Peripheral nervous system involvement in SARS-CoV-2 infection: a review of the current pediatric literature.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the pathogen responsible for the pandemic health emergency declared by the World Health Organization in March 2020. During the first part of the pandemic, adults showed mild to severe respiratory symptoms. Children seemed initially exempt, both from acute and subsequent complications. Hyposmia or anosmia were promptly identified as the main symptoms of acute infection, so neurotropism of SARS-CoV-2 was immediately suspected. (1, 2). As the emergency progressed, post infectious neurological complications were described also in pediatric population (3). Cases of cranial neuropathy in connection with acute SARS-CoV-2 infection have been reported in pediatric patients, as an isolate post infectious complication or in the context of the multisystem inflammatory syndrome in children (MIS-C) (4-6). Neuroinflammation is thought to be caused by several mechanisms, among which immune/autoimmune reactions (7), but so far, no specific autoantibody has been identified. SARS-CoV-2 can enter the central nervous system (CNS) directly and/or infect it retrogradely, through the peripheral nervous system (PNS), after replicating peripherally; several factors regulate invasion and subsequent neuroinflammation. Indeed, direct/secondary entry and replication can activate CNS-resident immune cells that, together with peripheral leukocytes, induce an immune response and promote neuroinflammation. In addition, as we will discuss in the following review, many cases of peripheral neuropathy (cranial and non-cranial) have been reported during or after SARS-CoV-2 infection. However, some authors have pointed out that the increase of cranial roots and ganglia in neurological imaging is not always observed in children with cranial neuropathy. (8). Even if a variety of case reports were published, opinions about an increased incidence of such neurologic diseases, linked to SARS-CoV-2 infection, are still controversial (9-11). Facial nerve palsy, ocular movements abnormalities and vestibular alterations are among the most reported issues in pediatric population (3-5). Moreover, an increased screen exposure imposed by social distancing led to acute oculomotion's disturbance in children, not primarily caused by neuritis (12, 13). The aim of this review is to suggest food for thought on the role of SARS-CoV-2 in neurological conditions, affecting the peripheral nervous system to optimize the management and care of pediatric patients.

Acute Neurological Presentation in Children With SARS-CoV-2 Infection.

Background: In the pediatric population, the knowledge of the acute presentation of SARS-CoV-2 infection is mainly limited to small series and case reports, particularly when dealing with neurological symptoms. We describe a large cohort of children with acute SARS-CoV-2 infection, focusing on the neurological manifestations and investigating correlations between disease severity and population demographics. Methods: Patients aged 0-18 years with a positive molecular swab were recruited between April 2020 and March 2021 from a tertiary Italian pediatric centre. Clinical data, imaging, and laboratory test results were retrieved from our local dataset and statistically analyzed. Results: A total of 237 patients with a median age of 3.2 years were eligible; thirty-two (13.5%) presented with neurological symptoms, including headache (65.6%), altered awareness (18.8%), ageusia/anosmia (12.5%), seizures (6.3%), and vertigo (6.3%), combined in 7 (21.9%) cases. Respiratory (59.5%) and gastrointestinal (25.3%) symptoms were the most common among the 205 (86.5%) patients without neurological involvement. Neurological symptoms did not significantly influence the severity of the triage access codes. Moreover, pre-existing medical conditions were not higher in the group with neurological manifestations. Overall, fifty-nine patients (25%, 14/59 with neurological symptoms) required treatment, being antibiotics, systemic steroids, and heparin those most prescribed. Conclusion: Our study supports the overall benign course of the SARS-CoV-2 infection in children. Neurological manifestations, except for headache, remain a rare presenting symptom, and disease severity seems unrelated to pre-existing medical conditions.

Definitive pathognomonic signs and symptoms of paediatric neurological COVID-19 are still emerging.

Children with COVID-19 tend to show milder symptoms than adults during the pandemic, but growing evidence of neurological involvement has emerged. Some studies have reported neurological symptoms in children with COVID-19, which include multisystem inflammatory syndrome, a disease that shares some, but not all, of the characteristics of Kawasaki disease. This review presents, and discusses, the evidence to date. Our initial findings suggest that neurological manifestations can be considered to be the direct result of central nervous system viral invasion or post-infection immuno-mediated disease.

Microbiota-gut brain axis involvement in neuropsychiatric disorders.

Introduction: The microbiota-gut brain (MGB) axis is the bidirectional communication between the intestinal microbiota and the brain. An increasing body of preclinical and clinical evidence has revealed that the gut microbial ecosystem can affect neuropsychiatric health. However, there is still a need of further studies to elucidate the complex gene-environment interactions and the role of the MGB axis in neuropsychiatric diseases, with the aim of identifying biomarkers and new therapeutic targets, to allow early diagnosis and improving treatments. Areas covered: To review the role of MGB axis in neuropsychiatric disorders, prediction and prevention of disease through exploitation, integration, and combination of data from existing gut microbiome/microbiota projects and appropriate other International '-Omics' studies. The authors also evaluated the new technological advances to investigate and modulate, through nutritional and other interventions, the gut microbiota. Expert opinion: The clinical studies have documented an association between alterations in gut microbiota composition and/or function, whereas the preclinical studies support a role for the gut microbiota in impacting behaviors which are of relevance to psychiatry and other central nervous system (CNS) disorders. Targeting MGB axis could be an additional approach for treating CNS disorders and all conditions in which alterations of the gut microbiota are involved.

The possible use of the L-type calcium channel antagonist verapamil in drug-resistant epilepsy.

Multidrug transporters (MDTs) are likely to play a role in the pathogenesis of drug resistance in epilepsy, acting at the level of the blood-brain barrier by returning antiepileptic drugs to the blood vessels and lowering brain penetration and concentration (e.g. the so-called multidrug transporter hypothesis). In the last ten years experimental studies on both animal models and human brain tissues have highlighted a potential role of the P-glycoprotein-one of the multidrug transporters of the blood-brain barrier-in the pathophysiology of drug-resistant epilepsies. At the same time, verapamil has been administered to patients with drug-resistant epilepsy (e.g., Dravet syndrome, Lennox-Gastaut syndrome, focal epilepsies) or status epilepticus with promising results. In this drug profile paper the authors review current knowledge and main published studies regarding the role of the L-type calcium channel antagonist verapamil in drug-resistant epilepsy.

Efficacy of verapamil as an adjunctive treatment in children with drug-resistant epilepsy: a pilot study.

PURPOSE: Verapamil, a voltage-gated calcium channel blocker, has been occasionally reported to have some effect on reducing seizure frequency in drug-resistant epilepsy or status epilepticus. We aimed to investigate the efficacy of verapamil as add-on treatment in children with drug-resistant epilepsy. METHODS: Seven children with drug-resistant structural-metabolic, unknown or genetic (e.g., Dravet syndrome [DS]) epilepsy received verapamil as an add-on drug to baseline antiepileptic therapy. Verapamil was slowly introduced at the dosage of 1mg/kg/day and titrated up to 1.5mg/kg/day. After completing the titration period, patients entered a 14-month maintenance period and were followed up at 3, 8, and 14 months. Heart monitoring was performed at baseline and at each follow-up. The primary outcome measure was the response of seizures to verapamil. RESULTS: Three subjects with genetically determined DS showed a partial (reduction of 50-99%) response for all types of seizures. A patient with DS without known mutation showed a partial control of all types of seizures in the first 13 months; then seizures worsened and verapamil was suspended. Two patients with structural epilepsy and one with Lennox-Gastaut syndrome showed no improvement. Any side effects were recorded. CONCLUSIONS: Add-on treatment with verapamil seems to have some effect in controlling seizures in patients with genetically determined DS. Our observations justify further research on the relationship between calcium channels, calcium channel blockers, and channelopathies.

Fiber tractography assessment in double cortex syndrome.

INTRODUCTION: Subcortical band heterotopia (SBH) or double cortex syndrome is a malformation of cortical development that may be related to intractable epilepsy and severe mental retardation or to mild epilepsy and slight mental delay or normal cognitive functions. Several studies have been performed using neuroradiological or neurophysiological techniques, like SPECT, PET, MRS, fMRI, and MEG, in attempt to better characterize this neuronal migration disorder. Recently, also diffusion tensor imaging (DTI) and fiber tracking (FT) have been used to investigate on white matter anomalies in SBH, adding more information about such gray matter anomaly. METHODS: We report on three cases of SBH, evaluated with MRI, DTI, and FT. CONCLUSIONS: The data gathered from DTI and TF allow us to hypothesize a new functional role for heterotopic gray matter.

Bilateral middle cerebral artery thromboembolic occlusion. Could maternal hyperthermia be a detrimental factor?

We describe a six-month-old girl with microcephaly, developmental delay, truncal hypotonia, left pyramidal signs, partial seizures and myoclonic spasms, born to a feverish mother. MRI showed bilateral vascular lesions in the territory of the middle cerebral arteries, prevalent in the right hemisphere, together with hypoplasia of the posterior part of the corpus callosum and Wallerian degeneration of the cerebral peduncle. There may be many reasons for these lesions. In the reported patient the presence of maternal hyperthermia could have exacerbated cerebral thromboembolic occlusion.

Should "migralepsy" be considered an obsolete concept? A multicenter retrospective clinical/EEG study and review of the literature.

The few reports that have been published on the current International Classification of Headache Disorders, Second Edition (ICHD-II), criteria for migralepsy and hemicrania epileptica have highlighted the considerable confusion regarding this "hot topic" within both headache and epilepsy classifications (ICHD-II and International League Against Epilepsy [ILAE]). Indeed, the ICHD-II describes a migraine-triggered seizure as a rare event in which a seizure occurs during migraine aura; on the other hand, hemicrania epileptica is described as an "ictal headache" that occurs "synchronously" with a partial seizure. To confuse matters even further, neither the term migralepsy nor the term hemicrania epileptica is included in the currently used ILAE classification. On the basis of both a review of "migralepsy" cases in the literature and 16 additional retrospective multicenter cases, we suggest that the term migraine-triggered seizure or migralepsy be deleted from the ICHD-II classification until unequivocal evidence is provided of its existence, and that the term ictal epileptic headache be introduced into the ILAE classification.

Peri-ictal and inter-ictal headache in children and adolescents with idiopathic epilepsy: a multicenter cross-sectional study.

PURPOSE: Headache in epileptic population ranges from 8% to 15%. The aim of this paper was to study the clinical and temporal characteristics of primary headache comorbidity in idiopathic epileptic children. METHODS: From June 2006 to June 2009, a cross-sectional multi-center study involving five Italian Child Neurology University Centers (two in Rome, one in Chieti, one in Naples, and one in L'Aquila) was conducted. Among 1,264 consecutively newly diagnosed, idiopathic, partial, or generalized, epileptic children, according to ILAE diagnostic criteria (aged between 5 and 15 years of age), we selected 142 children (11.2%) (130 of whom completed the study) who showed an associated peri-ictal and/or inter-ictal headache diagnosed according to the International Headache Society Criteria. Rare cases of "ictal epileptic headache", in which headache represents the sole ictal epileptic manifestation, were excluded from this study. RESULTS AND CONCLUSIONS: Post-ictal headaches were most frequent (62%). Pre-ictal headaches were less common (30%). Inter-ictal headaches were described in 57.6%. Clear migrainous features were present in 93% of pre-ictal and 81.4% of post-ictal headaches. Inter-ictal headaches meet criteria for migraines in 87%. The association between partial epilepsy and migraine without aura is most common and reported in 82% of our patients with peri-ictal headache and in 76.5% of patients with post-ictal headache.

Bilateral (opercular and paracentral lobular) polymicrogyria and neurofibromatosis type 1.

Anecdotal cases of polymicrogyria (PMG; a malformation of cortical development consisting of an excessive number of small gyri with abnormal lamination) in patients with neurofibromatosis type 1 (NF1) have been described; however, the cases were unilateral and had negative NF1 genetic testing. We describe an 11-year-old girl with NF1 manifesting as a complex epileptic syndrome, including partial seizures secondarily generalized and status epilepticus, who had in association, bilateral, asymmetrical (opercular and paracentral lobular) PMG. She had a 1-bp deletion (c.1862delC) in exon 12b of the NF1 gene. It is notable that, given the key role played by the NF1 gene product, neurofibromin, in normal brain development, and the relatively high frequency of other brain findings in NF1, there are not more NF1 cases with brain malformations manifesting as PMG.

Long term outcome in children affected by absence epilepsy with onset before the age of three years.

OBJECTIVE: The goal of this study was to define the long-term outcome of absence epilepsy presenting before the age of 3 years. METHODS: We retrospectively studied the medical records of 40 children from eight neuropediatric centers in Italy with respect to the personal and family histories of epilepsy or febrile seizures, time of follow-up, cognitive functions, treatment, and outcome. RESULTS: Forty patients were enrolled in this study. They all fulfilled the criteria for absence epilepsy with 3-Hz spike-wave complexes on the EEG, normal neurological examination, and no other seizures types. Seizure onset occurred between 24.1 and 36.0 months. There was a family history of epilepsy in 28%, and of febrile seizures in 13%. Thirty-three patients were treated with valproic acid (VPA), mostly used in monotherapy (26 patients) or in association with ethosuximide. At final follow-up, 33 patients were seizure free and 29 had normal EEGs. Thirty-four patients had a normal intelligence quotient (IQ), whereas 6 had a decreased IQ, mainly associated with poor control of seizures. CONCLUSION: In our series, absence seizures presenting before the age of 3 appeared to have quite a good long-term clinical prognosis; the neuropsychological outcome was comparable to that of childhood epilepsy presenting after 3 years of age.

Neurocardiogenic syncope and epilepsy in pediatric age: the diagnostic value of electroencephalogram-electrocardiogram holter.

Neurocardiogenic syncope is induced by a hyperrecruitment of parasympathetic nerve tone elicited by emotional stress or pain. The presence of a transient loss of consciousness associated with involuntary motor activity or with urinary incontinence and the misinterpretation of anamnestic data or of electroencephalogram (EEG) abnormalities often leads to wrong diagnosis of epilepsy in children with this disorder.Careful and systematic history taking, pressure measurement, electrocardiogram (ECG), and, in selected cases, head-up tilt table testing are generally enough to rule out a cardiogenic or a neurocardiogenic syncope. Simultaneous EEG-ECG Holter represents a useful instrument for differential diagnosis between neurocardiogenic syncope and epilepsy.We report 3 case reports to demonstrate how simultaneous EEG-ECG Holter can contribute to characterize functional heart-brain interactions and the exact sequence of the physiopathologic events leading to the loss of consciousness in cases in which the clinical borders with epileptic disorders are particularly subtle.

Benign convulsions associated with mild gastroenteritis: a multicenter clinical study.

PURPOSE: To assess the clinical characteristics and the outcome of benign convulsions associated with mild gastroenteritis (CwG) in Italian children. METHODS: We studied clinical and EEG features of 128 children with CwG who were hospitalized between January 2004 and February 2008 and then followed for at least 12 months in 14 Italian centers. RESULTS: Age at onset ranged from 6 to 60 months. The seizures were generalized in 73 cases (57%), only focal in 16 (12.5%), and secondarily generalized in 39 (30.5%). The duration of the seizures was under 5 min in 97 patients (75.8%), between 5 and 30 min in 26 (20.3%), and longer than 30 min in 5 (3.9%). Seventy-three participants (57%) had 2 or more seizures, which recurred within 24-48 h. In the acute phase, antiepileptic drugs were used in 72 patients (56.3%). Although interictal abnormalities were present in EEG of 28 children (21.9%), these reverted to normal. During the follow up period, only 6 patients (4.7%) suffered from recurrence of CwG, 7 (5.5%) suffered from simple febrile seizures, and 3 (2.3%) developed epilepsy. CONCLUSIONS: Recognition of CwG in children allows pediatricians to avoid extensive evaluations and continuous antiepileptic therapy and to reassure parents regarding the lack of long-term complications.

Developmental anomalies of the medial septal area: possible implication for limbic epileptogenesis.

INTRODUCTION: The maldevelopment of the midline structures is connected with neurologic disorders. The cavum septum pellucidum (CSP) exists in the fetal period, then it is re-absorbed. The presence of unfused leaflets/fornices may be considered important in the genesis of neurodevelopmental abnormalities inclunding epilepsy. The limbic system includes a group of interconnected gray and white matter structures; in this circuit, the fornix is an important white matter connection with the septum pellucidum. METHODS: Five children, 3-10 years of age, with epilepsy and an unfused septum pellucidum and fornices on MRI, were evaluated by diffusion tensor imaging-fiber tracking (DTI-FT) in order to explore the integrity of the axonal microenviroment of these structures. RESULTS: The patients had generalized tonic-clonic seizures (GTCS). The electroencephalogram (EEG) showed focal-temporal abnormalities with secondary generalization. Magnetic resonance imaging (MRI) and DTI-FT demonstrated the CSP, and the presence of the fornix's body split into two bundles with the fornices separated. CONCLUSION: The fornix appears more involved than CSP alone, as suggested by fornix atrophy observed in MTLE. Even if epilepsy is suggested to be a grey matter disorder, changes in the underlying brain connectivity have an important contribution in seizure generation and diffusion. In addition, the interconnections of medial septal area with hyppocampus, amygdala and entorhinal cortex, have led to the hypothesis of functional limbic epilepsy. In our patients, the role of DTI was not conclusive since the definition of the number of unmyelinated fibers responsible for epilepsy could not be demonstrated probably for a limited number of seizures and for a short period of drug administration.

Clinical and pharmacological aspects of inflammatory demyelinating diseases in childhood: an update.

Inflammatory demyelinating diseases comprise a spectrum of disorders affecting the myelin of the central and peripheral nervous system. These diseases can usually be differentiated on the basis of clinical, radiological, laboratory and pathological findings. Recent studies have contributed to current awareness that inflammatory demyelinating diseases are not restricted to the adult age group, but are more common in pediatric age than previously believed. Some of pediatric inflammatory demyelinating diseases carry an unfavorable long-term prognosis but appropriate treatments can improve the outcome. The possibility of physical and cognitive disability resulting from these diseases, highlights the urgent need for therapeutic strategies for neurorehabilitation, neuroregeneration, and neurorepair. This review discusses characteristics of primary demyelinating diseases more frequently observed in childhood, focusing on epidemiology, clinical aspects and treatments.

Dysembryoplastic neuroepithelial tumors: a prospective clinicopathologic and outcome study of 13 children.

Dysembryoplastic neuroepithelial tumors (DNETs) are benign intracortical masses that are typically observed in children and young adults and are classified as glioneuronal tumors (WHO grade I). Large and retrospective series of patients with DNETs have been reported, but prospective studies on pediatric cohorts of patients with DNETs have been lacking. In the present study, 13 children (8 boys, 5 girls; age 8-18 years) who had simple (n = 2) or complex (n = 11) partial seizures (seizure duration range, 2-4 years; mean, 1.5 years; mode, 1.2 years) were prospectively enrolled and monitored over 13 years. The DNETs were located in the frontal (n = 2), temporal (n = 9), or occipital (n = 2) cortex. In 11/13 cases, the seizures were resistant to drug therapy, and all the children had surgery consisting of extended lesionectomy coupled with neuronavigation. Pathology examination revealed cortical dysplasia (n = 8), glial nodules (n = 11), calcification (n = 4), cellular atypia (n = 3), endothelial proliferation (n = 1), perivascular inflammation (n = 3), and meningeal involvement (n = 6). All children were seizure free throughout postsurgical follow-up of 2-11 years. This first prospective study with follow-up monitoring of a childhood population with DNETs confirms, on a long-term basis, that the coupled strategy of extended lesionectomy and neuronavigation has good outcome for long-term seizure control.