Publications by authors named "Russell C Dale"

244 Publications

Prevalence of autoimmune conditions in pregnant women in a tertiary maternity hospital: A cross-sectional survey and maternity database review.

Obstet Med 2021 Sep 3;14(3):158-163. Epub 2020 Nov 3.

Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.

Background: Autoimmune conditions are associated with adverse pregnancy and offspring outcomes; however, the prevalence in pregnant women is not well understood. Estimates based on administrative data alone may underestimate prevalence.

Methods: A cross-sectional survey of women attending a tertiary referral hospital for antenatal care in December 2018-February 2019 and review of the hospital's maternity database of women giving birth from October 2017-June 2018 to estimate autoimmune disease prevalence.

Results: A total of 400 women completed surveys (78% response rate) and 41 (10.3%) reported an autoimmune disease, most commonly Hashimoto's thyroiditis (2.8%) and psoriasis (2.5%). From the maternity database, 112 of 2756 women giving birth (4.1%) had a recorded autoimmune disease, most commonly Hashimoto's thyroiditis (1.3%) followed by coeliac disease, Graves' disease, and immune thrombocytopenic purpura (all 0.4%).

Conclusion: Autoimmune disease prevalence in pregnant women is higher when self-reported and may be more common than previously reported using administrative data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1753495X20964680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504298PMC
September 2021

Complement Activation Is a Prominent Feature of MOGAD.

Ann Neurol 2021 Sep 27. Epub 2021 Sep 27.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.

Myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated diseases (MOGADs) account for a substantial proportion of pediatric and adult patients who present with acquired demyelinating disorders. Its pathogenesis and optimal therapy are incompletely understood. We profiled systemic complement activation in adult and pediatric patients with MOGAD compared with patients with relapse-onset multiple sclerosis, patients with neuromyelitis optica spectrum disorder, and pediatric control and adult healthy donors. Proteins indicative of systemic classical and alternative complement activation were substantially increased in patients with MOGAD compared to control groups. Elevated levels were detected in both adult and pediatric cases and across all clinical syndromes. Complement inhibition should be explored for its therapeutic merit in patients with MOGAD. ANN NEUROL 2021.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.26226DOI Listing
September 2021

MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis.

Front Neurol 2021 9;12:722237. Epub 2021 Sep 9.

Menzies Health Institute Queensland, Gold Coast, Griffith University, Southport, QLD, Australia.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2021.722237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458658PMC
September 2021

Emerging evidence of Toll-like receptors as a putative pathway linking maternal inflammation and neurodevelopmental disorders in human offspring: A systematic review.

Brain Behav Immun 2021 Sep 22;99:91-105. Epub 2021 Sep 22.

Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; The Brain and Mind Centre, The University of Sydney, Sydney, Australia. Electronic address:

Inflammation is increasingly recognised to play a major role in gene-environment interactions in neurodevelopmental disorders (NDDs). The effects of aberrant immune responses to environmental stimuli in the mother and in the child can affect neuroimmune signalling that is central to brain development. Toll-like receptors (TLR) are the best known innate immune pattern and danger recognition sensors to various environmental threats. In animal models, maternal immune activation (MIA), secondary to inflammatory factors including maternal gestational infection, obesity, diabetes, and stress activate the TLR pathway in maternal blood, placenta, and fetal brain, which correlate with offspring neurobehavioral abnormalities. Given the central role of TLR activation in animal MIA models, we systematically reviewed the human evidence for TLR activation and response to stimulation across the maternal-fetal interface. Firstly, we included 59 TLR studies performed in peripheral blood of adults in general population (outside of pregnancy) with six chronic inflammatory factors which have epidemiological evidence for increased risk of offspring NDDs, namely, obesity, diabetes mellitus, depression, low socio-economic status, autoimmune diseases, and asthma. Secondly, eight TLR studies done in human pregnancies with chronic inflammatory factors, involving maternal blood, placenta, and cord blood, were reviewed. Lastly, ten TLR studies performed in peripheral blood of individuals with NDDs were included. Despite these studies, there were no studies which examined TLR function in both the pregnant mother and their offspring. Increased TLR2 and TLR4 mRNA and/or protein levels in peripheral blood were common in obesity, diabetes mellitus, depression, autoimmune thyroid disease, and rheumatoid arthritis. To a lesser degree, TLR 3, 7, 8, and 9 activation were found in peripheral blood of humans with autoimmune diseases and depression. In pregnancy, increased TLR4 mRNA levels were found in the peripheral blood of women with diabetes mellitus and systemic lupus erythematosus. Placental TLR activation was found in mothers with obesity or diabetes. Postnatally, dysregulated TLR response to stimulation was found in peripheral blood of individuals with NDDs. This systematic review found emerging evidence that TLR activation may represent a mechanistic link between maternal inflammation and offspring NDD, however the literature is incomplete and longitudinal outcome studies are lacking. Identification of pathogenic mechanisms in MIA could create preventive and therapeutic opportunities to mitigate NDD prevalence and severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2021.09.009DOI Listing
September 2021

Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor Antibody Encephalitis: A Meta-analysis.

JAMA Neurol 2021 Sep 20. Epub 2021 Sep 20.

Children's National Medical Center, Washington, DC.

Importance: Overall, immunotherapy has been shown to improve outcomes and reduce relapses in individuals with N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis (NMDARE); however, the superiority of specific treatments and combinations remains unclear.

Objective: To map the use and safety of immunotherapies in individuals with NMDARE, identify early predictors of poor functional outcome and relapse, evaluate changes in immunotherapy use and disease outcome over the 14 years since first reports of NMDARE, and assess the Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score.

Data Sources: Systematic search in PubMed from inception to January 1, 2019.

Study Selection: Published articles including patients with NMDARE with positive NMDAR antibodies and available individual immunotherapy data.

Data Extraction And Synthesis: Individual patient data on immunotherapies, clinical characteristics at presentation, disease course, and final functional outcome (modified Rankin Scale [mRS] score) were entered into multivariable logistic regression models.

Main Outcomes And Measures: The planned study outcomes were functional outcome at 12 months from disease onset (good, mRS score of 0 to 2; poor, mRS score greater than 2) and monophasic course (absence of relapse at 24 months or later from onset).

Results: Data from 1550 patients from 652 articles were evaluated. Of these, 1105 of 1508 (73.3%) were female and 707 of 1526 (46.3%) were 18 years or younger at disease onset. Factors at first event that were significantly associated with good functional outcome included adolescent age and first-line treatment with therapeutic apheresis, corticosteroids plus intravenous immunoglobulin (IVIG), or corticosteroids plus IVIG plus therapeutic apheresis. Factors significantly associated with poor functional outcome were age younger than 2 years or age of 65 years or older at onset, intensive care unit admission, extreme delta brush pattern on electroencephalography, lack of immunotherapy within the first 30 days of onset, and maintenance IVIG use for 6 months or more. Factors significantly associated with nonrelapsing disease were rituximab use or maintenance IVIG use for 6 months or more. Adolescent age at onset was significantly associated with relapsing disease. Rituximab use increased from 13.5% (52 of 384; 2007 to 2013) to 28.3% (311 of 1100; 2013 to 2019) (P < .001), concurrent with a falling relapse rate over the same period (22% [12 of 55] in 2008 and earlier; 10.9% [35 of 322] in 2017 and later; P = .006). Modified NEOS score (including 4 of 5 original NEOS items) was associated with probability of poor functional status at 1 year (20.1% [40 of 199] for a score of 0 to 1 points; 43.8% [77 of 176] for a score of 3 to 4 points; P = .05).

Conclusions And Relevance: Factors influencing functional outcomes and relapse are different and need to be considered independently in development of evidence-based optimal management guidelines of patients with NMDARE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2021.3188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453367PMC
September 2021

Clinical decision making in MOG antibody-associated disease.

Lancet Neurol 2021 09;20(9):695-697

Neuroimmunology Group, Kids Neuroscience Centre, Children's Hospital at Westmead, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Department of Neurology, Concord Hospital, Sydney, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(21)00247-7DOI Listing
September 2021

Cerebrospinal fluid neopterin as a biomarker of treatment response to Janus kinase inhibition in Aicardi-Goutières syndrome.

Dev Med Child Neurol 2021 Aug 20. Epub 2021 Aug 20.

Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.

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 sampling (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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dmcn.15025DOI Listing
August 2021

Cerebrospinal fluid metabolomics: detection of neuroinflammation in human central nervous system disease.

Clin Transl Immunology 2021 6;10(8):e1318. Epub 2021 Aug 6.

Centre for Forensic Science University of Technology Sydney Sydney NSW Australia.

The high morbidity and mortality of neuroinflammatory diseases drives significant interest in understanding the underlying mechanisms involved in the innate and adaptive immune response of the central nervous system (CNS). Diagnostic biomarkers are important to define treatable neuroinflammation. Metabolomics is a rapidly evolving research area offering novel insights into metabolic pathways, and elucidation of reliable metabolites as biomarkers for diseases. This review focuses on the emerging literature regarding the detection of neuroinflammation using cerebrospinal fluid (CSF) metabolomics in human cohort studies. Studies of classic neuroinflammatory disorders such as encephalitis, CNS infection and multiple sclerosis confirm the utility of CSF metabolomics. Additionally, studies in neurodegeneration and neuropsychiatry support the emerging potential of CSF metabolomics to detect neuroinflammation in common CNS diseases such as Alzheimer's disease and depression. We demonstrate metabolites in the tryptophan-kynurenine pathway, nitric oxide pathway, neopterin and major lipid species show moderately consistent ability to differentiate patients with neuroinflammation from controls. Integration of CSF metabolomics into clinical practice is warranted to improve recognition and treatment of neuroinflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cti2.1318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343457PMC
August 2021

Leucine-Rich Glioma-Inactivated 1 versus Contactin-Associated Protein-like 2 Antibody Neuropathic Pain: Clinical and Biological Comparisons.

Ann Neurol 2021 Oct 30;90(4):683-690. Epub 2021 Aug 30.

Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.

Pain is a under-recognized association of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2- versus 20 of 108 (19%) with LGI1 antibodies (p = 0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy (p = 0.008), often rapidly, with greater residual patient-rated impairment observed in CASPR2 antibody patients (p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683-690.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.26189DOI Listing
October 2021

Maternal immune activation and neuroinflammation in human neurodevelopmental disorders.

Nat Rev Neurol 2021 Sep 2;17(9):564-579. Epub 2021 Aug 2.

Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.

Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring. The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs). Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring. In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene-environment interface during NDD pathogenesis. For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways. In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome. We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic 'priming' of offspring microglia and postnatal immune-brain crosstalk. The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41582-021-00530-8DOI Listing
September 2021

Pathogenesis of autoimmune demyelination: from multiple sclerosis to neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody-associated disease.

Clin Transl Immunology 2021 26;10(7):e1316. Epub 2021 Jul 26.

Brain Autoimmunity Group Kids Neuroscience Centre Kids Research at the Children's Hospital at Westmead Sydney NSW Australia.

Autoimmunity plays a significant role in the pathogenesis of demyelination. Multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are now recognised as separate disease entities under the amalgam of human central nervous system demyelinating disorders. While these disorders share inherent similarities, investigations into their distinct clinical presentations and lesion pathologies have aided in differential diagnoses and understanding of disease pathogenesis. An interplay of various genetic and environmental factors contributes to each disease, many of which implicate an autoimmune response. The pivotal role of the adaptive immune system has been highlighted by the diagnostic autoantibodies in NMOSD and MOGAD, and the presence of autoreactive lymphocytes in MS lesions. While a number of autoantigens have been proposed in MS, recent emphasis on the contribution of B cells has shed new light on the well-established understanding of T cell involvement in pathogenesis. This review aims to synthesise the clinical characteristics and pathological findings, discuss existing and emerging hypotheses regarding the aetiology of demyelination and evaluate recent pathogenicity studies involving T cells, B cells, and autoantibodies and their implications in human demyelination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cti2.1316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312887PMC
July 2021

TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila.

Am J Hum Genet 2021 09 26;108(9):1669-1691. Epub 2021 Jul 26.

Phoenix Children's Hospital, Phoenix, AZ 85016, USA; Department of Child Health, University of Arizona College of Medicine Phoenix, Phoenix, AZ 85004, USA.

Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2021.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456166PMC
September 2021

International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis.

Neurol Neuroimmunol Neuroinflamm 2021 07 22;8(5). Epub 2021 Jul 22.

From the Paediatric Neurology and Neurophysiology Unit (M.N.), Department of Women's and Children's Health, University Hospital of Padova; Neuroimmunology Group (M.N.), Paediatric Research Institute "Città della Speranza," Padova, Italy; Department of Paediatrics (T.T.), Neurology Service, KK Women's and Children's Hospital, Singapore; School of Biomedical Engineering & Imaging Sciences (M.E.), King's College London; Children's Neurosciences (M.E.), Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, United Kingdom; Department of Pediatric Neurology (B.A.), Hacettepe University, Ankara, Turkey; Neuroimmunology Program (T.A.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona; Pediatric Neuroimmunology Unit (T.A.), Neurology Department, Sant Joan de Déu (SJD) Children's Hospital, University of Barcelona, Spain; Alberta Children's Hospital Research Institute (S.M.B.), Department of Pediatrics, Cumming School of Medicine, University of Calgary; Division of Rheumatology (T.C.), Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; Assistance Publique-Hôpitaux de Paris (K.D.), Pediatric Neurology Department, University Hospitals Paris Saclay, Bicêtre Hospital, France; French Reference Network of Rare Inflammatory Brain and Spinal Diseases (K.D.), Le Kremlin Bicêtre, France and European Reference Network-RITA; Departments of Neurology and Pediatrics (W.G.), Stanford University and Lucile Packard Children's Hospital, Palo Alto, CA; Division of Pediatric Neurology (G.G.), Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA; Department of Neurology (M.P.G.), Boston Children's Hospital, Harvard Medical School, Boston, MA; Department of Neuroinflammation (Y.H.), Queen Square MS Centre, UCL Institute of Neurology, University College London; Department of Paediatric Neurology (Y.H.), Great Ormond Street Hospital for Children, London, United Kingdom; Department of Pediatrics (Y.J.), Peking University First Hospital, Beijing, China; Department of Pediatrics (B.C.L.), Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, South Korea; Department of Pediatrics (E.M.), Section Rheumatology, Co-appointment in the Section of Neurology and Developmental Neuroscience, Texas Children's Hospital, Baylor College of Medicine, Houston; Division of Paediatric Neurology (A.N.), Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town; Faculty of Health Sciences (A.N.), University of Cape Town Neuroscience Institute, South Africa; Department of Neurology (R.N.), Erasmus Medical Center, Rotterdam, the Netherlands; Department of Pediatric Neurology (K.R.), Children's Hospital Datteln, University Witten/Herdecke, Germany; Department of Brain and Neural Science (H.S.), Tokyo Metropolitan Institute of Medical Science, Japan; Department of Pediatrics (Neurology Division) (S.S.), Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India; Department of Neurology (S.N.T.), National Pediatric Hospital Dr. J. Garrahan, Buenos Aires, Argentina; Department of Pediatrics (H.A.V.M.), Duke University, Durham, NC; Department of Neurology (E.W.), Children's National Medical Center, Washington, DC; Neuropaediatric Unit (R.W.), Karolinska University Hospital, Stockholm, Sweden; Department of Neurology (A.K.Y.), Icahn School of Medicine at Mount Sinai, New York; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital; Department of Neurology (S.R.I.), Oxford University Hospitals NHS Foundation Trust, United Kingdom; Neuroimmunology Program (J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; Children's Neurosciences (M.L.), Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust; King's Health Partners Academic Health Science Centre (M.L.); Faculty of Life Sciences and Medicine (M.L.), King's College Hospital, United Kingdom; and Kids Neuroscience Centre (R.C.D.), The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Objective: To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE).

Methods: After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ≥75% agreement).

Results: Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3-12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided.

Conclusion: These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000001052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299516PMC
July 2021

Neuroinflammation triggered by SARS-CoV-2 infection: syndromes and therapies.

Lancet Child Adolesc Health 2021 09 15;5(9):607-609. Epub 2021 Jul 15.

Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2145, Australia; Department of Infectious Disease, Children's Hospital at Westmead, Sydney, NSW, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-4642(21)00199-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279958PMC
September 2021

Respiratory Syncytial Virus-Associated Neurologic Complications in Children: A Systematic Review and Aggregated Case Series.

J Pediatr 2021 Jun 25. Epub 2021 Jun 25.

University of Sydney, Sydney, Australia; The Children's Hospital at Westmead, Sydney, Australia.

Objectives: To describe the features and frequency of respiratory syncytial virus (RSV)-associated severe acute neurologic disease in children.

Study Design: We performed a systematic review of the literature to identify reports of severe acute neurologic complications associated with acute RSV infection in children aged <15 years (PROSPERO Registration CRD42019125722). Main outcomes included neurologic, clinical, and demographic features of cases and the frequency of disease. We aggregated available case data from the published literature and from the Australian Acute Childhood Encephalitis (ACE) study.

Results: We identified 87 unique studies from 26 countries describing a spectrum of RSV-associated severe acute neurologic syndromes including proven encephalitis, acute encephalopathy, complex seizures, hyponatremic seizures, and immune-mediated disorders. The frequency of RSV infection in acute childhood encephalitis/encephalopathy was 1.2%-6.5%. We aggregated data from 155 individual cases with RSV-associated severe acute neurologic complications; median age was 11.0 months (IQR 2.0-21.5), most were previously healthy (71/104, 68%). Seizure was the most frequently reported neurologic feature (127/150, 85%). RSV was detected in the central nervous system of 12 cases. Most children recovered (81/122, 66%); however, some reports described partial recovery (33/122, 27%) and death (8/122, 7%).

Conclusions: RSV-associated neurologic complications have been widely reported, but there is substantial heterogeneity in the design and quality of existing studies. The findings from our study have implications for the investigation, management, and prevention of RSV-associated neurologic complications. Further, this systematic review can inform the design of future studies aiming to quantify the burden of childhood RSV-associated neurologic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpeds.2021.06.045DOI Listing
June 2021

Opsoclonus-myoclonus in Aicardi-Goutières syndrome.

Dev Med Child Neurol 2021 Jun 21. Epub 2021 Jun 21.

Starship Paediatric Neurology, Auckland, New Zealand.

Aicardi-Goutières syndrome (AGS) is a rare genetic neuroinflammatory disorder caused by abnormal upregulation of type 1 interferon signalling. Opsoclonus-myoclonus syndrome is a rare autoimmune phenotype demonstrating a disturbance in the humoral immune response mostly seen in the context of paraneoplastic or postinfectious states, although its pathophysiology is incompletely understood. We report the first three children described with AGS demonstrating transient opsoclonus and myoclonus after irritability and/or developmental regression, suggesting a pathological association. We describe the presentation, clinical features, progress, cerebrospinal fluid (CSF) inflammatory markers, electroencephalogram (EEG), and magnetic resonance imaging (MRI) findings in these children. Two patients had developmental regression but demonstrated a positive response to JAK1/2 inhibition clinically and on serial examination of CSF inflammatory markers. These findings suggest that AGS should be considered in children presenting with opsoclonus-myoclonus, and that the association between AGS and opsoclonus-myoclonus further supports the role of immune dysregulation as causal in the rare neurological phenomenon opsoclonus and myoclonus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dmcn.14969DOI Listing
June 2021

Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.

Genet Med 2021 09 17;23(9):1705-1714. Epub 2021 Jun 17.

United for Metabolic Diseases (UMD), Amsterdam, The Netherlands.

Purpose: To investigate monoallelic CLPB variants. Pathogenic variants in many genes cause congenital neutropenia. While most patients exhibit isolated hematological involvement, biallelic CLPB variants underlie a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia. CLPB was recently shown to be a mitochondrial refoldase; however, the exact function remains elusive.

Methods: We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing.

Results: In each individual, we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner. Complexome profiling in fibroblasts showed CLPB at very high molecular mass comigrating with the prohibitins. In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1.

Conclusion: Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01194-xDOI Listing
September 2021

A description of novel variants and review of phenotypic spectrum in -related early epileptic encephalopathy.

Cold Spring Harb Mol Case Stud 2021 06 11;7(3). Epub 2021 Jun 11.

Department of Pediatrics, Division of Medical Genetics and Metabolism, and Center for Genomic Medicine, Massachusetts 02114, USA.

Early infantile epileptic encephalopathy-44 (EIEE44, MIM: 617132) is a previously described condition resulting from biallelic variants in , 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 All five children presented with global developmental delay, epilepsy, axial hypotonia, appendicular hypertonia, and a movement disorder, including dystonia in four. Affected individuals in all four families have compound heterozygous pathogenic variants in All have the recurrent mild c.1111G > A (p.Ala371Thr) variant in with a second 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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a005827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208045PMC
June 2021

Cerebrospinal fluid free light chain quantitation is a specific biomarker for inflammatory neurological disorders in a paediatric patient cohort.

Pathology 2021 Oct 19;53(6):753-758. Epub 2021 Mar 19.

Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Brain Autoimmunity Lab, Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, NSW, Australia; T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, NSW, Australia.

The analysis of cerebrospinal fluid (CSF) is routinely used in the diagnostic work-up of a range of inflammatory, infective, and congenital neurological conditions. Many diagnostic tests used in this analysis have poor sensitivity; as such, we investigated the utility of CSF free light chain (FLC) analysis as an adjunct to currently used assays in a paediatric population with neurological disorders. Kappa (κ) and lambda (λ) FLC levels were quantitated in blinded CSF samples by two nephelometric platforms. Results were correlated to clinical diagnoses and classified according to inflammatory/infective or non-inflammatory pathogenesis. FLC results were also compared to currently used CSF diagnostic tests including oligoclonal bands (OCB), CSF IgG and albumin levels, and differential cell count. Of 70 samples analysed, 29 (41%) had an inflammatory or infective diagnosis and 41 (59%) presented with a range of non-inflammatory aetiologies. Thirteen patients had elevated κFLC or λFLC as detected on the IMMAGE 800, defined as greater than the detection limit of the assay (0.600 mg/L for CSF κFLC, and 0.490 mg/L for CSF λFLC), and of these 12 (92%) had an inflammatory disease (sensitivity 41.4%, specificity 97.6%). On the BN II using optimal cut-offs of 0.27 mg/L and 0.12 mg/L for CSF κFLC and λFLC respectively, 24 (34%) patients had elevated results, of which 21 (88%) had an inflammatory disease (sensitivity 72.4%, specificity 92.7%). Analysis of FLC correlated better with diagnostic classification of the diseases than OCB, cell counts and CSF IgG levels. The results of this study support the use of CSF FLC analysis in the diagnosis of paediatric neuroinflammatory conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pathol.2020.11.011DOI Listing
October 2021

Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management.

J Neurol Neurosurg Psychiatry 2021 Jul 1;92(7):757-768. Epub 2021 Mar 1.

Neurology, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2020-325300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223680PMC
July 2021

Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management.

J Neurol Neurosurg Psychiatry 2021 Mar 1. Epub 2021 Mar 1.

Neurology, Erasmus Medical Center, Rotterdam, Zuid-Holland, Netherlands.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Most responders opted to cancer screening for 4 years in patients with neuronal surface antibodies (49%) or limbic encephalitis (46%) as opposed to non-limbic seronegative autoimmune encephalitis (36%). Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2020-325302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292591PMC
March 2021

Magnetic resonance imaging pattern recognition in childhood bilateral basal ganglia disorders.

Brain Commun 2020 26;2(2):fcaa178. Epub 2020 Oct 26.

Kids Neuroscience Centre, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.

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-T-weighted hyperintensities in the putamen; Cluster 2-T-weighted hyperintensities or increased MRI susceptibility in the globus pallidus; Cluster 3-T-weighted hyperintensities in the globus pallidus, brainstem and cerebellum with diffusion restriction; Cluster 4-T-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 (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 ), 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 T-weighted hyperintensities in the basal ganglia and other brain regions in genetically determined hypermanganesemia due to and . 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, 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/braincomms/fcaa178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891249PMC
October 2020

Gain-of-function variants identified in vigabatrin-hypersensitive epileptic encephalopathies.

Brain Commun 2020 1;2(2):fcaa162. Epub 2020 Oct 1.

Faculty of Medicine and Health, School of Pharmacy, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia.

Variants in the 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 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A 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 variants in (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the 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 variant. The mRNA of these constructs was injected into oocytes and activation properties of each receptor measured by two-electrode voltage clamp electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the 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 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 variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/braincomms/fcaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869430PMC
October 2020

Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review.

Transl Psychiatry 2021 01 21;11(1):71. Epub 2021 Jan 21.

Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

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 individual studies were identified. Maternal states associated with ASD include obesity, gestational diabetes mellitus, pre-eclampsia, pollution, stress, depression, autoimmune diseases, and infection. Maternal states associated with ADHD include obesity, pre-eclampsia, 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-021-01198-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820474PMC
January 2021

Association of Maternal Autoimmune Disease With Attention-Deficit/Hyperactivity Disorder in Children.

JAMA Pediatr 2021 Mar 1;175(3):e205487. Epub 2021 Mar 1.

Faculty of Medicine and Health, Children's Hospital Westmead Clinical School, University of Sydney, Sydney, Australia.

Importance: Maternal autoimmune disease has been associated with increased risk of neurodevelopmental disorders in offspring, but few studies have assessed the association with attention-deficit/hyperactivity disorder (ADHD).

Objective: To examine the association between maternal autoimmune disease and ADHD within a population-based cohort and combine results in a subsequent systematic review and meta-analysis.

Design, Setting, And Participants: A cohort study was conducted of singleton children born at term gestation (37-41 weeks) in New South Wales, Australia, from July 1, 2000, to December 31, 2010, and followed up until the end of 2014; and a systematic review evaluated articles from the MEDLINE, Embase, and Web of Science databases to identify all studies published before November 20, 2019. A total of 12 610 children exposed to maternal autoimmune disease were propensity score matched (1:4) to 50 440 unexposed children, for a total cohort of 63 050. A child was considered to have ADHD if they had (1) an authorization or filled prescription for stimulant treatment for ADHD or (2) a hospital diagnosis of ADHD. Children linked to a first ADHD event before 3 years of age were excluded. Data were analyzed from January 13 to April 20, 2020.

Exposures: One or more maternal autoimmune diagnoses in linked hospital admission records between July 1, 2000, and December 31, 2012. Thirty-five conditions were considered together and individually.

Main Outcomes And Measures: The main outcome was child ADHD identified from stimulant authorization or prescription data and diagnoses in linked hospital admission records. Multivariable Cox regression was used to assess the association between maternal autoimmune disease and ADHD adjusted for child sex. Pooled hazard ratios (HRs) were calculated using random-effects meta-analysis with inverse-variance weights for each exposure reported by 2 or more studies.

Results: In the population-based cohort analysis, 831 718 singleton, term infants born to 831 718 mothers (mean [SD] age, 29.8 [5.6] years) were assessed. Of 12 767 infants (1.5%) who were linked to a maternal autoimmune diagnosis, 12 610 were propensity score matched to 50 440 control infants, for a total study cohort of 63 050 infants. In this cohort, any autoimmune disease was associated with ADHD in offspring (HR, 1.30; 95% CI 1.15-1.46), as was type 1 diabetes (HR, 2.23; 95% CI, 1.66-3.00), psoriasis (HR, 1.66; 95% CI, 1.02-2.70), and rheumatic fever or rheumatic carditis (HR, 1.75; 95% CI, 1.06-2.89). Five studies (including the present study) were included in the meta-analysis. Any autoimmune disease (2 studies: HR, 1.20; 95% CI, 1.03-1.38), type 1 diabetes (4 studies: HR, 1.53; 95% CI, 1.27-1.85), hyperthyroidism (3 studies: HR, 1.15; 95% CI, 1.06-1.26), and psoriasis (2 studies: HR, 1.31; 95% CI, 1.10-1.56) were associated with ADHD.

Conclusions And Relevance: In this cohort study, maternal autoimmune diseases were associated with increased ADHD among children. These findings suggest possible shared genetic vulnerability between autoimmune disease and ADHD or a potential role for maternal immune activation in the expression of neurodevelopmental disorders in children. Future studies measuring disease activity, modifiers, and medication use are required to better understand the mechanisms underlying this association.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamapediatrics.2020.5487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816116PMC
March 2021

Pro-inflammatory dopamine-2 receptor-specific T cells in paediatric movement and psychiatric disorders.

Clin Transl Immunology 2020 17;9(12):e1229. Epub 2020 Dec 17.

Brain Autoimmunity Group Kids Neuroscience Centre Kids Research at the Children's Hospital at Westmead Sydney NSW Australia.

Objectives: A dysregulated inflammatory response against the dopamine-2 receptor (D2R) has been implicated in movement and psychiatric disorders. D2R antibodies were previously reported in a subset of these patients; however, the role of T cells in these disorders remains unknown. Our objective was to identify and characterise pro-inflammatory D2R-specific T cells in movement and psychiatric disorders.

Methods: Blood from paediatric patients with movement and psychiatric disorders of suspected autoimmune and neurodevelopmental aetiology ( = 24) and controls ( = 16) was cultured with a human D2R peptide library, and D2R-specific T cells were identified by flow cytometric quantification of CD4CD25CD134 T cells. Cytokine secretion was analysed using a cytometric bead array and ELISA. HLA genotypes were examined in D2R-specific T-cell-positive patients. D2R antibody seropositivity was determined using a flow cytometry live cell-based assay.

Results: Three immunodominant regions of D2R, amino acid (aa)121-131, aa171-181 and aa396-416, specifically activated CD4 T cells in 8/24 patients. Peptides corresponding to these regions were predicted to bind with high affinity to the HLA of the eight positive patients and had also elicited the secretion of pro-inflammatory cytokines IL-2, IFN- γ, TNF, IL-6, IL-17A and IL-17F. All eight patients were seronegative for D2R antibodies.

Conclusion: Autoreactive D2R-specific T cells and a pro-inflammatory Th1 and Th17 cytokine profile characterise a subset of paediatric patients with movement and psychiatric disorders, further underpinning the theory of immune dysregulation in these disorders. These findings offer new perspectives into the neuroinflammatory mechanisms of movement and psychiatric disorders and can influence patient diagnosis and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cti2.1229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780098PMC
December 2020

Maternal autoimmunity and inflammation are associated with childhood tics and obsessive-compulsive disorder: Transcriptomic data show common enriched innate immune pathways.

Brain Behav Immun 2021 05 8;94:308-317. Epub 2021 Jan 8.

Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia; The Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia. Electronic address:

Although genetic variation is a major risk factor of neurodevelopmental disorders, environmental factors during pregnancy and early life are also important in disease expression. Animal models demonstrate that maternal inflammation causes fetal neuroinflammation and neurodevelopmental deficits, and brain transcriptomics of neurodevelopmental disorders in humans show upregulated differentially expressed genes are enriched in immune pathways. We prospectively recruited 200 sequentially referred children with tic disorders/obsessive-compulsive disorder (OCD), 100 autoimmune neurological controls, and 100 age-matched healthy controls. A structured interview captured the maternal and family history of autoimmune disease and other pro-inflammatory states. Maternal blood and published Tourette brain transcriptomes were analysed for overlapping enriched pathways. Mothers of children with tics/OCD had a higher rate of autoimmune disease compared with mothers of children with autoimmune neurological conditions (p = 0.054), and mothers of healthy controls (p = 0.0004). Autoimmunity was similarly elevated in first- and second-degree maternal relatives of children with tics/OCD (p < 0.0001 and p = 0.014 respectively). Other pro-inflammatory states were also more common in mothers of children with tics/OCD than controls (p < 0.0001). Upregulated differentially expressed genes in maternal autoimmune disease and Tourette brain transcriptomes were commonly enriched in innate immune processes. Pro-inflammatory states, including autoimmune disease, are more common in the mothers and families of children with tics/OCD. Exploratory transcriptome analysis indicates innate immune signalling may link maternal inflammation and childhood tics/OCD. Targeting inflammation may represent preventative strategies in pregnancy and treatment opportunities for children with neurodevelopmental disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2020.12.035DOI Listing
May 2021

Cerebrospinal fluid metabolites in tryptophan-kynurenine and nitric oxide pathways: biomarkers for acute neuroinflammation.

Dev Med Child Neurol 2021 05 17;63(5):552-559. Epub 2020 Dec 17.

Centre for Forensic Science, University of Technology Sydney, Sydney, New South Wales, Australia.

Aim: To explore the cerebrospinal fluid (CSF) metabolite features in acute neuroinflammatory diseases and identify potential biomarkers to diagnose and monitor neuroinflammation.

Method: A cohort of 14 patients (five females, nine males; mean [median] age 7y 9mo [9y], range 6mo-13y) with acute encephalitis (acute disseminated encephalomyelitis n=6, unknown suspected viral encephalitis n=3, enteroviral encephalitis n=2, seronegative autoimmune encephalitis n=2, herpes simplex encephalitis n=1) and age-matched non-inflammatory neurological disease controls (n=14) were investigated using an untargeted metabolomics approach. CSF metabolites were analyzed with liquid chromatography coupled to high resolution mass spectrometry, followed by subsequent multivariate and univariate statistical methods.

Results: A total of 35 metabolites could be discriminated statistically between the groups using supervised orthogonal partial least squares discriminant analysis and analysis of variance. The tryptophan-kynurenine pathway contributed nine key metabolites. There was a statistical increase of kynurenine, quinolinic acid, and anthranilic acid in patients with encephalitis, whereas tryptophan, 3-hydroxyanthrnailic acid, and kynurenic acid were decreased. The nitric oxide pathway contributed four metabolites, with elevated asymmetric dimethylarginine and argininosuccinic acid, and decreased arginine and citrulline in patients with encephalitis. An increase in the CSF kynurenine/tryptophan ratio (p<0.001), anthranilic acid/3-hydroxyanthranilic acid ratio (p<0.001), asymmetric dimethylarginine/arginine ratio (p<0.001), and neopterin (p<0.001) strongly predicted neuroinflammation.

Interpretation: The combination of alterations in the tryptophan-kynurenine pathway, nitric oxide pathway, and neopterin represent a useful potential panel for neuroinflammation and holds potential for clinical translation practice.

What This Paper Adds: The kynurenine/tryptophan and anthranilic acid/3-hydroxyanthranilic acid ratios hold great potential as biomarkers of neuroinflammation. Elevation of the asymmetric dimethylarginine/arginine ratio in acute brain inflammation shows dysregulation of the nitric oxide pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dmcn.14774DOI Listing
May 2021
-->