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Introduction: Intradural, extra-axial cerebral cavernous malformations (CCMs) are rare entities and are mostly reported in relation to the optic apparatus or the facial/vestibulocochlear complex. Cranial nerve CCMs tend to follow a clinically aggressive course, with a tendency to progressive neurological dysfunction following intra-lesional haemorrhage or less commonly due to the effects of subarachnoid haemorrhage. Case Presentation: We report the first case of a trigeminal CCM presenting in a child with otalgia and left-sided headaches. The patient was initially managed with radiological surveillance but required surgical management following deterioration. We describe the successful treatment of the lesion with microsurgical resection. Conclusion: A CCM should be considered in the differential diagnosis of mass lesions arising in the region of the trigeminal nerve. Surgical resection is recommended to prevent neurological deterioration and may result in significant symptomatic improvement.

ObjectiveTo report a prospectively planned analysis of two randomised controlled trials with embedded comparisons of prednisolone versus tetracosactide depot for the treatment of infantile epileptic spasms syndrome (IESS).MethodsIndividual patient data from patients randomly allocated to prednisolone or tetracosactide depot were analysed from two trials (UKISS, ICISS). The comparison was embedded within trials in which some patients also received vigabatrin but only patients receiving monotherapy with randomly allocated hormonal treatments are included in this analysis. The main outcome was cessation of spasms (Days 13–14 after randomisation). Lead time to treatment and underlying aetiology were taken into account. Cessation of spasms on Days 14–42 inclusive, electroclinical response (EEG Day 14), plus developmental and epilepsy outcomes (at 14 months in UKISS and 18 months in ICISS) are also reported. Minimum treatment was prednisolone 40 mg per day for two weeks or tetracosactide depot 0·5 mg IM on alternate days for two weeks, all followed by a reducing dose of prednisolone over two weeks.Results126 infants were included in this study. On tetracosactide depot, 47 of 62 (76%) were free of spasms on Days 13–14 compared to 43 of 64 (67%) on prednisolone (difference 9%, 95% CI -7·2% to +25·2%, chi square 1·15, p = 0·28). For Day 14–42 cessation of spasms, on tetracosactide depot, 41 of 61 (67%) were free of spasms compared to 35 of 62 (56%) on prednisolone (difference 11%, 95% CI -6·4% to +28·4%, chi square 1·51, p = 0·22). There was no significant difference in mean VABS score between infants who received prednisolone compared with those who received tetracosactide depot (74·8 (SD 18·3) versus 78·0 (SD 20·2) t = −0·91 p = 0·36). The proportion with ongoing epilepsy at the time of developmental assessment was 20 of 61 (33%) in the tetracosactide group compared with 26 out of 63 (41%) in the prednisolone group (difference 8%, 95% CI -9·2% to +25·2%, Chi [2] 0·95, p = 0·33).SignificanceWith hormone monotherapy, either prednisolone or tetracosactide depot may be recommended for infantile epileptic spasms syndrome.

ObjectiveTakotsubo stress cardiomyopathy is characterized by dysfunction of the left ventricle of the heart including apical ballooning and focal wall‐motion abnormalities. Although reported in association with seizures and intracerebral hemorrhage, there are no studies reporting its occurrence in patients having stereoelectroencephalography (sEEG).MethodsA 38‐year‐old lady with no prior history of cardiac disease experienced sudden onset chest pain and acute left ventricular failure 4 hours following explantation of stereoelectroencephalogram electrodes.ResultsA small parenchymal hematoma related to the right posterior temporal electrode had been noted postelectrode insertion but was asymptomatic. Focal‐onset seizures from nondominant mesial temporal structures were recorded during sEEG. Following the presentation with LVF, new‐onset anterolateral T‐wave inversion with reciprocal changes in leads II, III, and aVF was noted on electrocardiogram (ECG) and the chest X‐ray findings were consistent with pulmonary edema. Echocardiography demonstrated hypokinesis of the cardiac apex and septum consistent with Takotsubo stress cardiomyopathy.SignificanceAwareness of the possible complication of Takotsubo stress cardiomyopathy is required in an epilepsy surgery program.

Enteroviruses are a diverse selection of viruses which include polioviruses, coxsackieviruses, echoviruses and others. Severe or persistent enteroviral infection is well-documented in patients with antibody deficiency, mostly in those with X-linked agammaglobulinemia (XLA) or following anti-CD20 monoclonal antibody therapy[1]. Here we report the first case of enteroviral meningoencephalitis in a patient with Good’s syndrome and discuss the possible aetiopathogenic mechanisms involved.

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted ‘gold-standard’ subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy.

Funder: National Institute for Health Research (NIHR) GOSH BRC, OBJECTIVE: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome. METHODS: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom. RESULTS: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%. SIGNIFICANCE: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy.

IntroductionOne outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualise on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide.MethodsThe Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonised a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance.ResultsOur pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. Overall, after including a border-zone around lesions, the developed MELD FCD surface-based algorithm had a sensitivity of 67% and a specificity of 54% on the withheld test cohort, and a sensitivity of 85% on a restricted subcohort of seizure free patients with FCD type IIB who had T1 and FLAIR MRI data.ConclusionsThis multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions.HighlightsThis large, multi-centre, multi-scanner neuroimaging cohort captures the heterogeneity of histopathological subtypes and imaging features of patients with FCD.We developed a robust and interpretable surface-based algorithm which detects FCDs with a sensitivity of 67% and a specificity of 54%.The algorithm generates individual patient reports that “open the AI black-box” highlighting predicted lesion locations, alongside the imaging features and their relative saliency to the classifier.

ImportanceStereoelectroencephalography (SEEG) is more frequently being used in the pre-surgical evaluation of children with focal epilepsy. Many factors affect the rate of identification of a definable seizure onset zone (SOZ) and subsequent seizure freedom following SEEG-guided epilepsy surgery, which have not been systematically examined in multi-centre studies.ObjectivesDetermine the rates and factors that predict (a) whether or not a definable putative SOZ was identified on SEEG and (b) subsequent seizure freedom following surgical intervention.DesignRetrospective cohort studySettingMulticentre study involving 6 of 7 UK Children’s Epilepsy Surgery Service centres that perform paediatric SEEG in the UK.ParticipantsAll children undergoing SEEG from 2014 - March 2019 were included. Demographic, non-invasive evaluation, SEEG and operative factors were collected retrospectively from patient records.Main OutcomesThe two main outcome measures were (a) whether or not a definable putative SOZ was identified on SEEG (binary yes/no outcome) and (b) subsequent seizure freedom following surgical intervention (Engel classification)FindingsOne hundred and thirty-five patients underwent 139 SEEG explorations using a total of 1767 electrodes. A definable SOZ was identified in 117 patients (85.7%); odds of successfully finding a SOZ were 6.4x greater for non-motor seizures compared to motor seizures (p=0.02) and 3.6x more if ≥ 4 seizures were recorded during SEEG (p=0.03). Of 100 patients undergoing surgical treatment, 47 (47.0%) had an Engel class I outcome at a median follow-up of 1.3 years; the only factor associated with outcome was indication for SEEG (p=0.03). SEEG was safe with one (0.7%) haematoma requiring surgical evacuation and no long-term neurological deficits as a result of the procedure.Conclusions and RelevanceThis large nationally representative cohort illustrates that, in these patients who may not have otherwise been offered resective surgery, SEEG-guided surgery can still achieve high rates of seizure freedom. Seizure semiology and the number of seizures recorded during SEEG are important factors in the identification of a definable SOZ and the indication for SEEG is an important factor in post-operative outcomes.

Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome.The Multi-centre Epilepsy Lesion Detection (MELD) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centres worldwide. MRI-based maps of individual FCDs with accompanying demographic, clinical and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom.FCDs were non-uniformly distributed, concentrating in the superior frontal sulcus, frontal pole and temporal pole. Epilepsy onset was typically before age 10. Earlier epilepsy onset was associated with lesions in primary sensory areas while later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%.FCD location is an important determinant of its size, the age of epilepsy onset and the likelihood of seizure freedom post-surgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counselling in neurology.

ObjectiveTo determine the underlying etiologies in a contemporary cohort of infants with infantile spasms and to examine response to treatment.MethodsIdentification 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).ResultsA 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.SignificanceThis 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.

Context Traumatic brain injury (TBI) is a recognised cause of hypopituitarism in adults but the prevalence after childhood TBI remains controversial. Objective To investigate long-term endocrine outcomes and quality of life (PedsQL and QoL-AGHDA (Quality of Life in Adult Growth Hormone Deficiency Assessment)) following childhood TBI. Design Prospective study. Methods Participants with moderate/severe TBI (n = 31) and controls (n = 17). Mean (range) age: 19.8 ± 4.2 (11–26), time post TBI: 9 (7–11) years. Detailed endocrine evaluation of stimulated (insulin tolerance test (ITT)) and spontaneous GH secretion (overnight profile) was undertaken in the TBI group; QoL and neuroimaging in both groups. Results No participant had seizures, short stature, precocious puberty or hypothyroidism. In 6/25 the ITT GH response was below age-defined cut-offs and cortisol P = .011 and P = .020). Fatigue correlated with measures of spontaneous but not stimulated GH secretion. Overall QoL (PedsQL) did not differ between groups but specific attributes of health state (cognition, memory) were impaired in TBI patients. Pituitary neuroimaging was normal in all participants. Conclusions Fatigue and depression were common 8–10 years post childhood TBI. One individual had GHD (1/22) using rigorous diagnostic criteria. A single ITT potentially over-diagnosed GHD in 25% (6/25) without clear correlation with symptoms underlying the importance of using two diagnostic tests in TBI survivors.

BackgroundTuberous Sclerosis Complex (TSC) is a genetic disorder characterised by the development of benign tumours secondary to loss of inhibitory regulation of the mTOR (mechanistic Target of Rapamycin) intracellular growth pathway. Metformin inhibits the mTOR pathway. We investigated whether metformin would reduce growth of hamartomas associated with tuberous sclerosis complex.MethodsIn this multicentre randomized, double-blind, placebo-controlled trial, patients with a clinical diagnosis of tuberous sclerosis, aged over 10 years and with at least one renal angiomyolipoma of greater than 1 cm in diameter were enrolled. Participants were randomly allocated (1:1) by a secure website to receive metformin or placebo for 12 months. The primary outcome was percentage volume change of renal angiomyolipomas (AML) at 12 months compared to baseline. Secondary outcomes were percentage change at 12 months from baseline in volume of cerebral Subependymal Giant Cell Astrocytomas (SEGA); appearance of facial and ungual hamartomas; frequency of epileptic seizures; and adaptive behaviour. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 92545532, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2011-001319-30.• View related content for this articleFindingsBetween 1 November 2012 and 30 September 2015 72 patients were screened and 55 were randomly assigned to metformin (28) or placebo (27). Four participants withdrew between randomisation and starting treatment. All 51 patients who started therapy completed the trial and were assessed for outcome at 12 months. The median percentage change in angiomyolipoma (AML) volume was +7.6% (IQR -1.8% to +42.6%) for the placebo group and +8.9% (IQR 1.3% to 19.5%) for the metformin group (p = 0.28). Twenty-seven patients had SEGAs: 13 received placebo and 14 metformin. The median percentage change in SEGA volume was +3.0% (IQR -22.8% to +27.7%) for the placebo group and – 20.8% (IQR – 47.1% to - 5.0%) for the metformin group (p = 0.03). Twenty-one patients were assessed for seizure frequency: 9 received placebo and 12 received metformin. In the metformin group, a mean reduction of 43.7% from baseline in seizures was observed and in the placebo group a 3.1% mean reduction was observed, with a difference in response of 40.6% (95% CI -3.1% to +84.2%, p = 0.03). There were no significant differences between metformin and placebo groups for the other secondary outcomes. There were no deaths. Three serious adverse events (SAEs) occurred during the trial (all patients on metformin).InterpretationMetformin did not reduce AML volume. Metformin did reduce SEGA volume and seizure frequency compared with placebo. There may be a role for metformin in slowing or reversing growth of some life-threatening hamartomas in TSC and for reducing seizure frequency. Further study is justified.FundingThis study was funded by the National Institute for Health and Research (NIHR) through the The Research for Patient Benefit Programme (RfPB).

A previously well 16-year-old boy developed a rapid-onset hypokinetic syndrome, coupled with a radiological appearance of extensive and highly symmetrical basal ganglia and white matter change. The diagnostic process was challenging and we systematically considered potential causes. After excluding common causes of this clinico-radiological picture, we considered common disorders with this unusual radiological picture and vice versa, before finally concluding that this was a rare presentation of a rare disease. We considered the broad categories of: metabolic; toxic; infective; inflammatory, postinfective and immune-mediated; neoplastic; paraneoplastic and heredodegenerative. Long-term follow-up gave insight into the nature of the insult, confirming the monophasic course. During recovery, and following presumed secondary aberrant reinnervation, his disorder evolved from predominantly hypokinetic to hyperkinetic. Here, we explore the process of finding a 'best-fit' diagnosis: in this case, acute necrotising encephalopathy.

BACKGROUND: Infantile spasms constitute a severe form of epileptic encephalopathy. In the International Collaborative Infantile Spasms Study (ICISS), we showed that combining vigabatrin with hormonal therapy was more effective than hormonal therapy alone at stopping spasms between days 14 and 42 of treatment. In this planned follow-up, we aimed to assess whether combination therapy was associated with improved developmental and epilepsy outcomes at 18 months of age.METHODS: In ICISS, a multicentre, open-label, randomised controlled trial, infants were enrolled from 102 hospitals (three in Australia, 11 in Germany, two in New Zealand, three in Switzerland, and 83 in the UK). Eligible infants had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) electroencephalogram (EEG) no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing epilepsy and developmental outcomes at 18 months were masked to treatment allocation. Minimum doses were oral prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without oral vigabatrin 100 mg/kg per day. The primary outcome at 18 months was development as assessed by the Vineland Adaptive Behaviour Scales (VABS) composite score. Secondary outcomes were the presence or absence of epileptic seizures or infantile spasms in the previous 28 days, as recorded by parents and carers, and the use of any anti-epileptic treatment (including ketogenic diet) in the previous 28 days. Analysis was by intention to treat. The trial is registered with the ISRCTN registry, number 54363174, and EudraCT, number 2006-000788-27.FINDINGS: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (n=186) or hormonal therapy alone (n=191). 362 infants were assessed for developmental and epilepsy outcomes at 18 months, 181 in each treatment group. Mean VABS scores did not differ significantly between the combination therapy group and the hormonal therapy alone group (73·9 [SE 1·3] vs 72·7 [1·4], difference -1·2 [95% CI -4·9 to 2·6], p=0·55). Presence of epilepsy at the assessment at age 18 months was similar in both treatment groups (54 [30·0%] of 180 infants who received combination therapy vs 52 [29·2%] of 178 who received hormonal therapy alone; difference 0·8% [95% CI -8·8 to 10·4], p=0·90). Presence of spasms was also similar in both treatment groups (27 [15·0%] of 180 infants on combination therapy vs 28 [15·7%] of 178 on hormonal therapy alone; difference 0·7% [95% CI -6·9 to 8·3], p=0·85). At the 18-month assessment, 158 (44·1%) of 358 infants were on some form of anti-epileptic treatment. Initial control of spasms between days 14 and 42 of treatment was associated with higher mean VABS scores at 18 months (79·1 [SE 1·2] vs 63·2 [1·1], difference 15·9 [95% CI 12·4 to 19·5], pINTERPRETATION: Combination therapy did not result in improved developmental or epilepsy outcomes at 18 months. However, early clinical response to treatment was associated with improved developmental and epilepsy outcomes at 18 months. Longer lead-time to treatment was associated with poorer outcomes. Rapid diagnosis and effective treatment of infantile spasms could therefore improve outcomes.FUNDING: The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, BRONNER-BENDER Stiftung/Gernsbach, University Children's Hospital Zurich.

Introduction Tuberous Sclerosis Complex (TSC) is a genetic disorder characterised by the development of benign tumours, secondary to the loss of inhibitory regulation of the mTOR (mammalian Target Of Rapamycin) intracellular growth pathway. Metformin inhibits the mTOR pathway. We investigated the effect of Metformin in patients with TSC. Methods This was a multicentre randomised, double-blind, parallel group, placebo-controlled trial of metformin in children and adults with TSC. Patients were randomly allocated to placebo or metformin (1:1) for 12 months. The main outcomes were percentage volume change of renal angiomyolipomas (AML) and cerebral Subependymal Giant Cell Astrocytomas (SEGA). Blinded MRI assessments of AMLs and SEGAs were performed at baseline and at 12 months. Results Fifty-one patients participated, of whom 43 were adults (age range 10–50 years, median age 27, IQR 17). 24 received placebo and 27 received metformin. The mean AML volume increase from baseline was 25.5% for the placebo group and 9.6% for the metformin group. Difference in response, 15.9% (95% CI −9% to 41%) p=0.221. Twenty-seven patients had SEGAs: 13 received placebo and 14 metformin. The mean SEGA volume increased from baseline by 37% in the placebo group but reduced from baseline by 23.3% in the metformin group. Difference in response, 60.3% (95% CI −0.4% to 111, p=0.048). Three serious adverse events occurred that reflected the underlying disease. Two were AML haemorrhages and one was worsening seizures requiring hospitalisation. Conclusions Metformin is safe and well tolerated in children and adults with TSC. Patients on metformin had a significant reduction in SEGA volume compared with placebo. Metformin did not reduce AML size but growth appeared slower than in the placebo group, although this difference was not statistically significant. There may be a role for metformin in slowing or reversing the growth of life-threatening hamartomas in TSC. Further study is justified.

A 7-year-old previously well boy presented to the emergency department (ED) with diplopia and pain in his right eye for 2 days. The previous week, while on holiday abroad, he developed right ear pain and vomiting. He was seen by the local physician, diagnosed with right otitis media and was treated with eardrops. On returning to the UK, his general practitioner started him on oral amoxicillin, but his parents brought him to the ED due to worsening symptoms. There was no history of trauma, headache, vomiting or fever. He was fully immunised, was not on any regular medications and had no known allergies. On examination, he was distressed due to photophobia in his right eye and diplopia. There was crusted discharge in his right ear canal with a perforated tympanic membrane. Cranial nerve examination revealed a loss of abduction of the right eye, but the rest of the neurological and systemic examination was normal. 1. What …

Central pontine myelinolysis (CPM) is a neurological demyelinating disease of the pons. Although usually associated with rapid correction of hyponatremia, CPM may occur despite normonatremia, is often associated with chronic alcoholism and may be asymptomatic. Histological confirmation of asymptomatic CPM is rare. We describe an unusual post-mortem case of extensive but asymptomatic CPM in a chronic alcoholic patient with normonatremia. The affected part of the pons contained thinly myelinated axons with appearances supporting remyelination. We suggest that remyelination may account for the subclinical nature of this patient's CPM.

BackgroundInfantile spasms constitutes a severe infantile epilepsy syndrome that is difficult to treat and has a high morbidity. Hormonal therapies or vigabatrin are the most commonly used treatments. We aimed to assess whether combining the treatments would be more effective than hormonal therapy alone.MethodsIn this multicentre, open-label randomised trial, 102 hospitals (Australia [three], Germany [11], New Zealand [two], Switzerland [three], and the UK [83]) enrolled infants who had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) EEG no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing electro-clinical outcome were masked to treatment allocation. Minimum doses were prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without vigabatrin 100 mg/kg per day. The primary outcome was cessation of spasms, which was defined as no witnessed spasms on and between day 14 and day 42 from trial entry, as recorded by parents and carers in a seizure diary. Analysis was by intention to treat. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 54363174, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2006-000788-27.FindingsBetween March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (186) or hormonal therapy alone (191). All 377 infants were assessed for the primary outcome. Between days 14 and 42 inclusive no spasms were witnessed in 133 (72%) of 186 patients on hormonal therapy with vigabatrin compared with 108 (57%) of 191 patients on hormonal therapy alone (difference 15·0%, 95% CI 5·1–24·9, p=0·002). Serious adverse reactions necessitating hospitalisation occurred in 33 infants (16 on hormonal therapy alone and 17 on hormonal therapy with vigabatrin). The most common serious adverse reaction was infection occurring in five infants on hormonal therapy alone and four on hormonal therapy with vigabatrin. There were no deaths attributable to treatment.InterpretationHormonal therapy with vigabatrin is significantly more effective at stopping infantile spasms than hormonal therapy alone. The 4 week period of spasm cessation required to achieve a primary clinical response to treatment suggests that the effect seen might be sustained, but this needs to be confirmed at the 18 month follow-up.FundingThe Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, the BRONNER-BENDUNG Stifung/Gernsbach, and University Children's Hospital Zurich.

MRI is now commonly used in the assessment of neonates for diagnosis and prognosis. The advantages over ultrasound are increased contrast resolution, complete coverage and multiplanar imaging. MRI is most commonly used for the assessment of neonatal encephalopathy to determine an underlying cause such as hypoglycaemia, neonatal infarction, or viral encephalitis, and may also be useful in determining complications of meningitis and planning surgical treatment. In hypoxic-ischaemic injury, where the diagnosis is typically made clinically, MRI has conventionally confirmed the diagnosis and provided prognostic information. However advanced techniques such as magnetic resonance spectroscopy and arterial spin labelling allow for earlier diagnosis and may guide treatment options. MRI may also detect less common patterns of brain injury in term infants such as punctuate white matter lesion. Imaging of preterm infants at term equivalent age can demonstrate complications such as periventricular leucomalacia or periventricular haemorrhagic infarction and provide information on neurological outcome.

Aim To determine the aetiological associations, neurological sequelae and role of magnetic resonance imaging (MRI) in term newborn infants with seizures. Methods Cohort study of infants ≥37 weeks' gestation delivered in a tertiary level centre, prospectively identified and followed longitudinally for 18–24 months. Results An underlying aetiology was found in 95% of the 77 infants identified with seizures (3.0/1000 live births). The most common diagnosis was hypoxic–ischaemic encephalopathy (HIE) (65%), followed by neonatal stroke (12%). Nine infants died, 28 of the 68 survivors developed neurodevelopmental impairment (NDI), and 15 had recurrent seizures in the first 2 years, with both outcomes more likely in those with a diagnosis other than HIE. Abnormal MRI findings were found in 45 of the 70 infants imaged. The absence of major cerebral lesions was highly predictive of a normal neurological outcome. Conclusion We report the first cohort of term infants with seizures fully investigated by MRI. The universal use of MRI enabled a cause to be identified in 95% of cases. The probability of having NDI or recurrence of seizures was extremely low with absence of major cerebral lesions on MRI. This study demonstrates the added value of MRI for diagnosis of aetiology and the prediction of neurological outcome.

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

This is a review of the use of neuroimaging in epilepsy outlining the imaging strategy for new onset seizures and also those with intractable focal seizures being investigated as potential epilepsy surgery candidates. The review describes the radiological features of conditions which may be encountered in each clinical context, together with advice on the optimum imaging protocols to detect epileptogenic lesions. The review also presents the role of imaging in presurgical planning, the demonstration of eloquent function, grid placement and postoperative assessment.

Objective: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time. Methods: We conducted a population active surveillance study. All paediatricians, and ophthalmologists ( n = 4095) were sent monthly reporting cards (September 2009–September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review. Results: Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3–15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years ( n = 63) was 1.52:1 ( p = 0.045). The incidence of first onset ADS in children aged 1–15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18–11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria. Conclusions: We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design.

We report two sisters with extensive bilateral periventricular haemorrhagic infarction (PVHI) causing cerebral palsy (CP). The older sister presented at 20 months with cortical visual blindness, spastic diplegia, and purpura fulminans. The younger sister presented aged 3 days old with apnoeas and multifocal seizures. She subsequently had global developmental delay, cortical visual blindness, spastic quadriplegia, epilepsy, and purpura fulminans at age 2 years. Neuroimaging of both siblings showed bilateral PVHI consistent with bilateral cerebral intramedullary venous thrombosis occurring at under 28 weeks' gestation for the older sister and around time of birth for the younger sister. At latest follow-up, the older sister (13y) has spastic diplegia at Gross Motor Function Classification System (GMFCS) level II, and the younger sister (10y) has spastic quadriplegia at GMFCS level IV. Both sisters showed partial quantitative reduction in plasma protein C antigen and severe qualitative reduction in plasma protein C anticoagulant activity. They were heterozygous for two independent mutations in the protein C gene (PROC). There was no other risk factor for CP. To our knowledge, this is the first family reported with compound heterozygous PROC mutations as the likely genetic cause of familial CP. This report adds to the list of known monogenic causes of CP.

Over 800 000 people in the UK are demented. Alzheimer's disease, dementia with Lewy bodies, vascular dementia and frontotemporal lobar degeneration account for the majority. Although detailed clinical assessment forms the basis of evaluating a patient with cognitive impairment, structural and functional imaging techniques are increasingly being used. Neuroimaging can identify changes to supplement the clinical diagnosis and help to distinguish dementia subtypes. This may be important for treatment, prognosis and care planning. Furthermore, early changes on structural and functional imaging may have a role in preclinical detection, perhaps allowing people to start any treatments early. In this review, we explain the tools available to the neuroradiologist and examine the implications of imaging findings in assessing patients with cognitive impairment or dementia.

Background Identification of causes of dementia soon after symptom onset is important, because appropriate treatment of some causes of dementia can slow or halt its progression or enable symptomatic treatment where appropriate. The accuracy of MRI and CT, and whether MRI is superior to CT, in detecting a vascular component to dementia in autopsy confirmed and clinical cohorts of patients with VaD, combined AD and VaD (“mixed dementia”), and AD remain unclear. We conducted a systematic review and meta-analysis to investigate this question. Methods We searched eight databases and screened reference lists to identify studies addressing the review question. We assessed study quality using QUADAS. We estimated summary diagnostic accuracy according to imaging finding, and ratios of diagnostic odds ratios (RDORs) for MRI versus CT and high versus low risk of bias. Results We included 7 autopsy and 31 non-autopsy studies. There was little evidence that selective patient enrolment and risk of incorporation bias impacted on diagnostic accuracy (p = 0.12 to 0.95). The most widely reported imaging finding was white matter hyperintensities. For CT (11 studies) summary sensitivity and specificity were 71% (95% CI 53%-85%) and 55% (44%-66%). Corresponding figures for MRI (6 studies) were 95% (87%-98%) and 26% (12%-50%). General infarcts was the most specific imaging finding on MRI (96%; 95% CI 94%-97%) and CT (96%; 93%-98%). However, sensitivity was low for both MRI (53%; 36%-70%) and CT (52%; 22% to 80%). No imaging finding had consistently high sensitivity. Based on non-autopsy studies, MRI was more accurate than CT for six of seven imaging findings, but confidence intervals were wide. Conclusion There is insufficient evidence to suggest that MRI is superior to CT with respect to identifying cerebrovascular changes in autopsy-confirmed and clinical cohorts of VaD, AD, and ‘mixed dementia’.

The management of medically intractable epilepsy is frequently assisted by the identification of structural abnormalities made possible by modern imaging techniques. The association between meningoencephaloceles and epileptic seizures is well reported in the literature. We report a patient with refractory right frontal lobe epilepsy caused by a right nasal meningoencephalocele who was rendered seizure free by endoscopic nasal excision and skull base repair, obviating the need for resective epilepsy surgery. Epilepsy patterns associated with encephalocele and their management are reviewed.

We report the case of a 13-year-old boy presenting with profound bradycardia following minor trauma. Our patient had gastroschisis at birth and has moderate learning difficulties but is otherwise fit and well. Whilst playing at home he fell sustaining a minor cervical hyperextension injury. He immediately complained of tetraplegia and hyposensibility. The ambulance crew noted profound bradycardia with normotension and he was transported to hospital with full spinal immobilisation precautions. Over the subsequent 2 hours he made a full neurological recovery. Bradycardia persisted with a beat-to-beat variation of 30-60 bpm. ECG showed sinus bradycardia with atrial ectopics and he remained haemodynamically normal. Neuroimaging studies revealed hypoplasia of the odontoid peg with a relative narrowing of the spinal canal at this level. There was no evidence of spinal cord contusion or compression. His bradycardia resolved over 36 hours without further intervention. On discharge the patient was advised to wear a cervical hard collar when mobilising. This association of a craniocervical abnormality with learning difficulties, and gastroschisis has not been previously described. We discuss several other causes of odontoid peg instability, which may lead to severe autonomic effects with relatively insignificant trauma.

Aim To determine the etiological association, neurodevelopmental sequelae and role of Magnetic Resonance Imaging (MRI) in term newborn infants with seizures. Methods Cohort study of infants >37 weeks gestation delivered in a single level 3 centre in the UK from 1/12/2004 to 31/10/2009 (59 months), prospectively identified by a perinatal morbidity surveillance system and followed longitudinally for 18–24 months. Results 77 infants were identified with seizures during the study period (3.0/1000 live births). 9 infants died (12%). 73/77 (95%) had an aEEG recording and 70/77 (91%) had an MRI scan. In 95% of cases an underlying cause of seizures was elucidated. The most common diagnosis was HIE (65%) with neonatal stroke as the second most common diagnosis (12%). Overall, 28/77 (36%) of the cohort had a neurodevelopmental impairment (NDI), ranging from mild to severe. 37/50 infants with HIE (74%) received therapeutic hypothermia and 9 (24%) had NDI. Of the remaining 13 managed with normothermia, 4 had NDI (31%). NDI was prevalent in those with a diagnosis other than HIE (15/27; 56%), in particular stroke, hypoglycaemia and cerebral dysgenesis. 15/77 (19%) had recurrence of seizure in the first 2 years of life. The highest risk of seizure recurrence was in cerebral dysgenesis, hypoglycaemia and stroke. Infants with HIE had a very low risk of seizure recurrence (1/50; 2%). 45/70 (64%) had abnormal MRI findings. The negative predictive value of a normal MRI in survivors of developing any disability was 0.93. Conclusion This is the first report of a cohort of term infants with seizures fully investigated by MRI and aEEG. HIE was the most common cause of seizures in this population. Neonatal stroke was the most likely diagnosis for term infants presenting with seizures on day two of life. The universal use of MRI allows a cause to be identified in 95% of term infants with seizures. A normal MRI scan was highly predictive of a normal neurodevelopmental outcome. There was significant risk of NDI and seizure recurrence, particularly in those with a diagnosis other than HIE, supporting formal neurological surveillance.

Aims Childhood central nervous system inflammatory demyelinating diseases (CNS-IDs) are rare disorders presenting to paediatricians but may be the first manifestation of Multiple Sclerosis (MS), a chronic neurological disorder. We aimed to determine the incidence, clinico-epidemiological and neuroradiological features of first episode childhood CNS-ID in the UK and Ireland. Methods Children under 16 years with events consistent with first episode CNS-ID confirmed with magnetic resonance imaging (MRI) white matter changes (except in optic neuritis) were included. International Paediatric MS Study Group 2007 definitions were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis-optica (NMO). All paediatricians, paediatric neurologists, and ophthalmologists were sent monthly cards (n=4095) through the British Paediatric and Ophthalmological Surveillance Units (BPSU and BOSU) from Sep 2009-Sep 2010. Clinicians completed a standard questionnaire and provided the MRI copy to be classified by neuroradiologists blinded to clinical features. An expert panel met quarterly to review notifications. Incidence rates were calculated using mid-2010 population estimates. Results Card return rates were 94% BPSU and 78% BOSU. Information was available for 200/222 cases (90%) notified. After removal of duplicates and cases not fitting inclusion criteria, 125 cases (64 females, 101 white, median age 10.9 years) were included giving a minimum incidence of first onset CNS-ID in children aged 1-15 years old in the British Isles as 9.83 per million children per year (95% CI 8.18-11.71). Sex ratios varied significantly when evaluated as a function of age with more females in older age groups. Children with ADEM were significantly younger than CIS cases. Childhood CNS-ID disorders were classified as ADEM in 32%, CIS in 66%, and neuromyeltis optic (NMO) in 2%. There was one ADEM death. Of the CIS cases with gadolinium scans, 10/38 (26%) fulfilled McDonald 2010 MRI criteria for MS diagnosis. Children with ADEM had higher CSF white cell counts (p=0.005) and fewer CSF positive oligoclonal bands (p=0.011) compared to CIS. The majority (89%) received either intravenous corticosteroids (84%) and/or oral prednisolone. Conclusions This population study establishes minimum incidence, clinical, MRI and investigative features of childhood CNS-IDs and of MS on the revised 2010 McDonald criteria at presentation in the British Isles.

Background There is evidence that at least 5% of Multiple sclerosis (MS) cases manifest in childhood. Children with MS present with a demyelinating episode involving single or multiple symptoms prior to developing a second event (usually within two years) to then meet criteria for diagnosis. There is evidence from adult cohorts that the incidence and sex ratios of MS are changing and that children of immigrants have a higher risk for developing MS. A paediatric population should reflect the vanguard of such changes and may reflect trends yet to be observed in adult cohorts. Studying a paediatric population from the first demyelinating event will allow us to test these hypotheses, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS. Methods/Design The Paediatric UK Demyelinating Disease Longitudinal Study (PUDDLS) is a prospective longitudinal observational study which aims to determine the natural history, predictors and outcomes of childhood CNS inflammatory demyelinating diseases. PUDDLS will involve centres in the UK, and will establish a cohort of children affected with a first CNS inflammatory demyelinating event for long-term follow up by recruiting for approximately 5 years. PUDDLS will also establish a biological sample archive (CSF, serum, and DNA), allowing future hypothesis driven research. For example, the future discovery of a biomarker will allow validation within this dataset for the evaluation of novel biomarkers. Patients will also be requested to consent to be contacted in the future. A secondary aim is to collaborate internationally with the International Paediatric Multiple Sclerosis Study Group when future collaborative studies are proposed, whilst sharing a minimal anonymised dataset. PUDDLS is the second of two jointly funded studies. The first (UCID-SS) is an epidemiological surveillance study that already received ethical approvals, and started on the 1st September 2009. There is no direct patient involvement, and UCID-SS aims to determine the UK and Ireland incidence of CNS inflammatory demyelinating disorders in children under 16 years. Discussion A paediatric population should reflect the vanguard of MS epidemiological changes and may reflect trends yet to be observed in adult MS cohorts. The restricted window between clinical expression of disease and exposure to environmental factors in children offers a unique research opportunity. Studying a paediatric population from the first demyelinating event will allow us to investigate the changing epidemiology of MS, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS.