in adults. Poor outcomes of TBI sustained in early childhood may be explained considerably by the timing of injury in a period of rapid brain and behavioral development. Thus, TBI has a negative impact on the cognitive function development, behavior, school education, and social skills acquisition. Cognitive and behavioral disorders in children and adolescents in the long-term period of TBI become more prominent in co-occurrence with paroxysmal disorders, including posttraumatic headaches, posttraumatic epilepsy, and subclinical epileptiform activity on the EEG. In general, a favorable outcome is possible in children more often than adults even after severe TBI, due to the high neuroplasticity of the developing brain. Therapeutic and rehabilitation measures in the long-term period of TBI in children and adolescents should be intensively carried out both in the first 12 months after TBI, when the most significant results from their use are expected, and in the long-term period, considering the ongoing processes of morpho-functional maturation and neuroplasticity mechanisms

Maternal and neonatal morbidity and mortality among pregnant women with and without COVID-19 Infection: The INTERCOVID multinational cohort study

Importance: Detailed information about the association of COVID-19 with outcomes in pregnant individuals compared with not-infected pregnant individuals is much needed.Objective: To evaluate the risks associated with COVID-19 in pregnancy on maternal and neonatal outcomes compared with not-infected, concomitant pregnant individuals.Design, setting, and participants: In this cohort study that took place from March to October 2020, involving 43 institutions in 18 countries, 2 unmatched, consecutive, not-infected women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge.Exposures: COVID-19 in pregnancy determined by laboratory confirmation of COVID-19 and/or radiological pulmonary findings or 2 or more predefined COVID-19 symptoms.Main outcomes and measures: The primary outcome measures were indices of (maternal and severe neonatal/perinatal) morbidity and mortality; the individual components of these indices were secondary outcomes. Models for these outcomes were adjusted for country, month entering study, maternal age, and history of morbidity.Results: A total of 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women without COVID-19 diagnosis were enrolled, all with broadly similar demographic characteristics (mean [SD] age, 30.2 [6.1] years). Overweight early in pregnancy occurred in 323 women (48.6%) with COVID-19 diagnosis and 554 women (40.2%) without. Women with COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR], 1.76; 95% CI, 1.27-2.43), severe infections (RR, 3.38; 95% CI, 1.63-7.01), intensive care unit admission (RR, 5.04; 95% CI, 3.13-8.10), maternal mortality (RR, 22.3; 95% CI, 2.88-172), preterm birth (RR, 1.59; 95% CI, 1.30-1.94), medically indicated preterm birth (RR, 1.97; 95% CI, 1.56-2.51), severe neonatal morbidity index (RR, 2.66; 95% CI, 1.69-4.18), and severe perinatal morbidity and mortality index (RR, 2.14; 95% CI, 1.66-2.75). Fever and shortness of breath for any duration was associated with increased risk of severe maternal complications (RR, 2.56; 95% CI, 1.92-3.40) and neonatal complications (RR, 4.97; 95% CI, 2.11-11.69). Asymptomatic women with COVID-19 diagnosis remained at higher risk only for maternal morbidity (RR, 1.24; 95% CI, 1.00-1.54) and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). Among women who tested positive (98.1% by real-time polymerase chain reaction), 54 (13%) of their neonates tested positive. Cesarean delivery (RR, 2.15; 95% CI, 1.18-3.91) but not breastfeeding (RR, 1.10; 95% CI, 0.66-1.85) was associated with increased risk for neonatal test positivity.Conclusions and relevance: In this multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were compared. The findings should alert pregnant individuals and clinicians to implement strictly all the recommended COVID-19 preventive measures

Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study

Background: It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors. Objective: This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality. Study Design: This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions. Results: We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32–2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25–2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17–3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99–2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99–5.49) and 6.26 (95% confidence interval, 4.35–9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63–2.86; risk ratio, 2.53; 95% confidence interval, 1.44–4.45; and risk ratio, 2.84; 95% confidence interval, 1.67–4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32–2.35), 2.07 (95% confidence interval, 1.20–3.57), and 2.77 (95% confidence interval, 1.66–4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios. Conclusion: COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol

Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Methods and analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. Ethics and dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. Trial registration number: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200

Fluorescent magnetic nanoparticles for modulating the level of intracellular Ca2+ in motoneurons

This report introduces both synthesis and in vitro biological behaviour of dual magnetic-fluorescent silica nanoparticles. The amino group-decoration of 78 nm sized silica nanoparticles enables their efficient internalization into motoneurons, which is visualized by the red fluorescence arising from [Ru(dipy)(3)](2+) complexes encapsulated into a silica matrix. The internalized nanoparticles are predominantly located in the cell cytoplasm as revealed by confocal microscopy imaging. The magnetic function of the nanoparticles resulted from the incorporation of 17 nm sized superparamagnetic iron oxide cores into the silica matrix, enabling their responsivity to magnetic fields. Fluorescence analysis revealed the "on-off" switching of Ca2+ influx under the application and further removal of the permanent magnetic field. This result for the first time highlights the movement of the nanoparticles within the cell cytoplasm in the permanent magnetic field as a promising tool to enhance the neuronal activity of motoneurons.Web of Science1134161131610

Silica-Supported Assemblage of CuII Ions with Carbon Dots for Self-Boosting and Glutathione-Induced ROS Generation

The present work introduces coordinative binding of CuII ions with both amino-functionalized silica nanoparticles (SNs) and green-emitting carbon dots (CDs) as the pregrequisite for the CuII-assisted self-assembly of the CDs at the surface of the SNs. The produced composite SNs exhibit stable in time stimuli-responsive green fluorescence derived from the CuII-assisted assemblage of CDs. The fluorescence response of the composite SNs is sensitive to the complex formation with glutathione (GSH), enabling them to detect it with the lower limit of detection of 0.15 μM. The spin-trap-facilitated electron spin resonance technique indicated that the composite SNs are capable of self-boosting generation of ROS due to CuII→CuI reduction by carbon in low oxidation states as a part of the CDs. The intensity of the ESR signals is enhanced under the heating to 38 °C. The intensity is suppressed at the GSH concentration of 0.35 mM but is enhanced at 1.0 mM of glutathione, while it is suppressed once more at the highest intracellular concentration level of GSH (10 mM). These tendencies reveal the concentrations optimal for the scavenger or reductive potential of GSH. Flow cytometry and fluorescence and confocal microscopy methods revealed efficient cell internalization of SNs-NH2-CuII-CDs comparable with that of “free” CDs

T2- and T1 relaxivities and magnetic hyperthermia of iron-oxide nanoparticles combined with paramagnetic Gd complexes

The present paper reports the synthesis of iron-oxide nanoparticles (diameter 12.8 +/- 2.2 nm) coated with silica shell doped with paramagnetic Gd(III)-based complexes. The resulting nanoparticles with a silica shell thickness of about 45 nm have an average diameter of 113.1 +/- 14.3 nm and feature high transverse and longitudinal relaxivities (356 and 25 mM(-1) s(-1), respectively) at 1.5 T and 25 degrees C on a medical whole body NMR scanner. It has been also revealed using magnetic heating measurements that the prepared core-shell nanoparticles possess a high specific adsorption rate of around 236 W/g in aqueous media. The surface of the composite nanoparticles was decorated by amino-groups for a greater cellular uptake behaviour. The cell viability measurements reveal the concentration-dependent cytotoxicity of the nanoparticles, which agrees well with the high content of Gd(III) complexes in the nanomaterial. The obtained results show that the core-shell design of nanoparticles with superparamagnetic and paramagnetic parts can be promising for high transverse (and longitudinal) relaxivity as well as magnetic hyperthermia.Web of Science1332art. no. 4

ROS-generation and cellular uptake behavior of amino-silica nanoparticles arisen from their uploading by both iron-oxides and hexamolybdenum clusters

The present work introduces combination of superparamagnetic iron oxides (SPIONs) and hexamolybdenum cluster ([{Mo6I8}I6]2−) units within amino-decorated silica nanoparticles (SNs) as promising design of the hybrid SNs as efficient cellular contrast and therapeutic agents. The heating generated by SNs doped with SPIONs (Fe3O4@SNs) under alternating magnetic field is characterized by high specific absorption rate (SAR = 446 W/g). The cluster units deposition onto both Fe3O4@SNs and “empty” silica nanoparticles (SNs) results in Fe3O4@SNs[{Mo6I8}I6] and SNs[{Mo6I8}I6] with red cluster-centered luminescence and ability to generate reactive oxygen species (ROS) under the irradiation. The monitoring of spin-trapped ROS by ESR spectroscopy technique indicates that the ROS-generation decreases in time for SNs[{Mo6I8}I6] and [{Mo6I8}I6]2− in aqueous solutions, while it remains constant for Fe3O4@SNs[{Mo6I8}I6]. The cytotoxicity is low for both Fe3O4@SNs[{Mo6I8}I6] and SNs[{Mo6I8}I6], while the flow cytometry indicates preferable cellular uptake of the former versus the latter type of the nanoparticles. Moreover, entering into nucleus along with cytoplasm differentiates the intracellular distribution of Fe3O4@SNs[{Mo6I8}I6] from that of SNs[{Mo6I8}I6], which remain in the cell cytoplasm only. The exceptional behavior of Fe3O4@SNs[{Mo6I8}I6] is explained by residual amounts of iron ions at the silica surface