Arterial ischemic stroke in non-neonate children: Diagnostic and therapeutic specificities.

Pediatric arterial ischemic stroke (AIS) is a severe condition, with long-lasting devastating consequences on motor and cognitive abilities, academic and social inclusion, and global life projects. Awareness about initial symptoms, implementation of pediatric stroke code protocols using MRI first and only and adapted management in the acute phase, individually tailored recanalization treatment strategies, and multidisciplinary rehabilitation programs with specific goal-centered actions are the key elements to improve pediatric AIS management and outcomes. The main cause of pediatric AIS is focal cerebral arteriopathy, a condition with unilateral focal stenosis and time-limited course requiring specific management. Sickle cell disease and moyamoya angiopathy patients need adapted screening and therapeutics.

Lethal form of spinocerebellar ataxia type 7 with early onset in childhood.

Progressive cerebellar ataxias are well-known hereditary neurological disorders. Among them, spinocerebellar ataxia type 7 (SCA7) is inherited as an autosomal dominant trait and is ascribed to the expansion of a CAG trinucleotide repeat within the ATXN7 gene. An anticipation phenomenon can occur during paternal transmission and sometimes is responsible for a severe infantile form. The specificity of SCA7 is the retinal involvement with retinitis pigmentosa and cone rod dystrophy. We describe a familial form with two siblings who died of a severe infantile form. Diagnosis was made in their father, who had a recent history of macular atrophy and presented with gait disturbance thereafter. Retrospectively, substantial triplet repeat expansion was confirmed in the two affected infants. These infantile forms are rare and difficult to diagnose in the absence of suggestive family symptoms.

[Neonatal arterial ischemic stroke in term or near-term newborns: prevalence and risk factors]. / Accident vasculaire cérébral ischémique artériel chez le nouveau-né à terme ou proche du terme : prévalence et facteurs de risque.

The general designation ischemic perinatal stroke includes several disease states that differ in pathophysiology, timing of occurrence and presentation. While it seems logical to assume that their prevalence and their risk factors depend primarily on the considered type of stroke, most studies used inconsistent definitions or included heterogeneous populations, which limits their accuracy. Given these biases, the French Society of Neonatology and the French Centre for Paediatric Stroke wished to update the knowledge in this domain, focusing on a specific form of perinatal stroke, i.e neonatal arterial ischemic stroke (NAIS) in term or near term newborns. A comprehensive analysis of published epidemiological data was dedicated to the following issues: Is the prevalence of NAIS well defined from epidemiological studies? What are the best recognized risk factors and is it possible to delineate a maternal and fetal population at risk for this condition? On July 31, 2015 a total of four hospitalized-based and five population-based studies, and six case-control studies were found. The conclusions are the following: The prevalence of NAIS in term or near term newborns varies from 6 to 17/100,000 live births (level of evidence 2). NAIS represents a half of total ischemic perinatal strokes (i.e. including those with delayed presentation as well) and one fourth of perinatal strokes (i.e. including cerebral haemorrhage stroke as well). Four sets of risk factors are consistent across different studies (level of evidence 3): (1) male sex, (2) obstetrical determinants (first pregnancy, caesarean section), and two peripartum complications: (3) intrapartum hypoxia and (4) materno-fetal/neonatal infection. Bacterial meningitis, cardiac disorders/procedures and invasive care such as extra-corporeal circulation carry a risk of NAIS as well. A registry could help refining epidemiological descriptive data. It could also be used to develop etiological studies focusing on pathophysiological hypotheses derived from the identified aforementioned risk factors.

[Neonatal arterial ischemic stroke: Review of the current guidelines]. / Accidents vasculaires cérébraux ischémiques artériels néonatals : synthèse des recommandations.

Neonatal arterial ischemic stroke (NAIS) is a rare event that occurs in approximately one in 5000 term or close-to-term infants. Most affected infants will present with seizures. Although a well-recognized clinical entity, many questions remain regarding diagnosis, risk factors, treatment, and follow-up modalities. In the absence of a known pathophysiological mechanism and lack of evidence-based guidelines, only supportive care is currently provided. To address these issues, a French national committee set up by the French Neonatal Society (Société française de néonatologie) and the national referral center (Centre national de référence) for arterial ischemic stroke in children drew up guidelines based on an HAS (Haute Autorité de santé [HAS]; French national authority for health) methodology. The main findings and recommendations established by the study group are: (1) among the risk factors, male sex, primiparity, caesarean section, perinatal hypoxia, and fetal/neonatal infection (mainly bacterial meningitis) seem to be the most frequent. As for guidelines, the study group recommends the following: (1) the transfer of neonates with suspected NAIS to a neonatal intensive care unit with available equipment to establish a reliable diagnosis with MRI imaging and neurophysiological monitoring, preferably by continuous video EEG; (2) acute treatment of suspected infection or other life-threatening processes should be addressed immediately by the primary medical team. Persistent seizures should be treated with a loading dose of phenobarbital 20mg/kg i.v.; (3) MRI of the brain is considered optimal for the diagnosis of NAIS. Diffusion-weighted imaging with apparent diffusion coefficient is considered the most sensitive measure for identifying infarct in the neonatal brain. The location and extent of the lesions are best assessed between 2 and 4 days after the onset of stroke; (4) routine testing for thrombophilia (AT, PC PS deficiency, FV Leiden or FII20210A) or for detecting other biological risk factors such as antiphospholipid antibodies, high FVIII, homocysteinemia, the Lp(a) test, the MTHFR thermolabile variant should not be considered in neonates with NAIS. Testing for FV Leiden can be performed only in case of a documented family history of venous thromboembolic disease. Testing neonates for the presence of antiphospholipid antibodies should be considered only in case of clinical events arguing in favor of antiphospholipid syndrome in the mother; (5) unlike childhood arterial ischemic stroke, NAIS has a low 5-year recurrence rate (approximately 1 %), except in those children with congenital heart disease or multiple genetic thrombophilia. Therefore, initiation of anticoagulation or antithrombotic agents, including heparin products, is not recommended in the newborn without identifiable risk factors; (6) the study group recommends that in case of delayed motor milestones or early handedness, multidisciplinary rehabilitation is recommended as early as possible. Newborns should have physical therapy evaluation and ongoing outpatient follow-up. Given the risk of later-onset cognitive, language, and behavioral disabilities, neuropsychological testing in preschool and at school age is highly recommended.

Perspectives in neonatal and childhood arterial ischemic stroke.

INTRODUCTION: Over the last decade considerable advances have been made in the identification, understanding and management of pediatric arterial ischemic stroke. Such increasing knowledge has also brought new perspectives and interrogations in the current acute and rehabilitative care of these patients. Areas covered: In developed countries, focal cerebral arteriopathy is one of the most common causes of arterial ischemic stroke in childhood and imaging features are well characterized. However, there are ongoing debates regarding its underlying mechanisms, natural evolution and proper management. The implementation of thrombolytic therapy in acute pediatric stroke has been shown to be efficient in anecdotal cases but is still limited by a number of caveats, even in large tertiary centers. Finally, neonatal stroke represents a unique circumstance of possible early intervention before the onset of any neurological disability but this appears meaningful only in a selective group of neonates. Expert commentary: While perinatal stroke, a leading cause of cerebral palsy, appears to be multifactorial, a large number of childhood ischemic stroke are probably essentially triggered by infectious factors leading to vessel wall damage. Current research is aiming at better identifying risk factors in both conditions, and to define optimal acute and preventive therapeutic strategies in order to reduce significant long-term morbidity.

Management and 2-year follow-up of children aged 29 days to 17 years hospitalized for a first stroke in France (2009-2010).

INTRODUCTION: Childhood stroke is a little-known disease in France. The objective of this study was to report the characteristics, management, treatment and outcome of stroke in terms of survival and 2-year recurrence rates. METHOD: The study population included children aged 29 days to 17 years, identified by their first hospitalization for stroke (excluding transient ischemic attack) in 2009 and 2010 and not hospitalized for stroke between 2005 and 2008. Data were derived from the système national d'information inter-régimes de l'assurance maladie (SNIIRAM) [national health insurance information system]. RESULTS: For the 428 children with stroke in 2009 and the 441 children with stroke in 2010, the mean annual hospitalization rate was 3/100,000 children, comprising 0.5/100,000 for cerebral infarction (CI) and 1.5/100,000 for intracerebral hemorrhage (ICH). The youngest children presented the highest ICH rate, while, to a lesser extent, adolescents presented a higher proportion of CI. A male predominance was observed for ICH. Comorbidities were relatively common among these children prior to hospitalization: 21% had already been granted an affection de longue durée (ALD) [chronic disease] status and 37% had been hospitalized at least once during the previous year. The mean length of the hospital stay was 7.2 days and the hospital mortality was 3.9% (3.4% for ICH, 3.2% for CI). The 1-year mortality rate was 5.7% and the 2-year mortality rate was 6.0% (6% for ICH and 5% for CI). The readmission rate for stroke was 13% during the 1st year and 2% during the 2nd year. At 1 year, 18% of children (26% for CI) had been admitted at least once to a rehabilitation unit. CONCLUSION: This is the first study to report the epidemiology of childhood stroke in France. The validity of this study is supported by the fact that it demonstrated homogeneous descriptive indicators to those obtained by means of various methodologies in other populations. The high mortality, recurrence, and disability rates observed during the year following the initial stroke encourage continuation of the ongoing process of standardizing the management of childhood stroke in France.

Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia.

Nondystrophic myotonias are characterized by muscle stiffness triggered by voluntary movement. They are caused by mutations in either the CLCN1 gene in myotonia congenita or in the SCN4A gene in paramyotonia congenita and sodium channel myotonias. Clinical and electrophysiological phenotypes of these disorders have been well described. No concomitant mutations in both genes have been reported yet. We report five patients from three families showing myotonia with both chloride and sodium channel mutations. Their clinical and electrophysiological phenotypes did not fit with the phenotype known to be associated with the mutation initially found in SCN4A gene, which led us to screen and find an additional mutation in CLCN1 gene. Our electrophysiological and clinical observations suggest that heterozygous CLCN1 mutations can modify the clinical and electrophysiological expression of SCN4A mutation.

[Childhood cerebral vasculitis]. / Vascularites du système nerveux central.

Central nervous system vasculitides are defined as the invasion of the vascular wall by blood-borne inflammatory cells. In childhood, they may be classified according to their trigger event (infectious vs. non-infectious), their temporal course (time-limited vs. chronic), and the size of the affected vessel. Diseases apparently confined to the central nervous system are also distinguished from secondary forms, associated with infection or rheumatic or systemic inflammatory disorders. Large-vessel vasculitis, the most frequent form, causes stroke and presents with acute focal deficits. MR, or more seldom contrast angiography is required for the positive diagnosis, while the child's medical history conveys the etiological diagnosis. The clinical manifestations of small-vessel vasculitis include headaches, seizures, focal deficits, cognitive decline, and behavior changes that can occur insidiously over a few weeks or a few months. The diagnosis is based on the associated clinical and biological symptoms in secondary forms and on cerebromeningeal biopsy in primary forms. Secondary forms of vasculitides are treated according to the etiology. The injury of large basal arteries is often observed after infection, especially varicella, and is also called transient focal cerebral arteriopathy (TCA) or post-varicella arteriopathy (PVA). This focal, monophasic, and time-limited entity is highly specific of childhood. There are no arguments in the current literature supporting the hypothesis that an aggressive immunomodulatory treatment would be more effective, in terms of recurrence rate or functional outcome, than aspirin alone. In contrast, the diffuse, prolonged, and aggressive course of the rare primary vasculitis of the central nervous system requires a prolonged immunosuppressive treatment. The management of associated symptoms, treatment-related adverse effects, and sequelae is based on a multidisciplinary approach.

[Multicentric study of medical care and practices in spinal muscular atrophy type 1 over two 10-year periods]. / Amyotrophie spinale type 1 : enquête multicentrique des pratiques de soins et d'accompagnement palliatif sur deux périodes successives de 10ans.

AIM: Questions about care practices and the role of palliative care in pediatric neurodegenerative diseases have led the Neuromuscular Committee of the French Society of Neurology to conduct a retrospective study in spinal muscular atrophy type 1, a genetic disease most often leading to death before the age of 1 year. MATERIAL AND METHODS: A retrospective multicenter study from pediatricians included in the reference centers of pediatric neuromuscular diseases was carried out on two 10-year periods (1989-1998 and 1999-2009). RESULTS: The 1989-1998 period included 12 centers with 106 patients, the 1999-2009 period 13 centers with 116 children. The mean age of onset of clinical signs was 2.1 months (range, 0-5.5 months), the median age at diagnosis was 4 months (range, 0-9 months) vs 3 months. The median age of death was 7.5 months (range, 0-24 months) vs 6 months. The care modalities included physiotherapy (90 %), motor support (61 % vs 26 % for the previous period), enteral nutrition by nasogastric tube (52 % vs 24 %), and 3.4 % of children had a gastrostomy (vs 1.8 %). At home, pharyngeal aspiration was used in 64 % (vs 41 %), oxygen therapy in 8 %, noninvasive ventilatory support in 7 %. The mean age at death was 8.1 months (range, 0-24 months) vs 7 months, the time from diagnosis to death was 4 months vs 3 months. Death occurred at home in 23 % vs 17 %, in a pediatric unit in 62 % vs 41 %. The use of analgesics and sedative drugs was reported in 60 % of cases: 40 % morphine (vs 18 %) and benzodiazepines in 48 % (vs 29 %). Respiratory support was limited mostly to oxygen by nasal tube (55 % vs 54 %), noninvasive ventilation in 9 % of the cases, and intubation and assisted mechanical ventilation (2 %). DISCUSSION AND CONCLUSION: These results confirm a change in practices and the development of palliative care in children with a French consensus of practices quite different from the standard care in North-America and closer to the thinking of English medical teams. A prospective study within the 2011 national hospital clinical research program (PHRC 2011) is beginning in order to evaluate practices and the role of families and caregivers.

Quality of life and functional outcome in early school-aged children after neonatal stroke: a prospective cohort study.

BACKGROUND: Quality of life (QoL) is recognized internationally as an efficient tool for evaluating health interventions. To our knowledge, QoL has not been specifically assessed in children after neonatal arterial ischemic stroke (AIS). AIM: To study the QoL of early school-aged children who suffered from neonatal AIS, and QoL correlation to functional outcome. METHOD: We conducted a multicenter prospective cohort study as part of a larger study in full-term newborns with symptomatic AIS. Participating families were sent anonymous QoL questionnaires (QUALIN). Functional outcome was measured using the Wee-FIM scale. Healthy controls in the same age range were recruited in public schools. Their primary caregivers filled in the QUALIN questionnaires anonymously. We used Student's t-test and a rank test to compare patients and controls' QoL and functional outcomes. RESULTS: 84 children with neonatal AIS were included. The control group was composed of 74 children, of which ten were later excluded due to chronic conditions. Mean ages and QUALIN median scores did not differ between patients and controls. Median Wee-FIM scores were lower in hemiplegic children than in non-hemiplegic ones (p < 0.001). QoL scores did not seem correlated to functional outcome. INTERPRETATION: Those results could support the presence of a "disability paradox" in young children following neonatal AIS.

[Current management of post-varicella stroke in children: a literature review]. / Prise en charge diagnostique et thérapeutique actuelle des accidents vasculaires cérébraux post-varicelleux chez l'enfant : revue de la littérature.

Among infectious factors, varicella-zoster virus (VZV) is a leading cause of central nervous system vasculopathy and stroke in childhood. Not only have viral markers been detected in the cerebrospinal fluid of affected patients, but also direct evidence of viral particles in the wall of cerebral arteries has been demonstrated in rare pathological specimens. This certainly reflects a localized infectious process likely associated with variable indirect inflammatory responses. Yet the usefulness in this setting of a lumbar puncture as well as of subsequent targeted antiviral and/or anti-inflammatory therapies is uncertain. Indeed, in the majority of cases, the so-called post-varicella angiopathy has a monophasic evolution with spontaneous resolution or stabilization, explaining diverging diagnostic and treatment approaches. In this paper, we have addressed this problematic area by reviewing 26 published cases from the year 2000 and three unpublished cases. Post-varicella stroke is typically associated with angiopathy most often involving the initial portion of the middle cerebral artery, causing a basal ganglia stroke. It tends to occur in young immunocompetent children. Thrombophilia work-up is in general negative. Lumbar puncture was performed in 17 out of 29 cases. Viral markers were examined in 14 cases, but were positive in only eight cases. Antiviral therapy was administrated in 11 children. In this small retrospective study, the treated children's vasculopathy did not progress more favorably nor was there a better outcome compared with untreated subjects.

[Experts' recommendations: stroke management in the intensive care unit. Pediatric specificities (excluding neonates)]. / Recommandations formalisées d'experts : prise en charge de l'AVC par le réanimateur. Particularités pédiatriques (nouveau-né exclu).

Stroke in children is not rare. Although there are no randomized trials on childhood stroke, except in sickle cell disease patients, several international guidelines have described quality criteria for stroke management in children. Age-adapted management is required, involving collaboration with a pediatric neurologist and hospitalization in a pediatric intensive care or continuous care unit. All symptomatic treatments used in adults can be recommended in children, including homeostasis assessment and maintenance or blood exchange in sickle cell disease patients. Specific treatments such as thrombolysis or mechanical thrombectomy are not recommended in children, except in the framework of clinical trials, but can be beneficial in adolescents. Multidisciplinary decision-making should be the rule in such situations. Adolescents may be managed in adult stroke units. Indications for surgery in children are adapted from adult guidelines. Appropriate management of cerebral venous thrombosis in children is similar to that in adults. The best management possible can be achieved through a multidisciplinary dialogue between the pediatric neurologist and the adult intensivist or neurologist.

Paediatric moyamoya in mainland France: a comprehensive survey of academic neuropaediatric centres.

BACKGROUND: Epidemiological data of paediatric moyamoya disease/syndrome (MMD/MMS) in non-Asian populations are scarce. METHODS: A questionnaire was sent to every French neuropaediatric academic centre to estimate the prevalence, incidence, familial form rate and location of paediatric MMD/MMS cases. Specific paediatric data were also retrieved from the most recent nationwide Japanese study. RESULTS: A 100% response rate was obtained. The prevalence of paediatric MMD/MMS was estimated at 0.39/100,000 children (95% CI: 0.28-0.49), and the incidence was estimated at 0.065/100,000 children/year (95% CI: 0.025-0.12), with 7.5% familial cases. The prevalence was homogenous within the different administrative areas. CONCLUSIONS: This comprehensive survey of MMD/MMS in academic neuropaediatric centres suggests that the prevalence of the disease in children in France is approximately 1/20th of that estimated in Asia.

Acute varicella zoster encephalitis without evidence of primary vasculopathy in a case-series of 20 patients.

Varicella zoster virus (VZV) is a leading cause of acute viral encephalitis but little is known about its clinical, biological and imaging features. Furthermore, the most favourable treatment regimen has not been determined. We studied a prospective cohort of 20 HIV-negative patients presenting with acute VZV encephalitis caused by primary infection or reactivation. VZV was identified in 16 of 20 cases by PCR detection of the DNA in the cerebrospinal fluid. The four remaining cases occurred during or soon after a VZV rash. The median age of the 17 adults was 76 (19-86) years; the three other patients were children (0.5-5 years). Three patients were immunocompromised. Nine adult patients presented with a rash. Eighteen patients presented with fever and an acute encephalitic syndrome: diffuse brain dysfunction, focal neurological signs, seizures and cranial nerve palsies. Three patients presented with either ventricular or subdural haemorrhage, one with myelitis, and one with asymptomatic stenosis of the middle cerebral artery. The imaging was either normal or revealed non-specific abnormalities such as cortical atrophy but no evidence of stroke. All patients were given acyclovir at various dosages and durations but the case fatality rate remained high (15%) and sequelae were frequently observed either at discharge or at follow-up 3 years later.

[Anticoagulant treatment for cerebral venous thromboses in children and newborns. French Society of Pediatric Neurology guidelines]. / Traitement anticoagulant des thromboses veineuses cérébrales de l'enfant et du nouveau-né. Les recommandations de la Société française de neurologie pédiatrique (SFNP).

Anticoagulation is recommended in the acute phase of cerebral venous thrombosis in adults, then for 3-12 months. In children, 2 consensus reports published in 2008 also recommend use of anticoagulants, whereas conclusions diverge for newborns. These consensus reports are based on observational studies, authors' experience, and comparisons with adult pathology. In view of the original studies published since then, the French Society of Pediatric Neurology (Société française de neurologie pédiatrique [SFNP]) wished to update the level of evidence and the knowledge in this domain. The results from the analysis of the literature show that anticoagulation is widely used in pediatrics. It is well-tolerated in children (class I, level of evidence B) and probably in the newborn (class IIa, level of evidence B). In the acute phase of cerebral venous thrombosis, anticoagulation is probably effective in reducing the risk of death in children (class IIa, level of evidence B). It is not possible to draw a conclusion on newborns (class IIb). Over the longer term, anticoagulation is effective in reducing the risk of recurrence (class I, level of evidence B). Since this risk is highly dependent on a number of individual factors (the main ones being the child's age, the cause of the thrombosis, and the kinetics of the sinus recanalization), the duration of anticoagulation should be analyzed individually (class I, level of evidence B). All in all, the convergence of the results, the physiopathologic arguments, and the concordance with the data on adult patients has led to the following recommendations: in the absence of a contra-indication, it is reasonable to propose anticoagulation in the acute phase of cerebral venous thrombosis in children. Prolonging this treatment for 3-6 months is indicated depending on the number of individual factors. In the absence of a contra-indication, anticoagulation may be considered individually in the acute phase of cerebral venous thrombosis in newborns for 6-12 weeks.

[New developments in spastic unilateral cerebral palsy]. / Hémiplégie cérébrale infantile: épidémiologie, aspects étiologiques et développements thérapeutiques récents.

INTRODUCTION: Hemiplegic (or spastic unilateral) cerebral palsy accounts for about 30% of all cases of cerebral palsy. With a population prevalence of 0.6 per 1000 live births, it is the most common type of cerebral palsy among term-born children and the second most common type after diplegia among preterm infants. STATE OF THE ART: Many types of prenatal and perinatal brain injury can lead to congenital hemiplegia and brain MRI is the most useful tool to classify them with accuracy and to provide early prognostic information. Perinatal arterial ischemic stroke thus appears as the leading cause in term infants, whereas encephalopathy of prematurity is the most common cause in premature babies. Other causes include brain malformations, neonatal sinovenous thrombosis, parenchymal hemorrhage (for example due to coagulopathy or alloimmune thrombocytopenia) and the more recently described familial forms of porencephaly associated with mutations in the COL4A1 gene. PERSPECTIVES: In adjunction with pharmacologic treatment (botulinium neurotoxin injection), new evidence-based rehabilitational interventions, such as constraint-induced movement therapy and mirror therapy, are increasingly being used.