Acute Febrile Encephalopathy

COVID-19 in Children and Newborn

COVID 19 has already affected more than 191 million people worldwide and has claimed more than 4 million lives to date (22nd July 2021). Yet, we still do not completely understand this disease. Data on children are even more sparse, making it difficult to lay down a comprehensive guideline for the same.

However, thanks to a handful of studies, we now understand that children are less affected, are less infectious, have lesser mortality and risk of complications. Children with underlying chronic diseases and infants under 1 year are especially at risk and are advised selective shielding. Diagnosis is done by RT-PCR or serology, just like in adults. Most affected children are asymptomatic, and even the symptomatic children have a good outcome and usually need supportive management and monitoring only. Up to 7% of children were found to require PICU support, and mortality was less than 2%. Most deaths were attributed to underlying conditions and immunological complications, especially MIS-C. Treatment is predominantly supportive, with little consensus on specific treatments, including corticosteroids, remdesivir, and IVIg. Management is best individualized by a multidisciplinary team involving pediatricians, hematologists, immunologists, and intensivists. Prevention of COVID 19 can be achieved by proper hygiene, face masks, and social distancing. The upcoming vaccines are expected to bring down the cases and hopefully bring this pandemic to a halt.

Subject Index

Updates on Childhood-Onset Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is a chronic, autoimmune, and multisystem disease. Childhood-onset SLE (cSLE) contributes up to 20% of all cases of SLE and refers to patients who develop the disease before their 18th anniversary. Impressive discoveries in all aspects of the disease emerge every day; one of the most interesting is whether cSLE is a single or a group of diseases, with diverse physiopathologic processes but sharing a rough phenotype. Patients with early onset disease (<5 years), with associated infections and severe disease manifestations, should urge the possibility of monogenic SLE, which represents a small proportion of all cSLE cases, but often with a more complicated clinical course. Despite its being considered a rare disease, the clinical outcomes could be devastating. Patients with cSLE had higher disease activity indexes than adults. Although the survival has improved, it also implies that patients remain a longer period under the effects of the disease. Enormous advances in the understanding of the physiopathological processes are helping to better diagnose children with lupus; still, we are distant to have a perfectly fitted therapy for all our patients. The outstanding efforts of clinicians and researchers to find new therapeutic strategies are encouraging. In this chapter, you will find a concise description of the novel advancements concerning the disease pathogenesis, classification, assessment of disease activity, treatment, and outcomes.

Updates on Pediatric Demyelinating Disorders

Myelin is a protective layer that enwraps the axonal terminals and is an essential component of the central nervous system white matter. Loss of myelin leads to conduction block in the axon leading to demyelinating disorders. Inherited poor formation of myelin is known as hypomyelination, and abnormally formed myelin is called dysmyelination. Demyelinating disorders exclude diseases where degeneration of the axon is the initial event and myelin is degraded secondarily. Most neurologists use the term demyelination only for acquired forms of loss of myelin with relative preservations of axons due to inflammation such as multiple sclerosis. Demyelinating disease in children may be monophasic (e.g., acute disseminated encephalomyelitis, optic neuritis, and transverse myelitis) or chronic (multiple sclerosis and neuromyelitis optica). Pediatric multiple sclerosis is the most common demyelinating disorder in children. Recent genetic and clinical researches have significantly improved our understanding of the diverse spectrum of pediatric demyelinating disorders. In this chapter, an updated summary of the current knowledge on the categories, diagnosis, as well as management of pediatric demyelinating disorders has been presented.

Anthelmintic Drug Discovery: Current Situation and Future Perspectives

Nematode parasites cause several neglected tropical diseases in humans such as lymphatic filariasis, onchocerciasis (river blindness), and soil-transmitted helminthiasis. Approximately 30% of the human world population is infected with at least one parasite and this prevalence could be even higher in rural areas and lowincome countries. Although nematode infections are rarely lethal, they are associated with morbidity and severe consequences, particularly in children.

There are several concerns about the management and treatment of these diseases. Currently, the repertoire of nematocidal agents is limited, and these drugs are not 100% effective against all nematode parasitosis. In addition, the extensive use of these few drugs in massive administration campaigns in humans would probably lead to the development of resistance very soon. Further worsening the situation, the interest of the pharmacological industry in developing novel anthelmintics is low since these infections are mostly endemic in poor countries that do not constitute a profitable market. Under this alarming scenario, there is an urgent need to develop new and broad-spectrum antiparasitic drugs.

Traditional preclinical drug discovery is a long, expensive, and complex process. Thus, innovative strategies and alternative models, such as the free-living nematode Caenorhabditis elegans, are required to reduce costs and accelerate times. Its genetic amenability and the feasibility of performing high-throughput screening assays, convert this nematode into an excellent platform for nematocidal drug screening.

This chapter summarizes the current situation on antiparasitic drug discovery and discusses the use of C. elegans at the initial steps of drug development to accelerate the appearance of new drugs.

Clinical, Epidemiological, Immunological and Molecular Characteristics of Malaria

Malaria remains a major health problem with 0.58 million of deaths in 2013. Malaria pathogenesis involves complex molecular interactions between parasite and host that lead to a wide variety of clinical symptoms. Among people living in endemic regions, only a fraction of infected people develops severe disease such as cerebral malaria, severe anemia and respiratory distress. This inter-individual variability may be explained by the parasite genetic diversity and the host genetic susceptibility. Children are susceptible to malaria disease and death until they develop an adaptive immunity after multiple exposures to parasite during their childhood. Several host genetic factors that may alter this immune response have already been identified. However, the molecular aspects are not fully understood and a major challenge is to identify these factors to progress in the understanding of the pathophysiological mechanisms and to propose new therapeutic strategies.

Stem Cell Therapy for Brain Injury in Neonates

Neonatal brain injury encompasses hypoxic-ischemic encephalopathy (HIE), perinatal stroke, and white matter injury. The estimated incidence of HIE in developed countries is 1.5 in 1,000 live births. Hypothermia therapy improves neurodevelopmental outcomes in only 53% of treated HIE patients. Perinatal stroke occurs in 1 per 1,600 births and is a major cause of cerebral palsy and developmental impairments. Periventricular white matter injury affects 50% of premature neonates and accounts for 90% of neurologic deficits in survivors.

Stem cell therapy has emerged as a potential treatment for neonatal brain injury. This review will present the state of the art for stem cell therapy in neonatal brain injury.

Uncommon Cause of Stroke: Diagnosis and Treatment (Part II)

This chapter contains detailed, up-to-date information about the nature, diagnosis, and treatment of those relatively uncommon types of cerebrovascular disease that cause strokes. Although many of the conditions discussed are rare, the chapter covers the causes of up to 10% to 15% of all strokes and of up to 40% of strokes in young adults. This chapter may be an essential resource to help physicians diagnose and treat stroke patients who do not fit well into the usual clinical categories.

Discussed in this chapter are the various form of inherited small vessel disease such as CADASIL but even the less known Col 4A1/2 related syndromes, CARASIL, TREX1- gene mutations disorders and the cerebroretinal microangiopathy with calcifications and cysts. Three form of metabolic disorders causing stroke such as Fabry disease, Homocystinuria and MELAS as well as the most relevant form of hematological disorders (antifospholipid syndrome and sickle cell disease) are discussed. Finally intriguing disorders such as migrainous infarction and drugs related stroke disorders are detailed as well as some other rare disease such as Kohlmeier–Degos disease and acute posterior multifocal placoid pigment epiteliopathy.

Principles and Current Issues of Antiepileptic Drug Therapy

The armamentarium to treat epilepsy includes today more than twenty drugs. These are classically distinguished as standard, traditional or first generation antiepileptic drugs (AEDs), which include phenobarbital, phenytoin, carbamazepine, valproic acid, ethosuximide and benzodiazepines, and new or second generation AEDs, which are vigabatrin, lamotrigine, felbamate, gabapentin, oxcarbazepine, tiagabine, topiramate, stiripentol, pregabalin, levetiracetam, rufinamide, zonisamide. More recently, other four compounds have been introduced, i.e., lacosamide, retigabine, eslicarbazepine acetate and perampanel, also defined as third generation AEDs. The mechanism of antiepileptic action is mainly mediated by increase in inhibitory GABA activity and/or prolongation of sodium and/or calcium channel inactivation. From a pharmacokinetic point of view, the most relevant difference characterizing a number of the recent AEDs as compared to the traditional ones is the lack of or a milder induction of hepatic enzymes with consequent reduced risk of drug-drug interactions. Concerning therapeutic features, valproic acid exhibits the broadest spectrum of action and still remains the only AED which can be used to treat all types of seizures, from absences and other primarily generalized seizures to focal ones, and almost all syndromes. Among the recent compounds, lamotrigine, topiramate, levetiracetam and zonisamide have shown to be efficacious in primarily generalized seizures and in some idiopathic generalized epilepsies, but their effect against absence seizures is less potent than that of valproic acid or even irrelevant. All AEDs, except ethosuximide, exhibit similar efficacy against focal seizures and, apart from traditional drugs, lamotrigine, oxcarbazepine, gabapentin, topiramate and levetiracetam, and ZNS in Europe, have the indication of mono-therapy. Some of the new compounds have specific paediatric indications: vigabatrin against infantile spasms in West syndrome, felbamate and rufinamide against mixed seizures in the Lennox-Gastaut syndrome, and stiripentol against some types of seizures in Dravet syndrome. In spite of this variety of AEDs, the percentage of patients with refractory epilepsy has not changed over the last 50 years and is still stabilized around 30-40%. Adverse events are observed in one-third of patients on AED therapy. Frequent, unspecific and usually dose dependent CNS side effects occur with almost all AEDs and encompass sedation, somnolence, fatigue, and dizziness, usually attenuating or even disappearing over time. Acute idiosyncratic effects, such as skin rush, may be particularly troubling and may configure a hypersensitivity syndrome with rapid degeneration to a severe and even life-threatening condition. Felbamate and vigabatrin are used exceptionally because of high incidence of aplastic anemia and liver failure occurring with the first and irreversible loss of visual field occurring with the second one. Subtle and slowly developing adverse effects, like bone mineral density reduction associated especially with traditional enzyme-inducing AEDs, require a continuous monitoring of the patient clinical condition. Antiepileptic therapy has special implications for women of child bearing age with regard to contraception, pregnancy and teratogenicity. There is some evidence that teratogenic effects, particularly frightening with valproic acid, with > 400mg/day dose of carbamazepine, and with polytherapies, are less frequent with lamotrigine. Given the large number of available AEDs, opportunities to tailor drug therapy on the individual patient are various. Treatment decisions, however, are complex and need to be individualised on the basis of careful evaluation of a number factors related to drug, disease and the patient. Choice of first-line therapy for a specific form of epilepsy, the time at which the drug should be started, and which strategy is most appropriate after failure of the first drug are key decision steps. Patient-specific factors include age, sex, childbearing potential, co-morbidities, and concomitant medications. Future directions include discovery of drugs with an improved safety profile, with more potent anti-seizure effect, able to prevent epileptogenesis and, possibly, to interact with specific genetic substrates.