Recurrent Stroke as a Presenting Feature of Takayasu Arteritis in an Adolescent: A Case Report and Literature Review.

Takayasu arteritis is a large vessel vasculitis, characterized by granulomatous inflammation of arterial vessels, that typically affects the aorta, its main branches and pulmonary arteries. Disease diagnosis is a challenge and requires awareness of the condition, as clinical signs can be not specific. We report a case of an adolescent with recurrent stroke diagnosed with Takayasu arteritis. A diagnosis of Takayasu arteritis was established due to angiographic findings in the magnetic resonance angiography in conjunction with systolic blood pressure discrepancy, arterial hypertension and increased acute phase reactants. Takayasu arteritis is a rare cause of ischemic stroke in children. However, stroke may be the first manifestation of the disease. Clinical experience and multidisciplinary approach, including aggressive treatment, is essential for the favourable outcome of the disease and the reduction of the associated morbidity and mortality.

Natural history of Wolcott-Rallison syndrome: A systematic review and follow-up study.

BACKGROUND AND AIMS: To systematically review the literature for reports on Wolcott-Rallison syndrome, focusing on the spectrum and natural history, genotype-phenotype correlations, patient and native liver survival, and long-term outcomes. METHODS: PubMed, Livio, Google Scholar, Scopus and Web of Science databases were searched. Data on genotype, phenotype, therapy, cause of death and follow-up were extracted. Survival and correlation analyses were performed. RESULTS: Sixty-two studies with 159 patients met the inclusion criteria and additional 30 WRS individuals were collected by personal contact. The median age of presentation was 2.5 months (IQR 2) and of death was 36 months (IQR 50.75). The most frequent clinical feature was neonatal diabetes in all patients, followed by liver impairment in 73%, impaired growth in 72%, skeletal abnormalities in 59.8%, the nervous system in 37.6%, the kidney in 35.4%, insufficient haematopoiesis in 34.4%, hypothyroidism in 14.8% and exocrine pancreas insufficiency in 10.6%. Episodes of acute liver failure were frequently reported. Liver transplantation was performed in six, combined liver-pancreas in one and combined liver-pancreas-kidney transplantation in two individuals. Patient survival was significantly better in the transplant cohort (p = .0057). One-, five- and ten-year patient survival rates were 89.4%, 65.5% and 53.1%, respectively. Liver failure was reported as the leading cause of death in 17.9% of cases. Overall survival was better in individuals with missense mutations (p = .013). CONCLUSION: Wolcott-Rallison syndrome has variable clinical courses. Overall survival is better in individuals with missense mutations. Liver- or multi-organ transplantation is a feasible treatment option to improve survival.

Neuropsychiatric manifestations associated with Juvenile Systemic Lupus Erythematosus: An overview focusing on early diagnosis.

Juvenile systemic lupus erythematosus (jSLE) is a chronic multisystem inflammatory disease that manifests before the age of 16 years, following a remitting - relapsing course. The clinical presentation in children is multifaceted, most commonly including constitutional, hematological, cutaneous, renal, and neuropsychiatric symptoms. Neuropsychiatric manifestations range widely, affecting approximately 14-95 % of jSLE patients. They are associated with high morbidity and mortality, particularly at a younger age. Headaches, seizures, cognitive dysfunction, and mood disorders are the most frequent neuropsychiatric manifestations. The pathophysiological mechanism is quite complex and has not yet been fully investigated, with autoantibodies being the focus of research. The diagnosis of neuropsychiatric jSLE remains challenging and exclusionary. In this article we review the clinical neuropsychiatric manifestations associated with jSLE with the aim that early diagnosis and prompt treatment is achieved in children and adolescents with the disease.

Branched-chain amino acids as adjunctive-alternative treatment in patients with autism: a pilot study.

The branched-chain amino acid (BCAA) is a group of essential amino acids that are involved in maintaining the energy balance of a human being as well as the homoeostasis of GABAergic, glutamatergic, serotonergic and dopaminergic systems. Disruption of these systems has been associated with the pathophysiology of autism while low levels of these amino acids have been discovered in patients with autism. A pilot open-label, prospective, follow-up study of the use of BCAA in children with autistic behaviour was carried out. Fifty-five children between the ages of 6 and 18 participated in the study from May 2015 to May 2018. We used a carbohydrate-free BCAA-powdered mixture containing 45·5 g of leucine, 30 g of isoleucine and 24·5 g of valine in a daily dose of 0·4 g/kg of body weight which was administered every morning. Following the initiation of BCAA administration, children were submitted to a monthly psychological examination. Beyond the 4-week mark, BCAA were given to thirty-two people (58·18 %). Six of them (10·9 %) discontinued after 4-10 weeks owing to lack of improvement. The remaining twenty-six children (47·27 %) who took BCAA for longer than 10 weeks displayed improved social behaviour and interactions, as well as improvements in their speech, cooperation, stereotypy and, principally, their hyperactivity. There were no adverse reactions reported during the course of the treatment. Although these data are preliminary, there is some evidence that BCAA could be used as adjunctive treatment to conventional therapeutic methods for the management of autism.

The association of serum vitamin D concentrations in paediatric migraine.

INTRODUCTION: Migraine is a neurologic condition characterized by hypersensitivity to auditory, olfactory, visual, and cutaneous stimuli; vomiting and nausea; and severe headache. It is the most frequent headache syndrome in children and can be categorized in chronic and/or episodic. Multiple dietary supplements have been inaugurated for the management of migraine, the most prevalent of which is vitamin D. BACKGROUND: In recent years, vitamin D deficiency has been a global public health problem, with 30-80% of the worldwide population having vitamin D deficiency. The significant role of vitamin D in neurological disorders is underlined by its key role in the brain function of the central nervous system (CNS). Current approaches in paediatric neurology include nonsteroidal anti-inflammatory drugs (NSAID) for the treatment of paediatric migraine, among others. Vitamin D is one of the dietary factors that has been linked to migraine, however, this association has mostly been examined in the adult population. OBJECTIVE: The aim of this study is to investigate the association between serum vitamin D and paediatric migraine by conducting a review of existing literature. The main question is described with the PICO format (population, intervention, control, and outcomes), while the assessment of the present research is under the PRISMA guidelines for systematic reviews. RESULTS/CONCLUSION: A systematic review of the literature reveals a remarkable association between vitamin D and migraine presentation in the paediatric population, affecting the frequency and duration of the episodes. That being the case, vitamin D supplementation could potentially improve the quality of life of paediatric patients suffering from migraine headaches.

Pediatric Optic Pathway Gliomas: A Report From Northern Greece.

Optic pathway gliomas (OPGs) are the most common pediatric optic nerve tumors. Their behavior ranges between rapid growth, stability, or spontaneous regression. Τhey are characterized by low mortality albeit with significant morbidity. We present the characteristics, management, and outcome of 23 OPG patients (16 females, median age: 4.8 y) managed in a Pediatric Oncology Department in Northern Greece over a 25-year period. Overall, 57% had a background of neurofibromatosis type 1. Diagnosis was based on imaging (10 patients) or biopsy (13 patients). Presenting symptoms were mostly visual impairment/squint (52%). Proptosis/exophthalmos, raised intracranial pressure, and headache were also noted. In 2 occasions, it was detected with surveillance magnetic resonance imaging in the context of neurofibromatosis type 1. Eight patients had unilateral and 2 bilateral optic nerve tumors (Modified Dodge Classification, stage 1a/1b), 3 had chiasmatic (stage 2a/b), and 10 had multiple tumors (stage 3/4). Predominant histology was pilocytic astrocytoma (77%). Management included: observation (4), chemotherapy only (9), surgery only (3), or various combinations (7). Chemotherapy regimens included vincristine and carboplatin, vinblastine, or bevacizumab with irinotecan. Most patients demonstrated a slow disease course with complete response/partial response to chemotherapy and/or surgery, whereas 39% presented ≥1 recurrences. After a median follow-up of 8.5 years (range to 19 y), 20 patients (87%) are still alive with stable disease, in partial/complete remission, or on treatment.

Blood pressure in children with sickle cell disease is higher than in the general pediatric population.

BACKGROUND: Sickle cell disease (SCD) is associated with an increased risk of cardiovascular disease that may be due to a variety of possible risk factors, including abnormal blood pressure. Blood pressure (BP) of children and adolescents with SCD has been reported to be lower compared to the BP of the general pediatric population. METHODS: To confirm this prior observation, we compared reference BP values for children with SCD with reference BP values of the general pediatric population. We hypothesized that children with SCD do not have lower BPs than children without SCD. RESULTS: Systolic BP differed for both males and females, over the different age groups between pediatric subjects with and without SCD. Systolic BP was higher in children with SCD, in both obese and non-obese populations. Diastolic BP did not differ between the groups. CONCLUSIONS: Our analysis demonstrated that systolic BP values are indeed higher in children with SCD than in the general pediatric population. This finding is consistent with the most recent literature showing abnormal BP patterns in the SCD pediatric population utilizing 24-hour BP monitoring devices. This is an important step for recognizing abnormal BP as a risk factor for cardio- and neurovascular events in SCD.

Targeted Genotyping of MIS-C Patients Reveals a Potential Alternative Pathway Mediated Complement Dysregulation during COVID-19 Infection.

Complement dysregulation has been documented in adults with COVID-19 and implicated in relevant pediatric inflammatory responses against SARS-CoV-2. We propose that signatures of complement missense coding SNPs associated with dysregulation could also be identified in children with multisystem inflammatory syndrome (MIS-C). We investigated 71 pediatric patients with RT-PCR validated SARS-CoV-2 hospitalized in pediatric COVID-19 care units (November 2020-March 2021) in three major groups. Seven (7) patients suffered from MIS-C (MIS-C group), 32 suffered from COVID-19 and were hospitalized (admitted group), whereas 32 suffered from COVID-19, but were sent home. All patients survived and were genotyped for variations in the C3, C5, CFB, CFD, CFH, CFHR1, CFI, CD46, CD55, MASP1, MASP2, MBL2, COLEC11, FCN1, and FCN3 genes. Upon evaluation of the missense coding SNP distribution patterns along the three study groups, we noticed similarities, but also considerably increased frequencies of the alternative pathway (AP) associated with SNPs rs12614 CFB, rs1061170, and rs1065489 CFH in the MIS-C patients. Our analysis suggests that the corresponding substitutions potentially reduce the C3b-inactivation efficiency and promote slower and weaker AP C3bBb pre-convertase assembly on virions. Under these circumstances, the complement AP opsonization capacity may be impaired, leading to compromised immune clearance and systemic inflammation in the MIS-C syndrome.

Neuromuscular diseases and their cardiac manifestations under the spectrum of cardiovascular imaging.

Neuromuscular diseases (NMDs) include a broad spectrum of disorders that affect motor unit in every possible site, extending from the cell body of peripheral nerves to the muscle. The different lesion sites make this group of inherited disorders difficult to diagnose. Many NMDs, especially those involving skeletal muscles, can present significant cardiovascular complications, ranging from rhythm disturbances to the development of dilated or hypertrophic cardiomyopathy. Heart disease represents a major cause of morbidity and mortality among NMD patients, underlining the vital need for further familiarization with the pathogenesis and assessment of cardiac involvement. Cardiovascular imaging is the cornerstone for the evaluation of heart disorders in NMDs, with conventional echocardiography still offering a portable, affordable, and easily accessible solution. Meanwhile, newer echocardiographic techniques such as speckle tracking imaging in combination with cardiac magnetic resonance add new insights into further substrate characterization. The purpose of this review is to offer a brief presentation of the main NMDs and their cardiovascular complications, as well as the presentation of data that highlight the importance of cardiovascular imaging in early diagnosis, monitoring, and prognosis of these patients. Lastly, the authors provide a simple guide about which clinical features, imaging findings, and follow-up plan to adopt in each myopathic disorder.

Consensus statement on enzyme replacement therapy for mucopolysaccharidosis IVA in Central and South-Eastern European countries.

BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA), or Morquio A syndrome, is a rare inherited metabolic disorder caused by deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. A progressive systemic skeletal chondrodysplasia, leading to significant morbidity and reduced life expectancy is the main clinical feature of this multisystemic disease. Although enzyme replacement therapy with elosulfase alfa is established in Europe, the rarity of disease and other factors still set hurdles in having patients treated in some countries. Aim of this statement is to provide evidence-based guidance for the enzyme replacement treatment of Morquio A patients, harmonizing recommendations from published guidelines with the real-life clinical practice in the Central and South-Eastern European region. PARTICIPANTS: The Consensus Group, convened by 8 Steering Committee (SC) members from 7 Central and South-Eastern European countries, consisted of a multidisciplinary group of 17 experts in the management of MPS in Central and South-Eastern Europe. CONSENSUS PROCESS: The SC met in a first virtual meeting with an external scientific coordinator, to discuss on clinical issues to be analyzed in guidance statements. Statements were developed by the scientific coordinator, evaluated by the SC members in a first modified-Delphi voting and adapted accordingly, to be submitted to the widest audience in the Consensus Conference. Following discussion and further modifications, all participants contributed to a second round of modified-Delphi voting. RESULTS: Nine of ten statements, concerning general guidelines for management of MPS IVA patients and specific recommendations for treatment, received final consensus. CONCLUSIONS: European guidelines and evidence-based recommendations for Morquio A patients should be considered in the real life of Central and South-Eastern European countries and adapted to unique clinical practice approaches and criteria for patients' access to treatment and reimbursement in the region.

Integrative Approach to Predict Severity in Nonketotic Hyperglycinemia.

OBJECTIVE: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inherited neurometabolic disorder with variable clinical course and severity, ranging from infantile epileptic encephalopathy to psychiatric disorders. A precise phenotypic characterization and an evaluation of predictive approaches are needed. METHODS: Longitudinal clinical and biochemical data of 25 individuals with NKH from the patient registry of the International Working Group on Neurotransmitter Related Disorders were studied with in silico analyses, pathogenicity scores, and molecular modeling of GLDC and AMT variants. RESULTS: Symptom onset (p < 0.01) and diagnosis occur earlier in life in severe NKH (p < 0.01). Presenting symptoms affect the age at diagnosis. Psychiatric problems occur predominantly in attenuated NKH. Onset age ≥ 3 months (66% specificity, 100% sensitivity, area under the curve [AUC] = 0.87) and cerebrospinal fluid (CSF)/plasma glycine ratio ≤ 0.09 (57% specificity, 100% sensitivity, AUC = 0.88) are sensitive indicators for attenuated NKH, whereas CSF glycine concentration ≥ 116.5µmol/l (100% specificity, 93% sensitivity, AUC = 0.97) and CSF/plasma glycine ratio ≥ 0.15 (100% specificity, 64% sensitivity, AUC = 0.88) are specific for severe forms. A ratio threshold of 0.128 discriminates the overlapping range. We present 10 new GLDC variants. Two mild variants resulted in attenuated, whereas 2 severe variants or 1 mild and 1 severe variant led to severe phenotype. Based on clinical, biochemical, and genetic parameters, we propose a severity prediction model. INTERPRETATION: This study widens the phenotypic spectrum of attenuated NKH and expands the number of pathogenic variants. The multiparametric approach provides a promising tool to predict disease severity, helping to improve clinical management strategies. ANN NEUROL 2022;92:292-303.

International Prevalence and Mechanisms of SARS-CoV-2 in Childhood Arterial Ischemic Stroke During the COVID-19 Pandemic.

BACKGROUND: Data from the early pandemic revealed that 0.62% of children hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had an acute arterial ischemic stroke (AIS). In a larger cohort from June 2020 to December 2020, we sought to determine whether our initial point estimate was stable as the pandemic continued and to understand radiographic and laboratory data that may clarify mechanisms of pediatric AIS in the setting of SARS-CoV-2. METHODS: We surveyed international sites with pediatric stroke expertise to determine numbers of hospitalized SARS-CoV-2 patients <18 years, numbers of incident AIS cases among children (29 days to <18 years), frequency of SARS-CoV-2 testing for children with AIS, and numbers of childhood AIS cases positive for SARS-CoV-2 June 1 to December 31, 2020. Two stroke neurologists with 1 neuroradiologist determined whether SARS-CoV-2 was the main stroke risk factor, contributory, or incidental. RESULTS: Sixty-one centers from 21 countries provided AIS data. Forty-eight centers (78.7%) provided SARS-CoV-2 hospitalization data. SARS-CoV-2 testing was performed in 335/373 acute AIS cases (89.8%) compared with 99/166 (59.6%) in March to May 2020, P<0.0001. Twenty-three of 335 AIS cases tested (6.9%) were positive for SARS-CoV-2 compared with 6/99 tested (6.1%) in March to May 2020, P=0.78. Of the 22 of 23 AIS cases with SARS-CoV-2 in whom we could collect additional data, SARS-CoV-2 was the main stroke risk factor in 6 (3 with arteritis/vasculitis, 3 with focal cerebral arteriopathy), a contributory factor in 13, and incidental in 3. Elevated inflammatory markers were common, occurring in 17 (77.3%). From centers with SARS-CoV-2 hospitalization data, of 7231 pediatric patients hospitalized with SARS-CoV-2, 23 had AIS (0.32%) compared with 6/971 (0.62%) from March to May 2020, P=0.14. CONCLUSIONS: The risk of AIS among children hospitalized with SARS-CoV-2 appeared stable compared with our earlier estimate. Among children in whom SARS-CoV-2 was considered the main stroke risk factor, inflammatory arteriopathies were the stroke mechanism.

The landscape of Mucopolysaccharidosis in Southern and Eastern European countries: a survey from 19 specialistic centers.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defects in genes coding for different lysosomal enzymes which degrade glycosaminoglycans. Impaired lysosomal degradation causes cell dysfunction leading to progressive multiorgan involvement, disabling consequences and poor life expectancy. Enzyme replacement therapy (ERT) is now available for most MPS types, offering beneficial effects on disease progression and improving quality of life of patients. The landscape of MPS in Europe is not completely described and studies on availability of treatment show that ERT is not adequately implemented, particularly in Southern and Eastern Europe. In this study we performed a survey analysis in main specialist centers in Southern and Eastern European countries, to outline the picture of disease management in the region and understand ERT implementation. Since the considerable number of MPS IVA patients in the region, particularly adults, the study mainly focused on MPS IVA management and treatment. RESULTS: 19 experts from 14 Southern and Eastern European countries in total responded to the survey. Results outlined a picture of MPS management in the region, with a high number of MPS patients managed in the centers and a high level of care. MPS II was the most prevalent followed by MPS IVA, with a particular high number of adult patients. The study particularly focused on management and treatment of MPS IVA patients. Adherence to current European Guidelines for follow-up of MPS IVA patients is generally adequate, although some important assessments are reported as difficult due to the lack of MPS skilled specialists. Availability of ERT in Southern and Eastern European countries is generally in line with other European regions, even though regulatory, organizational and reimbursement constrains are demanding. CONCLUSIONS: The landscape of MPS in Southern and Eastern European countries is generally comparable to that of other European regions, regarding epidemiology, treatment accessibility and follow up difficulties. However, issues limiting ERT availability and reimbursement should be simplified, to start treatment as early as possible and make it available for more patients. Besides, educational programs dedicated to specialists should be implemented, particularly for pediatricians, clinical geneticists, surgeons, anesthesiologists and neurologists.

Blood pressure and glomerular filtration rate in youth with tuberous sclerosis complex.

Renal involvement is very common in tuberous sclerosis complex (TSC) and is characterized by the development of angiomyolipoma and cysts. The aims of the present study were to assess kidney function and clinical features of renal involvement in TSC, including kidney function and blood pressure (BP) levels in children, adolescents and young adults. Non-selected patients with a definite diagnosis of TSC attending the paediatric neurology outpatient department of a tertiary hospital were included in a cross-sectional study. All participants had a renal imaging study within 6 months of ambulatory blood pressure (BP) and glomerular filtration rate (GFR) assessment. Data on demographics, history, genotype, kidney function at diagnosis and last imaging were collected. Twenty patients were enrolled in this study with a median age of 15 years (IQR range 9 to 18). About 23.5% of the participants had ambulatory hypertension. Systolic BP levels correlated significantly with GFRDTPA values despite the absence of hyperfiltration. Patients that developed hypertension and possibly those with angiomyolipoma or cysts had higher GFR levels in childhood and adolescence. All the patients with ambulatory hypertension had angiomyolipoma or cysts on renal imaging studies. CONCLUSIONS: Hypertension may present with increased frequency in young patients with kidney disease associated with TSC. Routine ambulatory BP measurement should be part of the annual clinical assessment in patients with TSC. WHAT IS KNOWN: • Nearly half of the patients with TSC have a premature decline in their renal function in their fifth decade of life. • Hypertension and hyperfiltration have been proposed as modifiable factors of progression of renal decline in patients with TSC-related renal disease. WHAT IS NEW: • Hypertension is prevalent in youth with tuberous sclerosis complex. • SBP levels have a positive relation with GFR levels within the normal range of GFRDTPA values.

Is the prevalence of thyroid disease higher in children receiving antiepileptic medication? A systematic review and meta-analysis.

PURPOSE: Antiseizure medications (ASM) have long been examined for their potential to induce thyroid dysfunction. The aim of this systematic review and meta-analysis was to assess the prevalence of thyroid disease in children up to 16 years receiving monotherapy with valproate (VPA), carbamazepine (CBZ) and levetiracetam (LEV). METHODS: PubMed/MEDLINE, Cochrane/CENTRAL databases and the gray literature were searched to identify observational studies providing the prevalence of thyroid dysfunction in the target population under VPA, CBZ, or LEV monotherapy schemes. The results were pooled using a random-effects model, and additional subgroup analyses were performed for the three ASM groups. RESULTS: Fifteen and thirteen studies met inclusion criteria for the qualitative and the quantitative analysis, respectively, with a total of 945 pediatric patients with prevalence data. Only VPA and CBZ were associated with thyroid dysfunction. The overall prevalence of thyroid abnormality was higher in children receiving ASM [odds ratio (OR) 6.82, 95% confidence interval (CI) 3.96-11.75]. In the subgroup analysis, the prevalence of biochemical thyroid abnormality with increased TSH was higher in the VPA (OR 9.54, 95%CI 5.25-17.34) and the CBZ group (OR 4.08, 95%CI 1.84-9.04) compared with controls. CONCLUSION: This study confirms the higher prevalence of biochemical thyroid abnormality in children under VPA and CBZ monotherapy, whereas no such evidence is present for LEV. In children with a predisposition for thyroid disease, LEV should be considered over VPA and CBZ, if appropriate for seizure type and epilepsy syndrome. More studies are needed to reach a consensus on monitoring and management of thyroid dysfunction in children receiving ASM therapy.