Movement disorders associated with pediatric encephalitis.

New onset movement disorders are a common clinical problem in pediatric neurology and can be infectious, inflammatory, metabolic, or functional in origin. Encephalitis is one of the more important causes of new onset movement disorders, and movement disorders are a common feature (~25%) of all encephalitis. However, all encephalitides are not the same, and movement disorders are a key diagnostic feature that can help the clinician identify the etiology of the encephalitis, and therefore appropriate treatment is required. Movement disorders are a characteristic feature of autoimmune encephalitis such as anti-NMDAR encephalitis, herpes simplex virus encephalitis-induced autoimmune encephalitis, and basal ganglia encephalitis. Other rarer autoantibody-associated encephalitis syndromes with movement disorder associations include encephalitis associated with glycine receptor, DPPX, and neurexin-3 alpha autoantibodies. In addition, movement disorders can accompany acute disseminated encephalomyelitis with and without myelin oligodendrocyte glycoprotein antibodies. Extremely important infectious encephalitides that have characteristic movement disorder associations include Japanese encephalitis, dengue fever, West Nile virus, subacute sclerosing panencephalitis (SSPE), and SARS-CoV-2 (COVID-19). This chapter discusses how specific movement disorder phenomenology can aid clinician diagnostic suspicion, such as stereotypy, perseveration, and catatonia in anti-NMDAR encephalitis, dystonia-Parkinsonism in basal ganglia encephalitis, and myoclonus in SSPE. In addition, the chapter discusses how the age of the patients can influence the movement disorder phenomenology, such as in anti-NMDAR encephalitis where chorea is typical in young children, even though catatonia and akinesia is more common in adolescents and adults.

Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations.

This study aimed to determine the diagnostic yield of singleton exome sequencing and subsequent research-based trio exome analysis in children with a spectrum of brain malformations seen commonly in clinical practice. We recruited children ≤ 18 years old with a brain malformation diagnosed by magnetic resonance imaging and consistent with an established list of known genetic causes. Patients were ascertained nationally from eight tertiary paediatric centres as part of the Australian Genomics Brain Malformation Flagship. Chromosome microarray was required for all children, and those with pathogenic copy number changes were excluded. Cytomegalovirus polymerase chain reaction on neonatal blood spots was performed on all children with polymicrogyria with positive patients excluded. Singleton exome sequencing was performed through a diagnostic laboratory and analysed using a clinical exome sequencing pipeline. Undiagnosed patients were followed up in a research setting, including reanalysis of the singleton exome data and subsequent trio exome sequencing. A total of 102 children were recruited. Ten malformation subtypes were identified with the commonest being polymicrogyria (36%), pontocerebellar hypoplasia (14%), periventricular nodular heterotopia (11%), tubulinopathy (10%), lissencephaly (10%) and cortical dysplasia (9%). The overall diagnostic yield for the clinical singleton exome sequencing was 36%, which increased to 43% after research follow-up. The main source of increased diagnostic yield was the reanalysis of the singleton exome data to include newly discovered gene-disease associations. One additional diagnosis was made by trio exome sequencing. The highest phenotype-based diagnostic yields were for cobblestone malformation, tubulinopathy and lissencephaly and the lowest for cortical dysplasia and polymicrogyria. Pathogenic variants were identified in 32 genes, with variants in 6/32 genes occurring in more than one patient. The most frequent genetic diagnosis was pathogenic variants in TUBA1A. This study shows that over 40% of patients with common brain malformations have a genetic aetiology identified by exome sequencing. Periodic reanalysis of exome data to include newly identified genes was of greater value in increasing diagnostic yield than the expansion to trio exome. This study highlights the genetic and phenotypic heterogeneity of brain malformations, the importance of a multidisciplinary approach to diagnosis and the large number of patients that remain without a genetic diagnosis despite clinical exome sequencing and research reanalysis.

DHDDS and NUS1: A Converging Pathway and Common Phenotype.

BACKGROUND: Variants in dehydrodolichol diphosphate synthetase (DHDDS) and nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) cause a neurodevelopmental disorder, classically with prominent epilepsy. Recent reports suggest a complex movement disorder and an overlapping phenotype has been postulated due to their combined role in dolichol synthesis. CASES: We describe three patients with heterozygous variants in DHDDS and five with variants affecting NUS1. They bear a remarkably similar phenotype of a movement disorder dominated by multifocal myoclonus. Diagnostic clues include myoclonus exacerbated by action and facial involvement, and slowly progressive or stable, gait ataxia with disproportionately impaired tandem gait. Myoclonus is confirmed with neurophysiology, including EMG of facial muscles. LITERATURE REVIEW: Ninety-eight reports of heterozygous variants in DHDDS, NUS1 and chromosome 6q22.1 structural alterations spanning NUS1, confirm the convergent phenotype of hypotonia at birth, developmental delay, multifocal myoclonus, ataxia, dystonia and later parkinsonism with or without generalized epilepsy. Other features include periodic exacerbations, stereotypies, anxiety, and dysmorphisms. Although their gene products contribute to dolichol biosynthesis, a key step in N-glycosylation, transferrin isoform profiles are typically normal. Imaging is normal or non-specific. CONCLUSIONS: Recognition of their shared phenotype may expedite diagnosis through chromosomal microarray and by including DHDDS/NUS1 in movement disorder gene panels.

The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders.

BACKGROUND AND OBJECTIVE: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Postinfectious Acute Cerebellar Syndromes in Children: A Nationally Ascertained Case Series From Australia 2013-2018.

INTRODUCTION: 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. METHOD: 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. RESULTS: 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. DISCUSSION: 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.

SPG11 presenting with dystonic tremor in childhood.

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.

Improving epilepsy control among children with cerebral palsy in rural Bangladesh: a prospective cohort-based study.

OBJECTIVE: To define the prevalence and seizure subtypes among children with cerebral palsy (CP) in rural Bangladesh and explore barriers to optimum epilepsy control. DESIGN: Prospective cohort study. SETTING: The study was conducted in Shahjadpur, a rural subdistrict of Bangladesh. PARTICIPANTS: Children (<18 years) with CP and epilepsy identified using the Bangladesh CP Register (BCPR) in the study site. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Efficacy of Caffeine in ADCY5-Related Dyskinesia: A Retrospective Study.

BACKGROUND: 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. OBJECTIVE: The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Rapid onset functional tic-like behaviours in children and adolescents during COVID-19: Clinical features, assessment and biopsychosocial treatment approach.

AIM: To report the prevalence and clinical characteristics of children with rapid onset functional tic-like behaviours during the COVID-19 pandemic. METHODS: Single centre, retrospective cohort study of children (<18 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). RESULTS: 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. CONCLUSIONS: 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.

Possible EIF2AK2-Associated Stress-Related Neurological Decompensation with Combined Dystonia and Striatal Lesions.

BACKGROUND: 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. CASE: 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. LITERATURE REVIEW: Disease-causing variants in EIF2AK2 have been reported in 24 individuals 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. CONCLUSIONS: 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.

A case of QARS1 associated epileptic encephalopathy and review of epilepsy in aminoacyl-tRNA synthetase disorders.

INTRODUCTION: 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. CASE REPORT: 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 tRNAGln aminoacylation with the c.1574G > A variant. CONCLUSION: 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.

Autosomal dominant ADAR c.3019G>A (p.(G1007R)) variant is an important mimic of hereditary spastic paraplegia and cerebral palsy.

BACKGROUND: 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). CASE SUMMARIES: 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. CONCLUSION: 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.

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

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.

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

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.