A national surveillance study of childhood epilepsy mortality in the UK and Ireland

BACKGROUND: Patients with epilepsy are significantly more likely to die prematurely than the general population, with causes ranging from associated comorbidities to sudden unexpected death in epilepsy (SUDEP). The aim was to estimate the UK and Ireland incidence of childhood epilepsy deaths and to describe case demographics and clinical characteristics. METHODS: This was a prospective, population‐based surveillance study using established active surveillance methodology designed by the British Paediatric Surveillance Unit. RESULTS: Eighty‐eight confirmed cases were reported with an overall annual incidence of 0.65 per 100 000 children aged <16 years (95% confidence interval 0.52–0.81). More cases were male (65%) and cases fell across all age groups, with more deaths reported in older children. Twenty‐five per cent of deaths were epilepsy‐related (including SUDEP); 75% of deaths were non‐epilepsy‐related. SUDEP was the most common cause of seizure‐related deaths, accounting for 13 out of 17 children (76%). An underlying epilepsy syndrome was present in 36% of deaths, and 88% had global developmental delay. In addition, 90% of the children had comorbid conditions in addition to epilepsy. CONCLUSIONS: In this study, it has been demonstrated that death in children diagnosed with epilepsy occurs mainly in ‘complicated epilepsy’ secondary to factors associated with neurodisability, consolidating previous data. SUDEP is also a significant cause of paediatric epilepsy mortality that needs further attention. There is a clear need to better understand and reduce the number of epilepsy deaths in children in the UK, and national surveillance of SUDEP is warranted to better understand this entity in paediatric populations

Dynamic MRI lesion evolution in paediatric MOG-Ab associated disease (MOGAD)

INTRODUCTION: Myelin oligodendrocyte glycoprotein (MOG) antibodies are associated clinically with either a monophasic or relapsing disease course in both children and adults. There are few studies studying lesion evolution in children with myelin oligodendrocyte glycoprotein antibody associated disorder (MOGAD). AIM: The aim of this study was to examine MRI lesion evolution over time in a large single-centre paediatric MOGAD cohort. METHODS: We retrospectively identified patients with MOGAD from a tertiary paediatric neurosciences centre (Great Ormond Street Hospital) between 2001 to 2022. RESULTS: A total of 363 MRI scans from 59 included patients were available for analysis. Median age at presentation was 4 yrs (IQR 4-9), 32 (54.2%) were female and 34 (57.6%) were of non-white ethnicities. Twenty-seven children (45.8%) had a monophasic illness and 32 (54.2%) had a relapsing disease course. In the relapsing MOGAD group, median number of relapses was 4 (range 2-30). Initial presentation was ADEM in 27(46%), ON in 18 (31%) ADEM-ON in 4 (7%), ADEM-TM in 6 (10%) TM in 2 (3%) ADEM-TM-ON in 1 (2%) and ON-Brainstem syndrome in 1 (2%). There was no difference in demographics or clinical presentation between monophasic and relapsing groups. Fifteen patients (25.4%) had gadolinium enhancement on initial attack MRI. Seven out of 32 (21.9%) relapsing patients had persistent enhancement on follow-up MRI scans. One patient with a clinical transverse myelitis at presentation was MRI negative. New asymptomatic lesions following first clinical event were seen in 5/27 (18.5%) monophasic patients and 8/32 (25%) relapsing patients. During follow-up interval scanning,38 out of 59 have had follow up neuroimaging after their first attack whereas15/32 had relapsed before having a follow up MRI. Complete lesion resolution was reported in 9/38 (23.6%) (8 monophasic, 1 relapsing) following 1st acute attack, 3/32 (9.3%) after 2nd acute attack, and 1/32 (3.1%) following 3rd acute attack and 0/32 following 4th acute attack. Partial resolution of MRI lesions was seen in 7/20 (35%) monophasic patients and 7/32 (21.8%) relapsing patients at follow-up scans. CONCLUSIONS: Demyelinating lesions in paediatric MOGAD are dynamic and timing of MRI scanning may influence CNS region involvement. Unlike in multiple sclerosis, a significant number of MOGAD patients will have complete lesion resolution at first follow-up, although the ability to repair is reduced following multiple relapses

Primary progressive multiple sclerosis presenting under the age of 18 years: fact or fiction?

Previous cohort studies on pediatric multiple sclerosis (MS) have reported very low frequencies for a primary progressive MS (PPMS) course ranging from 0 to 7%. We identified six patients presenting prior to the age of 18 years and fulfilling the 2017 McDonald Criteria for primary progressive multiple sclerosis (PPMS). Presentation with progressive neurological symptoms and signs in young people should prompt evaluation for genetic causes such as leukodystrophies, hereditary spastic paraparesis and mitochondrial diseases given the rarity of primary progressive course in pediatric MS. In the absence of an alternative diagnosis, with new therapeutic options becoming available for PPMS, this diagnosis should then be considered

Two Cases of Guillain-Barré Syndrome Variants Presenting With Dysautonomia

We describe 2 pediatric cases presenting with posterior reversible encephalopathy syndrome secondary to autonomic dysfunction preceding the onset of motor symptoms in Guillain-Barré syndrome variants. Patient 1 presented acutely with encephalopathy, cerebellar signs, hypertension, lower limb weakness, and respiratory decompensation. Magnetic resonance imaging (MRI) brain showed occipital lesions consistent with posterior reversible encephalopathy syndrome. Nerve conduction studies were consistent with Miller-Fisher syndrome. After intravenous immunoglobulin and plasmapheresis, he improved clinically with radiological resolution. Patient 2 presented with headache, leg pain, seizures, and significant hypertension. Brain MRI was normal but spine MRI revealed enhancement of the cauda equina ventral nerve roots. She was areflexic with lower limb weakness a few days after intensive care unit admission and made a significant improvement after treatment with intravenous immunoglobulin. In children presenting with posterior reversible encephalopathy syndrome in the absent of other causes of primary hypertension, Guillain-Barré syndrome variants are an important differential etiology, presenting with autonomic dysfunction, even before signs of motor weakness become evident

Leigh syndrome mimicking neuromyelitis optica spectrum disorder (NMOSD)

We report two children with molecularly confirmed mitochondrial disease mimicking Neuromyelitis Optica Spectrum Disorder (NMOSD). The first patient presented at the age of 15 months with acute deterioration following a pyrexial illness with clinical features localising to the brainstem and spinal cord. The second patient presented at 5 years with acute bilateral visual loss. In both cases, MOG and AQP4 antibodies were negative. Both patients died within a year of symptoms onset from respiratory failure. Arriving at an early genetic diagnosis is important for redirection of care and avoiding potentially harmful immunosuppressant therapies

Isolated central nervous system familial hemophagocytic lymphohistiocytosis (fHLH) presenting as a mimic of demyelination in children

Isolated central nervous system (CNS) presentations of haemophagocytic lymphohistiocytosis (HLH), traditionally a systemic inflammatory condition, have been reported in adults and children. We identified nine patients with a diagnosis of isolated CNS familial hemophagocytic lymphohistiocytosis (fHLH) with symptom onset <18 years of age, and one asymptomatic sibling. Children with atypical chronic/recurrent CNS inflammation should be considered for immunological and genetic panel testing for fHLH even in the absence of any systemic inflammatory features. Despite haematopoietic stem cell transplantation (HSCT) being a mainstay of treatment, treatment failure and high morbidity and mortality post-HSCT suggest that alternative immune therapies may be worth considering

Incidence of paediatric multiple sclerosis and other acquired demyelinating syndromes: 10-year follow-up surveillance study

AIM: To describe a 10-year follow-up of children (<16y) with acquired demyelinating syndromes (ADS) from a UK-wide prospective surveillance study. METHOD: Diagnoses were retrieved from the patients' records via the patients' paediatric or adult neurologist using a questionnaire. Demyelinating phenotypes at follow-up were classified by an expert review panel. RESULTS: Twenty-four out of 125 (19.2%) children (64 males, 61 females; median age 10y, range 1y 4mo-15y 11mo), identified in the original study, were diagnosed with multiple sclerosis (incidence of 2.04/million children/year); 23 of 24 fulfilled 2017 McDonald criteria at onset. Aquaporin-4-antibody neuromyelitis optica spectrum disorders were diagnosed in three (2.4%, 0.26/million children/year), and relapsing myelin oligodendrocyte glycoprotein antibody-associated disease in five (4%, 0.43/million children/year). Three out of 125 seronegative patients relapsed and 85 of 125 (68%) remained monophasic over 10 years. Five of 125 patients (4%) originally diagnosed with ADS were reclassified during follow-up: three children diagnosed initially with acute disseminated encephalomyelitis were subsequently diagnosed with acute necrotising encephalopathy (RAN-binding protein 2 mutation), primary haemophagocytic lymphohistiocytosis (Munc 13-4 gene inversion), and anti-N-methyl-d-aspartate receptor encephalitis. One child initially diagnosed with optic neuritis was later diagnosed with vitamin B12 deficiency, and one presenting with transverse myelitis was subsequently diagnosed with Sjögren syndrome. INTERPRETATION: The majority of ADS presentations in children are monophasic, even at 10-year follow-up. Given the implications for treatment strategies, multiple sclerosis and central nervous system autoantibody mimics warrant extensive investigation

6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study.

BACKGROUND: Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a new, rare, post-infectious complication of SARS-CoV-2 infection in children. We aimed to describe the 6-month outcomes of PIMS-TS. METHODS: This retrospective cohort study comprised children (aged <18 years) who fulfilled the UK Royal College of Paediatrics and Child Health (RCPCH) diagnostic criteria for PIMS-TS and were admitted to Great Ormond Street Hospital (London, UK) between April 4 and Sept 1, 2020. Patients were followed up by a multidisciplinary team of specialists at 6 weeks and 6 months after admission. Biochemical and functional outcomes were analysed. FINDINGS: 46 children were included in this study. The median age at presentation was 10·2 years (IQR 8·8-13·3), 30 (65%) patients were male and 16 (35%) were female, 37 (80%) were from minority ethnic groups, and eight (17%) had pre-existing comorbidities. All patients had elevated markers of systemic inflammation at baseline. None of the patients died. By 6 months, systemic inflammation was resolved in all but one patient. 38 (90%) of 42 patients who had positive SARS-CoV-2 IgG antibodies within 6 weeks of admission remained seropositive at 6 months. Echocardiograms were normal in 44 (96%) of 46 patients by 6 months, and gastrointestinal symptoms that were reported in 45 (98%) of 46 patients at onset were present in six (13%) of 46 patients at 6 months. Renal, haematological, and otolaryngological findings largely resolved by 6 months. Although minor abnormalities were identified on neurological examination in 24 (52%) of 46 patients at 6 weeks and in 18 (39%) of 46 at 6 months, we found minimal functional impairment at 6 months (median Expanded Disability Status Scale score 0 [IQR 0-1]). Median manual muscle test-8 scores improved from 53 (IQR 43-64) during hospital admission to 80 (IQR 68-80) at 6 months, but 18 (45%) of 40 patients showed 6-min walk test results below the third centile for their age or sex at 6 months. PedsQL responses revealed severe emotional difficulties at 6 months (seven [18%] of 38 by parental report and eight [22%] of 38 by self report). 45 (98%) of 46 patients were back in full-time education (virtually or face to face) by 6 months. INTERPRETATION: Despite initial severe illness, few organ-specific sequelae were observed at 6 months. Ongoing concerns requiring physical re-conditioning and mental health support remained, and physiotherapy assessments revealed persisting poor exercise tolerance. Longer-term follow-up will help define the extended natural history of PIMS-TS. FUNDING: None