The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency.

PURPOSE: Mitochondrial DNA (mtDNA) depletion syndrome (MDDS) encompasses a group of genetic disorders of mtDNA maintenance. Mutation of RRM2B is an uncommon cause of infantile-onset encephalomyopathic MDDS. Here we describe the natural history of this disease. METHODS: Multinational series of new genetically confirmed cases from six pediatric centers. RESULTS: Nine new cases of infantile-onset RRM2B deficiency, and 22 previously published cases comprised a total cohort of 31 patients. Infants presented at a mean of 1.95 months with truncal hypotonia, generalized weakness, and faltering growth. Seizures evolved in 39% at a mean of 3.1 months. Non-neurological manifestations included respiratory distress/failure (58%), renal tubulopathy (55%), sensorineural hearing loss (36%), gastrointestinal disturbance (32%), eye abnormalities (13%), and anemia (13%). Laboratory features included elevated lactate (blood, cerebrospinal fluid (CSF), urine, magnetic resonance (MR), spectroscopy), ragged-red and cytochrome c oxidase-deficient fibers, lipid myopathy, and multiple oxidative phosphorylation enzyme deficiencies in skeletal muscle. Eight new RRM2B variants were identified. Patients with biallelic truncating variants had the worst survival. Overall survival was 29% at 6 months and 16% at 1 year. CONCLUSIONS: Infantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis. Presently management is supportive as there is no effective treatment. Novel treatments are urgently needed.

Whole Exon Deletion in the GFAP Gene Is a Novel Molecular Mechanism Causing Alexander Disease.

Alexander disease (AD) is a leukodystrophy caused by heterozygous mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Currently, de novo heterozygous missense mutations in the GFAP gene are identified in over 95% of patients with AD. However, patients with biopsy-proven AD have been reported in whom no GFAP mutation has been identified. We report identical twin boys presenting in infancy with seizures and developmental delay in whom MR appearances were suggestive of AD with the exception of an unusual, bilateral, arc of calcification at the frontal white-gray junction. Initial mutation screening of the GFAP gene did not identify a mutation. Whole exome sequencing in both brothers revealed a de novo heterozygous in-frame deletion of the whole of exon 5 of the GFAP gene. Mutations in the GFAP gene are thought to result in a toxic effect of mutant GFAP disrupting the formation of the normal intermediate filament network and resulting in Rosenthal fiber formation, which has hitherto not been linked to exonic scale copy number variants in GFAP. Further studies on mutation negative AD patients are warranted to determine whether a similar mechanism underlies their disease.

Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial.

BACKGROUND: Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy. METHODS: In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1-24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6-8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding. FINDINGS: Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6-8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1-16]) and antiseizure medication group (3 [IQR 2-11]; IRR 1·33, 95% CI 0·84-2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee. INTERPRETATION: In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications. FUNDING: National Institute for Health and Care Research.

Bradycardia without associated hypertension: a common sign of ventriculo-peritoneal shunt malfunction.

INTRODUCTION: Delayed diagnosis of ventriculo-peritoneal (VP) shunt malfunction results in avoidable morbidity and mortality. One reason is that most of the signs of shunt malfunction have low specificity. OBJECTIVE: The objective of this study was to evaluate the presence of bradycardia as a sign of VP shunt malfunction in children with treated hydrocephalus. METHODS: Children presenting with clinical features suggestive of possible VP shunt malfunction were retrospectively identified. Children with confirmed shunt malfunction formed the study group. Those who did not have shunt malfunction formed the control group, and the symptoms and signs were compared between the two groups. In particular, the presence of bradycardia (a heart rate less than the second centile of age-related norms) was sought. The positive predictive value (PPV) of bradycardia was compared with other common features of shunt malfunction. RESULTS: Data were obtained for 52 patients: 34 in the study group (data from 40 admissions) and 18 controls. Bradycardia was present in 18 of 40 (45%) of the study group and 2 of 18(11%) controls (p = 0.011). Only two of the patients with bradycardia had associated hypertension. The PPV for bradycardia was 90% compared with 92% for reduced conscious level and 65% for both headache and vomiting (the four commonest presenting features). CONCLUSIONS: Bradycardia without hypertension is common in children with VP shunt malfunction. The significance of bradycardia is often not recognised; the value of this sign should be emphasised.

Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study.

BACKGROUND: The spectrum of neurological and psychiatric complications associated with paediatric SARS-CoV-2 infection is poorly understood. We aimed to analyse the range and prevalence of these complications in hospitalised children and adolescents. METHODS: We did a prospective national cohort study in the UK using an online network of secure rapid-response notification portals established by the CoroNerve study group. Paediatric neurologists were invited to notify any children and adolescents (age <18 years) admitted to hospital with neurological or psychiatric disorders in whom they considered SARS-CoV-2 infection to be relevant to the presentation. Patients were excluded if they did not have a neurological consultation or neurological investigations or both, or did not meet the definition for confirmed SARS-CoV-2 infection (a positive PCR of respiratory or spinal fluid samples, serology for anti-SARS-CoV-2 IgG, or both), or the Royal College of Paediatrics and Child Health criteria for paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Individuals were classified as having either a primary neurological disorder associated with COVID-19 (COVID-19 neurology group) or PIMS-TS with neurological features (PIMS-TS neurology group). The denominator of all hospitalised children and adolescents with COVID-19 was collated from National Health Service England data. FINDINGS: Between April 2, 2020, and Feb 1, 2021, 52 cases were identified; in England, there were 51 cases among 1334 children and adolescents hospitalised with COVID-19, giving an estimated prevalence of 3·8 (95% CI 2·9-5·0) cases per 100 paediatric patients. 22 (42%) patients were female and 30 (58%) were male; the median age was 9 years (range 1-17). 36 (69%) patients were Black or Asian, 16 (31%) were White. 27 (52%) of 52 patients were classified into the COVID-19 neurology group and 25 (48%) were classified into the PIMS-TS neurology group. In the COVID-19 neurology group, diagnoses included status epilepticus (n=7), encephalitis (n=5), Guillain-Barré syndrome (n=5), acute demyelinating syndrome (n=3), chorea (n=2), psychosis (n=2), isolated encephalopathy (n=2), and transient ischaemic attack (n=1). The PIMS-TS neurology group more often had multiple features, which included encephalopathy (n=22 [88%]), peripheral nervous system involvement (n=10 [40%]), behavioural change (n=9 [36%]), and hallucinations at presentation (n=6 [24%]). Recognised neuroimmune disorders were more common in the COVID-19 neurology group than in the PIMS-TS neurology group (13 [48%] of 27 patients vs 1 [<1%] of 25 patients, p=0·0003). Compared with the COVID-19 neurology group, more patients in the PIMS-TS neurology group were admitted to intensive care (20 [80%] of 25 patients vs six [22%] of 27 patients, p=0·0001) and received immunomodulatory treatment (22 [88%] patients vs 12 [44%] patients, p=0·045). 17 (33%) patients (10 [37%] in the COVID-19 neurology group and 7 [28%] in the PIMS-TS neurology group) were discharged with disability; one (2%) died (who had stroke, in the PIMS-TS neurology group). INTERPRETATION: This study identified key differences between those with a primary neurological disorder versus those with PIMS-TS. Compared with patients with a primary neurological disorder, more patients with PIMS-TS needed intensive care, but outcomes were similar overall. Further studies should investigate underlying mechanisms for neurological involvement in COVID-19 and the longer-term outcomes. FUNDING: UK Research and Innovation, Medical Research Council, Wellcome Trust, National Institute for Health Research.

PedsQL Score Post Encephalo-duro-arterio-myo-synangiosis Procedure for Moyamoya Disease: A Single Center Experience.

BACKGROUND: Moyamoya disease is a progressive, occlusive arteriopathy of the intracranial vessels causing an increased risk of stroke. It often results in functional impairment and decrease in quality of life, both in the presence and absence of stroke. Revascularization is the accepted treatment for patients with symptomatic moyamoya disease, preventing further stroke. At Leeds Children's Hospital we use the encephalo-duro-arterio-myo-synangiosis (EDAMS) technique to facilitate revascularization. We aim to assess the quality of life outcomes of patients who have undergone operative intervention at our unit for moyamoya disease. METHODS: Pediatric patients with operated moyamoya disease from Leeds Children Hospital between February 2009 and January 2019 were included. Patients awaiting primary surgery were excluded. Patients were contacted via telephone and the Pediatric Quality of Life Inventory 4.0 (PedsQL) questionnaire administered via parent proxy. Quality of life outcomes were assessed using the PedsQL questionnaire score, which measures physical, emotional social and school functioning domains. This score was then converted to a health-related quality of life score. Scores in each domain and mean scores were compared with normative data. RESULTS: This study included 11 children (5 boys), median age 6.8 years (range: 22 months to 15.5 years), and 9 children underwent bilateral operations. Mean parent proxy PedsQL score was 66 (range: 12.5-98.4), with a mean score of 61.9 in physical function, 88.9 in emotional function, 70.9 in social function, and 58.7 in school function. This was lower than healthy controls overall and in each individual domain except emotional function, which was similar to normative data. CONCLUSIONS: Children with moyamoya disease have a lower quality of life than healthy controls within this series. This suggests that children with moyamoya should be offered additional psychosocial support within the community.

Surgical Disconnection of a Residual Pediatric Pial Arterio-Venous Fistula Following Partial Embolization: A Case Study.

BACKGROUND: Pial arteriovenous fistulas (AVFs) are rare intracranial vascular lesions consisting of 1 or more feeder arteries connecting directly to a venous system without a nidus, in the subpial space. Because of the high-flow system, they are commonly associated with a large varix. They are thought to represent between 1.6% and 7.3% of all pediatric arteriovenous malformations (AVMs). Morbidity and mortality is high in this condition and surgical or endovascular treatment options are usually considered. There have been limited reports on the clinical features, treatment options, and outcomes of pial AVMs due to its rarity. We present a case study of a pediatric patient in our institution and her clinical course, focusing on her presenting clinical features and management. CASE DESCRIPTION: A 1-year-old girl presents with progressively prominent and dilated facial veins and no other features suggestive of pial AVF. She was diagnosed with pial AVF with two feeder arteries and a large varix on imaging. Embolization was undertaken 3 times before successful surgical disconnection was done. Genetic testing for associated syndromes were all negative. CONCLUSIONS: Prominence of facial veins could be 1 of the more uncommon presenting features of pial AVFs. Genetic testing should always be considered in the pediatric population diagnosed with AVFs because of their association to various syndromes. Despite endovascular embolization being considered the less invasive choice, decision on mode of treatment should be a multifactorial decision.

Delayed mid-basilar artery stenosis following paediatric acute mechanical thrombectomy: a rare complication from a rare case.

There is limited literature on the use of mechanical thrombectomy with stent-retrievers in paediatric stroke, especially in the posterior circulation. We report a paediatric case of acute basilar artery occlusion successfully treated by mechanical thrombectomy using stent-retriever but complicated by delayed basilar artery stenosis. This case emphasises prudent selection of thrombectomy device and meticulous long-term follow-up when employed in paediatric stroke.

Clinical features, course, and outcomes of a UK cohort of pediatric moyamoya.

OBJECTIVE: To describe characteristics and course of a large UK cohort of children with moyamoya from multiple centers and examine prognostic predictors. METHODS: Retrospective review of case notes/radiology, with use of logistic regression to explore predictors of outcome. RESULTS: Eighty-eight children (median presentation age 5.1 years) were included. Thirty-six presented with arterial ischemic stroke (AIS) and 29 with TIA. Eighty had bilateral and 8 unilateral carotid circulation disease; 29 patients had posterior circulation involvement. Acute infarction was present in 36/176 hemispheres and chronic infarction in 86/176 hemispheres at the index presentation. Sixty-two of 82 with symptomatic presentation had at least one clinical recurrence. Fifty-five patients were treated surgically, with 37 experiencing fewer recurrences after surgery. Outcome was categorized as good using the Recovery and Recurrence Questionnaire in 39/85 patients. On multivariable analysis, presentation with TIA (odds ratio [OR] 0.09, 95% confidence interval [CI] 0.02-0.35), headache (OR 0.10, 95% CI 0.02-0.58), or no symptoms (OR 0.08, 95% CI 0.01-0.68) was less likely to predict poor outcome than AIS presentation. Posterior circulation involvement predicted poor outcome (OR 4.22, 95% CI 1.23-15.53). Surgical revascularization was not a significant predictor of outcome. CONCLUSIONS: Moyamoya is associated with multiple recurrences, progressive arteriopathy, and poor outcome in half of patients, especially with AIS presentation and posterior circulation involvement. Recurrent AIS is rare after surgery. Surgery was not a determinant of overall outcome, likely reflecting surgical case selection and presentation clinical status.

Ketogenic diet in the treatment of epilepsy in children under the age of 2 years: study protocol for a randomised controlled trial.

BACKGROUND: The incidence of epilepsy is greatest in the first 2 years of life, an age group where there is generally a poor prognosis for both seizure control and neurodevelopmental outcome. Early control of seizures can be associated with better developmental outcome but many of the epilepsies presenting in infancy are poorly responsive to antiepileptic medication. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet designed to mimic the effects of starvation on the body. Dietary fat is converted into ketones in the body and used as an energy source by the brain. The KD has been shown to be successful in controlling seizures in many observational studies, and in two randomised controlled trials (RCTs) in older children. However, little evidence is available in the very young. METHODS/DESIGN: An open-label RCT where eligible children (age 3 months to 2 years with epilepsy who have failed two antiepileptic drugs (AEDs)) undergo baseline assessment, including medical and seizure history. Participants then start an observation period (7 or 14 days) with documentation of seizure frequency. Randomisation will occur on day 8 or day 15 to receive the KD or a further AED; the allocated treatment will commence on day 15, with instruction and training. A second assessment (4 weeks after start of treatment) will include a clinical review and tolerability questionnaire (modified Hague Scale of Side Effects - for those allocated to the KD group). Assessments will be repeated at 8 weeks after the start of treatment including biochemical investigations, after which, according to patient response, KD (diet group) or AED (standard AED group) will then be continued or changed. Those in the AED group who have failed to achieve seizure control at the 8-week assessment will then be offered KD outside the context of the trial. Those in the KD arm who fail to achieve seizure control will be changed to standard clinical management. All patients will be followed up for 12 months from randomisation for retention, seizure outcome, quality of life and neurodevelopmental status. DISCUSSION: The slow rate of recruitment is an ongoing practical issue. There is a limitation to the number of eligible patients compared to what was predicted, mainly due to the nature of this patient group. After a substantial amendment to widen inclusion criteria and reduce the baseline period to 7 days for patients with a high seizure burden, the rate of recruitment steadily increased. A number of operational concerns regarding dietetic time were also highlighted impacting on the recruitment rate. However, the combination of a low dropout rate and the opening of further centres, the trial should successfully meet the final recruitment target. All nine centres are now recruiting and we hope to open further centres within the UK. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02205931 . Registered on 16 December 2013.

Experience of mechanical thrombectomy for paediatric arterial ischaemic stroke.

BACKGROUND: Paediatric arterial ischaemic stroke (AIS) is an important cause of acute neurological symptoms in children, it causes significant morbidity and is one of the top ten causes of childhood deaths. Consensus papers have suggested guidelines for the management of AIS in childhood, although none recommend thrombectomy. Despite this, children within our institution have undergone mechanical thrombectomy for large vessel occlusion. This is the first series of mechanical thrombectomy and outcomes performed in children in the U.K. METHODS: We describe the endovascular management of paediatric arterial ischaemic stroke (AIS) in four children (5-15 years) with PedNIHSS > 17. RESULTS: Three had basilar artery (BA) occlusion and one left middle cerebral artery (MCA) occlusion. All underwent uncomplicated thrombectomy followed by intravenous heparin. One had a successful second attempt. The BA cases underwent thrombectomy 17-36 h after symptom onset; the left MCA case <6 h after symptom onset. Modified Rankin Scale (MRS) was 0-3, 50% had MRS 0. DISCUSSION: Adult AIS guidelines recommend IV recombinant tissue plasminogen activator (r-tPA) within 4.5 h of onset and intra-arterial r-tPA within 6 h; thrombectomy being reserved for carefully selected patients. Paediatric AIS recognition is problematic, often with delayed imaging. There is little evidence regarding efficacy of thrombectomy for paediatric AIS. Our experience suggests there may be a role for endovascular clot retrieval in selected patients managed by an experienced multidisciplinary team. Careful data collection is mandatory.