N-methyl-D-aspartate receptor antibody (NMDAR-Ab) encephalitis is a well-recognised clinico-immunological syndrome that presents with neuropsychiatric symptoms cognitive decline, movement disorder ...and seizures. This study reports the clinical features, management and neurological outcomes of paediatric NMDAR-Ab-mediated neurological disease in the UK.
A prospective surveillance study. Children with NMDAR-Ab-mediated neurological diseases were voluntarily reported to the British Neurological Surveillance Unit (BPNSU) from November 2010 to December 2011. Initial and follow-up questionnaires were sent out to physicians.
Thirty-one children fulfilled the criteria for the study. Eight presented during the study period giving an incidence of 0.85 per million children per year (95% CI 0.64 to 1.06); 23 cases were historical. Behavioural change and neuropsychiatric features were present in 90% of patients, and seizures and movement disorders both in 67%. Typical NMDAR-Ab encephalitis was reported in 24 children and partial phenotype without encephalopathy in seven, including predominantly psychiatric (four) and movement disorder (three). All patients received steroids, 22 (71%) received intravenous immunoglobulin, 9 (29%) received plasma exchange,and 10 (32%) received second-line immunotherapy. Of the 23 patients who were diagnosed early, 18 (78%) made a full recovery compared with only 1 of 8 (13%) of the late diagnosed patients (p=0.002, Fisher's exact test). Seven patients relapsed, with four needing additional second-line immunotherapy.
Paediatric NMDAR-Ab-mediated neurological disease appears to be similar to adult NMDAR-Ab encephalitis, but some presented with a partial phenotype. Early treatment was associated with a quick and often full recovery.
Objective
To identify the etiology of a novel, heritable encephalopathy in a small group of patients.
Methods
Magnetic resonance imaging (MRI) pattern analysis was used to select patients with the ...same pattern. Homozygosity mapping and whole exome sequencing (WES) were performed to find the causal gene mutations.
Results
Seven patients from 4 families (2 consanguineous) were identified with a similar MRI pattern characterized by T2 signal abnormalities and diffusion restriction in the posterior limb of the internal capsule, often also optic radiation, brainstem tracts, and cerebellar white matter, in combination with delayed myelination and progressive brain atrophy. Patients presented with early infantile onset encephalopathy characterized by progressive microcephaly, seizures, variable cardiac defects, and early death. Metabolic testing was unrevealing. Single nucleotide polymorphism array revealed 1 overlapping homozygous region on chromosome 20 in the consanguineous families. In all patients, WES subsequently revealed recessive predicted loss of function mutations in ITPA, encoding inosine triphosphate pyrophosphatase (ITPase). ITPase activity in patients' erythrocytes and fibroblasts was severely reduced.
Interpretation
Until now ITPA variants have only been associated with adverse reactions to specific drugs. This is the first report associating ITPA mutations with a human disorder. ITPase is important in purine metabolism because it removes noncanonical nucleotides from the cellular nucleotide pool. Toxicity of accumulated noncanonical nucleotides, leading to neuronal apoptosis and interference with proteins normally using adenosine triphosphate/guanosine triphosphate, probably explains the disease. This study confirms that combining MRI pattern recognition to define small, homogeneous patient groups with WES is a powerful approach for providing a fast diagnosis in patients with an unclassified genetic encephalopathy. Ann Neurol 2015;78:649–658
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.
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.
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.
ClinicalTrials.gov, identifier: NCT02205931 . Registered on 16 December 2013.
Objective
The amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) is increasingly recognized as a therapeutic target in drug‐refractory pediatric epilepsy. Perampanel (PER) is a ...non‐competitive AMPAR antagonist, and pre‐clinical studies have shown the AMPAR‐mediated anticonvulsant effects of decanoic acid (DEC), a major medium‐chain fatty acid provided in the medium‐chain triglyceride ketogenic diet.
Methods
Using brain tissue resected from children with intractable epilepsy, we recorded the effects of PER and DEC in vitro.
Results
We found resected pediatric epilepsy tissue exhibits spontaneous epileptic activity in vitro, and showed that DEC and PER inhibit this epileptiform activity in local field potential recordings as well as excitatory synaptic transmission.
Interpretation
This study confirms AMPAR antagonists inhibit epileptiform discharges in brain tissue resected in a wide range of pediatric epilepsies.
The aim of the present study was to review the history, clinical course, treatment, and outcome of movement disorders in children and young people with complex regional pain syndrome (CRPS). Case ...notes were reviewed retrospectively of children and young people who presented with movement disorders in CRPS to our tertiary paediatric pain service over a period of 13 years. Ten children with CRPS presented with movement disorders (eight females, two males). The age at first presentation with symptoms of CRPS ranged from 8 to 15 years (mean 11y 2mo, median 13y). The most common movement disorder was dystonia (n=8), followed by tremors (n=3) and myoclonus (n=3); two patients had all three movement disorders. The movement disorder affected mainly the lower limb (n=9) with a predilection for the foot (n=7) and was frequently initiated by minor trauma (n=7). Follow‐up ranged from 6 months to 14 years. The outcome was variable, with good prognosis in nearly half of the cases: four children experienced complete resolution of symptoms. Two children showed a slight improvement. Four children showed no improvement. Movement disorders in CRPS are under‐recognized in children. The management has to be multidisciplinary with an expertize in paediatric pain.
To report the clinical and investigative features of children with a clinical diagnosis of probable autoimmune encephalopathy, both with and without antibodies to central nervous system antigens.
...Patients with encephalopathy plus one or more of neuropsychiatric symptoms, seizures, movement disorder or cognitive dysfunction, were identified from 111 paediatric serum samples referred from five tertiary paediatric neurology centres to Oxford for antibody testing in 2007-2010. A blinded clinical review panel identified 48 patients with a diagnosis of probable autoimmune encephalitis whose features are described. All samples were tested/retested for antibodies to N-methyl-D-aspartate receptor (NMDAR), VGKC-complex, LGI1, CASPR2 and contactin-2, GlyR, D1R, D2R, AMPAR, GABA(B)R and glutamic acid decarboxylase.
Seizures (83%), behavioural change (63%), confusion (50%), movement disorder (38%) and hallucinations (25%) were common. 52% required intensive care support for seizure control or profound encephalopathy. An acute infective organism (15%) or abnormal cerebrospinal fluid (32%), EEG (70%) or MRI (37%) abnormalities were found. One 14-year-old girl had an ovarian teratoma. Serum antibodies were detected in 21/48 (44%) patients: NMDAR 13/48 (27%), VGKC-complex 7/48(15%) and GlyR 1/48(2%). Antibody negative patients shared similar clinical features to those who had specific antibodies detected. 18/34 patients (52%) who received immunotherapy made a complete recovery compared to 4/14 (28%) who were not treated; reductions in modified Rankin Scale for children scores were more common following immunotherapies. Antibody status did not appear to influence the treatment effect.
Our study outlines the common clinical and paraclinical features of children and adolescents with probable autoimmune encephalopathies. These patients, irrespective of positivity for the known antibody targets, appeared to benefit from immunotherapies and further antibody targets may be defined in the future.
Purpose
The recent VNS models (AspireSR® Model 106, SenTiva™ Model 1000 (VNS Therapy®, LivaNova)) include a new function of cardiac-based seizure detection (CBSD) automatic stimulation, known as ...‘AutoStim’. This algorithm uses tachycardia as a proxy to a seizure, and the battery delivers a closed-loop electrical current in addition to its programmed stimulation. This function leads to further seizure reduction in adults, but this advantage has not been reported in the paediatric population. This study aims to investigate whether battery change with AutoStim leads to further seizure reduction in children.
Methods
This observational study included the first 10 cases of VNS battery change from non-AutoStim to AutoStim function. During the battery change operation, the new VNS was switched on, with the same normal and magnet mode settings as the previous VNS. The AutoStim mode was activated at the same time. Data on seizure burden were collected at 3 time points: (1) before the first VNS insertion, (2) before battery replacement (post-1st VNS) and (3) 12 months post-battery change (post-AutoStim). The net effect of AutoStim, the only changed parameter, was evaluated by comparing the seizure burden prior to and 12 months following battery change in each child.
Results
The seizure reduction improved significantly from 60 to 83% following battery change with AutoStim. Categorising the outcome according the McHugh classification, children achieving class I and II outcome (≥ 50% seizure reduction) improved from 70 to 90%.
Conclusion
This is the first study to demonstrate the additional efficacy of AutoStim in children treated with VNS.
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.
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.
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.
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.
National Institute for Health and Care Research.
Headache is very common in children and young people. The correct advice and treatment requires consideration of a wide differential diagnosis between primary and secondary headaches, and also of the ...different types of primary headache. The International Classification of Headache Disorders gives useful descriptions and diagnostic criteria that are especially useful for primary headaches. The National Institute for Health and Care Excellence (NICE) Clinical Guideline 150 provides evidence-based recommendations on treatments for adults and young people from age 12 years. However, the same principles can be applied to younger children when a specific diagnosis can be made. Key recommendations from the NICE Quality Standards include, establishing a precise diagnosis if possible, avoiding, diagnosing and treating medication overuse headache, and combining a triptan with a non-steroidal anti-inflammatory drug or paracetamol as the first-line acute/rescue treatment for migraine with or without aura. Although rare in children and young people, it is important to diagnose new daily persistent headache, as it responds poorly or not at all to medication; and paroxysmal hemicrania as it responds very well to indomethacin but not to other commonly used analgesics. When faced with difficulties in reaching a precise diagnosis or in finding effective therapies, further advice should be sought from a children's headache clinic or specialist.
To describe characteristics and course of a large UK cohort of children with moyamoya from multiple centers and examine prognostic predictors.
Retrospective review of case notes/radiology, with use ...of logistic regression to explore predictors of outcome.
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.
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.
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