ORCID Profile
0000-0003-1219-4781
Current Organisation
University of Sydney
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Publisher: Wiley
Date: 10-09-2019
DOI: 10.1002/MDS.27817
Abstract: Tics are conceptualized as a sensorimotor phenomenon with a premonitory urge typically described by patients. As observed in other neurodevelopmental disorders, we have observed sensory dysregulation symptoms, such as tactile hypersensitivity to clothing, in children with tic disorders however, formal clinical research in this area is limited. To define the presence of sensory dysregulation symptoms in tic disorders, and their clinical associations. Prevalence of sensory dysregulation in 102 children with tic disorders was compared to 61 age- and sex-matched healthy controls. Sensory dysregulation, executive function, and quality of life data were obtained through the Short Sensory Profile-2, Sensory Profile-2, Sensory Processing Measure, Behaviour Rating Inventory of Executive Function-2, and Strength and Difficulties Questionnaire and Pediatric Quality of Life Inventory. Tics were assessed with the Yale Global Tic Severity Scale. Children with tics, in the presence of comorbidity, had elevated sensory dysregulation compared to healthy controls (P < 0.001). There was a positive correlation between sensory dysregulation and global executive difficulties in children with tics and comorbidity (n = 87 rho = 0.716 P < 0.001) and a negative correlation of sensory dysregulation with quality of life (n = 87 rho = -0.595 P < 0.001). In children with tics, there was an association between sensory dysregulation and number of comorbidities (P < 0.001). In the presence of comorbidity, children with tic disorders have broad sensory dysregulation symptoms beyond the premonitory urge. There was a statistically significant association between sensory dysregulation and executive function difficulties and the presence of neurodevelopmental and psychiatric comorbidity. Sensory dysregulation can be considered neurodevelopmental symptoms, providing insight into the neurobiology of tics and opportunities for therapeutic intervention. © 2019 International Parkinson and Movement Disorder Society.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 10-2023
Publisher: Wiley
Date: 22-08-2014
DOI: 10.1002/MDS.25999
Abstract: Accurate recognition of movement disorder phenomenology may differentiate children with anti-N-methyl D-aspartate receptor (NMDAR) encephalitis, autoimmune basal ganglia encephalitis (BGE), and Sydenham's chorea (SC). Three neurologists blinded to the diagnoses recorded dominant and associated movement disorders seen on videos of 31 patients with anti-NMDAR encephalitis (n = 10), BGE (n = 12), and SC (n = 9). Stereotypy was only seen in anti-NMDAR encephalitis (8/10) and not in BGE and SC (P < 0.001). Perseveration was only seen in anti-NMDAR encephalitis (5/10) and not in BGE and SC (P < 0.001). Akinesia was more commonly seen in BGE (5/12) than in anti-NMDAR encephalitis (1/10, P = 0.097). Tremor was more commonly seen in BGE (5/12) than in anti-NMDAR encephalitis (1/10, P = 0.097). Chorea was seen in all groups: anti-NMDAR encephalitis (4/10), BGE (3/12), and SC (9/9). Likewise, dystonia was seen in all groups: anti-NMDAR encephalitis (6/10), BGE (7/12), and SC (2/9). Stereotypies or perseveration are suggestive of anti-NMDAR encephalitis, whereas their absence and the presence of akinesia and tremor is more suggestive of BGE. Chorea and dystonia are least discriminating.
Publisher: Wiley
Date: 20-08-2022
DOI: 10.1111/DMCN.15025
Abstract: Janus kinase (JAK) 1 inhibition represents a precision medicine approach in the treatment of Aicardi-Goutières syndrome (AGS), through targeting of type I interferon-mediated cell signalling. Blood interferon mRNAseq has been proposed as a biomarker of disease with utility in therapeutic monitoring. Objective cerebrospinal fluid (CSF) biomarkers tracking treatment efficacy are currently lacking. Here, we report a retrospective case series of 13 patients (median age 6y, range 2y 6mo-17y five females, eight males) with AGS demonstrating significantly elevated CSF neopterin levels at first s ling (median 200nmol/L, range 45-2024nmol/L), compared to 13 age-matched controls with non-inflammatory neurological conditions (median 23nmol/L, range 5-34nmol/L, p<0.001). Five patients with AGS treated with JAK inhibitors demonstrated a median 81.5% reduction of CSF neopterin (range -36% to -88% change from baseline), compared to eight untreated patients with AGS demonstrating a median 7% reduction in CSF neopterin (range -63% to +117% change) (p=0.047). Our data indicate a biological effect of JAK inhibitors, and the potential role of CSF neopterin as a biomarker of treatment response.
Publisher: Wiley
Date: 25-04-2017
DOI: 10.1111/DMCN.13448
Abstract: To conduct a systematic literature review on patients with biphasic disease with herpes simplex virus (HSV) encephalitis followed by anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. We conducted a case report and systematic literature review (up to 10 December 2016), focused on differences between herpes simplex encephalitis (HSE) and anti-NMDAR encephalitis phases, age-related characteristics of HSV-induced anti-NMDAR encephalitis, and therapy. For statistical analyses, McNemar's test, Fisher's test, and Wilcoxon rank sum test were used (two-tailed significance level set at 5%). Forty-three patients with biphasic disease were identified (31 children). Latency between HSE and anti-NMDAR encephalitis was significantly shorter in children than adults (median 24 vs 40.5d p=0.006). Compared with HSE, anti-NMDAR encephalitis was characterized by significantly higher frequency of movement disorder (2.5% vs 75% respectively p<0.001), and significantly lower rate of seizures (70% vs 30% respectively p=0.001). Compared with adults, during anti-NMDAR encephalitis children had significantly more movement disorders (86.7% children vs 40% adults p=0.006), fewer psychiatric symptoms (41.9% children vs 90.0% adults p=0.025), and a slightly higher median modified Rankin Scale score (5 in children vs 4 in adults p=0.015). During anti-NMDAR encephalitis, 84.6 per cent of patients received aciclovir (for ≤7d in 22.7% long-term antivirals in 18.0% only), and 92.7 per cent immune therapy, but none had recurrence of HSE clinically or using cerebrospinal fluid HSV polymerase chain reaction (median follow-up 7mo). Our review suggests that movement disorder may help differentiate clinically an episode of HSV-induced anti-NMDAR encephalitis from HSE relapse. Compared with adults, children have shorter latency between HSE and anti-NMDAR encephalitis and, during anti-NMDAR encephalitis, more movement disorder, fewer psychiatric symptoms, and slightly more severe disease. According to our results, immune therapy given for HSV-induced anti-NMDAR encephalitis does not predispose patients to HSE recurrence.
Publisher: Wiley
Date: 14-06-2023
DOI: 10.1111/DMCN.15308
Abstract: To assess the clinical utility of exome sequencing for patients with developmental and epileptic encephalopathies (DEEs). Over 2 years, patients with DEEs were recruited for singleton exome sequencing. Parental segregation was performed where indicated. Of the 103 patients recruited (54 males, 49 females aged 2 weeks–17 years), the genetic aetiology was identified in 36 out of 103 (35%) with management implications in 13 out of 36. Exome sequencing revealed pathogenic or likely pathogenic variants in 30 out of 103 (29%) patients, variants of unknown significance in 39 out of 103 (38%), and 34 out of 103 (33%) were negative on exome analysis. After the description of new genetic diseases, a molecular diagnosis was subsequently made for six patients or through newly available high‐density chromosomal microarray testing. We demonstrate the utility of exome sequencing in routine clinical care of children with DEEs. We highlight that molecular diagnosis often leads to changes in management and informs accurate prognostic and reproductive counselling. Our findings reinforce the need for ongoing analysis of genomic data to identify the aetiology in patients in whom the cause is unknown. The implementation of genomic testing in the care of children with DEEs should become routine in clinical practice. The cause was identified in 35% of patients with developmental and epileptic encephalopathies. KCNQ2 , CDKL5 , SCN1A , and STXBP1 were the most frequently identified genes. Reanalysis of genomic data found the cause in an additional six patients. Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset. Finding the molecular cause led to management changes in 36% of patients with DEEs.
Publisher: Springer Science and Business Media LLC
Date: 07-2020
Publisher: Wiley
Date: 16-12-2021
DOI: 10.1002/MDC3.13384
Abstract: Variants in EIF2AK2 have been recently associated with a spectrum of neurological disease encompassing isolated dystonia to fever‐related neurological decompensation, movement disorders and leukodystrophy. A 32‐year old patient presented with childhood‐onset episodes of neurological decompensation after febrile illness, progressive anarthria, dystonia and spasticity. The T2/FLAIR MRI showed bilateral posterolateral putamen hyperintensities and white matter changes suggestive of leukodystrophy. Initial extensive metabolic workup and whole genome sequencing (WGS) was unremarkable. Re‐analysis of the WGS data revealed a variant in exon 3 of the EIF2AK2 gene [ (NM_001135651.3): c.92C G (p.Pro31Arg)]. EIF2AK2 ‐associated disorders should be incorporated into the differential diagnosis of the syndrome of fever‐related neurological decompensation with movement disorders, especially in the presence of abnormal neuroimaging. Disease‐causing variants in EIF2AK2 have been reported in 24 in iduals from 16 families in the literature to date. Two broad phenotypes have been described, including: (1) childhood‐onset generalized dystonia and a normal brain MRI and (2) early childhood‐onset developmental delay combined with movement disorders, spasticity, and seizures in some. Notably, 92% of these patients have neurological deterioration after febrile illness or other physiological stress. Hypomyelination or delayed myelination and thin corpus callosum are seen in most patients and lower medullary lessions are common. Basal ganglia lesions have been reported previously in one case. EIF2AK2 ‐associated disorders should be incorporated into the differential diagnosis of the syndrome of fever‐related neurological decompensation with movement disorders, especially in the presence of abnormal neuroimaging.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.JOCN.2013.07.017
Abstract: The knowledge of immune dysregulation and autoimmunity in neurological disorders has expanded considerably in recent times. Recognition of clinical syndromes, reliable methods of diagnosis, and early targeted immunotherapy can lead to a favourable outcome in acute and subacute neurological disorders that may be associated with significant morbidity and mortality if left untreated. This review focuses on the rapidly expanding field of autoimmune encephalitis. We describe the differences between limbic encephalitis associated with antibodies targeting intracellular antigens, and neuronal surface antibody syndromes (NSAS) where the antigens are primarily receptors or synaptic proteins located on the neuronal cell surface. We chronologically highlight important developments in NSAS by focusing on voltage gated potassium channel complex-associated antibody mediated encephalitis, anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, and anti-dopamine 2 receptor antibody-associated basal ganglia encephalitis. Contentious issues such as the complexities of using serum antibodies as biomarkers, the initiation of central nervous system autoimmunity, and possible pathogenic mechanisms of these antibodies will be reviewed. The therapeutic challenges that clinicians face such as the timing of therapy and the role of second-line therapy will be discussed, with crucial concepts highlighted in the form of clinical vignettes. Future directions will involve the identification of novel antigens and methods to establish their pathogenicity, as well as evaluation of the most efficacious therapeutic strategies in patients with established NSAS.
Publisher: BMJ
Date: 21-07-2018
Publisher: Springer Science and Business Media LLC
Date: 09-2007
DOI: 10.1007/S12098-007-0153-4
Abstract: Stroke is not an uncommon problem in children. However, stroke following intraoral trauma is rare. A high index of suspicion of neurological complications following apparently asymptomatic oral trauma helps to identify this peculiar form of childhood stroke.
Publisher: Wiley
Date: 28-03-2019
DOI: 10.1002/MDS.27661
Abstract: Movement disorders differ in children to adults. First, neurodevelopmental movement disorders such as tics and stereotypies are more prevalent than parkinsonism, and second, there is a genomic revolution which is now explaining many early-onset dystonic syndromes. We outline an approach to children with movement disorders starting with defining the movement phenomenology, determining the level of functional impairment due to abnormal movements, and screening for comorbid psychiatric conditions and cognitive impairments which often contribute more to disability than the movements themselves. The rapid improvement in our understanding of the etiology of movement disorders has resulted in an increasing focus on precision medicine, targeting treatable conditions and defining modifiable disease processes. We profile some of the key disease-modifying therapies in metabolic, neurotransmitter, inflammatory, and autoimmune conditions and the increasing focus on gene or cellular therapies. When no disease-modifying therapies are possible, symptomatic therapies are often all that is available. These classically target dopaminergic, cholinergic, alpha-adrenergic, or GABAergic neurochemistry. Increasing interest in neuromodulation has highlighted that some clinical syndromes respond better to DBS, and further highlights the importance of "disease-specific" therapies with a future focus on in idualized therapies according to the genomic findings or disease pathways that are disrupted. We summarize some pragmatic applications of symptomatic therapies, neuromodulation techniques, and some rehabilitative interventions and provide a contemporary overview of treatment in childhood-onset movement disorders. © 2019 International Parkinson and Movement Disorder Society.
Publisher: BMJ
Date: 15-11-2017
Abstract: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.
Publisher: Wiley
Date: 05-04-2022
DOI: 10.1002/MDS.29006
Abstract: ADCY5-related dyskinesia is characterized by early-onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine. The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia. A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire. Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality-of-life improvement. Three patients reported worsening. Our findings suggest that caffeine should be considered as a first-line therapeutic option in ADCY5-related dyskinesia. © 2022 International Parkinson and Movement Disorder Society.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-01-2016
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.JOCN.2013.06.017
Abstract: Evaluation of hereditary axonal neuropathy in childhood is complex. Often, the child has to be subjected to general anaesthesia for a nerve biopsy to guide further genetic testing, which may or may not be readily available. We describe a toddler with clinical features suggesting giant axonal neuropathy (GAN), whose diagnosis was confirmed by minimally invasive skin biopsy and corroborated by the finding of compound heterozygous mutations involving the GAN gene, including a novel interstitial microdeletion at 16q23.2 detected by microarray and a point mutation detected by direct sequencing.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Springer Science and Business Media LLC
Date: 02-2022
DOI: 10.1007/S11940-022-00708-5
Abstract: Functional neurological disorder (FND) is a multi-network brain disorder that encompasses a broad range of neurological symptoms. FND is common in pediatric practice. It places substantial strains on children, families, and health care systems. Treatment begins at assessment, which requires the following: the medical task of making the diagnosis, the interpersonal task of engaging the child and family so that they feel heard and respected, the communication task of communicating and explaining the diagnosis, and the logistical task of organizing treatment. Over the past decade, three treatment approaches—Retraining and Control Therapy (ReACT), other cognitive-behavioral therapies, and multidisciplinary rehabilitation—have been evaluated in the USA, Canada, and Australia. Of children treated in such programs, 63 − 95% showed full resolution of FND symptoms. The common thread across the programs is their biopsychosocial approach—consideration of biological, psychological, relational, and school-related factors that contribute to the child’s clinical presentation. Current research strongly supports a biopsychosocial approach to pediatric FND and provides a foundation for a stepped approach to treatment. Stepped care is initially tailored to the needs of the in idual child (and family) based on the pattern and severity of FND presentation. The level of care and type of intervention may then be adjusted to consider the child’s response, over time, to treatment or treatment combinations. Future research is needed to confirm effective treatment targets, to inform the development of stepped care, and to improve methodologies that can assess the efficacy of stepped-care interventions.
Publisher: Elsevier BV
Date: 2017
Publisher: Wiley
Date: 08-2023
DOI: 10.1002/MDC3.13775
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-10-2019
DOI: 10.1212/NXG.0000000000000367
Abstract: The present study investigated the diagnostic yield of array comparative genomic hybridization (aCGH) in a large cohort of children with erse neurologic disorders as seen in child neurology practice to test whether pathogenic copy number variants (CNVs) were more likely to be detected in specific neurologic phenotypes. A retrospective cross-sectional analysis was performed on 555 children in whom a genetic etiology was suspected and who underwent whole-genome aCGH testing between 2006 and 2012. Neurologic phenotyping was performed using hospital medical records. An assessment of pathogenicity was made for each CNV, based on recent developments in the literature. Forty-seven patients were found to carry a pathogenic CNV, giving an overall diagnostic yield of 8.59%. Certain phenotypes predicted for the presence of a pathogenic CNV, including developmental delay (odds ratio [OR] 3.69 [1.30–10.51]), cortical visual impairment (OR 2.73 [1.18–6.28]), dysmorphism (OR 2.75 [1.38–5.50]), and microcephaly (OR 2.16 [1.01–4.61]). The combination of developmental delay/intellectual disability with dysmorphism and abnormal head circumference was also predictive for a pathogenic CNV (OR 2.86 [1.02–8.00]). For every additional clinical feature, there was an increased likelihood of detecting a pathogenic CNV (OR 1.18 [1.01–1.38]). The use of aCGH led to a pathogenic finding in 8.59% of patients. The results support the use of aCGH as a first tier investigation in children with erse neurologic disorders, although whole-genome sequencing may replace aCGH as the detection method in the future. In particular, the yield was increased in children with developmental delay, dysmorphism, cortical visual impairment, and microcephaly.
Publisher: Wiley
Date: 25-04-2017
DOI: 10.1111/DMCN.13431
Abstract: To examine the cytokine/chemokine profile of cerebrospinal fluid (CSF) during acute herpes simplex virus-induced N-methyl-d-aspartate receptor (NMDAR) autoimmunity and in chronic/relapsing post-herpes simplex virus encephalitis (HSE) neurological syndromes. We measured longitudinal serial CSF cyto-/chemokines (n=34) and a glial marker (calcium-binding astroglial protein, S100B) in one patient during acute HSE and subsequent anti-NMDAR encephalitis, and compared the results with those from two patients with anti-NMDAR encephalitis without preceding HSE. We also compared cyto-/chemokines in cross-sectional CSF s les from three children with previous HSE who had ongoing chronic or relapsing neurological symptoms (2yr 9 mo-16y after HSE) with those in a group of children having non-inflammatory neurological conditions (n=20). Acute HSE showed elevation of a broad range of all T-helper-subset-related cyto-/chemokines and S100B whereas the post-HSE anti-NMDAR encephalitis phase showed persistent elevation of two of five T-helper-1 (chemokine [C-X-C motif] ligand 9 [CXCL9], CXCL10), three of five predominantly B-cell (CXCL13, CCL19, a proliferation-inducing ligand [APRIL])-mediated cyto-/chemokines, and interferon-α. The post-HSE anti-NMDAR encephalitis inflammatory response was more pronounced than anti-NMDAR encephalitis. All three chronic post-HSE cases showed persistent elevation of CXCL9, CXCL10, and interferon-α, and there was histopathological evidence of chronic lymphocytic inflammation in one biopsied case 7 years after HSE. Two of three chronic cases showed a modest response to immune therapy. HSE-induced anti-NMDAR encephalitis is a complex and pronounced inflammatory syndrome. There is persistent CSF upregulation of cyto-/chemokines in chronic or relapsing post-HSE neurological symptoms, which may be modifiable with immune therapy. The elevated cyto-/chemokines may be targets of monoclonal therapies.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.EJPN.2018.09.008
Abstract: Available data on mycophenolate mofetil (MMF), azathioprine (AZA) and methotrexate (MTX) for paediatric-onset anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is limited. Systematic literature review on patients treated with MMF/AZA/MTX for paediatric-onset anti-NMDARE, with focus on modes of use, efficacy and safety. 87 patients were included (age at onset median 11 years, range 0.8-18 years 69% females). 46% had a relapsing course. 52% received MMF, 27% AZA, 15% MTX, and 6% a combination of MMF/AZA/MTX (7 patients received intrathecal MTX). Before MMF/AZA/MTX, 100% patients received steroids, 83% intravenous immunoglobulin and 45% plasma exchange, and 50% received second-line treatments (rituximab/cyclophosphamide). MMF/AZA/MTX were administered >6 months from onset in 51%, and only after relapse in 40%. Worst mRS before MMF/AZA/MTX was median 4.5 (range 3-5). At last follow-up (median 2 years, range 0.2-8.6), median mRS was 1 (range 0-6). Median annualised relapse rate was 0.4 (range 0-6.7) pre-MMF/AZA/MTX (excluding first events), and 0 on MMF/AZA/MTX (mean 0.03, range 0-0.8). 7% patients relapsed on MMF/AZA/MTX. These relapsing patients had low rate of second-line treatments before MMF/AZA/MTX (25%), long median time between onset and MMF/AZA/MTX usage (18 months), and frequently they were started on MMF/AZA/MTX only after relapse (75%). Relapse rate was lower among patients who received first immune therapy ≤30 days (25%) than later (64%), who received second-line treatments at first event (14%) rather than not (64%), who were started on MMF/AZA/MTX after the first (12%) rather than subsequent events (17%), and who were started on MMF/AZA/MTX ≤3 months from onset (33%) rather than later (53%). Adverse reactions to MMF/AZA/MTX occurred in 2 cases (cytomegalovirus colitis and respiratory infection), of grade 3 Common Terminology Criteria for Adverse Events v4.0. Our literature review disclosed heterogeneity in the use of MMF/AZA/MTX in paediatric-onset anti-NMDARE. MMF/AZA/MTX usage is mostly restricted to retrospective cohort descriptions. These agents may reduce risk of relapse, and have a reasonable safety profile, however data on larger cohorts are required to definitively determine effect.
Publisher: Wiley
Date: 05-02-2019
DOI: 10.1111/DMCN.14167
Abstract: Epidemiological studies, animal models, and case-control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), Tourette syndrome, and obsessive-compulsive disorder (OCD). We report eight children (mean age 6y 6mo [range 4-15y] six males and two females) referred over a 2-year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD [n=6], tics [n=5], and/or psychosis [n=1]), associated with an autistic or global regression. Four children had a pre-existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing-remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli. WHAT THIS PAPER ADDS: Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring. Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero.
Publisher: Sociedade Portuguesa de Neurologia
Date: 30-06-2020
Publisher: Wiley
Date: 10-2013
DOI: 10.1002/MDS.25623
Abstract: Movement disorder relapses after herpes simplex virus 1 (HSV1) encephalitis have been hypothesized to be secondary to postviral autoimmunity. Recently, a proportion of patients with HSV1 encephalitis (HSE) were shown to produce autoantibodies against N-methyl-D-aspartate receptor (NMDAR). We measured autoantibodies against NMDAR and dopamine-2 receptor (D2R) expressed at the cell surface in the stored acute serum of 9 children with HSE, 3 of whom had a relapsing course with chorea. The 3 patients with chorea had elevated autoantibodies against NMDAR (n = 1), D2R (n = 1), or both (n = 1), whereas patients without chorea were negative (n = 6). The prospectively identified patient with chorea and NMDAR autoantibodies improved after early treatment with steroids, intravenous immunoglobulin, and cyclophosphamide, with reduction in serum NMDAR antibody titers. These autoantibody findings lend support to the autoimmune hypothesis and the early use of immune suppression in post-HSE chorea.
Publisher: Wiley
Date: 05-03-2022
DOI: 10.1111/JPC.15932
Abstract: To report the prevalence and clinical characteristics of children with rapid onset functional tic‐like behaviours during the COVID‐19 pandemic. Single centre, retrospective cohort study of children ( years) referred to the tic clinic from January 2018 to July 2021. We calculate the prevalence of newly diagnosed functional tics, and compare the clinical features to chronic tic disorder/Tourette syndrome (CTD/TS). A total of 185 new patients were referred to the tic clinic between 2018 and 2021. There was a significant increase in the percentage of functional tics in 2020 and 2021 (2% in 2018, 5.6% in 2019, 10.6% in 2020 and 36% in 2021). Differences between functional tics ( n = 22) and CTD/TS ( n = 163) include female predominance (100 vs. 28%, P 0.0001), later age of onset (mean age 13.8 vs. 6.8 years, P 0.0001) and higher rates of anxiety/depression (95 vs. 41%, P 0.0001). The functional tic group were more likely to present with coprolalia‐like behaviours (77 vs. 10%, P 0.0001), complex phrases (45 vs. 0.6%, P 0.0001), copropraxia (45 vs. 2%, P 0.0001), self‐injury (50 vs. 4%, P 0.0001), hospitalisation/emergency visits (36 vs. 2%, P 0.0001) and school absenteeism (56 vs. 7%, P 0.0001). A total of 18.2% of patients with functional tics reported preceding exposure to social media content involving tics. There is an increase in adolescent females presenting with rapid onset functional tic‐like behaviours during the COVID‐19 pandemic. We highlight differences in clinical features between the functional tic group and CTD/TS to aid diagnosis and management in the community. Based on our findings, we propose a mixed model of neuropsychiatric vulnerability and social media contagion in this group of adolescents with functional tics.
Publisher: Wiley
Date: 19-12-2016
DOI: 10.1111/DMCN.13351
Abstract: Inflammatory basal ganglia encephalitis (BGE) is a rare but distinct entity of putative autoimmune aetiology, with specific basal ganglia inflammation and acute movement disorders. Unlike most brain injuries, BGE is a radiologically pure basal ganglia syndrome. The current study systematically describes the neuropsychological outcomes of four paediatric cases of BGE, and thus the neuropsychological outcomes of focal basal ganglia insult in childhood. Although all patients made significant motor recoveries, all four cases displayed executive dysfunction, fine motor difficulties, and anxiety. Three out of four cases displayed attention deficits. The case who received intravenous immunoglobulin (IVIg) treatment and steroids during the acute phase of the disease had the best cognitive outcome. These findings highlight the need for detailed neuropsychological assessment and long-term follow-up.
Publisher: SAGE Publications
Date: 12-05-2022
DOI: 10.1177/08830738221093209
Abstract: Postinfectious acute cerebellar syndromes show a wide spectrum of acute severity and can occur with acute febrile illness or vaccine receipt. Varicella has historically been the most common cause, associated with up to 25% of cases in large cohorts. This study aimed to describe the spectrum of syndromes in a setting with high varicella vaccine coverage. Data were collected on children initially identified as “suspected encephalitis” subsequently designated “not-encephalitis” at participating children's hospitals in the Paediatric Active Enhanced Disease Surveillance (PAEDS) network, Australia, as part of the Acute Childhood Encephalitis study. A comprehensive descriptive analysis was undertaken on prospectively identified, national series of children with postinfectious acute cerebellar syndromes from 2013 to 2018. Cases were classified using a previously validated severity score, and the outcome was assessed at 12 months using the Liverpool Outcome Scale score. A total of 20 cases (65% were vaccinated for varicella) were included, of which 70% were subcategorized as acute cerebellar ataxia (ACA), 20% acute cerebellitis (AC), and 10% acute fulminant cerebellitis (AFC). An acute febrile illness was noted in 55% and none were related to varicella or were temporally related to varicella vaccination or other childhood vaccines. A subset (total of 7 children) followed up at 12 months all showed reduced Liverpool Outcome Scale scores. The study provides an overall description of this uncommon spectrum of neurologic syndromes and shows the infrequency of varicella zoster virus as a cause in a vaccinated population.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.BRAINDEV.2021.10.001
Abstract: The type 1 interferonopathy, Aicardi-Goutières syndrome 6 (AGS6), is classically caused by biallelic ADAR mutations whereas dominant ADAR mutations are associated with dyschromatosis symmetrica hereditaria (DSH). The unique dominant ADAR c.3019G>A variant is associated with neurological manifestations which mimic spastic paraplegia and cerebral palsy (CP). We report three cases of spastic paraplegia or CP diagnosed with AGS6 caused by the ADAR c.3019G>A variant. Two children inherited the variant from an asymptomatic parent, and each child had a different clinical course. The youngest case demonstrated relentless progressive symptoms but responded to immunomodulation using steroids and ruxolitinib. The ADAR c.3019G>A variant has incomplete penetrance and is a likely underrecognized imitator of spastic paraplegia and dystonic CP. A high level of clinical suspicion is required to diagnose this form of AGS, and disease progression may be ameliorated by immunomodulatory treatment with selective Janus kinase inhibitors.
Publisher: BMJ
Date: 22-06-2020
DOI: 10.1136/JMEDGENET-2019-106740
Abstract: Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. In order to further refine the phenotypical spectrum associated with TUBB2A , clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five in iduals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype–phenotype correlations could be established, suggesting the role of additional modifiers.
Publisher: Oxford University Press (OUP)
Date: 11-2020
Abstract: Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen in iduals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5–37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden’s Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012 disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, & % of subjects showed BFMDRS-M and BFMDRS-D improvements of & %. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for & years, n = 8), improvement of & % was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.BRAINDEV.2021.10.009
Abstract: Mutations in QARS1, which encodes human glutaminyl-tRNA synthetase, have been associated with epilepsy, developmental regression, progressive microcephaly and cerebral atrophy. Epilepsy caused by variants in QARS1 is usually drug-resistant and intractable. Childhood onset epilepsy is also reported in various aminoacyl-tRNA synthetase disorders. We describe a case with a milder neurological phenotype than previously reported with QARS1 variants and review the seizure associations with aminoacyl-tRNA synthetase disorders. The patient is a 4-year-old girl presenting at 6 weeks of age with orofacial dyskinesia and hand stereotypies. She developed focal seizures at 7 months of age. Serial electroencephalograms showed shifting focality. Her seizures were controlled after introduction of carbamazepine. Progress MRI showed very mild cortical volume loss without myelination abnormalities or cerebellar atrophy. She was found to have novel compound heterozygous variants in QARS1 (NM_005051.2): c.[1132C > T] [1574G > A], p.[(Arg378Cys)] [(Arg525Gln)] originally classified as "variants of uncertain significance" and later upgraded to "likely pathogenic" based on functional testing and updated variant database review. Functional testing showed reduced solubility of the corresponding QARS1 mutants in vitro, but only mild two-fold loss in catalytic efficiency with the c.1132C > T variant and no noted change in tRNA We describe two QARS1 variants associated with overall conserved tRNA aminoacylation activity but characterized by significantly reduced QARS protein solubility, resulting in a milder clinical phenotype. 86% of previous patients reported with QARS1 had epilepsy and 79% were pharmaco-resistant. We also summarise literature regarding epilepsy in aminoacyl-tRNA synthetase disorders, which is also often early onset, severe and drug-refractory.
Publisher: Wiley
Date: 31-05-2016
DOI: 10.1111/DMCN.13159
Abstract: Intravenous immunoglobulin (IVIG) is an expensive therapy used in immunodeficiency and autoimmune disorders. Increasing demands and consequent shortages result in a need for usage to conform to guidelines. We retrospectively evaluated IVIG use for neuroimmunological indications and adherence to existing guidelines in a major Australian paediatric hospital between 2000 and 2014. One-hundred and ninety-six children (96 male, 100 female mean age at disease onset 6y 5mo [range 3mo-15y 10mo], mean age at first IVIG dose 7y 2mo [range 3mo-16y 5mo]) received IVIG for neuroimmunological indications during the study period (28.1% had Guillain-Barré syndrome), representing 15.5% of all hospital indications. In total, 1669 IVIG courses were administered (total 57 221g, median 78g atient, range 12-5748g). The highest median numbers of courses were in chronic inflammatory demyelinating polyneuropathies, opsoclonus-myoclonus ataxia syndrome, suspected immune-mediated epilepsies, and Rasmussen's encephalitis. Adverse reactions occurred in 25.5% of patients, but these were mostly minor. Outcome at follow-up was best in anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, Guillain-Barré syndrome, and myasthenia gravis, and worst in Rasmussen's encephalitis and epilepsies. The total cost of IVIG was US$2 595 907 (median $3538 atient, range $544-260 766). Of patients receiving IVIG, 45.4% to 57.1% were given the therapy for 'weak' indications or indications 'not listed' in international guidelines. Some entities commonly treated with IVIG in current practice, such as anti-NMDAR encephalitis and transverse myelitis, are not listed in most guidelines. Our study demonstrates that IVIG is generally well tolerated but expensive, and discloses discrepancies between guidelines and clinical practice in paediatric neurology, suggesting both the need for greater adherence to current recommendations, and for recommendations to be updated to accommodate emerging indications.
Publisher: Elsevier BV
Date: 11-2017
Publisher: Wiley
Date: 09-2022
DOI: 10.1002/MDC3.13538
Publisher: Wiley
Date: 15-04-2022
DOI: 10.1111/JPC.15981
Publisher: Wiley
Date: 28-02-2018
DOI: 10.1002/MDS.27294
Publisher: Wiley
Date: 22-03-2017
DOI: 10.1111/DMCN.13420
Abstract: To investigate the incidence and severity of anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis in children from New Zealand. A retrospective case series was undertaken of all children (≤18y) diagnosed with anti-NMDA receptor encephalitis from January 2008 to October 2015. Sixteen patients were identified with anti-NMDA receptor antibodies in the cerebrospinal fluid, three of whom had an associated teratoma. Fifteen children had Māori and/or Pacific Island ancestry. The incidence of anti-NMDA receptor encephalitis in Māori children was 3.4 per million children per year (95% confidence interval [CI] 1.4-7.0) and the incidence in Pacific children was 10.0 per million children per year (95% CI 4.3-19.8) compared with 0.2 per million children per year (95% CI 0.0-1.0) in children without Māori or Pacific Island ancestry. Sixty-seven per cent of children had a good outcome (modified Rankin Score ≤2) at 2 years' follow-up. This compares unfavourably with other cohorts despite a shorter median time to first-line immunotherapy (13d range 4-89) and a higher proportion of children being treated with second-line therapy (50%). Māori and Pacific Island children have a higher incidence of anti-NMDA receptor encephalitis and possibly a more severe phenotype. These data suggest a genetic predisposition to anti-NMDA receptor encephalitis in these populations.
Publisher: BMJ
Date: 24-07-2020
DOI: 10.1136/ARCHDISCHILD-2020-319541
Abstract: To determine rates of psychiatric comorbidity in a clinical s le of childhood movement disorders (MDs). Cohort study. Tertiary children’s hospital MD clinics in Sydney, Australia and London, UK. Cases were children with tic MDs (n=158) and non-tic MDs (n=102), including 66 children with dystonia. Comparison was made with emergency department controls (n=100), neurology controls with peripheral neuropathy or epilepsy (n=37), and community controls (n=10 438). On-line development and well-being assessment which was additionally clinically rated by experienced child psychiatrists. Diagnostic schedule and manual of mental disorders-5 criteria for psychiatric diagnoses. Psychiatric comorbidity in the non-tic MD cohort (39.2%) was comparable to the tic cohort (41.8%) (not significant). Psychiatric comorbidity in the non-tic MD cohort was greater than the emergency control group (18%, p .0001) and the community cohort (9.5%, p .00001), but not the neurology controls (29.7%, p=0.31). Almost half of the patients within the tic cohort with psychiatric comorbidity were receiving medical psychiatric treatment (45.5%) or psychology interventions (43.9%), compared with only 22.5% and 15.0%, respectively, of the non-tic MD cohort with psychiatric comorbidity. Psychiatric comorbidity is common in non-tic MDs such as dystonia. These psychiatric comorbidities appear to be under-recognised and undertreated.
Publisher: Wiley
Date: 10-12-2018
DOI: 10.1111/DMCN.14114
Abstract: We used magnetic resonance imaging (MRI) to compare the neuroimaging of children with their first episode of clinical enterovirus 71-associated transverse myelitis (EV71-TM), myelin oligodendrocyte glycoprotein antibody positive transverse myelitis (MOG-TM), aquaporin-4 antibody positive transverse myelitis (AQP4-TM), transverse myelitis in multiple sclerosis (MS-TM), and unclassified transverse myelitis (UNC-TM). We performed a retrospective blinded radiological assessment and compared the neuroimaging of 52 children (32 females, 20 males mean age 9y 8mo, SD 5y 5mo, range 5mo-17y) presenting with their first episode of myelitis caused by EV71-TM (n=11), MOG-TM (n=10), AQP4-TM (n=9), MS-TM (n=13), and UNC-TM (n=9). In the EV71-TM group, lesions were distributed throughout the cord and enhancement of nerve roots (ventral and dorsal) was common. The MOG-TM group had lesions distributed throughout the cord and most commonly longitudinally extensive transverse myelitis and lesions involving the grey matter alone on axial scans. The AQP4-TM group had lesions distributed in the cervicothoracic spine, cavitation, and contrast enhancing lesions. All patients with AQP4-TM had an abnormal brain MRI scan. The MS-TM group characteristically had multiple short segment lesions of the cord involving the cervicothoracic spine. The UNC-TM group did not have distinctive spinal MRI findings but had a relative paucity of lesions on their brain MRI scans. There are neuroimaging findings that are helpful in differentiating between myelitis associated with EV71, MOG, AQP4, and multiple sclerosis in children. These features may be useful early in the presentation of transverse myelitis while awaiting infectious/immunological testing, and/or further demyelinating events. Magnetic resonance imaging can help identify aetiologies for children presenting with a first episode of myelitis. Entervirus-71-associated myelitis lesions are distributed throughout the cord and enhancement of nerve roots is common. Lesions distributed throughout the cord are commonly seen in myelin oligodendrocyte-associated myelitis. Aquaporin-4-associated myelitis lesions are distributed in the cervicothoracic spine, cavitation and contrast enhancing lesions are common. Short segment lesions in the cervicothoracic spine are commonly seen in multiple sclerosis-associated myelitis.
Publisher: Springer International Publishing
Date: 2023
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.PARKRELDIS.2022.05.011
Abstract: This is a unique case of SPG11 mutation presenting as childhood onset dystonic tremor without weakness or spastic paraplegia. Hereditary spastic paraplegia is the most common phenotype of SPG11 mutation though there are reports of an extended phenotype of SPG11 including dopa-responsive dystonia and tremor.
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.GIM.2021.09.001
Abstract: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). A total of 74 families with erse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with s les from ≥2 affected in iduals or heterozygotes and 10 cases with ≥2 biospecimens. PCR licons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long licons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.
Publisher: Wiley
Date: 22-11-2015
DOI: 10.1111/EPI.13253
Abstract: To define the risk factors for postencephalitic epilepsy (PE) and drug-resistant epilepsy (DRE) in childhood following infectious and autoimmune encephalitis, we included 147 acute encephalitis patients with a median follow-up of 7.3 years (range 2-15.8 years). PE was defined as the use of antiepileptic drugs (AEDs) for ≥24 months, and DRE was defined as the persistence of seizures despite ≥2 appropriate AEDs at final follow-up. PE and DRE were diagnosed in 31 (21%) and 15 (10%) of patients, respectively. The features during acute encephalitis predictive of DRE (presented as odds ratio [OR] with confidence intervals [CIs]) were status epilepticus (OR 10.8, CI 3.4-34.3), visual disturbance (6.4, 1.4-29.9), focal seizures (6.2, 1.9-20.6), magnetic resonance imaging (MRI) hippoc al/amygdala involvement (5.0, 1.7-15.4), intensive care admission (4.7, 1.4-15.4), use of >3 AEDs (4.5, 1.2-16.1), MRI gadolinium enhancement (4.1, 1.2-14.2), any seizure (3.9, 1.1-14.4), and electroencephalography (EEG) epileptiform discharges (3.9, 1.3-12.0). On multivariable regression analysis, only status epilepticus remained predictive of DRE in all models. DRE was common in herpes simplex virus (3/9, 33%) and unknown (8/40, 20%) encephalitis, but absent in acute disseminated encephalomyelitis (ADEM) (0/32, 0%), enterovirus (0/18), and anti-N-methyl-d-aspartate receptor-NMDAR encephalitis (0/9). We have identified risk factors for DRE and demonstrated "high-risk," and "low-risk" etiologies.
Publisher: Cold Spring Harbor Laboratory
Date: 02-04-2021
DOI: 10.1101/MCS.A005827
Abstract: Early infantile epileptic encephalopathy-44 (EIEE44, MIM: 617132) is a previously described condition resulting from biallelic variants in UBA5 , a gene involved in a ubiquitin-like post-translational modification system called UFMylation. Here we report five children from four families with biallelic pathogenic variants in UBA5 . All five children presented with global developmental delay, epilepsy, axial hypotonia, appendicular hypertonia, and a movement disorder, including dystonia in four. Affected in iduals in all four families have compound heterozygous pathogenic variants in UBA5 . All have the recurrent mild c.1111G A (p.Ala371Thr) variant in trans with a second UBA5 variant. One patient has the previously described c.562C T (p. Arg188*) variant, two other unrelated patients have a novel missense variant, c.907T C (p.Cys303Arg), and the two siblings have a novel missense variant, c.761T C (p.Leu254Pro). Functional analyses demonstrate that both the p.Cys303Arg variant and the p.Leu254Pro variants result in a significant decrease in protein function. We also review the phenotypes and genotypes of all 15 previously reported families with biallelic UBA5 variants, of which two families have presented with distinct phenotypes, and we describe evidence for some limited genotype–phenotype correlation. The overlap of motor and developmental phenotypes noted in our cohort and literature review adds to the increasing understanding of genetic syndromes with movement disorders-epilepsy.
Publisher: Elsevier
Date: 2021
Publisher: Wiley
Date: 12-2015
DOI: 10.1111/JPC.12915
Abstract: Sydenham's chorea (SC) is a major manifestation seen in 25% of patients with acute rheumatic fever. SC is the prototypic autoimmune neurological disorder, which has a less appreciated associated risk of psychiatric morbidity. We undertook a systematic review to examine whether the use of intravenous immunoglobulin affects clinical recovery and morbidity.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 27-05-2016
DOI: 10.1038/NCOMMS11601
Abstract: Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism–dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.
Publisher: Elsevier BV
Date: 10-2022
Publisher: Informa UK Limited
Date: 03-2023
DOI: 10.2147/TACG.S363485
Publisher: Oxford University Press (OUP)
Date: 2020
DOI: 10.1093/BRAINCOMMS/FCAA162
Abstract: Variants in the GABRB3 gene encoding the β3-subunit of the γ-aminobutyric acid type A ( receptor are associated with various developmental and epileptic encephalopathies. Typically, these variants cause a loss-of-function molecular phenotype whereby γ-aminobutyric acid has reduced inhibitory effectiveness leading to seizures. Drugs that potentiate inhibitory GABAergic activity, such as nitrazepam, phenobarbital or vigabatrin, are expected to compensate for this and thereby reduce seizure frequency. However, vigabatrin, a drug that inhibits γ-aminobutyric acid transaminase to increase tonic γ-aminobutyric acid currents, has mixed success in treating seizures in patients with GABRB3 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A GABRB3 variant that responds well to vigabatrin involves a truncation variant (p.Arg194*) resulting in a clear loss-of-function. We hypothesized that patients with a hypersensitive response to vigabatrin may exhibit a different γ-aminobutyric acid A receptor phenotype. To test this hypothesis, we evaluated the phenotype of de novo variants in GABRB3 (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the GABRB3 p.Glu77Lys and p.Thr287Ile variants into a concatenated synaptic and extrasynaptic γ-aminobutyric acid A receptor construct, to resemble the γ-aminobutyric acid A receptor expression by a patient heterozygous for the GABRB3 variant. The mRNA of these constructs was injected into Xenopus oocytes and activation properties of each receptor measured by two-electrode voltage cl electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the GABRB3 p.Glu77Lys and p.Thr287Ile variants characterized by increased potency of γ-aminobutyric acid A without change to the estimated maximum open channel probability, deactivation kinetics or absolute currents. Modelling of the activation properties of the receptors indicated that either variant caused increased chloride flux in response to low concentrations of γ-aminobutyric acid that mediate tonic currents. We therefore propose that the hypersensitivity reaction to vigabatrin is a result of GABRB3 variants that exacerbate GABAergic tonic currents and caution is required when prescribing vigabatrin. In contrast, drug strategies increasing tonic currents in loss-of-function variants are likely to be a safe and effective therapy. This study demonstrates that functional genomics can explain beneficial and adverse anti-epileptic drug effects, and propose that vigabatrin should be considered in patients with clear loss-of-function GABRB3 variants.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2019
Publisher: Georg Thieme Verlag KG
Date: 07-08-2015
Publisher: Wiley
Date: 25-08-2022
DOI: 10.1002/MDS.29182
Abstract: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders. Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria. One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH) chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years P 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia. This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Publisher: Springer Science and Business Media LLC
Date: 17-06-2008
DOI: 10.1007/S11010-008-9807-4
Abstract: In vitro studies have shown unequivocally that bilirubin is an antioxidant. We hypothesized that bilirubin serves a physiological role of an antioxidant in vivo. To investigate the probable protective role of bilirubin in vivo, term babies with clinical jaundice were grouped into four categories-serum total bilirubin (STB) 200 mg/l, and kernicterus. Serum bilirubin, serum albumin, plasma glucose-6-phosphate dehydrogenase (G6PD), lipid peroxidation in blood cells, and reduced glutathione (GSH) content in whole blood were investigated. We also measured superoxide dismutase (SOD) and catalase in hemolysate and total plasma antioxidant capacity (TAC). Lipid peroxidation and antioxidant enzymes were significantly lower in babies with STB 200 mg/l and in babies with bilirubin encephalopathy. Elevated levels of MDA, SOD, and catalase and significantly decreased levels of reduced glutathione and total antioxidant capacity were observed in STB >200 mg/l group. Antioxidant enzymes were also significantly inhibited in bilirubin encephalopathy babies. Post phototherapy, MDA production and antioxidant levels were significantly increased whilst total antioxidant capacity and reduced glutathione were significantly decreased compared to pre-phototherapy values. Exchange transfusion resulted in reduced oxidative stress in subjects with encephalopathy, whereas no significant difference was observed in other babies with STB >200 mg/l. Taken together, the present study propounds that bilirubin acts as a physiological antioxidant till 200 mg/l concentration in full-term normal neonates. It is conjectured that beyond 200 mg/l, it can no longer be considered physiologic. However, the cause of pathological jaundice needs to be identified and treated. The present data documents that phototherapy also induces oxidative stress.
Publisher: BMJ
Date: 07-2017
Publisher: Elsevier BV
Date: 2018
Publisher: Public Library of Science (PLoS)
Date: 30-08-2016
Publisher: Wiley
Date: 29-04-2019
DOI: 10.1002/MDS.27708
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-03-2016
Publisher: Wiley
Date: 28-08-2015
DOI: 10.1111/DMCN.12882
Abstract: We performed the first study on the perceived benefit and adverse effects of symptomatic management in children with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. A retrospective chart review was undertaken at two tertiary paediatric hospitals in Australia and New Zealand. We included 27 children (12 males, 15 females mean age at admission 7y 1mo) with anti-NMDAR antibodies in serum or cerebrospinal fluid with a typical clinical syndrome. Only two out of 27 patients were white, whereas 16 out of 27 patients were from the Pacific Islands/New Zealand Maori. The mean duration of admission was 69 days (10-224d) and 48% of patients (13/27) needed treatment in an intensive care setting. A mean of eight medications per patient was used for symptomatic management. Symptoms treated were agitation (n=25), seizures (n=24), movement disorders (n=23), sleep disruption (n=17), psychiatric symptoms (n=10), and dysautonomia (n=four). The medications used included five different benzodiazepines (n=25), seven anticonvulsants (n=25), eight sedatives and sleep medications (n=23), five antipsychotics (n=12), and five medications for movement disorders (n=10). Sedative and sleep medications other than benzodiazepines were the most effective, with a mean benefit of 67.4% per medication and a mean adverse effect-benefit ratio of 0.04 per medication. Antipsychotic drugs were used for a short duration (median 9d), and had the poorest mean benefit per medication of 35.4% and an adverse effect-benefit ratio of 2.0 per medication. Long-acting benzodiazepines, anticonvulsants, and clonidine can treat multiple symptoms. Patients with anti-NMDAR encephalitis appear vulnerable to antipsychotic-related adverse effects. Pacific Islanders appear to have a vulnerability to anti-NMDAR encephalitis in our region.
Publisher: Springer Science and Business Media LLC
Date: 16-11-2022
DOI: 10.1038/S41380-022-01852-9
Abstract: Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride roton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 in iduals from 67 families with CLCN4 -related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for in iduals with this diagnosis.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.CLINPH.2016.07.014
Abstract: To examine EEG features in a retrospective 13-year cohort of children with encephalitis. 354 EEGs from 119 patients during their admission were rated blind using a proforma with demonstrated inter-rater reliability (mean k=0.78). Patients belonged to 12 etiological groups that could be grouped into infectious and infection-associated (n=47), immune-mediated (n=36) and unknown (n=33). EEG features were analyzed between groups and for risk of abnormal Liverpool Outcome Score and drug resistant epilepsy (DRE) at last follow up. 86% children had an abnormal first EEG and 89% had at least one abnormal EEG. 55% had an abnormal outcome, and 13% had DRE after median follow-up of 7.3years (2.0-15.8years). Reactive background on first EEGs (9/11, p=0.04) and extreme spindles (4/11, p<0.001) distinguished patients with anti-N-Methyl-d-Aspartate Receptor encephalitis. Non-reactive EEG background (48% first EEGs) predicted abnormal outcome (OR 3.8, p<0.001). A shifting focal seizure pattern, seen in FIRES (4/5), anti-voltage gated potassium channel (2/3), Mycoplasma (1/10), other viral (1/10) and other unknown (1/28) encephalitis, was most predictive of DRE after multivariable analysis (OR 11.9, p<0.001). Non-reactive EEG background and the presence of shifting focal seizures resembling migrating partial seizures of infancy are predictors of abnormal outcome and DRE respectively in childhood encephalitis. EEG is a sensitive but non-discriminatory marker of childhood encephalitis. We highlight the EEG features that predict abnormal outcome and DRE.
Publisher: Oxford University Press (OUP)
Date: 03-07-2013
DOI: 10.1093/JPIDS/PIT033
Abstract: Balamuthia mandrillaris causes granulomatous amoebic encephalitis, which is frequently fatal. There are few reports of survival in children. A 4-year-old child developed severe meningoencephalitis with multiple intracranial ring-enhancing lesions. Empiric therapy was commenced after a biopsy was performed, and the patient had a good clinical response. Molecular testing and indirect immunofluorescence later confirmed the diagnosis of Balamuthia encephalitis. Diagnosis of Balamuthia encephalitis is often delayed. The literature is reviewed with particular reference to reported survival. Prompt tissue diagnosis and initiation of therapy are common features among survivors. In previous reports, miltefosine was not used to treat children, but it was well tolerated in this case and should be considered as a therapeutic option.
Publisher: Wiley
Date: 20-06-2023
DOI: 10.1002/ACN3.51832
Abstract: Infection‐triggered encephalopathy syndromes (ITES) are potentially devastating neuroinflammatory conditions. Although some ITES syndromes have recognisable MRI neuroimaging phenotypes, there are otherwise few biomarkers of disease. Early detection to enable immune modulatory treatments could improve outcomes. We measured CSF neopterin, quinolinic acid, kynurenine and kynurenine/tryptophan ratio using a liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) system. The CSF of 18 children with ITES were compared with acute encephalitis ( n = 20), and three control groups, namely epilepsy ( n = 20), status epilepticus ( n = 18) and neurogenetic controls ( n = 20). The main ITES phenotypes in 18 patients were acute encephalopathy with biphasic seizures and late restricted diffusion (AESD, n = 4), febrile infection‐related epilepsy syndrome (FIRES n = 4) and other ITES phenotypes. Influenza A was the most common infectious trigger ( n = 5), and 50% of patients had a preceding notable neurodevelopmental or family history. CSF neopterin, quinolinic acid and kynurenine were elevated in ITES group compared to the three control groups (all p 0.0002). The ROC (area under curve) for CSF neopterin (99.3%, CI 98.1–100) was significantly better than CSF pleocytosis (87.3% CI 76.4–98.2) ( p = 0.028). Elevated CSF neopterin could discriminate ITES from other causes of seizures, status epilepticus and febrile status epilepticus (all p 0.0002). The elevated CSF metabolites normalised during longitudinal testing in two patients with FIRES. CSF neopterin and quinolinic acid are neuroinflammatory and excitotoxic metabolites. This CSF metabolomic inflammatory panel can discriminate ITES from other causes of new onset seizures or status epilepticus, and rapid results (4 h) may facilitate early immune modulatory therapy.
Publisher: Informa UK Limited
Date: 24-11-2015
DOI: 10.1586/14737175.2015.1115720
Abstract: We have reviewed the literature of immune therapy in autoimmune encephalitis associated with antibodies to cell surface antigens including N-methyl-D-aspartate receptor (NMDAR), leucine-rich, glioma-inactivated protein-1 (LGI1), contactin-associated protein-2 (Caspr2), the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), γ-aminobutyric acid-A receptor (GABAAR), γ-aminobutyric acid-B receptor (GABABR), Glycine R and other rarer antigens. Most studies are retrospective cohorts, and there are no randomised controlled trials. Most clinicians use first-line therapy (steroids, intravenous immunoglobulin, plasma exchange), and if severe or refractory, second-line therapy (rituximab, cyclophosphamide). When present, tumours should be removed. There are common therapeutic themes emerging. Firstly, patients given immune therapy do better and relapse less than patients given no treatment. Secondly, patients given early treatment do better. And thirdly, when patients fail first-line therapy, second-line therapy improves outcomes and reduces relapses. Given the retrospective uncontrolled data, the literature has inherent bias, including severity and reporting bias.
Publisher: Elsevier BV
Date: 2021
Publisher: Elsevier BV
Date: 2022
Publisher: Springer Science and Business Media LLC
Date: 24-08-2018
DOI: 10.1007/S00787-018-1212-2
Abstract: There is accumulating evidence that patients with functional neurological symptom disorder (FND) show activation of multiple components of the stress system-the hypothalamic-pituitary-adrenal axis, autonomic nervous system, and brain regions involved in arousal- and emotion-processing. This study aims to examine whether the immune-inflammatory component of the stress system is also activated. C-reactive protein (CRP) blood titre levels were measured in 79 children and adolescents with FND. CRP values ≥ 2 mg/L suggest low-grade inflammation. CRP values > 10 mg/L suggest a disease process. Sixty-six percent of subjects (n = 52) had CRP titres ≥ 2 mg/L. The upward shift in the distribution of CRP levels suggested low-grade inflammation (median CRP concentration was 4.60 mg/L, with 75th and 90th percentiles of 6.1 and 10.3 mg/L, respectively). Elevated CRP titres were not explained by sex, pubertal status, BMI, or medical factors. Confounder analyses suggested that history of maltreatment (χ
Publisher: Georg Thieme Verlag KG
Date: 07-11-2013
Abstract: Autoantibodies to the extracellular domain of neuronal proteins cause different neurological conditions with movement disorders as a prominent feature. We reviewed the literature of autoantibody-mediated and autoantibody-associated diseases focusing on anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, autoimmune basal ganglia encephalitis, Sydenham chorea, and the rare syndrome of progressive encephalomyelitis with rigidity and myoclonus. NMDAR encephalitis is a diffuse encephalitis with psychiatric and cognitive features associated with autoantibodies against the NR1 subunit of the NMDAR. The movement disorder phenotype is erse and often generalized in young children. Although orofacial dyskinesia was the initial movement phenotype, chorea, dystonia, catatonia, and stereotypical movements are now described. The stereotypical movements can be bizarre and include cycling movements and compulsive self-injurious behavior. Autoimmune basal ganglia encephalitis is an inflammatory encephalitis localizing to the basal ganglia that is sometimes associated with serum antibodies against dopamine-2 receptor. Although psychiatric features are common, the dominant problem is a movement disorder, with dystonia-parkinsonism being characteristic. Sydenham chorea is the prototypic poststreptococcal autoimmune neuropsychiatric disorder and several autoantibodies may be involved in disease generation. The syndrome is characterized by a pure chorea, although hypotonia, dysarthria, and emotional lability are common. Progressive encephalomyelitis with rigidity and myoclonus is a rare autoimmune disorder causing rigidity, stimulus sensitive spasms, and myoclonus of nonepileptic origin and is associated with autoantibodies of multiple types including those against the glycine receptor. These disorders are important to recognize and diagnose, as immune therapy can shorten disease duration and improve outcome.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Wiley
Date: 03-10-2017
DOI: 10.1111/DMCN.13579
Abstract: To determine the validity of the proposed clinical diagnostic criteria for anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis in paediatric patients. The diagnostic criteria for anti-NMDAR encephalitis proposed by Graus et al. (2016) use clinical features and conventional investigations to facilitate early immunotherapy before antibody status is available. The criteria are satisfied if patients develop four out of six symptom groups within 3 months, together with at least one abnormal investigation (electroencephalography/cerebrospinal fluid) and reasonable exclusion of other disorders. We evaluated the validity of the criteria using a retrospective cohort of paediatric patients with encephalitis. Twenty-nine patients with anti-NMDAR encephalitis and 74 comparison children with encephalitis were included. As expected, the percentage of patients with anti-NMDAR encephalitis who fulfilled the clinical criteria increased over time. During the hospital inpatient admission, most patients (26/29, 90%) with anti-NMDAR encephalitis fulfilled the criteria, significantly more than the comparison group (3/74, 4%) (p<0.001). The median time of fulfilling the criteria in patients with anti-NMDAR encephalitis was 2 weeks from first symptom onset (range 1-6). The sensitivity of the criteria was 90% (95% confidence interval 73-98) and the specificity was 96% (95% confidence interval 89-99). The proposed diagnostic criteria for anti-NMDAR encephalitis have good sensitivity and specificity. Incomplete criteria do not exclude the diagnosis. The proposed clinical diagnostic criteria for anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis by Graus et al. (2016) have high sensitivity and specificity in paediatric patients. The median time of fulfilling the criteria in patients with anti-NMDAR was 2 weeks from first symptom onset.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Wiley
Date: 04-01-2022
DOI: 10.1002/MDS.28915
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1229
Publisher: Springer Science and Business Media LLC
Date: 21-01-2021
DOI: 10.1038/S41398-021-01198-W
Abstract: Inflammation is increasingly recognized as a cause or consequence of common problems of humanity including obesity, stress, depression, pollution and disease states such as autoimmunity, asthma, and infection. Maternal immune activation (MIA), triggered by both acute and systemic chronic inflammation, is hypothesized to be one of the mechanisms implicated in the pathogenesis of neurodevelopmental disorders (NDD). Although there is substantial preclinical evidence to support the MIA hypothesis, the human evidence is disparate. We performed a systematic review on human studies examining associations between maternal inflammatory states and offspring NDDs (autism spectrum disorder- ASD, attention deficit hyperactivity disorder-ADHD, Tourette syndrome-TS). 32 meta-analyses and 26 additional in idual studies were identified. Maternal states associated with ASD include obesity, gestational diabetes mellitus, pre-ecl sia, pollution, stress, depression, autoimmune diseases, and infection. Maternal states associated with ADHD include obesity, pre-ecl sia, smoking, low socioeconomic status (SES), stress, autoimmune disease, and asthma. Maternal states associated with TS include low SES, depression, and autoimmune diseases. Diverse maternal inflammatory states in pregnancy are associated with common offspring NDDs. Given the increased prevalence of NDDs, there is urgent need to explore relative and cumulative maternal risk factors and disease mechanisms. Defining preventable risk factors in high-risk pregnancies could mitigate the expression and severity of NDDs.
Publisher: Oxford University Press (OUP)
Date: 2020
DOI: 10.1093/BRAINCOMMS/FCAA178
Abstract: Bilateral basal ganglia abnormalities on MRI are observed in a wide variety of childhood disorders. MRI pattern recognition can enable rationalization of investigations and also complement clinical and molecular findings, particularly confirming genomic findings and also enabling new gene discovery. A pattern recognition approach in children with bilateral basal ganglia abnormalities on brain MRI was undertaken in this international multicentre cohort study. Three hundred and five MRI scans belonging to 201 children with 34 different disorders were rated using a standard radiological scoring proforma. In addition, literature review on MRI patterns was undertaken in these 34 disorders and 59 additional disorders reported with bilateral basal ganglia MRI abnormalities. Cluster analysis on first MRI findings from the study cohort grouped them into four clusters: Cluster 1—T2-weighted hyperintensities in the putamen Cluster 2—T2-weighted hyperintensities or increased MRI susceptibility in the globus pallidus Cluster 3—T2-weighted hyperintensities in the globus pallidus, brainstem and cerebellum with diffusion restriction Cluster 4—T1-weighted hyperintensities in the basal ganglia. The 34 diagnostic categories included in this study showed dominant clustering in one of the above four clusters. Inflammatory disorders grouped together in Cluster 1. Mitochondrial and other neurometabolic disorders were distributed across clusters 1, 2 and 3, according to lesions dominantly affecting the striatum (Cluster 1: glutaric aciduria type 1, propionic acidaemia, 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome and thiamine responsive basal ganglia disease associated with SLC19A3), pallidum (Cluster 2: methylmalonic acidaemia, Kearns Sayre syndrome, pyruvate dehydrogenase complex deficiency and succinic semialdehyde dehydrogenase deficiency) or pallidum, brainstem and cerebellum (Cluster 3: vigabatrin toxicity, Krabbe disease). The Cluster 4 pattern was exemplified by distinct T1-weighted hyperintensities in the basal ganglia and other brain regions in genetically determined hypermanganesemia due to SLC39A14 and SLC30A10. Within the clusters, distinctive basal ganglia MRI patterns were noted in acquired disorders such as cerebral palsy due to hypoxic ischaemic encephalopathy in full-term babies, kernicterus and vigabatrin toxicity and in rare genetic disorders such as 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome, thiamine responsive basal ganglia disease, pantothenate kinase-associated neurodegeneration, TUBB4A and hypermanganesemia. Integrated findings from the study cohort and literature review were used to propose a diagnostic algorithm to approach bilateral basal ganglia abnormalities on MRI. After integrating clinical summaries and MRI findings from the literature review, we developed a prototypic decision-making electronic tool to be tested using further cohorts and clinical practice.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.EJPN.2017.11.010
Abstract: Immune mediated movement disorders include movement disorders in the context of autoimmune encephalitis such as anti-NMDAR encephalitis, post-infectious autoimmune movement disorders such as Sydenham chorea, paraneoplastic autoimmune movement disorders such as opsoclonus myoclonus ataxia syndrome, and infection triggered conditions such as paediatric acute neuropsychiatric syndrome. This review focuses on the approach to treatment of immune mediated movement disorders, which requires an understanding of the immunopathogenesis, whether the disease is destructive or 'altering', and the natural history of disease. Factors that can influence outcome include the severity of disease, the delay before starting therapy, use of multimodal therapy and whether the course is monophasic or relapsing. Although the four main conditions listed above have different pathophysiological processes, there are general themes that broadly apply including: early diagnosis and treatment is better, minimise the severity of disease, escalate treatment if the patient is not responding to initial treatments, and minimise relapse.
Publisher: BMJ
Date: 04-2022
DOI: 10.1136/BMJOPEN-2021-052578
Abstract: To define the prevalence and seizure subtypes among children with cerebral palsy (CP) in rural Bangladesh and explore barriers to optimum epilepsy control. Prospective cohort study. The study was conducted in Shahjadpur, a rural subdistrict of Bangladesh. Children ( years) with CP and epilepsy identified using the Bangladesh CP Register (BCPR) in the study site. Assessments were conducted in three focused epilepsy clinics overseen by a paediatric neurologist between December 2016 and January 2018, with intervening phone and video-conference follow-ups. Details of event type, frequency and medication compliance were collected. Antiepileptic drugs (AEDs) were prescribed based on seizure type, family income, comorbidity and medication availability. 23.4% (170/726) of the BCPR cohort had a clinical diagnosis of epilepsy of whom 166 were assessed. Following the focused epilepsy clinics, 62.0% (103/166) children were clinically determined to have ongoing epileptic seizures. 62.1% (64/103) had generalised onset tonic clonic seizures, 27.2% (28/103) had focal onset seizures with impaired awareness and 10.7% (11/103) had other seizure types. None of the children with prolonged seizures (31/103) had an emergency seizure management plan. Non-epileptic events were being pharmacologically treated as seizures in 18.1% (30/166) children. Financial constraints were the main reason for non-compliance on follow-up. Gaps in optimum epilepsy management in rural Bangladesh are amenable to improvement anchored with local healthcare workers. Training and clinical care focused on recognition of common seizure types, seizure mimics and rationalising use of available AEDs can be facilitated by better referral pathways and telehealth support.
Publisher: Springer Science and Business Media LLC
Date: 19-12-2017
DOI: 10.1038/NG.3740
Abstract: Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated in iduals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected in iduals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.BRAINDEV.2019.07.007
Abstract: Acute necrotizing encephalopathy (ANE) is a rare form of acute encephalopathy, predominantly occurring in childhood, which has a typical radiological phenotype including bilateral, symmetrical, diffusion-restricted lesions of the thalami posterior putamen cerebellum and brainstem. To date, no study has systematically examined the long-term cognitive and psychological impact of ANE. The current study describes the neuropsychological outcomes of three paediatric cases of ANE, ranging from 18 months to 10 years post ANE. All three cases displayed inattention, fine motor difficulties and anxiety. Social difficulties were also reported in all cases. The severity of long-term impairment was associated with acute presentation, as well as convalescent neuroimaging. These findings highlight the need for detailed neuropsychological assessment and long-term rehabilitation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-03-2017
DOI: 10.1212/NXG.0000000000000143
Abstract: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1 -related disease. We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. Patients first presented in early childhood (median age of presentation 10 months, range 0–48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.
Publisher: American Medical Association (AMA)
Date: 03-2016
DOI: 10.1001/JAMANEUROL.2015.4388
Abstract: 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. To further characterize EV71-related neurological disease and neurological outcome in children. 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. Clinical, neuroimaging, laboratory, and pathological characteristics, together with treatment administered and functional motor outcomes, were assessed. 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 < .001). 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.
Location: India
No related grants have been discovered for Shekeeb Mohammad.