Reducing epilepsy diagnostic and treatment gaps: Standardized paediatric epilepsy training courses for health care professionals.

AIM: To evaluate improvement in knowledge and clinical behaviour among healthcare professionals after attendance at paediatric epilepsy training (PET) courses. METHOD: Since 2005, 1-day PET courses have taught evidence-based paediatric epilepsy management to doctors and nurses in low-, middle-, and high-income countries. A cohort study was performed of 7528 participants attending 252 1-day PET courses between 2005 and 2020 in 17 low-, middle-, and high-income countries, and which gathered data from participants immediately after the course and then 6 months later. Training outcomes were measured prospectively in three domains (reaction, learning, and behaviour) using a mixed-methods approach involving a feedback questionnaire, a knowledge quiz before and after the course, and a 6-month survey. RESULTS: Ninety-eight per cent (7217 of 7395) of participants rated the course as excellent or good. Participants demonstrated knowledge gain, answering a significantly higher proportion of questions correctly after the course compared to before the course (88% [47 883 of 54 196], correct answers/all quiz answers, vs 75% [40 424 of 54 196]; p < 0.001). Most survey responders reported that the course had improved their epilepsy diagnosis and management (73% [311 of 425]), clinical service (68% [290 of 427]), and local epilepsy training (68% [290 of 427]). INTERPRETATION: This was the largest evaluation of a global epilepsy training course. Participants reported high course satisfaction, showed knowledge gain, and described improvements in clinical behaviour 6 months later. PET supports the global reduction in the epilepsy 'treatment gap' as promoted by the World Health Organization.

Epilepsy and cannabis: so near, yet so far.

Following media attention on children with refractory epilepsies reportedly deriving benefit from cannabis-based medicinal products (CBMPs), the UK government changed the law in 2018 so that CBMPs could be legally prescribed. Subsequently, a pure cannabidiol (CBD) product has been licensed for two epilepsy syndromes. However, despite pressure from campaign groups and allied politicians, almost no children have received unlicensed CBMPs under the UK NHS. This review explores the science behind CBMPs in paediatric epilepsies and highlights the areas that warrant further research. It identifies a lack of level I evidence for efficacy and safety as, currently, the major obstacle to prescribing. Unlicensed medicines are often used in paediatrics but almost all are used 'off-label', with supporting evidence of efficacy and safety derived either from other age-groups or from disease conditions. CBMPs, except for pure CBD, are unique in that they are currently both unlicensed and fall outside the 'off-label' category. The review acknowledges the treatment gap in refractory epilepsies and the potential use of CBMPs. However, it argues against exceptionally circumventing the usual standard of evidence required by regulatory prescribing authorities and warns against allowing vulnerable children to become the 'trojan horse' for deregulation of the commercial cannabis market.

Diagnostic algorithm for children presenting with epilepsia partialis continua.

OBJECTIVE: To characterize a cohort of children with epilepsia partialis continua (EPC) and develop a diagnostic algorithm incorporating key differential diagnoses. METHODS: Children presenting with EPC to a tertiary pediatric neurology center between 2002 and 2019 were characterized. RESULTS: Fifty-four children fulfilled EPC criteria. Median age at onset was 7 years (range 0.6-15), with median follow-up of 4.3 years (range 0.2-16). The diagnosis was Rasmussen encephalitis (RE) in 30 of 54 (56%), a mitochondrial disorder in 12 of 54 (22.2%), and magnetic resonance imaging (MRI) lesion-positive focal epilepsy in 6 of 54 (11.1%). No diagnosis was made in 5 of 54 (9%). Children with mitochondrial disorders developed EPC earlier; each additional year at presentation reduced the odds of a mitochondrial diagnosis by 26% (P = .02). Preceding developmental concerns (odds ratio [OR] 22, P < .001), no seizures prior to EPC (OR 22, P < .001), bilateral slowing on electroencephalogram (EEG) (OR 26, P < .001), and increased cerebrospinal fluid (CSF) protein level (OR 16) predicted a mitochondrial disorder. Asymmetry or hemiatrophy was evident on MRI at presentation with EPC in 18 of 30 (60%) children with RE, and in the remainder at a median of 6 months (range 3-15) after EPC onset. The first diagnostic test is brain MRI. Hemiatrophy may permit a diagnosis of RE with unilateral clinical and EEG findings. For children in whom a diagnosis of RE cannot be made on first scan but the clinical and radiological presentation resembles RE, repeat imaging every 6 months is recommended to detect progressive unicortical hemiatrophy, and brain biopsy should be considered. Evidence of intrathecal inflammation (oligoclonal bands and raised neopterin) can be supportive. In children with bihemispheric EPC, rapid polymerase gamma testing is recommended and if negative, sequencing mtDNA and whole-exome sequencing on blood-derived DNA should be performed. SIGNIFICANCE: Children presenting with EPC due to a mitochondrial disorder show clinical features distinguishing them from RE and structural epilepsies. A diagnostic algorithm for children with EPC will allow targeted investigation and timely diagnosis.

The underlying etiology of infantile spasms (West syndrome): Information from the International Collaborative Infantile Spasms Study (ICISS).

OBJECTIVE: To determine the underlying etiologies in a contemporary cohort of infants with infantile spasms and to examine response to treatment. METHODS: Identification of the underlying etiology and response to treatment in 377 infants enrolled in a clinical trial of the treatment of infantile spasms between 2007 and 2014 using a systematic review of history, examination, and investigations. They were classified using the pediatric adaptation of International Classification of Diseases, Tenth Revision (ICD-10). RESULTS: A total of 219 of 377 (58%) had a proven etiology, of whom 128 (58%) responded, 58 of 108 (54%) were allocated hormonal treatment, and 70 of 111 (63%) had combination therapy. Fourteen of 17 (82%, 95% confidence interval [CI] 59% to 94%) infants with stroke and infarct responded (compared to 114 of 202 for the rest of the proven etiology group (56%, 95% CI 48% to 62%, chi-square 4.3, P = .037): the better response remains when treatment allocation and lead time are taken into account (odds ratio 5.1, 95% CI 1.1 to 23.6, P = .037). Twenty of 37 (54%, 95% CI 38% to 70%) infants with Down syndrome had cessation of spasms compared to 108 of 182 (59%, 95% CI 52% to 66%, chi-square 0.35, P = .55) for the rest of the proven etiology group. The lack of a significant difference remains after taking treatment modality and lead-time into account (odds ratio 0.8, 95% CI 0.4 to 1.7, P = .62). In Down syndrome infants, treatment modality did not appear to affect response: 11 of 20 (55%) allocated hormonal therapy responded, compared to 9 of 17 (53%) allocated combination therapy. SIGNIFICANCE: This classification allows easy comparison with other classifications and with our earlier reports. Stroke and infarct have a better outcome than other etiologies, whereas Down syndrome might not respond to the addition of vigabatrin to hormonal treatment.

Renal angiomyolipoma in patients with tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increase disease Awareness.

BACKGROUND: Renal angiomyolipoma occurs at a high frequency in patients with tuberous sclerosis complex (TSC) and is associated with potentially life-threatening complications. Despite this frequency and severity, there are no large population-based cohort studies. Here we present baseline and follow-up data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with an aim to provide detailed clinical characteristics of renal angiomyolipoma among patients with TSC. METHODS: Patients of any age with a documented clinic visit for TSC within 12 months or who were newly diagnosed with TSC before participation in the registry were eligible. Data specific to renal angiomyolipoma included physical tumour characteristics (multiple, bilateral, lesion size and growing lesions), clinical signs and symptoms, and management. The effects of age, gender and genotype on the prevalence of renal angiomyolipoma were also evaluated. RESULTS: Renal angiomyolipoma was reported in 51.8% of patients at baseline, with higher frequency in female patients (57.8% versus 42.2%). The median age at diagnosis was 12 years. Prevalence of angiomyolipoma was higher in patients with TSC2 compared with TSC1 mutations (59.2% versus 33.3%, P < 0.01). Of the 1031 patients with angiomyolipoma at baseline, multiple lesions were reported in 88.4% and bilateral in 83.9% of patients, while the size of angiomyolipoma was >3 cm in 34.3% of patients. Most patients were asymptomatic (82%). Frequently reported angiomyolipoma-related symptoms included bleeding, pain, elevated blood pressure and impaired renal function. Embolization and mammalian target of rapamycin inhibitors were the two most common treatment modalities. CONCLUSIONS: The TOSCA registry highlights the burden of renal angiomyolipoma in patients with TSC and shows that renal manifestations are initially asymptomatic and are influenced by gender and genotype. Furthermore, the occurrence of significant problems from angiomyolipoma in a minority of younger patients suggests that surveillance should begin in infancy or at initial diagnosis.

The journey of metformin from glycaemic control to mTOR inhibition and the suppression of tumour growth.

Our knowledge of the effect of metformin on human health is increasing. In addition to its ability to improve the control of hyperglycaemia, metformin has been shown to reduce the burden o,f ageing via effects on damaged DNA and the process of apoptosis. Studies have shown that metformin may reduce the risk of cardiovascular disease through influences on body weight, blood pressure, cholesterol levels and the progression of atherosclerosis. Studies also suggest that metformin may be beneficial for neuro-psychiatric disorders, cognitive impairment and in reducing the risk of dementia, erectile dysfunction and Duchenne muscular dystrophy. In vivo and in vitro studies have shown that metformin has anti-cancer properties, and population studies have suggested that metformin may reduce the risk of cancer or improve cancer prognosis. It is thought that it exerts its anti-cancer effect through the inhibition of the mammalian target of rapamycin (mTOR) signalling pathway. Because of its effect on the mTOR pathway, there may be a role for metformin in slowing or reversing growth of life-threatening hamartomas in tuberous sclerosis complex.

Outcome and recurrence 1 year after pediatric arterial ischemic stroke in a population-based cohort.

OBJECTIVE: Arterial ischemic stroke (AIS) is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood AIS have been completed. We aimed to investigate the outcome of childhood AIS 12 months after the event in a population-based cohort. METHODS: Children aged 29 days to < 16 years with radiologically confirmed AIS occurring over a 1-year period residing in southern England (population = 5.99 million children) were eligible for inclusion. Outcome was assessed during a home visit using the Pediatric Stroke Outcome Measure (PSOM). Parental impressions of recovery were assessed using the Pediatric Stroke Recurrence and Recovery Questionnaire. PSOM score was estimated via telephone interview or clinician interview whenever home visit was not possible. RESULTS: Ninety-six children with AIS were identified. Two children were lost to follow-up. Nine of 94 (10%) children died before the 12-month follow-up. One child had an AIS recurrence. PSOM scores were available for 78 of 85 living children at follow-up. Thirty-nine of 78 (50%) had a good outcome (total PSOM score < 1), and 39 of 78 (50%) had a poor outcome. Seizures at onset of AIS were associated with a poor outcome (odds ratio = 3.5, 95% confidence interval = 1.16-10.6). Twenty-eight of 73 (38%) children were judged by their carers to have fully recovered. Ten of 84 (12%) children had recurrent seizures, and 17 of 84 (20%) reported recurrent headaches. INTERPRETATION: AIS carries a significant risk of mortality and long-term neurological deficit. However, the rates of mortality, recurrence, and neurological impairment were markedly lower in this study than previously published figures in the United Kingdom. Ann Neurol 2016;79:784-793.

Planning interventional trials in childhood arterial ischaemic stroke using a Delphi consensus process.

AIM: There is a paucity of data from randomized controlled treatment trials in childhood arterial ischaemic stroke. Our objectives were to identify and plan a trial through use of a Delphi consensus process. METHOD: The Delphi panel consisted of Australian, New Zealand, and European paediatric neurologists with interests in childhood stroke. Four rounds were conducted using a REDCap (Research Electronic Data Capture) Web-based application: the first consisted of open-ended questions; the second evaluated agreement for the most important trial; the third and fourth reached consensus on design. RESULTS: Forty-seven out of 66 neurologists answered the first round. Eight areas of research for important and feasible trials were identified. In the second round, 43 paediatric neurologists ranked the three highest rated trials: (1) aspirin versus aspirin plus steroids in focal arteriopathy (n=31); (2) heparin versus aspirin (n=6); and (3) heparin versus aspirin versus modern anticoagulation (n=6). The third and fourth surveys reached consensus among 43 out of 44 respondents on design of the highest ranked trial, and allowed agreement on inclusion/exclusion criteria, clinical/neuroimaging data, and treatment protocols. CONCLUSION: The Delphi consensus process is an efficient method of identifying and planning paediatric stroke trials. An international, multicentre trial is now in preparation.

Causes of mortality in individuals with tuberous sclerosis complex.

AIM: The causes of death in patients with tuberous sclerosis complex (TSC) have rarely been studied, with only one published account, which was reported from the Mayo Clinic in 1991. We aimed to investigate mortality in a large cohort of patients with TSC from one of two national referral clinics in the UK. METHOD: We identified 284 patients who attended Bath TSC clinic between 1981 and 2015, and ascertained causes of death by reviewing medical records, death certificates, and postmortem reports. RESULTS: Sixteen patients died from complications of TSC: eight from TSC kidney diseases; four from sudden unexpected death in epilepsy (SUDEP); two from lymphangioleiomyomatosis; one from a subependymal giant cell astrocytoma; and one from a pancreatic malignancy. The median age of death was 33 years (interquartile range [IQR] 26-46). Mortality was significantly more common in patients with learning disabilities than in those without (13/135 [9%] vs 3/131 [2%]; two-tailed Fisher exact test p=0.020). INTERPRETATION: Renal disease is a major cause of mortality in TSC. Lifelong surveillance and early intervention is warranted. SUDEP is also an important cause of mortality. Patients with learning disabilities are at significantly greater risk of early mortality and this implies the need for greater vigilance for TSC-related complications in this group. Female patients are vulnerable to pulmonary and renal disease. Pancreatic lesions are a rare but potentially treatable cause of mortality.

Diagnostic delays in paediatric stroke.

BACKGROUND: Stroke is a major cause of mortality in children. Conditions that mimic stroke also cause severe morbidity and require prompt diagnosis and treatment. We have investigated the time to diagnosis in a cohort of children with stroke. METHODS: A population-based cohort of children with stroke was prospectively identified in the south of England. Case notes, electronic hospital admission databases and radiology records were reviewed. Timing of symptom onset, presentation to hospital, first neuroimaging, first diagnostic neuroimaging and presenting clinical features were recorded. RESULTS: Ninety-six children with an arterial ischaemic stroke (AIS) and 43 with a haemorrhagic stroke (HS) were identified. The median time from symptom onset to diagnostic neuroimaging was 24.3 h in AIS and 2.9 h in HS. The initial imaging modality was CT in 68% of cases of AIS. CT was diagnostic of AIS in 66% of cases. MRI was diagnostic in 100%. If initial neuroimaging was non-diagnostic in AIS, then median time to diagnosis was 44 h. CT was diagnostic in 95% of HS cases. Presentation outside normal working hours resulted in delayed neuroimaging in AIS (13 vs 3 h, p=0.032). Diffuse neurological signs or a Glasgow Coma Scale <9 resulted in more expeditious neuroimaging in both HS and AIS. CONCLUSIONS: The diagnosis of AIS in children is delayed at every stage of the pathway but most profoundly when the first neuroimaging is CT scanning, which is non-diagnostic. MRI should be the initial imaging modality of choice in any suspected case of childhood AIS.

An investigation into the relationship between vigabatrin, movement disorders, and brain magnetic resonance imaging abnormalities in children with infantile spasms.

AIM: We aimed to investigate the relationship between movement disorders, changes on brain magnetic resonance imaging (MRI), and vigabatrin therapy in children with infantile spasms. METHOD: Retrospective review and brain MRI analysis of children enrolled in the International Collaborative Infantile Spasms Study (ICISS) who developed a movement disorder on vigabatrin therapy. Comparisons were made with controls within ICISS who had no movement disorder. RESULTS: Ten of 124 infants had a movement disorder and in eight it had developed on vigabatrin therapy. Two had a movement disorder that resolved on dose-reduction of vigabatrin, one had improvement on withdrawing vigabatrin, two had resolution without any dose change, and in three it persisted despite vigabatrin withdrawal. The typical brain MRI changes associated with vigabatrin therapy were noted in two infants. Ten control infants were identified. Typical MRI changes noted with vigabatrin were noted in three controls. INTERPRETATION: It is possible that in two out of eight cases, vigabatrin was associated with the development of a movement disorder. In six out of eight cases a causal relationship was less plausible. The majority of infants treated with vigabatrin did not develop a movement disorder. MRI changes associated with vigabatrin do not appear to be specifically related to the movement disorder.

Toward responsible clinical n-of-1 strategies for rare diseases.

N-of-1 strategies can provide high-quality evidence of treatment efficacy at the individual level and optimize evidence-based selection of off-label treatments for patients with rare diseases. Given their design characteristics, n-of-1 strategies are considered to lay at the intersection between medical research and clinical care. Therefore, whether n-of-1 strategies should be governed by research or care regulations remains a debated issue. Here, we delineate differences between medical research and optimized clinical care, and distinguish the regulations which apply to either. We also set standards for responsible optimized clinical n-of-1 strategies with (off-label) treatments for rare diseases. Implementing clinical n-of-1 strategies as defined here could aid in optimized treatment selection for such diseases.

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.

The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study.

PURPOSE: Infantile spasms is a severe infantile seizure disorder. Several factors affect developmental outcome, especially the underlying etiology of the spasms. Treatment also affects outcome. Both age at onset of spasms and lead time to treatment (the time from onset of spasms to start of treatment) may be important. We investigated these factors. METHODS: Developmental assessment using Vineland Adaptive Behaviour Scales (VABS) at 4 years of age in infants enrolled in the United Kingdom Infantile Spasms Study. Date of or age at onset of spasms was obtained prospectively. Lead time to treatment was then categorized into five categories. The effects of lead time to treatment, age of onset of spasms, etiology, and treatment on developmental outcome were investigated using multiple linear regression. KEY FINDINGS: Age of onset ranged (77 infants) from <1 to 10 months (mean 5.2, standard deviation 2.1). Lead time to treatment was 7 days or less in 11, 8-14 days in 16, 15 days to 1 month in 8, 1-2 months in 15, >2 months in 21 and not known in 6. Each month of reduction in age at onset of spasms was associated with a 3.1 [95% confidence interval (CI) 0.64-5.5, p = 0.03] decrease, and each increase in category of lead time duration associated with a 3.9 (95% CI 7.3-0.4, p = 0.014) decrease in VABS, respectively. There was a significant interaction between treatment allocation and etiology with the benefit in VABS in those allocated steroid therapy being in children with no identified etiology (coefficient 29.9, p=0.004). SIGNIFICANCE: Both prompt diagnosis and prompt treatment of infantile spasms may help prevent subsequent developmental delay. Younger infants may be more at risk from the epileptic encephalopathy than older infants.

Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy.

The epileptic encephalopathies of infancy and childhood are a collection of epilepsy disorders characterized by refractory, severe seizures and poor neurological outcome, in which the mechanism of disease is poorly understood. We report the clinical presentation and evolution of epileptic encephalopathy in a patient, associated with a loss-of-function mutation in the phospholipase C-ß 1 gene. We ascertained a consanguineous family containing a male infant who presented with early-onset epileptic encephalopathy for detailed clinical phenotyping and molecular genetic investigation. In addition, a cohort of 12 consanguineous families of children with infantile spasms were analysed for linkage to the phospholipase C-ß 1 gene locus. The male infant presented with tonic seizures in early infancy and subsequently developed infantile spasms. Over time, he developed drug-resistant epilepsy associated with severe neurological regression and failure to thrive. Molecular genetic investigation revealed a homozygous loss-of-function 0.5-Mb deletion, encompassing the promoter element and exons 1, 2 and 3 of phospholipase C-ß 1 in the index case. Linkage to the phospholipase C-ß 1 locus was excluded in the 12 other consanguineous families, consistent with genetic heterogeneity in this disorder. Although phospholipase C-ß 1 deficiency has not previously been reported in humans, the Plcb1 homozygote knockout mouse displays early-onset severe tonic seizures and growth retardation, thus recapitulating the human phenotype. Phospholipase C-ß 1 has important functions in both hippocampal muscarinic acetylcholine receptor signalling and in cortical development. Thus, the discovery of a phospholipase C-ß 1 mutation allows us to propose a novel potential underlying mechanism in early-onset epileptic encephalopathy.

Prevention of infantile spasms in tuberous sclerosis complex.

Since the ground-breaking work of Gomez in the 1970s and the later epidemiological studies of Webb and Osborne [1], the link between early onset epilepsy, especially infantile spasms (IS), and intellectual disability in tuberous sclerosis complex (TSC) has been accepted. This association raises the question of whether prevention of epilepsy in early life in TSC patients may improve the longer-term cognitive outcome.