An embedded intracranial seizure monitor for objective outcome measurements and rhythm identification.

Providing clinicians with objective outcomes of neuromodulation therapy is a key unmet need, especially in emerging areas such as epilepsy and mood disorders. These diseases have episodic behavior and circadian/multidien rhythm characteristics that are difficult to capture in short clinical follow-ups. This work presents preliminary validation evidence for an implantable neuromodulation system with integrated physiological event monitoring, with an initial focus on seizure tracking for epilepsy. The system was developed to address currently unmet requirements for patients undergoing neuromodulation therapy for neurological disorders, specifically the ability to sense physiological data during stimulation and track events with seconds-level granularity. The system incorporates an interactive software tool to enable optimal configuration of the signal processing chain on an embedded implantable device (the Picostim-DyNeuMo Mk-2) including data ingestion from the device loop recorder, event labeling, generation of filter and classification parameters, as well as summary statistics. When the monitor parameters are optimized, the user can wirelessly update the system for chronic event tracking. The simulated performance of the device was assessed using an in silico model with human data to predict the real-time device performance at tracking recorded seizure activity. The in silico performance was then compared against its performance in an in vitro model to capture the full environmental constraints such as sensing during stimulation at the tissue electrode interface. In vitro modeling demonstrated comparable results to the in silico model, providing verification of the software tool and model. This study provides validation evidence of the suitability of the proposed system for tracking longitudinal seizure activity. Given its flexibility, the event monitor can be adapted to track other disorders with episodic and rhythmic symptoms represented by bioelectrical behavior.Clinical relevance-An implantable neuromodulation system is presented that enables chronic tracking of physiological events in disease. This physiological monitor provides the basis for longitudinal assessments of therapy outcomes for patients, such as those with epilepsy where objective identification of patient seizure activity and rhythms might help guide therapy optimization. The system is configurable for other disease states such as Parkinson's disease and mood disorders.

Neuroinflammation, autoinflammation, splenomegaly and anemia caused by bi-allelic mutations in IRAK4.

We describe a novel, severe autoinflammatory syndrome characterized by neuroinflammation, systemic autoinflammation, splenomegaly, and anemia (NASA) caused by bi-allelic mutations in IRAK4. IRAK-4 is a serine/threonine kinase with a pivotal role in innate immune signaling from toll-like receptors and production of pro-inflammatory cytokines. In humans, bi-allelic mutations in IRAK4 result in IRAK-4 deficiency and increased susceptibility to pyogenic bacterial infections, but autoinflammation has never been described. We describe 5 affected patients from 2 unrelated families with compound heterozygous mutations in IRAK4 (c.C877T (p.Q293*)/c.G958T (p.D320Y); and c.A86C (p.Q29P)/c.161 + 1G>A) resulting in severe systemic autoinflammation, massive splenomegaly and severe transfusion dependent anemia and, in 3/5 cases, severe neuroinflammation and seizures. IRAK-4 protein expression was reduced in peripheral blood mononuclear cells (PBMC) in affected patients. Immunological analysis demonstrated elevated serum tumor necrosis factor (TNF), interleukin (IL) 1 beta (IL-1ß), IL-6, IL-8, interferon α2a (IFN-α2a), and interferon ß (IFN-ß); and elevated cerebrospinal fluid (CSF) IL-6 without elevation of CSF IFN-α despite perturbed interferon gene signature. Mutations were located within the death domain (DD; p.Q29P and splice site mutation c.161 + 1G>A) and kinase domain (p.Q293*/p.D320Y) of IRAK-4. Structure-based modeling of the DD mutation p.Q29P showed alteration in the alignment of a loop within the DD with loss of contact distance and hydrogen bond interactions with IRAK-1/2 within the myddosome complex. The kinase domain mutation p.D320Y was predicted to stabilize interactions within the kinase active site. While precise mechanisms of autoinflammation in NASA remain uncertain, we speculate that loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production. Blockade of IL-6 resulted in immediate and complete amelioration of systemic autoinflammation and anemia in all 5 patients treated; however, neuroinflammation has, so far proven recalcitrant to IL-6 blockade and the janus kinase (JAK) inhibitor baricitinib, likely due to lack of central nervous system penetration of both drugs. We therefore highlight that bi-allelic mutation in IRAK4 may be associated with a severe and complex autoinflammatory and neuroinflammatory phenotype that we have called NASA (neuroinflammation, autoinflammation, splenomegaly and anemia), in addition to immunodeficiency in humans.

Clinical Phenotype in Individuals With Birk-Landau-Perez Syndrome Associated With Biallelic SLC30A9 Pathogenic Variants.

BACKGROUND AND OBJECTIVES: Birk-Landau-Perez syndrome is a genetic disorder caused by biallelic pathogenic variants in SLC30A9 presenting with a complex movement disorder, developmental regression, oculomotor abnormalities, and renal impairment. It has previously been reported in 2 families. We describe the clinical phenotype of 8 further individuals from 4 unrelated families with SLC30A9-related disease. METHOD: Following detailed clinical phenotyping, 1 family underwent research whole-genome sequencing (WGS), 1 research whole-exome sequencing, and 2 diagnostic WGS. Variants of interest were assessed for pathogenicity using in silico prediction tools, homology modeling, and, where relevant, sequencing of complementary DNA (cDNA) for splicing effect. RESULTS: In 2 unrelated families of Pakistani origin (1 consanguineous and 1 not), the same homozygous missense variant in SLC30A9 (c.1253G>T, p.Gly418Val) was identified. Family 1 included 2 affected brothers, and family 2 one affected boy. In family 3, also consanguineous, there were 4 affected siblings homozygous for the variant c.1049delCAG, pAla350del. The fourth family was nonconsanguineous: the 1 affected individual was compound heterozygous for c.1083dup, p.Val362Cysfs*5, and c.1413A>G, p.Ser471=. Despite phenotypic variability between the 4 families, all affected patients manifested with a progressive hyperkinetic movement disorder, associated with oculomotor apraxia and ptosis. None had evidence of severe renal impairment. For the novel missense variant, the conformation of the loop domain and packing of transmembrane helices are likely to be disrupted based on structure modeling. Its presence in 2 unrelated Pakistani families suggests a possible founder variant. For the synonymous variant p.Ser471=, an effect on splicing was confirmed through cDNA analysis. DISCUSSION: Pathogenic variants in SLC30A9 cause a progressive autosomal recessive neurologic syndrome associated with a complex hyperkinetic movement disorder. Our report highlights the expanding disease phenotype, which can present with a wider spectrum of severity than has previously been recognized.

A novel ELP1 mutation impairs the function of the Elongator complex and causes a severe neurodevelopmental phenotype.

BACKGROUND: Neurodevelopmental disorders (NDDs) are heterogeneous, debilitating conditions that include motor and cognitive disability and social deficits. The genetic factors underlying the complex phenotype of NDDs remain to be elucidated. Accumulating evidence suggest that the Elongator complex plays a role in NDDs, given that patient-derived mutations in its ELP2, ELP3, ELP4 and ELP6 subunits have been associated with these disorders. Pathogenic variants in its largest subunit ELP1 have been previously found in familial dysautonomia and medulloblastoma, with no link to NDDs affecting primarily the central nervous system. METHODS: Clinical investigation included patient history and physical, neurological and magnetic resonance imaging (MRI) examination. A novel homozygous likely pathogenic ELP1 variant was identified by whole-genome sequencing. Functional studies included in silico analysis of the mutated ELP1 in the context of the holo-complex, production and purification of the ELP1 harbouring the identified mutation and in vitro analyses using microscale thermophoresis for tRNA binding assay and acetyl-CoA hydrolysis assay. Patient fibroblasts were harvested for tRNA modification analysis using HPLC coupled to mass spectrometry. RESULTS: We report a novel missense mutation in the ELP1 identified in two siblings with intellectual disability and global developmental delay. We show that the mutation perturbs the ability of ELP123 to bind tRNAs and compromises the function of the Elongator in vitro and in human cells. CONCLUSION: Our study expands the mutational spectrum of ELP1 and its association with different neurodevelopmental conditions and provides a specific target for genetic counselling.

Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.

DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. Cases were identified clinically. Available records, including magnetic resonance imaging and electroencephalography, were reviewed. Genetic testing was performed by whole exome and whole-genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement and severe neutropenia were also observed in one or more patients. Five of the children died in infancy or childhood; the other four are currently aged between 5 months and 6 years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene.

Case report: Novel treatment regimen for enterovirus encephalitis in SCID.

Most non-polio enterovirus infections in immunocompetent individuals are acute and self-limiting in nature; however, infection can be severe, chronic and have devastating outcomes in immunocompromised hosts. Therapeutic strategies have predominantly involved supportive care, with the lack of approved antiviral treatments proving challenging for management. We report a case of an 8-month-old child who presented with severe enterovirus encephalitis following gene therapy for X-linked severe combined immunodeficiency (X-SCID) and who demonstrated clinical and microbiological improvement after a novel regimen of favipiravir, fluoxetine, and high-dose intravenous immunoglobulin (IVIg). The patient presented 6 weeks post-gene therapy with rapid neurological deterioration in the context of incomplete immune reconstitution, with microbiological and radiological evidence confirming enterovirus encephalitis. His neurologic examination stabilised 8 weeks after treatment, and he subsequently demonstrated excellent immune recovery. This is the first case report of combined therapy with favipiravir, fluoxetine, and high-dose IVIg in the context of severe enterovirus encephalitis in an immunocompromised host. This case highlights the importance of considering enterovirus encephalitis in immunocompromised patients presenting with both acute and chronic neurological signs, as well as developmental regression. The demonstrated treatment success and the associated low risk of toxicity warrant further investigation of this therapeutic regimen.

Clinical features, investigations, and outcomes of pediatric limbic encephalitis: A multicenter study.

OBJECTIVES: To describe the clinical presentation, investigations, management, and disease course in pediatric autoimmune limbic encephalitis (LE). METHODS: In this retrospective observational study, from the UK Childhood Neuroinflammatory Disease network, we identified children from six tertiary centers with LE <18 years old between 2008 and 2021. Clinical and paraclinical data were retrieved from medical records. RESULTS: Twenty-five children fulfilling LE criteria were identified, with median age of 11 years (IQR 8, 14) and median follow-up of 24 months (IQR 18, 48). All children presented with seizures; 15/25 (60%) were admitted to intensive care. Neuroimaging demonstrated asymmetric mesial temporal changes in 8/25 (32%), and extra-limbic changes with claustrum involvement in 9/25 (38%). None were positive for LGI1/CASPR2 antibodies (Abs), 2/25 were positive for serum anti-NMDAR Abs, and 2/15 positive for anti-Hu Abs; one died from relapsing neuroblastoma. Two children had serum and CSF anti-GAD antibodies. Initial immune therapy included steroids in 23/25 (92%), intravenous immunoglobulin (IVIg) in 14/25 (56%), and plasma exchange in 7/25 (28%). The commonest second-line treatment was rituximab in 15/25 (60%). Median duration of hospital admission was 21 days (IQR 11, 30). At last follow-up, 13/25 (52%) had refractory seizures and 16/25 (64%) had memory impairment. Six children (24%) had modified Rankin Scale (mRS) scores ≥3. There was no significant difference in mRS, or long-term cognitive and epilepsy outcomes in those who received rituximab versus those who did not. INTERPRETATION: A diagnosis of autoimmune LE was associated with significant morbidity and adverse outcomes in this pediatric cohort.

Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Pathogenic NR2F1 variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic NR2F1 variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously. The visual impairment became apparent in early childhood with small and/or tilted hypoplastic optic nerves observed in 10 cases. High-resolution optical coherence tomography imaging confirmed significant loss of retinal ganglion cells with thinning of the ganglion cell layer, consistent with electrophysiological evidence of retinal ganglion cells dysfunction. Interestingly, for those individuals with available longitudinal ophthalmological data, there was no significant deterioration in visual function during the period of follow-up. Diffusion tensor imaging tractography studies showed defective connections and disorganization of the extracortical visual pathways. To further investigate how pathogenic NR2F1 variants impact on retinal and optic nerve development, we took advantage of an Nr2f1 mutant mouse disease model. Abnormal retinogenesis in early stages of development was observed in Nr2f1 mutant mice with decreased retinal ganglion cell density and disruption of retinal ganglion cell axonal guidance from the neural retina into the optic stalk, accounting for the development of optic nerve hypoplasia. The mutant mice showed significantly reduced visual acuity based on electrophysiological parameters with marked conduction delay and decreased amplitude of the recordings in the superficial layers of the visual cortex. The clinical observations in our study cohort, supported by the mouse data, suggest an early neurodevelopmental origin for the retinal and optic nerve head defects caused by NR2F1 pathogenic variants, resulting in congenital vision loss that seems to be non-progressive. We propose NR2F1 as a major gene that orchestrates early retinal and optic nerve head development, playing a key role in the maturation of the visual system.

Proposal to optimize evaluation and treatment of Febrile infection-related epilepsy syndrome (FIRES): A Report from FIRES workshop.

Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL-1 receptor antagonist that blocks biologic activity of IL-1ß) are recommended.

Diagnostic algorithm for children presenting with epilepsia partialis continua.

OBJECTIVE: To characterize a cohort of children with epilepsia partialis continua (EPC) and develop a diagnostic algorithm incorporating key differential diagnoses. METHODS: Children presenting with EPC to a tertiary pediatric neurology center between 2002 and 2019 were characterized. RESULTS: Fifty-four children fulfilled EPC criteria. Median age at onset was 7 years (range 0.6-15), with median follow-up of 4.3 years (range 0.2-16). The diagnosis was Rasmussen encephalitis (RE) in 30 of 54 (56%), a mitochondrial disorder in 12 of 54 (22.2%), and magnetic resonance imaging (MRI) lesion-positive focal epilepsy in 6 of 54 (11.1%). No diagnosis was made in 5 of 54 (9%). Children with mitochondrial disorders developed EPC earlier; each additional year at presentation reduced the odds of a mitochondrial diagnosis by 26% (P = .02). Preceding developmental concerns (odds ratio [OR] 22, P < .001), no seizures prior to EPC (OR 22, P < .001), bilateral slowing on electroencephalogram (EEG) (OR 26, P < .001), and increased cerebrospinal fluid (CSF) protein level (OR 16) predicted a mitochondrial disorder. Asymmetry or hemiatrophy was evident on MRI at presentation with EPC in 18 of 30 (60%) children with RE, and in the remainder at a median of 6 months (range 3-15) after EPC onset. The first diagnostic test is brain MRI. Hemiatrophy may permit a diagnosis of RE with unilateral clinical and EEG findings. For children in whom a diagnosis of RE cannot be made on first scan but the clinical and radiological presentation resembles RE, repeat imaging every 6 months is recommended to detect progressive unicortical hemiatrophy, and brain biopsy should be considered. Evidence of intrathecal inflammation (oligoclonal bands and raised neopterin) can be supportive. In children with bihemispheric EPC, rapid polymerase gamma testing is recommended and if negative, sequencing mtDNA and whole-exome sequencing on blood-derived DNA should be performed. SIGNIFICANCE: Children presenting with EPC due to a mitochondrial disorder show clinical features distinguishing them from RE and structural epilepsies. A diagnostic algorithm for children with EPC will allow targeted investigation and timely diagnosis.

Non-congenital viral infections of the central nervous system: from the immunocompetent to the immunocompromised child.

Non-congenital viral infections of the central nervous system in children can represent a severe clinical condition that needs a prompt diagnosis and management. However, the aetiological diagnosis can be challenging because symptoms are often nonspecific and cerebrospinal fluid analysis is not always diagnostic. In this context, neuroimaging represents a helpful tool, even though radiologic patterns sometimes overlap. The purpose of this pictorial essay is to suggest a schematic representation of different radiologic patterns of non-congenital viral encephalomyelitis based on the predominant viral tropism and vulnerability of specific regions: cortical grey matter, deep grey matter, white matter, brainstem, cerebellum and spine.

KIF1A-related disorders in children: A wide spectrum of central and peripheral nervous system involvement.

KIF1A-related disorders (KRD) were first described in 2011 and the phenotypic spectrum has subsequently expanded to encompass a range of central and peripheral nervous system involvement. Here we present a case series demonstrating the range of clinical, neurophysiological, and radiological features which may occur in childhood-onset KRD. We report on all the children and young people seen at a single large tertiary centre. Data were collected through a retrospective case-notes review. Twelve individuals from 10 families were identified. Eight different mutations were present, including four novel mutations. Two patients displayed a very severe phenotype including congenital contractures, severe spasticity and/or dystonia, dysautonomia, severe sensorimotor polyneuropathy and optic atrophy, significant white matter changes on brain MRI, respiratory insufficiency, and complete lack of neurodevelopmental progress. The remaining 10 patients represented a spectrum of severity with common features including a movement disorder with spasticity and/or dystonia, subtle features of dysautonomia, sensory axonal neuropathy, varying degrees of optic atrophy and of learning and/or behavioural difficulties, and subtle or absent-but sometimes progressive-changes in white matter on MRI. Epilepsy was common among the more severely affected children. This case series demonstrates that KRD comprise a range of neurological disorders, with both the milder and the more severe forms combining central and peripheral (including autonomic) nervous system deficits.

Epilepsy in paediatric patients with Parry-Romberg syndrome: A review of the literature.

BACKGROUND: Parry-Romberg syndrome (PRS) is a rare disorder characterized by unilateral slow progressive facial atrophy that can be associated with neurologic manifestations, namely seizures. There is scarce data about seizures in paediatric patients with PRS. The aim of our work was to clarify the clinical features of paediatric patients with PRS and seizures. METHODS: We performed a literature review based on a literature search using PubMed and EMBASE databases. We included original articles in which the main diagnosis was PRS and the patients were 17 years old or less when the first seizure occurred. RESULTS: We included 40 patients. Most of the patients had previously normal development and had their first seizure in the first decade of life. Neurologic examination was abnormal in 56 % of patients. Seizures are typically focal, frequently with impaired awareness, and became refractory in about 40 % of patients. Few patients have generalized seizures. On electroencephalogram, epileptic discharges are generally focal, on the same side as the facial atrophy, without a predominant cerebral lobe localization. Brain MRI is almost always abnormal, typically with T2 subcortical hyperintensities, and sometimes brain atrophy or calcifications. In addition to the classic antiepileptic drugs, immunosuppressive drugs should be considered as potential epilepsy treatment. CONCLUSION: To the best of our knowledge, this is the first review dedicated to the characteristics of paediatric patients with PRS and epilepsy. Seizures are usually focal, became refractory in 40 %, and have a significant impact on the quality of life and neurodevelopment of patients.

Anakinra usage in febrile infection related epilepsy syndrome: an international cohort.

Febrile-infection related epilepsy syndrome (FIRES) is a devastating neurological condition characterized by a febrile illness preceding new onset refractory status epilepticus (NORSE). Increasing evidence suggests innate immune dysfunction as a potential pathological mechanism. We report an international retrospective cohort of 25 children treated with anakinra, a recombinant interleukin-1 receptor antagonist, as an immunomodulator for FIRES. Anakinra was potentially safe with only one child discontinuing therapy due to infection. Earlier anakinra initiation was associated with shorter duration of mechanical ventilation, ICU and hospital length of stay. Our retrospective data lay the groundwork for prospective consensus-driven cohort studies of anakinra in FIRES.

Centromedian thalamic nuclei deep brain stimulation and Anakinra treatment for FIRES - Two different outcomes.

Febrile infection-related epilepsy syndrome (FIRES) is a severe epilepsy disorder that affects previously healthy children. It carries high likelihood of unfavourable outcome and putative aetiology relates to an auto-inflammatory process. Standard antiepileptic drug therapies including intravenous anaesthetic agents are largely ineffective in controlling status epilepticus in FIRES. Deep brain stimulation of the centromedian thalamic nuclei (CMN-DBS) has been previously used in refractory status epilepticus in only a few cases. The use of Anakinra (a recombinant version of the human interleukin-1 receptor antagonist) has been reported in one case with FIRES with good outcome. Here we describe two male paediatric patients with FIRES unresponsive to multiple anti-epileptic drugs, first-line immune modulation, ketogenic diet and cannabidiol. They both received Anakinra and underwent CMN-DBS. The primary aim for CMN-DBS therapy was to reduce generalized seizures. CMN-DBS abolished generalized seizures in both cases and Anakinra had a positive effect in one. This patient had a favourable outcome whereas the other did not. These are the first reported cases of FIRES where CMN-DBS has been used.

Two Cases of Guillain-Barré Syndrome Variants Presenting With Dysautonomia.

We describe 2 pediatric cases presenting with posterior reversible encephalopathy syndrome secondary to autonomic dysfunction preceding the onset of motor symptoms in Guillain-Barré syndrome variants. Patient 1 presented acutely with encephalopathy, cerebellar signs, hypertension, lower limb weakness, and respiratory decompensation. Magnetic resonance imaging (MRI) brain showed occipital lesions consistent with posterior reversible encephalopathy syndrome. Nerve conduction studies were consistent with Miller-Fisher syndrome. After intravenous immunoglobulin and plasmapheresis, he improved clinically with radiological resolution. Patient 2 presented with headache, leg pain, seizures, and significant hypertension. Brain MRI was normal but spine MRI revealed enhancement of the cauda equina ventral nerve roots. She was areflexic with lower limb weakness a few days after intensive care unit admission and made a significant improvement after treatment with intravenous immunoglobulin. In children presenting with posterior reversible encephalopathy syndrome in the absent of other causes of primary hypertension, Guillain-Barré syndrome variants are an important differential etiology, presenting with autonomic dysfunction, even before signs of motor weakness become evident.