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To improve delivery of acute therapies for acute ischaemic stroke (AIS).We identified factors influencing the speed of diagnosis and delivery of acute therapies in a prospective cohort of 21 children with suspected AIS (eight with AIS, 13 stroke mimics) and explored them in a retrospective cohort with confirmed AIS.Approximately half of the prospective and total AIS cohorts presented with acute, sustained hemiparesis, and were diagnosed relatively quickly. AIS was suspected and diagnosed more slowly in the half presenting with symptoms other than sustained hemiparesis. Thirty-one out of 51 patients with AIS (19 females, 32 males, mean age 8 years 6 months, SD 5 years 4 months) had arterial abnormalities identified by computed tomography angiography (CTA) or magnetic resonance angiography (MRA): 11 with large vessel occlusion, six with dissection, five with moyamoya disease, nine with other arteriopathies. Among these patients, those initially imaged with CTA were diagnosed more quickly than those with initial magnetic resonance imaging/angiography, which facilitated thrombectomy and thrombolytic therapy. Twenty out of 51 had AIS without arterial abnormalities on CTA or MRA: eight with lenticulostriate vasculopathy and 12 with other small-vessel AIS. Among these patients, 80% were ineligible for thrombolysis for reasons beyond delay to diagnosis, and all showed good outcomes with supportive treatments alone.Clinical features at presentation influence rapidity with which childhood AIS is suspected and diagnosed. Readily available CTA can direct thrombectomy in patients with large vessel occlusion and thrombolysis in most, but not all, eligible patients.Children with acute ischaemic stroke (AIS) commonly present with symptoms other than sustained hemiparesis. Stroke is more slowly recognized in these patients, which limits potential therapies. Computed tomography angiography (CTA) accurately identifies AIS with large vessel occlusion, enabling timely endovascular thrombectomy. CTA is sufficient to direct thrombolytic therapy in most eligible children. Most childhood AIS without arterial abnormalities identified by CTA had good outcomes.

Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis.

Background The most recent documented Australian outbreak of enterovirus A71 (EV-A71) occurred in Sydney from 2012 to 2013. Over a four-month period more than 100 children presented to four paediatric hospitals with encephalitic presentations including fever and myoclonic jerks. The heterogeneous presentations included typical encephalomyelitis, and cardiopulmonary complications. Objectives To characterise the genomes of enterovirus strains circulating during the 2013 Sydney EV-A71 outbreak and determine their phylogeny, phylogeography and association between genome and clinical phenotype. Study design We performed an analysis of enterovirus (EV) positive specimens from children presenting to hospitals in the greater Sydney region of Australia during the 2013 outbreak. We amplified near full-length genomes of EV, and used next generation sequencing technology to sequence the virus. We used phylogenetic/phylogeographic analysis to characterize the outbreak viruses. Results We amplified and sequenced 23/63 (37 %) genomes, and identified the majority (61 %) as EV-A71. The EV-A71 sequences showed high level sequence homology to C4a genogroups of EV-A71 circulating in China and Vietnam during 2012-13. Phylogenetic analysis showed EV-A71 strains associated with more severe symptoms, including encephalitis or cardiopulmonary failure, grouped together more closely than those from patients with hand, foot and mouth disease. Amongst the non-EV-A71 sequences were five other EV subtypes (representing enterovirus subtypes A and B), reflecting the diversity of EV co-circulation within the community. Conclusions This is the first Australian study investigating the near full-length genome of EV strains identified during a known outbreak of EV-A71. EV-A71 sequences were very similar to strains circulating in Asia during the same time period. Whole genome sequencing offers additional information over routine diagnostic testing such as characterisation of emerging recombinant strains and inform vaccine design.

BackgroundSpinal muscular atrophy (SMA) is a devastating motor neuron disorder causing progressive muscle weakness and respiratory insufficiency. We present the initial Australian experiences implementing the expanded access programme (EAP) to enable preapproval access to nusinersen, the first disease-modifying therapy, for SMA type 1.MethodsAn Australian multicentre, open-label EAP for nusinersen enrolled patients with infantile-onset SMA type 1 from November 2016 to September 2017. Standard-of-care medical therapy and treatment with intrathecal nusinersen were provided to all patients. Clinical and diagnostic characteristics, molecular genetics, treatment administered, and functional motor outcomes were assessed.ResultsA total of 20 patients with SMA type 1 met the inclusion criteria, of whom 16 consented and received nusinersen treatment. Median time to diagnosis from symptom onset was 5.0 months and was correlated with age of onset (r=0.54, PSMN2 copies.ConclusionsThe nusinersen EAP highlights difficulties in achieving early diagnosis and/or prevention, the evolution of optimal clinical care in a time of uncertain prognostication, resource implications and ethical issues in clinical practice for SMA type 1. These challenges are broadly relevant to the realisation of all novel therapeutics in neurological disorders.

Survival of motor neuron 1­­­­­­–negative spinal muscular atrophy (SMA) is heterogeneous and remains a diagnostic challenge. The clinical spectrum continues to expand and ∼33 genes have been identified to date. The present report describes a 9-year-old girl with novel clinical phenotype of a patient with polyarticular arthritis followed by symptoms of SMA due to acid ceramidase deficiency. Whole exome sequencing identified compound heterozygous pathogenic mutation in the N-acylsphingosine amidohydrolase 1 gene. Functional assay with leukocyte acid ceramidase activity showed a decreased level in the proband confirming pathogenicity of the mutations. Mutations of N-acylsphingosine amidohydrolase 1 are known to separately cause Farber disease (arthritis, subcutaneous nodules, and dysphonia) or SMA with progressive myoclonic epilepsy. The present combined phenotype is novel, bringing together SMA with progressive myoclonic epilepsy and Farber disease and establishing a phenotypic spectrum. Acid ceramidase deficiency is an important consideration in patients presenting with polyarticular arthritis and motor neuron disease.

Sir, We read with great interest the article by Kinghorn et al. (2015) reporting that loss of phospholipase A2 group 6 (PLA2G6) leads to mitochondrial dysfunction and elevated mitochondrial lipid peroxidation in Drosophila neurons and patient fibroblast cultures (Kinghorn et al. , 2015). Importantly this work suggests administration of deuterated polyunsaturated fatty acids, serving to lower lipid peroxidation, may be beneficial in patients with pathogenic variants in PLA2G6 , which is associated with infantile neuronal dystrophy (INAD). This extends findings of animal studies that have demonstrated PLA2G6 has an important role in neurons, with mutations producing significant changes in brain lipid metabolism and phospholipid fatty acid content (Cheon et al. , 2012). Disturbances in lipid metabolism are emerging as an important theme in motor neuron degeneration (Goizet et al. , 2009). PLA2G6 is widely distributed in various tissues and it has been suggested that the cell-specific mitochondrial abnormalities may relate to variations in lipid and protein components of the mitochondrial membrane (Beck et al. , 2011). While understanding the pathophysiological mechanisms of PLA2G6-associated neurodegeneration is providing promising therapeutic strategies, the involvement of other cell types within the nervous system is not yet established and may be of pathophysiological and therapeutic relevance. We report radiological, pathological and biochemical data obtained as part of the diagnostic work-up in a 4-year-old male patient with a clinical diagnosis of INAD secondary to homozygous pathogenic variants in PLA2G6, NM\_003560.1:c.2070\_2072del NP_001004426.1:[p.Val691del]. Respiratory chain enzymology studies were undertaken according to previously described techniques by Dr Thorburn’s …

The diagnosis of neuromuscular disorders traditionally involved clinical and neurophysiological assessment, pathological evaluation of muscle and/or nerve biopsy and sequential testing of individual genes. Next generation sequencing (NGS) has revolutionised the diagnostic paradigm in genetic disorders, with the capability to capture and sequence genes, the entire exome (1% of the protein coding genome) or the entire genome.1 ,2 While this may overcome the diagnostic odyssey of sequential single gene testing and reduce the need for biopsies, it is important for clinicians to be aware of the challenges and limitations of NGS.3 It is difficult to detect structural DNA differences with whole exome sequencing (WES), including copy number variants such as intragenic deletions or duplications due to variation in depth of coverage, or the number of times a nucleotide is sequenced. While balanced translocations and …

Importance Enterovirus 71 (EV71) causes a spectrum of neurological complications with significant morbidity and mortality. Further understanding of the characteristics of EV71-related neurological disease, factors related to outcome, and potential responsiveness to treatments is important in developing therapeutic guidelines. Objective To further characterize EV71-related neurological disease and neurological outcome in children. Design, Setting, and Participants Prospective 2-hospital (The Sydney Children’s Hospitals Network) inpatient study of 61 children with enterovirus-related neurological disease during a 2013 outbreak of EV71 in Sydney, Australia. The dates of our analysis were January 1, to June 30, 2013. Main Outcomes and Measures Clinical, neuroimaging, laboratory, and pathological characteristics, together with treatment administered and functional motor outcomes, were assessed. Results Among 61 patients, there were 4 precipitous deaths (7%), despite resuscitation at presentation. Among 57 surviving patients, the age range was 0.3 to 5.2 years (median age, 1.5 years), and 36 (63%) were male. Fever (100% [57 of 57]), myoclonic jerks (86% [49 of 57]), ataxia (54% [29 of 54]), and vomiting (54% [29 of 54]) were common initial clinical manifestations. In 57 surviving patients, EV71 neurological disease included encephalomyelitis in 23 (40%), brainstem encephalitis in 20 (35%), encephalitis in 6 (11%), acute flaccid paralysis in 4 (7%), and autonomic dysregulation with pulmonary edema in 4 (7%). Enterovirus RNA was more commonly identified in feces (42 of 44 [95%]), rectal swabs (35 of 37 [95%]), and throat swabs (33 of 39 [85%]) rather than in cerebrospinal fluid (10 of 41 [24%]). Magnetic resonance imaging revealed characteristic increased T2-weighted signal in the dorsal pons and spinal cord. All 4 patients with pulmonary edema (severe disease) demonstrated dorsal brainstem restricted diffusion (odds ratio, 2; 95% CI, 1-4; P = .001). Brainstem or motor dysfunction had resolved in 44 of 57 (77%) at 2 months and in 51 of 57 (90%) at 12 months. Focal paresis was evident in 23 of 57 (40%) at presentation and was the most common persisting clinical and functional problem at 12 months (observed in 5 of 6 patients), with 1 patient also requiring invasive ventilation. Patients initially seen with acute flaccid paralysis or pulmonary edema had significantly greater frequencies of motor dysfunction at follow-up compared with patients initially seen with other syndromes (odds ratio, 15; 95% CI, 3-79; P Conclusions and Relevance Enterovirus 71 may cause serious neurological disease in young patients. The distinct clinicoradiological syndromes, predominantly within the spinal cord and brainstem, enable rapid recognition within evolving outbreaks. Long-term functional neurological morbidity is associated with paresis linked to involvement of gray matter in the brainstem or spinal cord.

Between January 2013 and June 2013, 35 children presented with neurologic symptoms and enterovirus positivity. Twenty-six of 35 were genotyped and found to have enterovirus 71 (EV17). There were four deaths statewide. One of the difficulties is that neurologic symptoms of these children are variable, as are laboratory and medical imaging results. There do not appear to be robust predictors to indicate which children may have an adverse outcome. This research aims to develop a further understanding of the disease course and potential therapies in EV71. A severity score index will be developed for the first time, incorporating clinical, neuroimaging and laboratory data from EV71 patients. Clinical presentation, investigation results, imaging findings, treatment and short-term outcome of these 35 patients were collected. A score of one point was given for each the following clinical symptoms: myoclonic jerks, seizures, ataxia, vomiting, urinary retention, limb weakness, truncal weakness, cranial neuropathy, and autonomic instability (respiratory distress, tachycardia/bradycardia, hypertension/hypotension). When available, a score was also given for positive MRI findings of intracranial lesion and/or spinal cord lesion. Maximum severity score for each patient was 14. Mild severity score was 1–3, moderate was 4–10 and severe 10–14. Symptoms of these patients were variable, most common being myoclonic jerks and ataxia. Twenty-one patients had an MRI, two-thirds of which showed an abnormality. Treatment choice was variable with some patients receiving both intravenous immunoglobulin (IVIG) and high dose methylprednisolone and some no special treatment. Patients who had higher severity score were frequently treated. Three patients with severe scores needed full cardio-respiratory support and received both IVIG and methylprednisolone. Patients with moderate severity score who were treated had better outcome (p = 0.011). This finding is in keeping with World Health Organization comment that IVIG should be considered for the autonomic dysfunction group and possibly in the central nervous system group. EV71 outbreaks can have devastating consequences. In the context of an epidemic, fever, lethargy and myoclonus are pathognomonic. Other features include ataxia and flaccid weakness. There is a role for IG therapy in patients who are at risk of severe disease. Using a severity score is helpful in detecting patients at risk. MRI is a useful tool in diagnosis, with diffusion restriction in the brainstem associated with a poor outcome. Maintaining awareness for the potential for cardiopulmonary collapse is essential.