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.

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.

[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.

The course and outcome of unilateral intracranial arteriopathy in 79 children with ischaemic stroke.

Arteriopathies are the commonest cause of arterial ischaemic stroke (AIS) in children. Repeated vascular imaging in children with AIS demonstrated the existence of a 'transient cerebral arteriopathy' (TCA), characterized by lenticulostriate infarction due to non-progressive unilateral arterial disease affecting the supraclinoid internal carotid artery and its proximal branches. To further characterize the course of childhood arteriopathies, and to differentiate TCA from progressive arterial disease, we studied the long-term evolution of unilateral anterior circulation arteriopathy, and explored predictors of stroke outcome and recurrence. From three consecutive cohorts in London, Paris and Utrecht, we reviewed radiological studies and clinical charts of 79 previously healthy children with anterior circulation AIS and unilateral intracranial arteriopathy of the internal carotid bifurcation, who underwent repeated vascular imaging. The long-term evolution of arteriopathy was classified as progressive or TCA. Clinical and imaging characteristics were compared between both groups. Logistic regression modelling was used to determine possible predictors of the course of arteriopathy, functional outcome and recurrence. After a median follow-up of 1.4 years, 5 of 79 children (6%) had progressive arteriopathy, with increasing unilateral disease or bilateral involvement. In the others (94%), the course of arteriopathy was classified as TCA. In 23% of TCA patients, follow-up vascular imaging showed complete normalization, the remaining 77% had residual arterial abnormalities, with improvement in 45% and stabilization in 32%. Stroke was preceded by chickenpox in 44% of TCA patients, and in none of the patients with progressive arteriopathies. Most infarcts were localized in the basal ganglia. In 14 (19%) of TCA patients, transient worsening of the arterial lesion was demonstrated before the arteriopathy stabilized or improved. Thirteen TCA patients (18%) had a recurrent stroke or TIA. Thirty TCA patients (41%) had a good neurological outcome, compared with none of the five patients with progressive arteriopathy. Arterial occlusion, moyamoya vessels and ACA involvement were more frequent in progressive arteriopathies. Cortical infarct localization was significantly associated with poor neurological outcome (OR 6.14, 95% CI 1.29-29.22, P = 0.02), while there was a trend for occlusive arterial disease to predict poor outcome (OR 3.00, 95% CI 0.98-9.23, P = 0.06). Progressive arteriopathy was associated with recurrence (OR 18.77, 95%CI 1.94-181.97, P = 0.01). The majority of childhood unilateral intracranial anterior circulation arteriopathies (94%) have a course that is consistent with TCA, in which transient worsening is common. Although the arterial inflammation probably causing TCA is 'transient', most children are left with permanent arterial abnormalities and residual neurological deficits.

[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.

Episodic ataxia type 2: unusual aspects in clinical and genetic presentation. Special emphasis in childhood.

OBJECTIVE: To describe aspects in clinical and genetic presentation in five patients with episodic ataxia type 2 (EA2). METHODS: CACNA1A gene screening identified a mutation in three probands and in two of their children. RESULTS: The three probands had attacks of imbalance, associated with dizziness/vertigo and/or headache. Two of them had independent migraine attacks. Interictal oculomotor examination revealed a gaze evoked nystagmus and central oculomotor signs. Two probands had a history of strabismus. All responded well to acetazolamide. Two children were found to have both clinical and genetic abnormalities. At 23 months, one child started to have short attacks of imbalance mimicking benign paroxysmal vertigo of childhood. Then, the frequency and duration of his attacks increased and some were associated with headache. The other child developed permanent imbalance with falls at the age of 2 years, strabismus, hyperactivity and slight to moderate cognitive deficiency. When aged 10 years, this was further complicated by episodic ataxia. Genetic analysis revealed three novel mutations in the calcium channel gene CACNA1A (chromosome 19p13). The two children had the same genetic abnormality as their parents. CONCLUSION: EA2 may present with still unknown genetic mutations in adults, and with large and various phenotypes in children, such as short attacks of imbalance or permanent imbalance, cognitive deficiency, and possibly strabismus and hyperactivity.

Neurological outcome and risk of recurrence depending on the anterior vs. posterior arterial distribution in children with stroke.

We report the outcome of 46 previously healthy children with arterial ischemic stroke. After a mean follow-up of 26 months, five (11%) children suffered a recurrence and 28 (61%) were left with sequelae. The prevalence and the severity of the sequelae were similar irrespective of whether the localization of the accident was anterior or posterior. However, a recurrence was significantly more frequent in the posterior than in the anterior group (4/14 vs. 1/32; p=0.025). These observations may lead to the establishment of therapeutic guidelines according to the localization of the infarct.

Early onset of hypokalaemic periodic paralysis caused by a novel mutation of the CACNA1S gene.

We report a precocious and atypical form of hypokalaemic periodic paralysis, with clinical manifestations at birth and first episodes of paralysis occurring as early as 1 year of age, although onset of this disease usually occurs between 5-35 years. Extensive molecular analysis showed that the disease was caused by a novel de novo p.Arg897Ser mutation in the CACNA1S gene. The mutation mapped to a new region of the protein, the S4 voltage sensing segment of domain III, at odds with previously reported mutations that exclusively affected domains II and IV.

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.

[Acute encephalitis: report on 32 consecutive pediatric cases observed in one hospital]. / Encéphalite aiguë: à propos de 32 enfants vus consécutivement dans un même service de pédiatrie.

We report 32 cases of acute encephalitis consecutively hospitalized in one hospital, from January 1991 to December 2002. The causative agent was identified in 26 cases (81%). The main associated viruses were varicella-zoster (10 children; 31%), Herpes simplex (6 children; 19%), and enteroviruses (4 children; 13%). At the acute phase, the most relevant biological findings were electroencephalogram results and CSF analysis. The initial encephalic imaging was primarily helpful to exclude other acute neurological diseases whereas long-term imaging was a prognostic factor for necrotizing encephalitis. The microbiological diagnosis required several days or weeks to be determined. It did not influence the initial management. In addition to the 6 cases of herpetic encephalitis, 19 children (78% altogether) were then treated by acyclovir before a definitive diagnosis was made. Twenty-two children (69%) had a favorable outcome, 2 (6%) had moderate sequels, 2 (6%) had important ones, and 5 (16%) had major ones. One (3%) child died. The outcome was highly dependant on the causative agent and the mechanism of encephalitis. This series gives information on the epidemiology of encephalitis in children in our region over a period of 12 years.

[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.

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.

[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.

Stroke in childhood: outcome and recurrence risk by mechanism in 59 patients.

This paper describes 59 patients, 3 months to 16 years of age, who were seen consecutively in the same center for cerebral arterial infarction. It focuses on the mechanism of stroke. The pathophysiologic process could be established for 78% of the children. Arteriopathic stroke (31 patients, or 53%) was the most common. The arteriopathies were either progressive (moyamoya in 4 patients, or 7%) or nonprogressive (27 patients, or 46%). The latter form occurred in two patterns: dissection of cervicocephalic arteries (12 patients, or 20%) and transient cerebral arteriopathy of unknown origin but probably angiitis (15 patients, or 25%). Cardiac or transcardiac embolic stroke occurred in 12% of the series and systemic diseases in 14%. There was a favorable outcome in 70% of patients having stroke due to nonprogressive arterial disease and stroke due to unidentified mechanisms. In contrast, only 26% of patients with embolic stroke, systemic disease, or moyamoya had a favorable outcome. Recurrences were more frequent and severe in this latter group. It is concluded that it is important to determine the mechanism of childhood stroke, because it strongly influences outcome, the recurrence risk, and treatment choice.

Transient cerebral arteriopathy: a disorder recognized by serial angiograms in children with stroke.

Repeated clinical evaluation and cerebral arteriography during the evolution of ischemic strokes of idiopathic origin allowed us to characterize a transient cerebral arteriopathy. We retrospectively studied the clinical characteristics, course, and neuroimaging features of this disorder in nine children. Of 34 children with ischemic strokes seen consecutively between 1984 and 1995, 9 (26%) were diagnosed as having transient attack of the cerebral arterial wall, termed transient cerebral arteriopathy. All of these patients had previously been in good health. The mean age at the time of the first stroke was 6 years (range, 2 9/12 years to 13 4/12 years). All children presented with acute hemiplegia. A recurrence of the stroke took place 3 months at the latest after the initial infarct in three children (mean clinical follow-up 2 7/12 years). Cerebral imaging in all the patients showed small subcortical infarcts located in basal ganglia or internal capsule. Arteriography revealed multifocal lesions of the arterial wall (focal stenosis or segmental narrowing), mostly located in the initial parts of basal arteries of the carotid system. Longitudinal arteriographic follow-up showed initial worsening of these arterial lesions (n = 5) for a maximum duration of 7 months followed by complete regression (n = 2), improvement (n = 5), or stabilization of the lesions (n = 2). Five patients had a complete clinical recovery. Further studies are necessary to confirm a presumed inflammatory cause of this arteriopathy.

Vaccination campaign following an increase in incidence of serogroup C meningococcal diseases in the department of Puy-de-Dôme (France).

In the department of Puy-de-Dôme, France, 17 cases of invasive meningococcal disease C were notified between March 2001 and the first week of 2002. Among the 15 confirmed cases, 11 (73%) were serogroup C, 2 (13%) serogroup B, and 2 could not be identified. The rapid increase in the number of cases in a period of low endemicity for the rest of the country and the severity of the disease (case fatality ratio 27%, purpura fulminans 64%) led the health authorities to initiate a vaccination campaign targeting children and young adults from 2 months up to 20 years living in a limited area of the department. Around 80,000 people were immunised between 16/01/02 and 09/02/02. More than half of the 1390 immediate side effects were headache and dizziness. As of mid-March, no further case of meningococcal disease has been notified since 6 January.

[Specifics in pediatric arterial cerebral infarctions]. / Spécificités pédiatriques des infarctus cérébraux artériels.

Despite the number of potential causes, most children with ischemic cerebrovascular disease are classified into a few major categories: 1) cardioembolic stroke; 2) moyamoya syndrome; 3) complication(s) connected with systemic disease, with a known risk of a cerebrovascular event; 4) cervicocephalic arterial dissection; and 5) transient cerebral arteriopathy of undefined origin (probable arteritis). The etiological diagnosis is rapidly established by complementary investigations based on the initial clinical and imaging findings: cardiac exploration, magnetic resonance imaging and angiography or echo-doppler of the cervical arteries if cervical dissection is suspected; intra-arterial catheter cerebral angiography and analysis of the cerebrospinal fluid to investigate an intracranial arteriopathy. The outcome and treatment depend on the type of stroke, on its accurate identification, and on prediction regarding the risk of recurrence. Although there is a constitutional predisposition to cerebrovascular accidents, environmental triggers such as trauma, infectious disease and cardiac surgery also play a major role.

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.