Using nirmatrelvir/ritonavir in patients with epilepsy: An update from the Israeli chapter of the International League Against Epilepsy.

Presented herein are recommendations for use of nirmatrelvir/ritonavir in patients with epilepsy, as issued by the Steering Committee of the Israeli chapter of the International League Against Epilepsy. The recommendations suggest that patients on moderate-to-strong enzyme-inducing antiseizure medications (ASMs) and everolimus should not be treated with nirmatrelvir/ritonavir; rectal diazepam may be used as an alternative to buccal midazolam; doses of ASMs that are cytochrome P450 (CYP3A4) substrates might be adjusted; and patients treated with combinations of nirmatrelvir/ritonavir and ASMs that are CYP3A4 substrates or lamotrigine should be monitored for drug efficacy and adverse drug reactions.

Treating Epilepsy Patients with Investigational Anti-COVID-19 Drugs: Recommendations by the Israeli Chapter of the ILAE.

BACKGROUND: The coronavirus disease-2019 (COVID-19) and its management in patients with epilepsy can be complex. Prescribers should consider potential effects of investigational anti-COVID-19 drugs on seizures, immunomodulation by anti-seizure medications (ASMs), changes in ASM pharmacokinetics, and the potential for drug-drug interactions (DDIs). The goal of the Board of the Israeli League Against Epilepsy (the Israeli Chapter of the International League Against Epilepsy, ILAE) was to summarize the main principles of the pharmacological treatment of COVID-19 in patients with epilepsy. This guide was based on current literature, drug labels, and drug interaction resources. We summarized the available data related to the potential implications of anti-COVID-19 co-medication in patients treated with ASMs. Our recommendations refer to drug selection, dosing, and patient monitoring. Given the limited availability of data, some recommendations are based on general pharmacokinetic or pharmacodynamic principles and might apply to additional future drug combinations as novel treatments emerge. They do not replace evidence-based guidelines, should those become available. Awareness to drug characteristics that increase the risk of interactions can help adjust anti-COVID-19 and ASM treatment for patients with epilepsy.

The molecular and phenotypic spectrum of IQSEC2-related epilepsy.

OBJECTIVE: IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants. METHODS: Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians. RESULTS: Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features. SIGNIFICANCE: The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.

Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome.

OBJECTIVE: We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions. METHODS: Detailed clinical data were collected from 36 families comprising two or more individuals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci. RESULTS: Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE); 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of individuals with KCNQ2 mutations; later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability; a molecular lesion was identified in two; the other family remains unsolved. SIGNIFICANCE: Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE; the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.

Epidemiologic, microbiologic and imaging characteristics of urinary tract infections in hospitalized children < 2 years of age diagnosed with anatomic abnormalities of the urinary tract.

BACKGROUND: To compare the epidemiologic, microbiologic and imaging characteristics of urinary tract infections (UTI) in children <2 years of age with and without anatomic urinary tract abnormalities (AA). METHODS: All children hospitalized with UTI during 1.1.2005-31.12.2018 were included. The study group (patients with AA) included 76 patients. The control group (99 patients) included patients without AA. RESULTS: 1163 children were hospitalized. Age at diagnosis was younger in the study group vs. controls (5.2 ± 6.0 vs. 7.9 ± 7.5 months, P = 0.038). Uropathogens distribution was different (P = 0.007), with lower Escherichia coli (Ec) and Proteus mirabilis (Pm) percentages in the study group and higher percentages of Enterococcus spp. (Ent) in controls. In the study group, Ec nonsusceptibility rates to ampicillin, amoxicillin/clavulanic acid, cefazolin, cefuroxime, TMP/SMX and ceftriaxone were 58%, 40%, 14%, 14%, 12% and 10%, respectively, with no differences vs. controls. Ultrasound (US) was performed in 69/76 (98%) patients with AA (84.1%, abnormal); bilateral (39.7%) and unilateral (32.7%) ureteral dilatation were the most frequent findings. Voiding cystourethrography was performed in 46 patients (pathologic in 35, 76%); 31 (81.6%) patients had vesicoureteral reflux (VUR) (bilateral in 11, 35.5%; grade 4/5 in 7 patients). Uropathogens distribution in VUR patients differed between study and control groups, with lower Ec and Pm in the first group and higher Pseudomonas aeruginosa and Ent percentages in the control group. CONCLUSION: Age at diagnosis was lower and pathogen distribution was different in patients with AA. Antibiotic susceptibility patterns of the main uropathogens were similar between patients with or without AA.

Clinical phenotypes of infantile onset CACNA1A-related disorder.

BACKGROUND: CACNA1A-related disorders present with persistent progressive and non-progressive cerebellar ataxia and paroxysmal events: epileptic seizures and non-epileptic attacks. These phenotypes overlap and co-exist in the majority of patients. OBJECTIVE: To describe phenotypes in infantile onset CACNA1A-related disorder and to explore intra-familial variations and genotype-phenotype correlations. MATERIAL AND METHODS: This study was a multicenter international collaboration. A retrospective chart review of CACNA1A patients was performed. Clinical, radiological, and genetic data were collected and analyzed in 47 patients with infantile-onset disorder. RESULTS: Paroxysmal non-epileptic events (PNEE) were observed in 68% of infants, with paroxysmal tonic upward gaze (PTU) noticed in 47% of infants. Congenital cerebellar ataxia (CCA) was diagnosed in 51% of patients including four patients with developmental delay and only one neurological sign. PNEEs were found in 63% of patients at follow-up, with episodic ataxia (EA) in 40% of the sample. Cerebellar ataxia was found in 58% of the patients at follow-up. Four patients had epilepsy in infancy and nine in childhood. Seven infants had febrile convulsions, three of which developed epilepsy later; all three patients had CCA. Cognitive difficulties were demonstrated in 70% of the children. Cerebellar atrophy was found in only one infant but was depicted in 64% of MRIs after age two. CONCLUSIONS: Nearly all of the infants had CCA, PNEE or both. Cognitive difficulties were frequent and appeared to be associated with CCA. Epilepsy was more frequent after age two. Febrile convulsions in association with CCA may indicate risk of epilepsy in later childhood. Brain MRI was normal in infancy. There were no genotype-phenotype correlations found.

Medical Cannabis for Pediatric Moderate to Severe Complex Motor Disorders.

A complex motor disorder is a combination of various types of abnormal movements that are associated with impaired quality of life (QOL). Current therapeutic options are limited. We studied the efficacy, safety, and tolerability of medical cannabis in children with complex motor disorder. This pilot study was approved by the institutional ethics committee. Two products of cannabidiol (CBD) enriched 5% oil formulation of cannabis were compared: one with 0.25% δ-9-tetrahydrocannabinol (THC) 20:1 group, the other with 0.83% THC 6:1 group. Patients aged 1 to 17 years (n = 25) with complex motor disorder were enrolled. The assigned medication was administered for 5 months. Significant improvement in spasticity and dystonia, sleep difficulties, pain severity, and QOL was observed in the total study cohort, regardless of treatment assignment. Adverse effects were rare and included worsening of seizures in 2 patients, behavioral changes in 2 and somnolence in 1.

The effect of open heart surgery on tuberculin skin test reactivity.

To examine whether treatment with cardiopulmonary bypass (CPB), which causes transient cellular immunity depression, influences tuberculin skin testing (TST) interpretation. The study was also aimed to assess the degree of cellular immunity depression following open heart surgery. Fifteen children from developing countries with latent tuberculosis (TST >or=10 mm), undergoing open heart surgery had their TST repeated within 48-72 h following surgery. We compared the size of skin test induration before and after surgery and the relation of postsurgery skin induration to time on CPB (pump time). There was no significant difference in the size of induration before and after surgery (mean: 14.7 mm versus 13 mm, respectively). Pump time ranged from 38 to 204 min (mean: 110 min). Two of the children had pump time over 3 h. The TST of both of them turned negative after surgery, as opposed to all other children (P = 0.01). Most patients retained skin test reactivity. Only patients with pump time longer than 3 h had a negative TST.

Utility of Whole Exome Sequencing for Genetic Diagnosis of Previously Undiagnosed Pediatric Neurology Patients.

Whole exome sequencing enables scanning a large number of genes for relatively low costs. The authors investigate its use for previously undiagnosed pediatric neurological patients. This retrospective cohort study performed whole exome sequencing on 57 patients of "Magen" neurogenetic clinics, with unknown diagnoses despite previous workup. The authors report on clinical features, causative genes, and treatment modifications and provide an analysis of whole exome sequencing utility per primary clinical feature. A causative gene was identified in 49.1% of patients, of which 17 had an autosomal dominant mutation, 9 autosomal recessive, and 2 X-linked. The highest rate of positive diagnosis was found for patients with developmental delay, ataxia, or suspected neuromuscular disease. Whole exome sequencing warranted a definitive change of treatment for 5 patients. Genetic databases were updated accordingly. In conclusion, whole exome sequencing is useful in obtaining a high detection rate for previously undiagnosed disorders. Use of this technique could affect diagnosis, treatment, and prognostics for both patients and relatives.

CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience.

PURPOSE: To describe the experience of five Israeli pediatric epilepsy clinics treating children and adolescents diagnosed as having intractable epilepsy with a regimen of medical cannabis oil. METHODS: A retrospective study describing the effect of cannabidiol (CBD)-enriched medical cannabis on children with epilepsy. The cohort included 74 patients (age range 1-18 years) with intractable epilepsy resistant to >7 antiepileptic drugs. Forty-nine (66%) also failed a ketogenic diet, vagal nerve stimulator implantation, or both. They all started medical cannabis oil treatment between 2-11/2014 and were treated for at least 3 months (average 6 months). The selected formula contained CBD and tetrahydrocannabinol at a ratio of 20:1 dissolved in olive oil. The CBD dose ranged from 1 to 20mg/kg/d. Seizure frequency was assessed by parental report during clinical visits. RESULTS: CBD treatment yielded a significant positive effect on seizure load. Most of the children (66/74, 89%) reported reduction in seizure frequency: 13 (18%) reported 75-100% reduction, 25 (34%) reported 50-75% reduction, 9 (12%) reported 25-50% reduction, and 19 (26%) reported <25% reduction. Five (7%) patients reported aggravation of seizures which led to CBD withdrawal. In addition, we observed improvement in behavior and alertness, language, communication, motor skills and sleep. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in 5 patients. CONCLUSIONS: The results of this multicenter study on CBD treatment for intractable epilepsy in a population of children and adolescents are highly promising. Further prospective, well-designed clinical trials using enriched CBD medical cannabis are warranted.

Immunoglobulin treatment for severe childhood epilepsy.

We have used intravenous immunoglobulin to treat pediatric patients with various severe epileptic conditions. This retrospective, multicenter study comprised 64 consecutive patients treated with immunoglobulins for either epileptic encephalopathy or refractory epilepsy. The rate of full or partial improvement according to specific syndrome involved three of four patients with idiopathic West syndrome, six of 12 patients with electrical status epilepticus in sleep, eight of 19 patients with an undefined syndrome, one of three patients with Landau-Kleffner syndrome, and one of two patients with Rasmussen encephalitis. Intravenous immunoglobulins were ineffective in 10 patients with symptomatic West syndrome, nine with febrile infection-related status epilepticus, three with myoclonic astatic epilepsy, and two with Lennox-Gastaut syndrome. Nine patients (14%) demonstrated complete resolution, and 10 (15.6%) exhibited partial improvement. Of these 19 responders (29.7%), eight relapsed. Although intravenous immunoglobulin is not suitable for all cases of epilepsy, it may prove efficacious for specific epileptic syndromes, mainly idiopathic West syndrome and electrical status epilepticus during sleep.

Neonatal seizures associated with a severe neonatal myoclonus like dyskinesia due to a familial KCNQ2 gene mutation.

UNLABELLED: Mutations in the potassium channel gene KCNQ2, usually cause benign familial neonatal epilepsy. This is an autosomal dominant disorder characterized by clusters of seizures occurring in the first days of life. Most patients have normal psychomotor development and spontaneous remission of seizures by 12 months of age. Since Rett and Teubel reported the first family in 1964 and the identification of KCNQ2 gene mutations in this family by Zimprich et al. in 2006, phenotypic variability has been recognized including: later onset of seizures, myokymia in isolation or accompanied by seizures, neurological deficit and mental retardation. We report a mother and son with an atypical presentation of familial neonatal epilepsy. The mother has persistent epilepsy and subnormal intelligence. The son developed a severe dyskinesia clinically compatible with multifocal myoclonus in the neonatal period that only responded to carbamazepine. He also has ataxia and delayed psychomotor development. EMG revealed a spontaneous occurrence of repetitive normal motor potentials in different muscle groups. Genetic analysis identified a heterozygous missense mutation in KCNQ2 in the child and his mother. CONCLUSION: KCNQ2 mutations can present with a neonatal onset multifocal myoclonus-like dyskinesia.

Clinical correlates of occipital intermittent rhythmic delta activity (OIRDA) in children.

PURPOSE: The clinical significance of occipital intermittent rhythmic delta activity (OIRDA) on the electroencephalogram has not been fully established. Recent studies suggest that this pattern occurs almost exclusively in children and is probably of epileptic origin in most cases. We sought to characterize the electrographic features and clinical correlates of occipital intermittent rhythmic delta activity. METHODS: A review of 697 consecutive pediatric electroencephalograms detected occipital intermittent rhythmic delta activity in 24 studies. Mean patient age was 7.96 years. RESULTS: Recent convulsions and absence seizures constituted the main indications for the study. Concomitant, independent epileptiform activity was noted in half of the cases. This activity was focal in all but one case. Conversely, in most cases of absence seizures, epileptiform activity intermixed with occipital intermittent rhythmic delta activity. Furthermore, the frequency of the occipital rhythmic discharges in studies of children with absences was generally faster (3-4 Hz) than in localization-related epilepsy (2-3 Hz). Most patients were awake when occipital intermittent rhythmic delta activity occurred. Chronic encephalopathy was seen in one child only. Analysis of neuroimaging studies in eight cases revealed no structural pathology associated with occipital intermittent rhythmic delta activity. CONCLUSIONS: Occipital intermittent rhythmic delta activity is probably an epileptiform pattern, although it is noted occasionally in encephalopathic children. Its electrographic characteristics appear to differ between localization-related epilepsy and primary generalized epilepsy, particularly absence seizures.