Correspondence to Dr Ikechukwu Okafor, Emergency Department, Temple Street Children's University Hospital, Dublin, Ireland; Ikechukwu.Okafor@cuh.ie A 73%–88% reduction in paediatric emergency ...department (PED) presentations has been reported during the severe acute respiratory syndrome coronavirus 2 (SARS-2-CoV-2) pandemic.1 The magnitude of this decrease suggests that a combination of biological, psychological and social factors influence the decisions of families to attend PED. Based on the Irish Children’s Triage System, the acuity of presentations has remained similar in proportion to the attendances.2 Category 1 presentations remained stable at 0.7%–0.8%, and a slight increase in category 2 presentations was seen in 2020 (20.3%) compared with 18.4% and 17.9% in 2018 and 2019.Table 1 Emergency department attendances categorised and percentage reduction in 2020 compared with preceding 2 years4 March+April 2018 March+April 2019 March+April 2020 Percentage change in 2018 and 2019 Injury and poisoning 2651 2691 1488 −43.9%; −44.7% Respiratory illnesses 1742 1742 864 −50.4%; −50.4% Digestive disorders 915 1033 449 −50.9%; 56.5% Nervous system disorders 195 187 104 −46.6%; −44.4% Mental health+safeguarding 118 113 83 −29.7%; −26.5% Surgical 222 183 133 −40%; −27.3% Emergency/life-threatening 26 23 19 −26.9%; −17.4% Total attendances 8199 9133 4434 −45.9%; −51.45% Online supplementary table available. Pandemic-related delay of life-altering presentations is a major social and political concern currently; many paediatricians worry that more deaths will be seen in children from collateral damage from the COVID-19 response than from COVID-19.1 This review has not demonstrated significant delays in the most serious presentations (leukaemia and space occupying lesions), with most of the disappearing attendances related to mild conditions due to non-specific viral triggers or stresses in normal life.
The critical appraisal of papers is summarised in table 1.Table 1 Summary of included studies (n=3) Citation Study group Study type Outcome Key result Comments Buonaguro et al7 Two groups Case: 150 ...children with CP and ITB; epilepsy: 40% (60/150) Control: 100 children with CP operated for other reasons; epilepsy: 37% (37/100) Retrospective Case–control Change in seizure frequency. No data given on the control group and change in seizure frequency during the study period. Spasticity is present in the majority of children with CP, characterised by increased tone with associated velocity-dependent resistance to stretch.2 3 Spasticity interferes with independent function, causes pain and negatively impacts the quality of life. 4 Epilepsy is common in CP with a prevalence of ~42%, higher in children with increasing motor impairment.5 Baclofen is an agonist at the beta subunit of GABA on synaptic neurons in the brain and spinal cord.6 Baclofen was initially manufactured as an anti-seizure medication and only later used in the management of tone. Though smaller numbers, Hoving et al noted improved or stable seizure frequency in five out of six children with pre-existing epilepsy.8 Though not included in our summary table (due to the inclusion of adult patients), Albright et al demonstrated similar data with epilepsy in 13% of the cohort, and eight of nine (89%) had no change in seizure frequency over the 4-year study period.9 Hansel et al reported that 14% (5 of 35) of children <10 years developed new-onset seizures over the 2-year study period.
The phenotypic spectrum of SCN2A-related epilepsy Reynolds, Claire; King, Mary D.; Gorman, Kathleen M.
European journal of paediatric neurology,
January 2020, 2020-Jan, 2020-01-00, 20200101, Volume:
24
Journal Article
Peer reviewed
Pathogenic variants in SCN2A are reported in a spectrum of neurodevelopmental disorders including developmental and epileptic encephalopathies, benign familial neonatal-infantile seizures, episodic ...ataxia, and autism spectrum disorder and intellectual disability with and without seizures. To date, more than 300 patients with SCN2A variants have been published, the majority presenting with epilepsy. Large cohort studies and variant-specific electrophysiology, have enabled the delineation of different SCN2A-epilepsy phenotypes, phenotype-genotype correlations, prediction of pharmacosensitivity to sodium channel blockers and long-term prognostication for clinicians and families. Herein, we summarise the core phenotypes of SCN2A-related epilepsy, genotype-phenotype correlations, response to medication and future research.
•SCN2A is one of the commonest causes of neurodevelopmental disorders, accounting for 1% of all epileptic encephalopathies.•SCN2A phenotypes include BFNIS, developmental and epileptic encephalopathies and ASD/intellectual disability with epilepsy.•Genotype-phenotype correlations and electrophysiology may predict response to sodium channel blockers and seizure outcome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
4.
Paroxysmal Movement Disorders Harvey, Susan; King, Mary D.; Gorman, Kathleen M.
Frontiers in neurology,
06/2021, Volume:
12
Journal Article
Peer reviewed
Open access
Paroxysmal movement disorders (PxMDs) are a clinical and genetically heterogeneous group of movement disorders characterized by episodic involuntary movements (dystonia, dyskinesia, chorea and/or ...ataxia). Historically, PxMDs were classified clinically (triggers and characteristics of the movements) and this directed single-gene testing. With the advent of next-generation sequencing (NGS), how we classify and investigate PxMDs has been transformed. Next-generation sequencing has enabled new gene discovery (
RHOBTB2, TBC1D24
), expansion of phenotypes in known PxMDs genes and a better understanding of disease mechanisms. However, PxMDs exhibit phenotypic pleiotropy and genetic heterogeneity, making it challenging to predict genotype based on the clinical phenotype. For example, paroxysmal kinesigenic dyskinesia is most commonly associated with variants in
PRRT2
but also variants identified in
PNKD, SCN8A, and SCL2A1
. There are no radiological or biochemical biomarkers to differentiate genetic causes. Even with NGS, diagnosis rates are variable, ranging from 11 to 51% depending on the cohort studied and technology employed. Thus, a large proportion of patients remain undiagnosed compared to other neurological disorders such as epilepsy, highlighting the need for further genomic research in PxMDs. Whole-genome sequencing, deep-sequencing, copy number variant analysis, detection of deep-intronic variants, mosaicism and repeat expansions, will improve diagnostic rates. Identifying the underlying genetic cause has a significant impact on patient care, modification of treatment, long-term prognostication and genetic counseling. This paper provides an update on the genetics of PxMDs, description of PxMDs classified according to causative gene rather than clinical phenotype, highlighting key clinical features and providing an algorithm for genetic testing of PxMDs.
Commentary Neonatal seizures are the most common neurological manifestation in the neonatal period, estimated to occur in 1 to 3.5 per 1000 term infants and 10–130 per 1000 preterm infants.1–4 The ...main causes of seizures in the neonatal period are hypoxic–ischaemic encephalopathy, intracranial haemorrhage, ischaemic stroke or infection. Seizures in this age group are usually focal, subtle and often difficult to detect clinically; a large percentage are subclinical or electrographic only.5 Increasing evidence suggests that neonatal seizures are associated with poorer neurodevelopmental outcomes, though unclear if neonatal seizures themselves propagate injury or are a marker of severity of the underlying injury.6 Therefore, quicker cessation of neonatal seizures may confer long-term, neurodevelopmental benefits. To date, there are no US Food and Drug Administration approved drugs for use in neonates, and most of the data obtained about the efficacy of different drugs is extrapolated from studies performed in infants and children.3 4 Practices are largely based on data from small retrospective studies and driven by clinician’s personal experience and preference. Majority of the studies reviewed favoured the use of LEV as first-line treatment for neonatal seizures; however, these studies have multiple limitations: seizures diagnosed clinically, lack of consistency between the doses and escalation protocols for each drug.
Objectives
The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to ...investigate this paucity of diagnoses.
Methods
We undertook weighted burden analysis of whole‐exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case‐finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient‐derived cells.
Results
Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome‐lysosome fusion. A total of 18 individuals harboring heterozygous loss‐of‐function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss‐of‐function variants in VPS41, another HOPS‐complex encoding gene, in an individual with infantile‐onset generalized dystonia. Electron microscopy of patient‐derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function.
Interpretation
Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867–877
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Developmental and epileptic encephalopathies are devastating disorders characterized by epilepsy, intellectual disability, and other neuropsychiatric symptoms, for which available treatments are ...largely ineffective. Following a precision medicine approach, we show for
-encephalopathy that the K
channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the K
1.2 subunit in vitro, by reducing current amplitudes and negative shifts of steady-state activation and increasing the firing rate of transfected neurons. In n-of-1 trials carried out in nine different centers, 9 of 11 patients carrying such variants benefitted from treatment with 4-aminopyridine. All six patients experiencing daily absence, myoclonic, or atonic seizures became seizure-free (except some remaining provoked seizures). Two of six patients experiencing generalized tonic-clonic seizures showed marked improvement, three showed no effect, and one worsening. Nine patients showed improved gait, ataxia, alertness, cognition, or speech. 4-Aminopyridine was well tolerated up to 2.6 mg/kg per day. We suggest 4-aminopyridine as a promising tailored treatment in
-(gain-of-function)–encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment.
ABSTRACT
Background
Adolescence is a time of significant change for patients, guardians and clinicians. The paediatrician must ensure patients develop the necessary skills and knowledge required to ...transition and to function as an independent entity, with autonomy over their own care. The transfer from paediatric to adult care carries an increased risk of graft-related complications attributable to a multitude of reasons, particularly non-adherence to immunosuppressive medicines and poor attendance at scheduled appointments. This systematic review was conducted to ascertain the transitional care models available to clinicians caring for kidney transplant recipients and to compare the approach in each respective case.
Methods
A systematic review was performed, in a methodology outlined by the PRISMA guidelines. OVID MEDLINE and EMBASE databases were searched for studies that outlined valid, replicable models pertaining to transitional care of paediatric kidney transplant recipients between 1946 and Quarter 3 of 2021. The reference lists of selected articles were also perused for further eligible studies and experts in the field were consulted for further eligible articles. Two investigators assessed all studies for eligibility and independently performed data extraction. Any discrepancies were settled by consensus.
Results
A total of 1121 abstracts were identified, which was reduced to 1029 upon removal of duplicates. A total of 51 articles were deemed appropriate for full-text review and critical appraisal. A total of 12 articles that described models for transition pertaining to kidney transplant patients were included in qualitative synthesis. Every paper utilized a different transition model. All but one model included a physician and nurse at minimum in the transition process. The involvement of adult nephrologists, medical social work, psychology and psychiatry was variable. The mean age for the initiation of transition was 13.4 years (range: 10–17.5 years). The mean age at transfer to adult services was 18.3 years (range: 16–20.5 years).
Conclusions
Despite the well-established need for good transitional care for paediatric solid-organ transplant recipients, models tailored specifically for kidney transplant recipients are lacking. Further research and validation studies are required to ascertain the best method of providing effective transitional care to these patients. Transitional care should become a standardized process for adolescents and young adults with kidney transplants.
Typical absence seizures (TAS) are seen in idiopathic generalized epilepsy. Electroencephalography (EEG) contributes to syndrome characterization and counseling in an area where genetics does not ...currently play a significant role. Prominent interictal EEG findings are seen in juvenile absence epilepsy (JAE) and are thus thought to be associated with less favorable outcome in any TAS case despite lack of evidence. Our study evaluates EEG findings and their association with seizure outcomes in children with TAS.
Retrospective cohort study of 123 children over 10 years with extensive EEG analysis and medical record review. Phone interviews ascertained longer-term outcomes. EEG reviewers were unaware of outcomes.
Total cohort included 123 children with phone review completed in 98. Median follow-up was 5 years 9 months. Seizure freedom was seen in 59% off antiseizure medicines (ASMs). Interictal findings included focal discharges in 29%, fragments of spike-wave (SW) discharges in 82.1%, and generalized interictal discharges in 63.4%. Interictal SW was more likely in those who slept (100%, 18 of 18) versus those who did not (57%, 60 of 105) (P < 0.001). Outcome analysis found no associations between focal or generalized interictal findings and seizure freedom, relapse off ASM, occurrence of other seizure types, or response to first ASM.
Focal and generalized interictal EEG discharges are common in children with TAS and are not associated with poorer outcomes. These interictal findings were traditionally associated with JAE rather than childhood absence epilepsy and were thus believed to be associated with potentially poorer outcome, which is probably not the case.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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