Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation.

Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα.

GABRA1-Related Disorders: From Genetic to Functional Pathways.

OBJECTIVE: Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyze the electroclinical features and the functional effects of GABRA1 variants to establish genotype-phenotype correlations. METHODS: Genetic and electroclinical data of 27 individuals (22 unrelated and 2 families) harboring 20 different GABRA1 variants were collected and accompanied by functional analysis of 19 variants. RESULTS: Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile onset epilepsy (focal seizures, fever sensitivity, and electroencephalographic posterior epileptiform discharges) was described for variants in the extracellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects, and the patients generally had a favorable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF variants were associated with severe early onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy. INTERPRETATION: Our data expand the genetic and phenotypic spectrum of GABRA1 epilepsies and permit delineation of specific subphenotypes for LoF and GoF variants, through the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the pathomechanism and a precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. ANN NEUROL 2023.

TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant.

A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibers with striking nemaline rods and hypertrophy of slow fibers that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G > A, NM_006757.3:c.681+1G > A). TNNT3 encodes skeletal troponin-Tfast and is associated with autosomal dominant distal arthrogryposis. TNNT3 has not previously been associated with nemaline myopathy (NM), a rare congenital myopathy linked to defects in proteins associated with thin filament structure and regulation. cDNA studies confirmed pathogenic consequences of the splice variant, eliciting exon-skipping and intron retention events leading to a frameshift. Western blot showed deficiency of troponin-Tfast protein with secondary loss of troponin-Ifast . We establish a homozygous splice variant in TNNT3 as the likely cause of severe congenital NM with distal arthrogryposis, characterized by specific involvement of Type-2 fibers and deficiency of troponin-Tfast .

Eye movement disorders are an early manifestation of CACNA1A mutations in children.

AIM: The alpha-1 isoform of the calcium channel gene is expressed abundantly in neuronal tissue, especially within the cerebellum. Mutations in this gene may manifest with hemiplegic migraine, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) in adults. There are reports of children with CACAN1A mutations presenting with paroxysmal tonic upgaze, abnormal saccades and congenital nystagmus as well as severe forms of hemiplegic migraine. The aim of this study was to review the clinical presentation and subsequent course of all children with a CACNA1A mutation who presented to a tertiary children's hospital. METHOD: We reviewed retrospectively nine children with a proven CACNA1A mutation who presented to the Children's Hospital at Westmead between 2005-2015. The initial and subsequent clinical presentation, radiological features and molecular genetic profile of each child was reviewed. RESULTS: Nine children presented to out institute over a 10 year period; six were female and three male. The median age of presentation was 1.2 years. Eye movement disorders were the presenting feature in eight children. Three of these children later presented with severe hemiplegic migraine episodes often requiring ICU care. Affected children also had developmental delay and developed classical hemiplegic migraine, episodic ataxia and seizures. Calcium channel blockers were used with some efficacy in preventing severe HM episodes. INTERPRETATION: Eye movement disorders are an early manifestation of CACNA1A mutations in children. Improved recognition of the CACNA1A phenotype in childhood is important for early diagnosis, counselling and appropriate emergency management. There is some early evidence that calcium channel blockers may be an effective prophylactic agent for the severe hemiplegic migraine episodes.

A negative waveform in the scotopic response in a patient with phosphoglycerate kinase deficiency: a visual electrophysiology report.

PURPOSE: Phosphoglycerate kinase (PGK) deficiency is an X-linked neurometabolic genetic disorder with variable systemic manifestations. So far, only one patient with retinal anomalies has been reported, but no visual electrophysiology findings were described. We report the first description of visual electrophysiology in a child with PGK deficiency. This provides further information for the site of involvement in the eye. METHOD: A case history of a nine-year-old boy with PGK deficiency is reported. RESULTS: This patient was diagnosed with PGK deficiency by screening soon after birth, as his mother was a known carrier of a PGK gene mutation. A bone marrow transplant was performed at the age of 9 months. He had two episodes of encephalopathy following the transplant but no acute episode of haemolysis. From the age of 6 years, his vision has been deteriorating. Visual electrophysiology results identified retinal involvement involving both rod and cone dysfunction. The visual evoked potential was normal. CONCLUSIONS: Retinal dystrophy may be one of the clinical manifestations of phosphoglycerate kinase deficiency.

Mechanical Thrombectomy for Pediatric Arterial Ischemic Stroke from Acute M2 Occlusion.

Pediatric large-vessel occlusion has a poor natural history. Recent retrospective studies have demonstrated the potential benefits, feasibility, and safety profile of mechanical thrombectomy in children. However, the role of thrombectomy in pediatric M2 occlusions remains uncertain. In this clinical report, we present a multicenter series of 6 pediatric patients with acute M2 occlusion (female = 1, male = 5; age range, 0.9-16.0 years, mean = 9.2). All 6 patients having undergone thrombectomy had excellent clinical outcomes (pediatric mRS = 0-1) at 3 months and final available follow-up (median, 12 months; range, 3-72 months). Factors relevant to treatment decision-making in pediatric M2 occlusions are discussed, including the important role of multidisciplinary team discussions during acute management.

Echovirus 19 associated with a case of acute flaccid paralysis.

Acute flaccid paralysis can be caused by many members of the enterovirus genus, most notably the three poliviruses types 1 to 3. We report the case of acute flaccid paralysis caused by echovirus 19. The Western Pacific region has been declared polio free by the WHO since 2000. Australia is now using inactivated polio vaccine in the National Immunization Schedule. This vaccine does not carry the extremely rare risk of vaccine associated acute flaccid paralysis but it does leave our newly vaccinated population open gastrointestinal infection with polioviruses and the risk of circulation of the wild-type virus. Continued surveillance of cases of acute flaccid paralysis is to detect polioviruses is essential until poliovirus is completely eradicated.

Association Between Thrombectomy and Functional Outcomes in Pediatric Patients With Acute Ischemic Stroke From Large Vessel Occlusion.

Importance: Pediatric large vessel occlusion (LVO) stroke has a poor natural history. However, uptake of mechanical thrombectomy is hindered by a lack of clinical trial data in children. A randomized clinical trial is not feasible due to small sample sizes and absence of equipoise. Objective: To evaluate whether pediatric patients with acute LVO stroke who undergo thrombectomy have better clinical outcomes than matched patients managed conservatively. Design, Setting, and Participants: This matched case-control study used pooled stroke registry data from 5 tertiary referral hospitals in Australia and Canada from January 2011 to April 2022. Patients were aged 1 month to younger than 18 years with acute LVO stroke. Pooled data identified 31 thrombectomy patients and 46 control patients. Five patients undergoing thrombectomy with basilar artery occlusion were excluded due to insufficient controls. Using a hierarchal matching system (site of occlusion, age group, side of occlusion, and sex), deidentified consensus matching of patients and controls was undertaken while blinded to clinical outcome. Data were analyzed from July to November 2022. Exposure: In the case cohort, mechanical thrombectomy was undertaken for management of acute LVO stroke. The control cohort received medical treatment only. Main Outcomes and Measures: The primary outcome was the functional clinical status 3 months following stroke, measured by the pediatric modified Rankin Scale (mRS). Clinical outcomes were compared between groups using ordinal regression analysis. Results: Of 52 included patients, 31 (60%) were male, and the mean (SD) age was 10.3 (4.4) years. Matching was achieved for 26 children undergoing thrombectomy with 26 controls. There was no significant difference between groups for site or side of occlusion, age, sex, etiology, thrombolysis status, baseline Alberta Stroke Programme Early CT Score, or time since last seen well to presentation. Patients undergoing thrombectomy had superior clinical outcomes than control patients at 3 months on the pediatric mRS (odds ratio, 3.76; 95% CI, 1.32-10.67; P = .01). These superior outcomes were maintained at final follow-up (odds ratio, 3.65; 95% CI, 1.25-10.68; P = .02). Conclusions and Relevance: In the absence of a randomized clinical trial, this case-control study demonstrates better clinical outcomes with thrombectomy than medical management alone for pediatric patients aged 2 to 18 years with anterior circulation LVO stroke.

CSF neopterin and quinolinic acid are biomarkers of neuroinflammation and neurotoxicity in FIRES and other infection-triggered encephalopathy syndromes.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. INTERPRETATION: 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.

CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammation.

BACKGROUND: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy. METHODS: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1-17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32). FINDINGS: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p < 0.0003). As biomarkers, at thresholds with 95% specificity, CSF neopterin had the best sensitivity for defining neuroinflammation (82%, CI 73-89), then quinolinic acid (57%, CI 47-67), KYN/TRP ratio (47%, CI 36-56) and kynurenine (37%, CI 28-48). CSF pleocytosis had sensitivity of 53%, CI 42-64). The area under the receiver operating characteristic curve (ROC AUC) of CSF neopterin (94.4% CI 91.0-97.7%) was superior to that of CSF pleocytosis (84.9% CI 79.5-90.4%) (p = 0.005). CSF kynurenic acid/kynurenine ratio (KYNA/KYN) was statistically decreased in the epilepsy group compared to all control groups (all p ≤ 0.0003), which was evident in most epilepsy subgroups. INTERPRETATION: Here we show that CSF neopterin, kynurenine, quinolinic acid and KYN/TRP are useful diagnostic and monitoring biomarkers of neuroinflammation. These findings provide biological insights into the role of inflammatory metabolism in neurological disorders and provide diagnostic and therapeutic opportunities for improved management of neurological diseases. FUNDING: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, University of Sydney, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP 1176660 and Macquarie University.

Mitochondrial respiratory chain dysfunction in a patient with a heterozygous de novo CTBP1 variant.

The C-terminal binding protein 1 (CTBP1) functions as a transcriptional corepressor in vertebrates and has been identified to have critical roles in nervous system growth and development. Pathogenic variants in the CTBP1 gene has been shown to cause hypotonia, ataxia, developmental delay and tooth enamel defect syndrome (HADDTS). There have only been 16 cases reported to date with heterozygous, pathogenic variants in CTBP1 manifesting with a neurodevelopmental phenotype. We report a further case of a pathogenic, heterozygous, de novo variant in CTBP1 identified by whole exome sequencing in a female with the typical phenotype of global developmental delay, hypotonia, cerebellar dysfunction and failure to thrive. Additionally, muscle biopsy demonstrates evidence of a respiratory chain defect, only previously reported once in the literature. This supports the role of CTBP1 in maintenance of normal mitochondrial activity and highlights the importance of considering secondary mitochondrial dysfunction in genes not directly involved in the mitochondrial respiratory chain.

Predictors of longitudinal seizure outcomes after epilepsy surgery in childhood.

There is a paucity of data on longitudinal seizure outcome of children undergoing epilepsy surgery. All children (n = 132) who underwent resective epilepsy surgery from January 1998 to December 2015 were identified. Relevant clinical, neurophysiological, imaging, surgical and seizure outcome data were extracted. Multivariable logistic regression analysis and Kaplan-Meier survival with Cox proportional hazard modelling were performed. The mean age at surgery was 7.8 years (range 0.2-17.9). 71% were seizure-free at a mean follow up of 5.3 ± 2.7 years. Of those who were seizure-free, 65 patients were able to completely wean off anti- seizure medications successfully. Using survival analysis, the probability of Engel Class I outcome at one year after surgery was 81% (95% confidence interval [CI] 87%-75%). This dropped to 73% at two years (95% CI 81%-65%), 58% at five years (95% CI 67.8%-48%), and 47% at ten years. Proportional hazard modelling showed that the presence of moderate to severe developmental disability (HR 6.5; p = 0.02) and lack of complete resection (HR 0.4; p = 0.02) maintain association as negative predictors of seizure-free outcome. Our study demonstrates favorable long-term seizure control following pediatric epilepsy surgery and highlights important predictors of seizure outcome guiding case selection and counseling of expectations prior to surgery.

Incidence and Natural History of Pediatric Large Vessel Occlusion Stroke: A Population Study.

Importance: The incidence and natural history of large vessel occlusion (LVO) stroke in children is largely unknown. These knowledge gaps limit the uptake of reperfusion therapies and reduce the efficiency of pediatric acute stroke pathways. Objective: To determine the incidence and natural history of pediatric LVO stroke. Design, Setting, and Participants: This retrospective population-based cohort study was conducted between January 2010 and December 2019, with a mean (SD) follow-up of 37.0 (28.8) months. Admissions from all pediatric hospitals in the state of New South Wales, Australia, with a final diagnosis of arterial ischemic stroke (AIS) in patients 1 month to younger than 17 years were included. A total of 85 of 251 identified cases were excluded based on selection criteria. Data were analyzed from July 2020 to June 2021. Exposures: One-third of patients with LVO received mechanical thrombectomy with or without intravenous thrombolysis while the remainder were treated conservatively. Main Outcomes and Measures: The primary outcome was the pediatric modified Rankin Scale (ped-mRS) score 3 months after stroke. Ordinal logistic regression was used to compare non-LVO, LVO without thrombectomy, and LVO with thrombectomy groups. Results: Of 161 included patients, 56 (34.8%) were female, and the mean (SD) age was 6.1 (5.4) years. A total of 166 AIS admissions were studied, and clinical follow-up was available for 164 of 166 admissions. LVO was present in 39 admissions (23.5%). The incidence of LVO stroke was 0.24 per 100 000 patients per year (95% CI, 0.13-0.35). Patients with LVO who did not receive thrombectomy (n = 26) had poor neurological outcomes, with 19 (73.1%) experiencing moderate to severe disability or death (ped-mRS score of 3 to 6) at 3 months (6 of 12 patients receiving thrombectomy [50.0%]; 25 of 38 patients with LVO [65.8%]). Patients with LVO without thrombectomy had significantly worse clinical outcomes than patients with non-LVO at 3 months (odds ratio, 3.64; 95% CI, 1.68-7.87; P = .001). Most patients with LVO presented within time windows suitable for thrombectomy (27 of 39 [69.2%] within 6 hours; 35 of 39 [89.7%] within 24 hours). Conclusions and Relevance: In this population-based cohort study, the natural history of pediatric patients with LVO stroke treated conservatively was poor, with most experiencing lifelong disability or death. Nearly 90% of pediatric patients with LVO presented within time windows suitable for thrombectomy.

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.

Decreased cerebrospinal fluid kynurenic acid in epileptic spasms: A biomarker of response to corticosteroids.

BACKGROUND: Epileptic (previously infantile) spasms is the most common epileptic encephalopathy occurring during infancy and is frequently associated with abnormal neurodevelopmental outcomes. Epileptic spasms have a diverse range of known (genetic, structural) and unknown aetiologies. High dose corticosteroid treatment for 4 weeks often induces remission of spasms, although the mechanism of action of corticosteroid is unclear. Animal models of epileptic spasms have shown decreased brain kynurenic acid, which is increased after treatment with the ketogenic diet. We quantified kynurenine pathway metabolites in the cerebrospinal fluid (CSF) of infants with epileptic spasms and explored clinical correlations. METHODS: A panel of nine metabolites in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid) were measured using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). CSF collected from paediatric patients less than 3 years of age with epileptic spasms (n=34, 19 males, mean age 0.85, median 0.6, range 0.3-3 yrs) were compared with other epilepsy syndromes (n=26, 9 males, mean age 1.44, median 1.45, range 0.3-3 yrs), other non-inflammatory neurological diseases (OND) (n=29, 18 males, mean age 1.47, median 1.6, range 0.1-2.9 yrs) and inflammatory neurological controls (n=12, 4 males, mean age 1.80, median 1.80, range 0.8-2.5 yrs). FINDINGS: There was a statistically significant decrease of CSF kynurenic acid in patients with epileptic spasms compared to OND (p<0.0001). In addition, the kynurenic acid/kynurenine (KYNA/KYN) ratio was lower in the epileptic spasms subgroup compared to OND (p<0.0001). Epileptic spasms patients who were steroid responders or partial steroid responders had lower KYNA/KYN ratio compared to patients who were refractory to steroids (p<0.005, p<0.05 respectively). INTERPRETATION: This study demonstrates decreased CSF kynurenic acid and KYNA/KYN in epileptic spasms, which may also represent a biomarker for steroid responsiveness. Given the anti-inflammatory and neuroprotective properties of kynurenic acid, further therapeutics able to increase kynurenic acid should be explored. FUNDING: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP1176660 and Macquarie University.

Immune-mediated steroid-responsive epileptic spasms and epileptic encephalopathy associated with VGKC-complex antibodies.

Autoantibodies that bind to voltage-gated potassium-channel complex proteins (VGKC-complex antibodies) occur frequently in adults with limbic encephalitis presenting with cognitive impairment and seizures. Recently, VGKC-complex antibodies have been described in a few children with limbic encephalitis, and children with unexplained encephalitis presenting with status epilepticus. We report a case of infantile-onset epileptic spasms and developmental delay compatible with epileptic encephalopathy. Our patient was a female infant, aged 4 months at presentation. She had evidence of immune activation in the central nervous system with elevated cerebrospinal fluid neopterin and mirrored oligoclonal bands, which prompted testing for autoantibodies. VGKC-complex antibodies were elevated (201 pmol/L, normal<100), but extended antibody testing, including leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2), was negative. The patient showed a partial response to steroid treatment, which was started late in the disease course. On review at 13 months of age, her development was consistent with an age of 5 to 6 months. These results suggest that VGKC-complex antibodies might represent a marker of immune therapy responsiveness in a subgroup of patients with infantile epileptic encephalopathy.