Five-year outcome of children with idiopathic nephrotic syndrome: the NEPHROVIR population-based cohort study.

BACKGROUND: The optimal therapeutic regimen for children at onset of idiopathic nephrotic syndrome (INS) is still under debate. A better knowledge of the disease's course is necessary to design more appropriate and/or personalized treatment protocols. METHODS: We report the 5-year outcome of patients included from December 2007 to May 2010 in the prospective multicentric and multiethnic population-based NEPHROVIR study. Patients were treated at onset according to the French steroid protocol (3990 mg/m2, 18 weeks). Data were collected at 5 years or last follow-up. RESULTS: Out of the 188 children with nephrotic syndrome (121 boys, 67 girls; median age 4.1 years), 174 (93%) were steroid-sensitive. Six percent of steroid-sensitive patients required intravenous steroid pulses to get into remission. Relapse-free rate for steroid-sensitive patients was 21% (36/174) at last follow-up (median 72 months). A first relapse occurred in138 steroid sensitive patients (79%) with a median time of 8.3 months (IQ 3.4-11.3). Out of the 138 relapsers, 43 were frequent relapsers. Age at onset below 4 years was the only predictive factor of relapse, while gender, ethnicity, and delay to first remission were not. At 96 months of follow-up, 83% of frequent relapsers were still under steroids and/or immunosuppressive drugs. CONCLUSIONS: The treatment of the first flare deserves major improvements in order to reduce the prevalence of relapsers and the subsequent long-lasting exposure to steroids and immunosuppression.

Safety of Obinutuzumab in Children With Autoimmune Encephalitis and Early B-Cell Repopulation on Rituximab.

BACKGROUND: Rituximab (RTX) resistance or early B-cells repopulation were observed in children but only few publications reported the use of Obinutuzumab and no recommendations were made concerning the dosage for children. METHODS: This study was a single-center retrospective cohort study of all the children followed-up in the Pediatric Neurology Department of Necker-Enfants malades Hospital in Paris, France, and treated with obinutuzumab, between November 1, 2019, and November 1, 2021. RESULTS: A total of eight children (three females, median age 4.5 years) were treated. Seven patients presented with autoimmune encephalitis and one with myeloradiculitis. The median delay of B-cell repopulation after a course of RTX was 87 days (range 41 to 160). A switch to obinutuzumab (anti-CD20) was performed for eight children. The median duration between the first RTX infusion and obinutuzumab administration was 6.6 months. The dosage regimen for obinutuzumab was one infusion of 1000 mg/1.73 m2, that is to say 580 mg/m2 (maximum 1000 mg/infusion), by extrapolation from the adult dosage. The median delay of B-cell repopulation after one course of obinutuzumab was 230 days (range 66 to 303 days) vs 87 days after one course of RTX (P < 0.01). None of the patients presented side effects with obinutuzumab treatment. All patients had a favorable evolution at the last-follow up. Median follow-up was 1.6 years. CONCLUSIONS: This study reports the use of obinutuzumab in neurological inflammatory diseases in a pediatric population. Obinutuzumab seems to have a better biological efficacy than RTX with a longer time of B-cell repopulation.

How can cobalamin injections be spaced in long-term therapy for inborn errors of vitamin B(12) absorption?

Inborn errors of cobalamin (Cbl, vitamin B(12)) absorption include hereditary intrinsic factor deficiency (HIFD) and Imerslund-Gräsbeck disease (IGD). HIFD is secondary to mutations in the HIF gene while IGD is due to mutations in one of the 2 subunits of the intrinsic factor receptor that is cubilin (CUBN) or amnionless (AMN). These disorders lead to intracellular Cbl depletion which in turn causes megaloblastic bone marrow failure, accumulation of homocysteine and methylmalonic acid (MMA), and methionine depletion. The clinical presentation reflects Cbl deficiency, with gastrointestinal symptoms, pancytopenia, and megaloblastic anemia. Mixed proteinuria, when it is present is strongly suggestive of IGD. Accurate diagnosis is always an emergency because early detection and treatment with life-long parenteral pharmacological doses of hydroxocobalamin are life saving and prevent further deterioration. However, the optimal frequency for cobalamin injections as a maintenance therapy is poorly reported. In order to evaluate the optimal maintenance schedule of cobalamin injections, we retrospectively collected clinical, biological, molecular and treatment data on 7 patients affected with congenital Cbl malabsorption. Unlike previous recommendations, we showed that a maintenance dosage of 1 mg cobalamin twice a year was enough to ensure a normal clinical status and keep the hematological and metabolic parameters in the normal range. These data suggest that patients affected with inborn errors of cobalamin absorption may be safely long-term treated with cobalamin injections every 6 months with careful follow-up of hematological and metabolic parameters. This maintenance regime is beneficial because the patients' quality of life improves.

Risk-adapted therapy for infantile myofibromatosis in children.

BACKGROUND: Infantile myofibromatosis is characterized by proliferation of benign fibrous tumors arising in skin, subcutaneous tissue, muscle, or bone. Solitary and multicentric forms are described. Few reports are available in the pediatric population. PROCEDURE: To improve the knowledge of this rare tumor in infants, the authors present a series of all cases of infantile myofibromatosis treated in their institution over a 9-year period in order to propose treatment guidelines based on their experience and a review of the literature. RESULTS: The authors report a series of 9 cases, 8 solitary forms and 1 multicentric form with visceral involvement treated from 2000 to 2009. Median age was 10 months (range: 2 days-14 years). Six patients with solitary forms underwent primary surgical resection leading to remission. Only biopsy was performed in 1 case, followed by tumor regression with no recurrence. The last patient with a solitary form was treated by chemotherapy and then surgery allowing remission. The patient with a multicentric form presented complete regression of tumors after 1 year of vinblastine and methotrexate combination chemotherapy. CONCLUSIONS: Infantile myofibromatosis is a rare soft tissue tumor mainly concerning infants. Surgery is the treatment of choice for solitary forms when excision is possible. Close follow-up may be proposed in the case of inoperable sites. In multicentric life-threatening forms, chemotherapy promotes tumor regression and the vinblastine and methotrexate combination is effective with few long-term adverse effects.

Indications and Safety of Rituximab in Pediatric Neurology: A 10-Year Retrospective Study.

BACKGROUND: RTX is used off-label in several neurological inflammatory diseases in adults children patients. We conducted a study to assess indications and safety of rituximab (RTX) for children and to identify risk factors for early B-cell repopulation. METHODS: A single-center retrospective study of children treated with RTX for a neurological disease between May 31, 2010, and May 31, 2020, was performed. RESULTS: A total of 77 children (median age, 8.9 years) were included. RTX was mostly used as second-line therapy in all groups of diseases (68%). Median dose was 1500 mg/m2 for each patient. There were 13 clinical relapses (17%), 5 when B-cell depletion was complete. Adverse events were present in 6% of the cases. The factors influencing early B-cell repopulation were the recent infusion of intravenous Ig (P < 0.01) and the administration of less than 1500 mg/m2 during the first RTX treatment (P = 0.04). The median time to B-cell repopulation seemed to be shorter (160 vs 186 days) when patients had plasmapheresis even when a 48-hour delay was observed with RTX infusions. CONCLUSIONS: This study confirms the good tolerance of RTX in the treatment of specific neurological disorders in a pediatric population. It also highlights risk factors for early B-cell repopulation and underlines the importance of B-cell monitoring.

Varicella post-exposure management for pediatric oncology patients.

INTRODUCTION: The objective was to evaluate health care providers' (HCP) adherence to and efficacy of varicella post-exposure prophylaxis (PEP) recommendations. It was an observational, prospective, multicenter study set in Ile-de-France, France. METHODS: All children under 18 with a cancer diagnosis, currently or within 3months of receiving cancer treatment, regardless of varicella zoster virus (VZV) serostatus or previous personal history of varicella, were eligible. Study participants with significant exposure were reviewed prospectively for PEP indications. Main outcome measures were the percentage of exposure situations for which HCP were guideline-compliant, the proportion of available VZV serostatuses and the incidence of breakthrough varicella after different PEP approaches. RESULTS: A total of 51 patients from 15 centers were enrolled after 52 exposure episodes. Median age at exposure was 5 years (range, 1-15). Exposure within the household led to 38% of episodes. Prophylactic treatment consisted in specific anti-VZV immunoglobulins (V-ZIG) (n=19) or in oral aciclovir (n=15). No prophylactic treatment was given for 18 patients (in compliance, n=16). In compliance with guidelines, 17 patients received V-ZIG, 11 did not develop varicella (65%, [95% CI, 39-90%]); 15 received aciclovir, 13 did not develop varicella (87%, [95% CI, 67-100%]). Breakthrough varicella occurred in 11 patients, with simple clinical course in all cases; in 8/47 (17%) episodes when PEP was guideline-compliant versus 3/5 (60%) when not. DISCUSSION: Recommendations have been respected and are efficient. PEP needs to be standardized and a study carried out to define the optimal approach. Anti-VZV immunization of seronegative family members should be encouraged.

[Care pathways before diagnosis in children and adolescents with malignancies]. / Parcours prédiagnostique des enfants et adolescents atteints de tumeurs solides.

OBJECTIVE: to describe medical care pathways between first symptoms and first oncologic consultation in children and adolescents with solid cancers in order to analyze a possible relationship between delayed diagnosis and its potential consequences. METHODS: Retrospective study on patients aged less than 25 years at first consultation in the oncology department of pediatric, adolescent and young adult in Institut Curie during one year. Were collected data on cancer characteristics, components of care pathways, and sociodemographic parents' characteristics. RESULTS: Hundred and six patients were selected, with median age of 6 years. Most represented tumor was low-grade cerebral tumor (17.0%). Pain was the most frequent type of disorder observed as first sign (34.3% of patients). First signs were unspecific in only 27.6% of cases. Most patients were first seen by a general practitioner (29.3%). Median total time to diagnosis was one month [ranges: 0-64]. Median number of consultations before referral to oncology expert was 2 [0-7]. Retrospective analysis found a possible delayed diagnosis in 44.3% of patients, with potential vital and functional risks estimated respectively at 14.1 and 20.7% of overall population. Time to diagnosis was shorter if father was of foreign nationality vs. French (34 days vs. 72 days, P<0.05), and longer if parents were separated (74.5 days vs. 42.5 days, P<0.03). CONCLUSIONS: Overall time to diagnosis is quite fast, even if first signs of pediatric cancers are very polymorphic. Some medical and sociodemographic factors could influence characteristics of care pathways.

Effects of interleukin-10 on neonatal excitotoxic brain lesions in mice.

Interleukin-10 markedly reduces production of proinflammatory cytokines by activated microglia or macrophages and downregulates the expression of activating molecules on these cells. In studies performed in adults or in cell cultures, interleukin-10 protected against hypoxic-ischemic neuronal death and against lipopolysaccharide-mediated oligodendrocyte cell death. Furthermore, it was recently shown that interleukin-10 counteracts metabolic and microcirculatory effects of hypoxia-ischemia in the perinatal pig brain. Intracerebral injection of the glutamatergic analogue ibotenate to newborn mice induces cortical plate and white matter lesions mimicking the brain damage associated with cerebral palsy, and pretreatment with proinflammatory cytokines such as interleukin-1-beta or with interleukin-9 significantly exacerbates these lesions. The present study evaluated the influence of interleukin-10 on ibotenate-induced brain lesions in newborn mice under basal conditions or after exposure to cytokines. Intraperitoneal injection of interleukin-10 for 3 days following ibotenate significantly reduced the size of excitotoxic brain lesions. Intraperitoneal injection of neutralizing anti-interleukin-10 antibody for 3 days following ibotenate had no detectable effect and no difference in ibotenate-induced brain lesion size was found between wild type pups and pups deleted for the interleukin-10 gene, suggesting that endogenous interleukin-10 in newborn mice may have limited effects. Co-administration of intracerebral ibotenate and interleukin-10 had no detectable effect, arguing against a direct neuroprotective effect of interleukin-10 on neurons. While pretreatment with intraperitoneal interleukin-10 alone had no detectable effect on excitotoxic brain lesions, interleukin-10 given with interleukin-1-beta pretreatment blunted the toxic effects of interleukin-1-beta. On the other hand, combined pretreatment with IL-9 and anti-IL-10 antibody largely reversed the exacerbating effect of IL-9 on excitotoxic brain lesions. Altogether, these data suggest that, in newborn mice, exogenous interleukin-10 can be neuroprotective when acting in an inflammatory context.

Unsuspected glucose-6-phosphate dehydrogenase deficiency presenting as symptomatic methemoglobinemia with severe hemolysis after fava bean ingestion in a 6-year-old boy.

We report the occurrence of symptomatic methemoglobinemia in a previously healthy boy, who presented with severe acute hemolysis after fava bean ingestion. The methemoglobinemia revealed a previously unrecognized glucose-6-phosphate dehydrogenase (G6PD) deficiency. We discuss the pathophysiology of severe methemoglobinemia when associated with acute hemolysis, favism, and the common African G6PD A-variant [G6PD, VAL68MET, ASN126ASP]. In conclusion, screening for G6PD deficiency must be considered in symptomatic methemoglobinemia, especially in young boys, when associated with intravascular hemolysis.

Neuronal TGF-beta1 mediates IL-9/mast cell interaction and exacerbates excitotoxicity in newborn mice.

Intraneocortical injection of ibotenate, a glutamate analog, in newborn mice produces damage mimicking lesions observed in human infants with cerebral palsy. Previous research using this model has demonstrated that pretreatment with IL-9, a Th2 cytokine, significantly exacerbated excitotoxic brain lesions. The goal of this study is to identify the underlying pathophysiological mechanism of lesion formation. Pretreatment with TGF-beta1 produced the same effects as IL-9 on ibotenate-induced lesions. IL-9 effects were abolished when a specific TGF-beta1 neutralizing antibody is administered at the same time. Real-time PCR, Western blot, and immunohistochemistry showed that pretreatment with IL-9 increased TGF-beta1 neocortical expression. In vitro studies using real-time PCR and immunocytochemistry demonstrated that neurons were a major contributor in IL-9-induced increase of TGF-beta1. In c-Kit mast cell-deficient mice, TGF-beta1 failed to exacerbate excitotoxic brain lesions, suggesting a key role of mast cells in TGF-beta1 effects. A specific inhibitor of mast cell degranulation and histamine receptor blockers abrogated TGF-beta1 effects on excitotoxic lesions, providing further evidence of mast cell involvement and the role of mast cell-derived histamine. Finally, in vitro studies using a mast cell line showed that TGF-beta1 increased histamine in the supernatant. In aggregate, these data support the notion that neuronal TGF-beta1 plays a key role in the IL-9/mast cell interaction, which leads to an exacerbation of neonatal excitotoxic damage through an increased extracellular histamine concentration. The identification of this pathway, if confirmed in human neonates, might have important implications for understanding and preventing cerebral palsy.

Animal models of shaken baby syndrome: revisiting the pathophysiology of this devastating injury.

To better understand outcomes after early brain injuries, studies must address multiple variables including age at injury, the mechanisms and severity of injury, environmental factors (before and after injury) and developmental factors. Animal models are helpful for elucidating these different aspects. First, this paper describes a new model of shaken baby syndrome (SBS) in mice, without impact or hypoxia. Mortality was 27%; 75% of survivors had focal brain lesions consisting of haemorrhagic or cystic lesions of the white matter, corpus callosum and cerebellum. All shaken animals, with and without focal lesions, showed delayed white matter atrophy. White matter damage and atrophy were reduced by pre-treatment with an NMDA receptor antagonist, indicating that excess glutamate release contributed to the pathophysiology of the lesions. Secondly, it discusses data on neuroprotection after early brain injuries; drugs targeting the NMDA receptors cannot be used in clinical practice but indirect neuroprotection strategies including anti-NO, anti-free radicals and trophic factors hold promise for limiting the excitotoxic white matter damage induced by early injury, in particular caused by shaking, during brain development. Thirdly, it describes two experimental models in which SBS outcomes are determined when the trauma is combined with environmental influences, namely medications during the acute phase, most notably anti-epileptic drugs and rearing conditions.

Neuroimaging of intraparenchymal lesions predicts outcome in shaken baby syndrome.

OBJECTIVE: Studies of long-term outcome on nonaccidental head injury (NAHI) in young children have shown severe neurodevelopmental sequelae in most cases. For improving the knowledge of outcome and for identifying prognostic factors, additional clinical and cerebral imaging data are needed. The aim of this study was to describe clinical and imaging features over time and to consider their value for predicting neurodevelopmental outcome. METHODS: A retrospective medical record review was conducted of 23 children with confirmed NAHI, for whom an extended follow-up of 2.5 to 13 years (mean: 6 years) was contemplated. Glasgow Coma Scale scores, severity of retinal hemorrhages, presence of skull fractures, cranial growth deceleration, and sequential neuroimaging data (computed tomography and/or magnetic resonance imaging) were compared with patterns of clinical evolution assessed by the Glasgow Outcome Scale. RESULTS: Clinical outcome showed that 14 (61%) children had severe disabilities, 8 (35%) had moderate disabilities, and 1 (4%) was normal. A low initial Glasgow Coma Scale score, severe retinal hemorrhages, presence of skull fracture, and cranial growth deceleration were significantly associated with poor developmental outcome. Eighteen of the 23 patients had abnormal magnetic resonance imaging scans. This examination disclosed atrophy when performed beyond 15 days of injury. Atrophy seemingly resulted from various brain lesions, namely, contusions, infarcts, and other lesions within the white matter. Presence of intraparenchymal brain lesions within the first 3 months was significantly associated with neurodevelopmental impairment. Severity of motor and cognitive dysfunctions was related to the extent of intraparenchymal lesions. CONCLUSIONS: Early clinical and radiologic findings in NAHI are of prognostic value for neurodevelopmental outcome.

Melatoninergic neuroprotection of the murine periventricular white matter against neonatal excitotoxic challenge.

Periventricular leukomalacia is one of the main causes of cerebral palsy. Perinatal white matter lesions associated with cerebral palsy appears to involve glutamate excitotoxicity and excess free radical production. When injected intracerebrally into newborn mice, the glutamatergic analog ibotenate induces white matter cysts mimicking human periventricular leukomalacia. Melatonin acts on specific receptors. It also exhibits intrinsic free radical scavenging properties. The goal of the present study is to determine whether melatonin can protect against excitotoxic lesions induced by ibotenate in newborn mice. Mice that received intraperitoneal melatonin had an 82% reduction in size of ibotenate-induced white matter cysts when compared with controls. Although melatonin did not prevent the initial appearance of white matter lesions, it did promote secondary lesion repair. Axonal markers supported the hypothesis that melatonin induced axonal regrowth or sprouting. The protective effects of melatonin were suppressed by coadministration of luzindole, a melatonin receptor antagonist. Forskolin, an adenylate cyclase activator, prevented the protective effects of melatonin; inhibitors of protein kinase C and mitogen-associated protein kinase had no detectable effect. Melatonin and derivatives that block cAMP production through activation of melatonin receptors could represent new avenues for treating human periventricular leukomalacia.