Clinical and neuroimaging phenotypes of autoimmune glial fibrillary acidic protein astrocytopathy: A systematic review and meta-analysis.

OBJECTIVE: This study was undertaken to provide a comprehensive review of neuroimaging characteristics and corresponding clinical phenotypes of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A), a rare but severe neuroinflammatory disorder, to facilitate early diagnosis and appropriate treatment. METHODS: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis)-conforming systematic review and meta-analysis was performed on all available data from January 2016 to June 2023. Clinical and neuroimaging phenotypes were extracted for both adult and paediatric forms. RESULTS: A total of 93 studies with 681 cases (55% males; median age = 46, range = 1-103 years) were included. Of these, 13 studies with a total of 535 cases were eligible for the meta-analysis. Clinically, GFAP-A was often preceded by a viral prodromal state (45% of cases) and manifested as meningitis, encephalitis, and/or myelitis. The most common symptoms were headache, fever, and movement disturbances. Coexisting autoantibodies (45%) and neoplasms (18%) were relatively frequent. Corticosteroid treatment resulted in partial/complete remission in a majority of cases (83%). Neuroimaging often revealed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities (74%) as well as perivascular (45%) and/or leptomeningeal (30%) enhancement. Spinal cord abnormalities were also frequent (49%), most commonly manifesting as longitudinally extensive myelitis. There were 88 paediatric cases; they had less prominent neuroimaging findings with lower frequencies of both T2/FLAIR hyperintensities (38%) and contrast enhancement (19%). CONCLUSIONS: This systematic review and meta-analysis provide high-level evidence for clinical and imaging phenotypes of GFAP-A, which will benefit the identification and clinical workup of suspected cases. Differential diagnostic cues to distinguish GFAP-A from common clinical and imaging mimics are provided as well as suitable magnetic resonance imaging protocol recommendations.

Arterial Stiffness and Carotid Intima-Media Thickness in Children Exposed to Smokeless Tobacco in Fetal Life.

BACKGROUND: Arterial stiffening and increased intima-media thickness can be seen as early as childhood and are associated with increased risk of cardiovascular events in adult life. The authors hypothesized that exposure to prenatal smokeless tobacco (Swedish snus) without additional nicotine exposure after the breastfeeding period would be associated with increased arterial stiffness and intima-media thickening in preschool children. METHODS AND RESULTS: This was a longitudinal follow-up cohort study of children aged 5 to 6 years exposed to high doses of nicotine in utero. Women exclusively using snus and unexposed controls were enrolled in early pregnancy (gestational age range, 6-12 weeks). Exposure data were collected during and after pregnancy with questionnaires from both groups. For this study, only children of women using >48 mg nicotine per day during their entire pregnancy were included in the exposure group. Outcomes were determined in 40 healthy children (21 exposed to snus in utero). Ultrasonography of the common carotid artery was used to determine carotid intima-media thickness and calculate arterial stiffness index from the relationship between pulsatile changes in arterial diameter and arterial pressure. Children exposed to snus in fetal life had higher carotid stiffness (median 4.1 [interquartile range (IQR), 2.4-5] versus 2.9 [IQR, 2.1-3.5]; P=0.014) than tobacco-free controls. Carotid strain (relative diameter change) was lower in children exposed to snus (mean 16% [SD, 5.7%] versus 21% [SD, 6.6%]) than in controls (P=0.015). Carotid intima-media thickness did not differ significantly between children exposed to snus and controls. CONCLUSIONS: Exposure to snus during fetal life was associated with a stiffer carotid artery in preschool children.

Retrospective Pediatric Cohort Study Validates NEOS Score and Demonstrates Applicability in Children With Anti-NMDAR Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is the most common form of autoimmune encephalitis in children and adults. Although our understanding of the disease mechanisms has progressed, little is known about estimating patient outcomes. Therefore, the NEOS (anti-NMDAR Encephalitis One-Year Functional Status) score was introduced as a tool to predict disease progression in NMDARE. Developed in a mixed-age cohort, it currently remains unclear whether NEOS can be optimized for pediatric NMDARE. METHODS: This retrospective observational study aimed to validate NEOS in a large pediatric-only cohort of 59 patients (median age of 8 years). We reconstructed the original score, adapted it, evaluated additional variables, and assessed its predictive power (median follow-up of 20 months). Generalized linear regression models were used to examine predictability of binary outcomes based on the modified Rankin Scale (mRS). In addition, neuropsychological test results were investigated as alternative cognitive outcome. RESULTS: The NEOS score reliably predicted poor clinical outcome (mRS ≥3) in children in the first year after diagnosis (p = 0.0014) and beyond (p = 0.036, 16 months after diagnosis). A score adapted to the pediatric cohort by adjusting the cutoffs of the 5 NEOS components did not improve predictive power. In addition to these 5 variables, further patient characteristics such as the "Herpes simplex virus encephalitis (HSE) status" and "age at disease onset" influenced predictability and could potentially be useful to define risk groups. NEOS also predicted cognitive outcome with higher scores associated with deficits of executive function (p = 0.048) and memory (p = 0.043). DISCUSSION: Our data support the applicability of the NEOS score in children with NMDARE. Although not yet validated in prospective studies, NEOS also predicted cognitive impairment in our cohort. Consequently, the score could help identify patients at risk of poor overall clinical outcome and poor cognitive outcome and thus aid in selecting not only optimized initial therapies for these patients but also cognitive rehabilitation to improve long-term outcomes.

[Epilepsy surgery seems underutilized in Sweden]. / Epilepsikirurgin är underutny­­ttjad ­ fler bör hänvisas till utredning.

Epilepsy surgery should be considered for individuals with drug-resistant focal epilepsy. The pre-surgical evaluation is highly multi-disciplinary and performed by a team consisting of neurologists, neurophysiologists, neurosurgeons, neuroradiologists, neuropsychologists, biomedical scientists, speech-language pathologists and nursing staff. The evaluation comprises of a meticulous medical history with focus on seizure semiology, a 3 Tesla MRI, ictal video-EEG, neuropsychological evaluation and sometimes also MEG, nTMS, fMRI, PET or SISCOM/ictal SPECT. Occasionally, invasive monitoring with intracranial electrodes is necessary. Surgical options in treatment of epilepsy range from open resections of epileptogenic areas to focal ablations and neurostimulation. There is evidence of epilepsy surgery being an effective treatment in carefully selected cases. Epilepsy surgery seems underutilized in Sweden and referrals for epilepsy surgery work-up need to increase.

Higher levels of Bifidobacteria and tumor necrosis factor in children with drug-resistant epilepsy are associated with anti-seizure response to the ketogenic diet.

BACKGROUND: Recently, studies have suggested a role for the gut microbiota in epilepsy. Gut microbial changes during ketogenic diet (KD) treatment of drug-resistant epilepsy have been described. Inflammation is associated with certain types of epilepsy and specific inflammation markers decrease during KD. The gut microbiota plays an important role in the regulation of the immune system and inflammation. METHODS: 28 children with drug-resistant epilepsy treated with the ketogenic diet were followed in this observational study. Fecal and serum samples were collected at baseline and three months after dietary intervention. FINDINGS: We identified both gut microbial and inflammatory changes during treatment. KD had a general anti-inflammatory effect. Novel bioinformatics and machine learning approaches identified signatures of specific Bifidobacteria and TNF (tumor necrosis factor) associated with responders before starting KD. During KD, taxonomic and inflammatory profiles between responders and non-responders were more similar than at baseline. INTERPRETATION: Our results suggest that children with drug-resistant epilepsy are more likely to benefit from KD treatment when specific Bifidobacteria and TNF are elevated. We here present a novel signature of interaction of the gut microbiota and the immune system associated with anti-epileptic response to KD treatment. This signature could be used as a prognostic biomarker to identify potential responders to KD before starting treatment. Our findings may also contribute to the development of new anti-seizure therapies by targeting specific components of the gut microbiota. FUNDING: This study was supported by the Swedish Brain Foundation, Margarethahemmet Society, Stiftelsen Sunnerdahls Handikappfond, Linnea & Josef Carlssons Foundation, and The McCormick Genomic & Proteomic Center.

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

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.

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

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.

Variants in CHRNB2 and CHRNA4 Identified in Patients with Insular Epilepsy.

PURPOSE: Our purpose was to determine the role of CHRNA4 and CHRNB2 in insular epilepsy. METHOD: We identified two patients with drug-resistant predominantly sleep-related hypermotor seizures, one harboring a heterozygous missense variant (c.77C>T; p. Thr26Met) in the CHRNB2 gene and the other a heterozygous missense variant (c.1079G>A; p. Arg360Gln) in the CHRNA4 gene. The patients underwent electrophysiological and neuroimaging studies, and we performed functional characterization of the p. Thr26Met (c.77C>T) in the CHRNB2 gene. RESULTS: We localized the epileptic foci to the left insula in the first case (now seizure-free following epilepsy surgery) and to both insulae in the second case. Based on tools predicting the possible impact of amino acid substitutions on the structure and function of proteins (sorting intolerant from tolerant and PolyPhen-2), variants identified in this report could be deleterious. Functional expression in human cell lines of α4ß2 (wild-type), α4ß2-Thr26Met (homozygote), and α4ß2/ß2-Thr26Met (heterozygote) nicotinic acetylcholine receptors revealed that the mutant subunit led to significantly higher whole-cell nicotinic currents. This feature was observed in both homo- and heterozygous conditions and was not accompanied by major alterations of the current reversal potential or the shape of the concentration-response relation. CONCLUSIONS: This study suggests that variants in CHRNB2 and CHRNA4, initially linked to autosomal dominant nocturnal frontal lobe epilepsy, are also found in patients with predominantly sleep-related insular epilepsy. Although the reported variants should be considered of unknown clinical significance for the moment, identification of additional similar cases and further functional studies could eventually strengthen this association.

Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

OBJECTIVE: To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) patients. METHODS: We studied 38 children with NMDARE (median age = 12.9 years, range =1-18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed-effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity. RESULTS: Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid-attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed-effect models and z score transformation showed failure of age-expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31-9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51-17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68-24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47-9.82, p = 0.031) as independent predictors of poor clinical outcome. INTERPRETATION: Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020 ANN NEUROL 2020;88:148-159.

The Cerebrospinal Fluid Interleukin-6/Interleukin-10 Ratio Differentiates Pediatric Tick-borne Infections.

BACKGROUND: Borrelia burgdorferi and tick-borne encephalitis (TBE) virus are 2 types of tick-borne pathogens that can cause central nervous system infection. Routine diagnostics have so far included analysis of cerebrospinal fluid (CSF) cell numbers, CSF serology for Borrelia burgdorferi and serum serology for TBE virus. However, early diagnosis may be difficult based on antibody detection which takes time to analyze, and with the possibility of false negative results, thus delaying treatment. Cytokine analyses are becoming increasingly available in clinical routine care and may offer important information. METHODS: Fifteen cytokines and chemokines were measured in the CSF from the diagnostic lumbar puncture of 37 children with TBE, 34 children with neuroborreliosis and 19 children without evidence of central nervous system infection, using Luminex technology. RESULTS: Significantly higher levels of proinflammatory interleukin-6 were detected in the samples from TBE-infected children, when compared with neuroborreliosis or controls. In comparison, children with neuroborreliosis had significantly higher levels of interleukin-7, interleukin-8, interleukin-10, and interleukin-13 when compared with TBE infected or controls. Furthermore, the ratio between interleukin-6 and interleukin-10 was significantly different between the 2 types of tick-borne infections. CONCLUSIONS: The interleukin-6/interleukin-10 ratio can be used as a rapid diagnostic cue upon suspected tick-borne infection, enabling fast and correct treatment. Also, in serology-negative results, such information may strengthen a clinical suspicion.

Blood Pressure and Heart Rate Variability in Preschool Children Exposed to Smokeless Tobacco in Fetal Life.

Background Maternal smoking during pregnancy has been associated with higher blood pressure and autonomic imbalance in the offspring. However, it has been difficult to determine the selective prenatal and postnatal contributions as children frequently have been exposed to smoking both before and after birth. The specific role of nicotine is also unclear. We aimed to determine whether exclusive prenatal exposure to nicotine from maternal use of smokeless tobacco (Swedish snus) in pregnancy was associated with blood pressure and autonomic heart rate control in their children. Methods and Results We measured oscillometric blood pressures in forty 5- to 6-year-old children with snus exposure in fetal life (n=21) and in tobacco-free controls (n=19). Taking the child's age and height into account, snus-exposed children had 4.2 (95% CI, 0.2-8.1) mm Hg higher systolic blood pressure than controls (P=0.038). The corresponding sex-, age-, and height-standardized systolic blood pressure centiles were 61 and 46 (95% CI of the difference, 2-28) (P=0.029). Heart rate variability was tested in 30 of the children. The spectral heart rate variability variable low-frequency/high-frequency ratio was higher (median, 0.69; interquartile range, 0.45-1.21) in snus-exposed children than in controls (median, 0.21; interquartile range, 0.32-0.57; P=0.034). Conclusions Prenatal snus exposure was associated with higher systolic blood pressure and altered heart rate variability at 6 years of age. These findings may indicate adverse prenatal programming of nicotine, but implications for cardiovascular health in later life remain to be studied. Meanwhile, women should be recommended to abstain from all types of tobacco and nicotine products during pregnancy.

High prevalence of pituitary hormone deficiency in both unilateral and bilateral optic nerve hypoplasia.

AIM: This study examined the prevalence of neurological impairment and pituitary hormone deficiency (PHD) in patients with unilateral and bilateral optic nerve hypoplasia (ONH). METHODS: A population-based cross-sectional cohort study of 65 patients (51% female) with ONH was conducted in Stockholm. Of these were 35 bilateral and 30 unilateral. The patients were below 20 years of age, living in Stockholm in December 2009 and found through database searching. The median age at the analysis of the results in January 2018 was 16.1 years (range 8.1-27.5 years). Neurological assessments and blood sampling were conducted, neuroradiology was reviewed and growth curves were analysed. Diagnoses of PHDs were based on clinical and biochemical evidence of hormone deficiency. RESULTS: Neurological impairments were identified in 47% of the patients and impairments in gross and fine motor function were more prevalent in bilateral ONH (p < 0.001). In addition, 9% had cerebral palsy and 14% had epilepsy. The prevalence of PHD was 29 and 19% had multiple PHD. CONCLUSION: Children with ONH had a high risk of neurological impairment, especially in bilateral disease. Both unilateral and bilateral ONH signified an increased prevalence of PHD and all these children should be endocrinologically followed up until completed puberty.

Snus users had high levels of nicotine, cotinine and 3-hydroxycotinine in their breastmilk, and the clearance was slower than in smoking mothers.

AIM: Using snus, an oral moist tobacco, has increased among pregnant women in Sweden, the only European Union country where sales are legal. This study evaluated whether snus generated similar concentrations of nicotine and its metabolites in breastmilk to cigarette smoking. METHODS: We analysed 49 breastmilk samples from 33 nursing mother - 13 snus users, six cigarette smokers and 14 controls - for concentrations of nicotine, cotinine and 3-hydroxycotinine. The mothers were recruited at antenatal clinics in Sweden from 2007 to 2012. RESULTS: The median nicotine concentration in breastmilk of the snus users was 38.7 ng/mL (0-137) versus 24.0 ng/mL (0-56) in smokers, with median cotinine levels of 327.6 ng/mL (37-958) versus 164.4 ng/mL and median 3-hydroxycotinine levels of 202.7 ng/mL (28-452) versus 112.4 (0-231), respectively. Nicotine was still detected in the breastmilk of eight of the 13 snus users after abstaining from tobacco for a median duration of 11 hours (0.6-12.5), while the breastmilk of the smokers was nicotine-free after four hours' abstinence. CONCLUSION: Snus users had high levels of nicotine and metabolites in their breastmilk and nicotine was found even after 12.5 hours of abstinence.

Maternal snuff use and cotinine in late pregnancy-A validation study.

INTRODUCTION: Oral moist snuff is widely used in Sweden including during pregnancy. Maternal snuff use has been associated with increased risks of adverse pregnancy outcomes in epidemiological studies. Self-reported maternal snuff use has not been validated previously. The main objective of this study was to validate self-reported snuff use in pregnancy in a prospective cohort study and in the Medical Birth Register. MATERIAL AND METHODS: A prospective Swedish cohort study, 2005-2011, in which 572 women were asked to participate. Of 474 recruited women, 381 non-smokers (263 snuff users and 118 non-tobacco users) were included in the main analyses. Participants prospectively reported snuff use through questionnaires. Medical Birth Register data on the participants was obtained. Maternal urine cotinine was collected in late pregnancy and was used as a biomarker. RESULTS: Cotinine levels in maternal urine confirmed a high validity of self-reported snuff use through questionnaires in late pregnancy; sensitivity and specificity values were 98% and 96%, respectively. In the Medical Birth Register, 45% of the snuff users were misclassified as nonusers in late pregnancy. There were significant differences in median cotinine levels between users of mini pouches and users of standard pouches, but there was a great difference of cotinine levels among users with similar number of pouches used daily. CONCLUSIONS: Self-reported snuff use through questionnaires has high validity. In the Medical Birth Register, in late pregnancy, many snuff users were misclassified as nonusers. As a consequence, there is a risk of underestimating the harmful effects of snuff use when using late pregnancy Medical Birth Register data.

How to Treat Involvement of the Central Nervous System in Hemophagocytic Lymphohistiocytosis?

OPINION STATEMENT: Central nervous system (CNS)-hemophagocytic lymphohistiocytosis (HLH) is not a disease in itself, but it is part of a systemic immune response. The vast majority of patients with CNS-HLH also have systemic HLH and a large number of patients with primary and secondary HLH have CNS involvement. Reactivations within the CNS are frequent during the course of HLH treatment and may occur concomitant with or independent of systemic relapses. It is also important to consider primary HLH as an underlying cause of "unknown CNS inflammation" as these patients may present with only CNS disease. To initiate proper treatment, a correct diagnosis must be made. A careful review of the patient's history and a thorough neurological examination are essential. In addition to the blood tests required to make a diagnosis of HLH, a lumbar puncture with cerebrospinal fluid (CSF) analysis and magnetic resonance imaging (MRI) should always be done in all cases regardless of the presence or absence of neurological signs or symptom. Treatment options for CNS-HLH include, but are not limited to, those commonly used in systemic HLH, including corticosteroids, etoposide, cyclosporine A, alemtuzumab, and ATG. In addition, intrathecal treatment with methotrexate and corticosteroids has become a standard care and is likely to be beneficial. Therapy must be initiated without inappropriate delay to prevent late effects in HLH. An interesting novel approach is an anti-IFN-gamma antibody (NI-0501), which is currently being tested. Hematopoietic stem cell transplantation (HSCT) also represents an important CNS-HLH treatment; patients with primary HLH may benefit from immediate HSCT even if there is active disease at time of transplantation, though care should be taken to monitor CNS inflammation through HSCT and treat if needed. Since CNS-HLH is a condition leading to the most severe late effects of HLH, early expert consultation is recommended.

Prenatal Exposure to Snus Alters Heart Rate Variability in the Infant.

INTRODUCTION: Maternal use of smoked tobacco during pregnancy causes significant morbidity and mortality in the human infant including alterations in autonomic control with increased risk of sudden infant death syndrome. We hypothesized that maternal snus (smokeless tobacco) use during pregnancy affects autonomic cardiac regulation in the infant, as measured by heart rate variability (HRV) and the low frequency and high frequency ratio (LF/HF ratio). METHODS: A prospective observational study of 56 infants of women who used snus (n = 23) or cigarettes (n = 13) during pregnancy versus tobacco- and nicotine-free controls (n = 19). The nicotine dose was estimated by questionnaires at 4 timepoints pre- and post-natally. The infants' urine cotinine concentration and HRV during 2 hours of sleep were studied 1-2 months after birth. RESULTS: LF/HF ratio was higher in snus (mean 3.31; 95% CI 2.78-3.83) and smoke (3.51;2.54-4.47) compared to controls (2.15; 1.76-2.54, p = .002). Early prenatal nicotine exposure "without" any further exposure increased the LF/HF ratio (3.19; 2.55-3.84, p = .02). Continuous prenatal nicotine exposure "without" postnatal exposure was also associated with a residual increase in LF/HF ratio (4.40; 3.38-5.42, p < .001). There was no difference between infants exposed to smokeless versus smoked tobacco, suggesting a common constituent (nicotine) altering autonomic cardiac regulation. CONCLUSION: Infants to mothers who used snus during pregnancy showed lower vagal activity with an increased LF/HF ratio compared to controls, and similar to infants of smokers. Even early prenatal exposure to snus has a lasting impact on autonomic cardiac regulation suggesting a fetal "re-programing" of the developing autonomic nervous system. IMPLICATIONS: The results indicate that smokeless tobacco (Swedish snus) affects the developing autonomic nervous system during gestation. Even if exposure is interrupted during the first or second trimester, effects in autonomic cardiac regulation are seen in the 1-2 month-old infant. This underlines the importance of abstaining from all types of tobacco use during the whole pregnancy. Our findings may also have more general relevance to other routes by which nicotine can be delivered to a fetus and newborn.

Cytokine and Chemokine Expression in CSF May Differentiate Viral and Autoimmune NMDAR Encephalitis in Children.

Childhood encephalitis is a potentially devastating condition with significant morbidity and mortality. Researchers currently lack biomarkers for differentiating infectious encephalitis from those with autoimmune causes which may delay adequate treatment. The authors studied the possibility of using cerebrospinal fluid cytokine and chemokine levels for this purpose. Children admitted to hospital care fulfilling criteria for encephalitis were prospectively included. Children who underwent lumbar puncture but were not classified as central nervous system infections served as controls. Cytokine and chemokine levels in the cerebrospinal fluid obtained upon initial presentation were analyzed using Luminex technology. In children with infectious encephalitis (n = 13), the cerebrospinal fluid displayed markedly elevated mean levels of IL6, IL7, and IL13 as compared to N-methyl-D-aspartate receptor (NMDAR) encephalitis (n = 4) and controls (n = 13). The expression of IL6 appeared to precede that of IL13. Analysis of selected cerebrospinal fluid cytokines may thus allow differential diagnosis of infectious and NMDAR encephalitis already at the initial lumbar puncture and enable immediate therapy.

Morning glory disc anomaly in childhood - a population-based study.

PURPOSE: To report prevalence, ocular characteristics and coexisting neurological, behavioural, somatic and neuroradiological abnormalities in children and adolescents with morning glory disc anomaly (MGDA). METHODS: In a cross-sectional population-based study, 12 patients with MGDA, aged 2-20 years, were identified. All 12 agreed to ophthalmological assessments including visual functions, refraction, fundus photography, optical coherence tomography (OCT) and ocular motor score (OMS). Neurological examinations and behavioural/developmental screening were carried out. Data from previous or new neuroradiological investigations were collected. RESULTS: The prevalence of MGDA was 2.6/100 000. MGDA was unilateral in 11/12 patients with a best-corrected visual acuity (BCVA) in the MGDA eye ranging from hand motion to 0.65 (median 0.06). Severe microphthalmus prevented unilaterality to be determined in one adolescent. All patients had a binocular BCVA of ≥0.5. OMS showed abnormalities in pupil response, vestibulo-ocular reflex, stereo visual acuity, strabismus and convergence. OCT revealed peripapillary or macular oedema in 5/8 patients and foveal aplasia in 3/8 patients. Three patients had extensive capillary hemangiomas, of which one had PHACES syndrome and one had additional cerebrovascular anomalies and corpus callosum agenesis. Neuroradiology showed craniovascular anomalies in two patients. Neurology was mostly normal. Behavioural/developmental screening showed attention deficit hyperactivity disorder in one patient. CONCLUSIONS: The prevalence data, previously not reported, of morning glory disc anomaly was 2.6/100 000. Coexisting retinal peripapillary or macular oedema was common, as were cerebral abnormalities and/or cutaneous vascular malformations. The associated findings may not be discovered through routine ophthalmological examination why OCT and neuroimaging are called for.

Characterising seizures in anti-NMDA-receptor encephalitis with dynamic causal modelling.

We characterised the pathophysiology of seizure onset in terms of slow fluctuations in synaptic efficacy using EEG in patients with anti-N-methyl-d-aspartate receptor (NMDA-R) encephalitis. EEG recordings were obtained from two female patients with anti-NMDA-R encephalitis with recurrent partial seizures (ages 19 and 31). Focal electrographic seizure activity was localised using an empirical Bayes beamformer. The spectral density of reconstructed source activity was then characterised with dynamic causal modelling (DCM). Eight models were compared for each patient, to evaluate the relative contribution of changes in intrinsic (excitatory and inhibitory) connectivity and endogenous afferent input. Bayesian model comparison established a role for changes in both excitatory and inhibitory connectivity during seizure activity (in addition to changes in the exogenous input). Seizures in both patients were associated with a sequence of changes in inhibitory and excitatory connectivity; a transient increase in inhibitory connectivity followed by a transient increase in excitatory connectivity and a final peak of excitatory-inhibitory balance at seizure offset. These systematic fluctuations in excitatory and inhibitory gain may be characteristic of (anti NMDA-R encephalitis) seizures. We present these results as a case study and replication to motivate analyses of larger patient cohorts, to see whether our findings generalise and further characterise the mechanisms of seizure activity in anti-NMDA-R encephalitis.

Viral triggering of anti-NMDA receptor encephalitis in a child - an important cause for disease relapse.

Herpes simplex encephalitis (HSE) in children is a potentially devastating condition which is occasionally complicated by a clinical relapse. An autoimmune component has long been suspected in these relapses and recent findings suggest that antibodies against N-methyl-D-aspartate receptors (NMDARs) may be part of this mechanism. We here report an 11 months old girl with acute HSE and with negative NMDAR antibody serology at presentation who after an initial response to antiviral treatment deteriorated with seizures, abnormal movements, focal neurologic deficits and psychiatric symptoms. We show that this relapse occurred as production of NMDAR antibodies developed and that clinical improvement followed immunotherapy with a concomitant decrease in NMDAR antibody titers in CSF. She also developed a characteristic 15-20 Hz activity over both hemispheres which has been previously described as an electroencephalographic presentation of anti-NMDAR encephalitis. We conclude that relapse or persisting symptoms in HSE in children may represent an immune-mediated mechanism rather than a viral reactivation and that NMDAR antibodies should be analyzed as this may be of importance for the choice of therapy.