Cognitive impairment in children with CACNA1A mutations.

AIM: To describe the clinico-radiological phenotype of children with a CACNA1A mutation and to precisely evaluate their learning ability and cognitive status. METHOD: Children between the ages of 3 and 18 years harboring a pathogenic CACNA1A mutation associated with episodic ataxia, hemiplegic migraine, benign paroxysmal torticollis, benign paroxysmal vertigo, or benign paroxysmal tonic upgaze, were enrolled in this cross-sectional study. Data concerning psychomotor development, academic performance, educational management, clinical examination at inclusion, and brain imaging were collected. Cognitive assessment was performed using age-standardized scales. RESULTS: Eighteen patients (nine males, nine females; mean age at inclusion: 11y 7mo [SD 4y 5mo; range 3y-17y 11mo]) from 14 families were enrolled. Eleven patients displayed the coexistence or consecutive occurrence of more than one type of episodic event. Nine patients exhibited abnormal neurological examination at inclusion. Brain magnetic resonance imaging (MRI) showed cerebellar atrophy in five patients. Psychomotor development was delayed in nine patients and academic difficulties were reported by the parents in 15 patients; nine patients were in special education. Impairment of intellectual function was assessed in six of the 12 patients with interpretable Full-scale IQ scores and was more frequent when cerebellar atrophy was present on MRI. INTERPRETATION: Cognitive impairment is commonly associated with CACNA1A mutations. We suggest that CACNA1A-associated phenotype should be considered a neurodevelopmental disorder. WHAT THIS PAPER ADDS: Cognitive disabilities and academic difficulties are common in children with CACNA1A mutations associated with episodic syndromes. Cognitive function ranges from normal to moderate intellectual disorder in wheelchair-dependent children. Patients with vermian atrophy are at a higher risk of cognitive impairment.

Benign paroxysmal torticollis, benign paroxysmal vertigo, and benign tonic upward gaze are not benign disorders.

AIM: Benign paroxysmal torticollis (BPT), benign paroxysmal vertigo (BPV), and benign tonic upward gaze (BTU) are characterized by transient and recurrent episodes of neurological manifestations. The purpose of this study was to analyse the clinical relationships between these syndromes, associated comorbidities, and genetic bases. METHOD: In this cross-sectional study, clinical data of patients with BPT, BPV, or BTU were collected with a focus on developmental achievements, learning abilities, and rehabilitation. Neuropsychological assessment and genetic testing were performed. RESULTS: Fifty patients (median age at inclusion 6y) were enrolled. Psychomotor delay, abnormal neurological examination, and low or borderline IQ were found in 19%, 32%, and 26% of the patients respectively. Cognitive dysfunction was present in 27% of the patients. CACNA1A gene mutation was identified in eight families, and KCNA1 and FGF14 mutation in one family respectively. The identification of a CACNA1A mutation was significantly associated with BTU (p=0.03) and with cognitive dysfunction (p=0.01). Patients with BPV were less likely to have cognitive dysfunction. INTERPRETATION: Children with BPT, BPV, or BTU are at high risk of impaired psychomotor and cognitive development. These syndromes should not be regarded as benign and should be considered as part of the spectrum of a neurodevelopmental disorder. WHAT THIS PAPER ADDS OK: Patients with benign paroxysmal torticollis (BPT), benign paroxysmal vertigo (BPV), and benign tonic upward gaze (BTU) have an increased risk of psychomotor delay. These patients also have an increased risk of abnormal neurological examination and cognitive dysfunction. Gene mutations, especially in CACNA1A, were identified in 21% of the families. BPT, BTU, and BPV should not be regarded as benign. BPT, BTU, and BPV should be considered as part of the spectrum of a neurodevelopmental disorder.

Longitudinal study shows that depression in childhood is associated with a worse evolution of headaches in adolescence.

AIM: The aim of this study was to examine the course of headache diagnosis, headache frequency, anxiety, comorbid depressive symptoms and school absenteeism in adolescents with migraine and tension-type headaches five years after baseline. METHODS: We followed a group of 122 children with a mean age of 10.1 (±1.3) years, with headache from a paediatric migraine centre in Paris who had taken part in a previous study from September 2007 to June 2008. This five-year longitudinal study took place in January to June 2012. The measures that were used included demographic variables, headache diagnosis, headache data and a psychological assessment. RESULTS: At the five-year point, about 22% of the children had become headache free, 34% had little to no disability, and 36% had a changed diagnosis. Moreover, a longer history of headache at baseline was associated with a worse evolution of headache at follow-up. Lastly, high depression scores, but not anxiety, were a predictor of more headache disability at follow-up. CONCLUSION: High depression scores in childhood were a risk factor that was associated with persistence and worsening of headaches in adolescence. This suggests that mental health assessments should be carried out in paediatric headache pain clinics.

[Measuring the intensity of restraint during care in children: Validation of the Pric scale]. / Mesurer l'intensité de la contention lors des soins chez les enfants : validation de l'échelle Pric.

Restraint is used relatively often during pediatric care. However, no scale has yet been validated to assess its intensity. The study presented here did this for the Procedural Restraint Intensity in Children tool in metrological terms (with some limitations). In the absence of a reference scale in this area, the reliability of this tool was studied under experimental conditions. It is nevertheless the first scale with metrological validation, measuring the intensity of physical constraint. Other work is underway to validate it in real clinical situations.

[Nocebo placebo, the hidden side of our treatments]. / Placebo/nocebo, la face cachée de nos traitements.

NOCEBO PLACEBO, THE HIDDEN SIDE OF OUR TREATMENTS. Our knowledge of the placebo effect and its opposite, the nocebo effect, has changed dramatically in the last 20 years. Any treatment activity induces this type of effect. The placebo groups in clinical studies have biases that profoundly alter their neutrality. The nocebo effect is omnipresent in daily practice, it contributes to induce many of the adverse drug effects. The use of «impure¼ placebos is also widespread in daily practice. The placebo effect has an objectivable and reproducible neurobiological substrate. Its therapeutic effects are well documented. Disorders, symptoms involving the central nervous system (CNS) respond more easily to placebo. These new data make it possible to improve clinical practices by developing the quality of relationships with patients and families as well as the methodology of clinical trials.

PLACEBO/NOCEBO, LA FACE CACHÉE DE NOS TRAITEMENTS. Nos connaissances sur l'effet placebo et son contraire, l'effet nocebo, ont radicalement changé dans les vingt dernières années. Toute activité de soins induit ce type d'effet. Les groupes placebo des études cliniques comportent des biais qui en altèrent profondément la neutralité. L'effet nocebo est omniprésent en pratique quotidienne, il contribue à induire beaucoup des effets indésirables médicamenteux. L'utilisation de placebos « impurs ¼ est également très répandue en pratique soignante quotidienne. L'effet placebo possède un substrat neurobiologique objectivable et reproductible. Ses effets thérapeutiques sont solidement documentés. Les troubles, les symptômes impliquant le système nerveux central répondent plus facilement au placebo. Ces nouvelles données permettent d'améliorer les pratiques cliniques en développant la qualité relationnelle avec les patients et les familles ainsi que la méthodologie des essais cliniques. Admettre que, pour le patient comme pour le médecin, le « mental ¼, les croyances, les émotions, des forces inconscientes puissent faire aussi bien, voire mieux, qu'un médicament actif reste compliqué, car cela questionne les fondements culturels de nos pratiques.

Electronic and paper versions of a faces pain intensity scale: concordance and preference in hospitalized children.

BACKGROUND: Assessment of pain in children is an important aspect of pain management and can be performed by observational methods or by self-assessment. The Faces Pain Scale-Revised (FPS-R) is a self-report tool which has strong positive correlations with other well established self-report pain intensity measures. It has been recommended for measuring pain intensity in school-aged children (4 years and older). The objective of this study is to compare the concordance and the preference for two versions, electronic and paper, of the FPS-R, and to determine whether an electronic version of the FPS-R can be used by children aged 4 and older. METHODS: The study is an observational, multicenter, randomized, cross-over, controlled, open trial. Medical and surgical patients in two pediatric hospitals (N=202, age 4-12 years, mean age 8.3 years, 58% male) provided self-reports of their present pain using the FPS-R on a personal digital assistant (PDA) and on a paper version. Paper and electronic versions of the FPS-R were administered by a nurse in a randomized order: half the patients were given the PDA version first and the other half the paper version first. The time between the administrations was planned to be less than 30 minutes but not simultaneous. Two hundred and thirty-seven patients were enrolled; 35 were excluded from analysis because of misunderstanding of instructions or abnormal time between the two assessments. RESULTS: Final population for analysis comprised 202 children. The overall weighted Kappa was 0.846 (95%CI: 0.795; 0.896) and the Spearman correlation between scores on the two versions was rs=0.911 (p<0.0001). The mean difference of pain scores was less than 0.1 out of 10, which was neither statistically nor clinically significant; 83.2% of children chose the same face on both versions of the FPS-R. Preference was not modified by order, sex, age, hospitalization unit (medical or surgical units), or previous analgesics. The PDA was preferred by 87.4% of the children who expressed a preference. CONCLUSION: The electronic version of the FPS-R can be recommended for use with children aged 4 to 12, either in clinical trials or in hospitals to monitor pain intensity.

Use of a combined oxygen/nitrous oxide/morphine chlorydrate protocol for analgesia in burned children requiring painful local care.

PURPOSE: We present the results of the use of a protocol of inhalational oxygen/nitrous oxide mixtures associated with oral opioids on a prospective cohort of 33 children undergoing local care for acute but limited burned skin lesions. METHODS: All the children were orally administered 0.4 mg/kg morphine chlorydrate, and nitrous oxide was administered as an equimolar mixture (50% N2O, 50% O2) via a face mask during the procedure. Pain and comfort of the patient were evaluated by the use of a validated behavioural score. After the end of the procedure, child and parent satisfactions were noted. RESULTS: Mean age was 3 years 6 months (10 months-11 years). A successful detersion procedure was performed in all the cases. Behavioural score was 6 in 15 cases out of 33, comprising between 7 and 9 in 15 patients and 10 in three patients. Subjective satisfaction of pain management was noted in 16 out of 20 patients after the procedure. Subjective satisfaction of the parents was noted in all the cases. DISCUSSION: Our study demonstrates that the use of a simple protocol of inhalational oxygen/nitrous oxide mixtures associated with oral opioids could be safe and effective. This association was well tolerated without any adverse effect.

A simple tool to measure procedural restraint intensity in children: validation of the PRIC (Procedural Restraint Intensity in Children) scale.

PURPOSE: Restraint is often used when administering procedures to children. However, no metrologically scale to measure the restraint intensity had yet been validated. This study validated the metrological criteria of a scale measuring the restraint intensity, Procedural Restraint Intensity in Children (PRIC), used during procedures in children. DESIGN AND METHODS: The PRIC scale performance was measured by a group of 7 health professionals working in a children's hospital, by watching 20 videos of health care procedures. This group included 2 physicians, 1 pediatric resident, and 4 nurses. The intra-class correlation coefficients were calculated to evaluate the inter-rater and test-retest reliability and the construct validity with the correlation between PRIC scale and a numerical rating scale. RESULTS: One hundred and forty measurements were made. Inter-rater and test-retest correlation coefficients were 0.98 and 0.98, respectively. The 2 scales were positively correlated with a Spearman coefficient of 0.93. CONCLUSIONS: This study validated the Procedural Restraint Intensity in Children (PRIC) scale in metrological terms with some limitation. However, there is not gold standard scale to precisely validate the reliability of this tool and this study has been conducted in "experimental" conditions. Nevertheless, this is the first scale measuring the intensity of physical restraint with a metrological validation. The next step will be to validate it in real clinical situations.

Epidemiology and treatment of painful procedures in neonates in intensive care units.

CONTEXT: Effective strategies to improve pain management in neonates require a clear understanding of the epidemiology and management of procedural pain. OBJECTIVE: To report epidemiological data on neonatal pain collected from a geographically defined region, based on direct bedside observation of neonates. DESIGN, SETTING, AND PATIENTS: Between September 2005 and January 2006, data on all painful and stressful procedures and corresponding analgesic therapy from the first 14 days of admission were prospectively collected within a 6-week period from 430 neonates admitted to tertiary care centers in the Paris region of France (11.3 millions inhabitants) for the Epidemiology of Procedural Pain in Neonates (EPIPPAIN) study. MAIN OUTCOME MEASURE: Number of procedures considered painful or stressful by health personnel and corresponding analgesic therapy. RESULTS: The mean (SD) gestational age and intensive care unit stay were 33.0 (4.6) weeks and 8.4 (4.6) calendar days, respectively. Neonates experienced 60,969 first-attempt procedures, with 42,413 (69.6%) painful and 18,556 (30.4%) stressful procedures; 11,546 supplemental attempts were performed during procedures including 10,366 (89.8%) for painful and 1180 (10.2%) for stressful procedures. Each neonate experienced a median of 115 (range, 4-613) procedures during the study period and 16 (range, 0-62) procedures per day of hospitalization. Of these, each neonate experienced a median of 75 (range, 3-364) painful procedures during the study period and 10 (range, 0-51) painful procedures per day of hospitalization. Of the 42,413 painful procedures, 2.1% were performed with pharmacological-only therapy; 18.2% with nonpharmacological-only interventions, 20.8% with pharmacological, nonpharmacological, or both types of therapy; and 79.2% without specific analgesia, and 34.2% were performed while the neonate was receiving concurrent analgesic or anesthetic infusions for other reasons. Prematurity, category of procedure, parental presence, surgery, daytime, and day of procedure after the first day of admission were associated with greater use of specific preprocedural analgesia, whereas mechanical ventilation, noninvasive ventilation and administration of nonspecific concurrent analgesia were associated with lower use of specific preprocedural analgesia. CONCLUSION: During neonatal intensive care in the Paris region, large numbers of painful and stressful procedures were performed, the majority of which were not accompanied by analgesia.

How can surgeonfish help pediatric surgeons? A pilot study investigating the antinociceptive effect of fish aquariums in adult volunteers.

BACKGROUND: Multiple distraction strategies have been proposed to reduce the incidence of anxiety and pain in children. Animal-assisted therapy is acknowledged and used in children as an adjunctive treatment with cognitive, physical, psychosocial and spiritual benefits. OBJECTIVE: To determine the effect of fish aquarium animal-assisted therapy (FA-AAT) on pain perception in a cohort of healthy volunteers. METHODS: Sixty-nine healthy subjects (mean age 27.3 years) were exposed to >20 different species of soft or hard corals and >25 fish in a 1000 L saltwater aquarium. Pain perception was assessed using an electrical stimulation device, the Pain Matcher (Cefar Medical AB, Sweden), after 5 min, 10 min, 20 min and 30 min of continuous aquarium viewing. The measurements were repeated 10 min after stopping aquarium viewing. RESULTS: A statistically significant pain perception threshold augmentation was observed after a 5 min aquarium viewing. This threshold augmentation was also increased after 10 min, 20 min and 30 min of FA-AAT. A remnant effect was noted up to 10 min after exposure. This short post-viewing time period could be useful in clinical practice to perform certain painful procedures in children, such as those involving needles, under improved conditions immediately after aquarium exposure. CONCLUSIONS: In the authors' department, FA-AAT is now used as a nonpharmacological antinociceptive technique in association with a protocol of inhalated oxygen/nitrous oxide mixtures for needle-related procedures. Children and parents are invited to watch the aquarium during the 10 min to 20 min before venous punctures.

Early Diagnosis of Migraine Necessary in Children: 10-Year Follow-Up.

BACKGROUND: The prevalence of migraine in individuals younger than 20 years old is 8%, with a mean age at onset of younger than 8 years. However, the long-term prognosis of migraine attacks has not been clearly established. OBJECTIVE: Our main objective was to evaluate disease course 10 years after migraine diagnosis in a cohort of children and adolescents. METHODS: Migraine was diagnosed in 1999 in a pediatric headache reference center using International Headache Society criteria. In 2009, all patients were interviewed by telephone on the persistence and characteristics of any headaches. The main end point was prevalence of persistent migraine attacks in 2009. Variables associated with persistent attacks were analyzed. RESULTS: Overall, 142 children were diagnosed with migraine in 1999. Of these, 84 were interviewed by telephone in 2009. In 1999, the mean age was 11.6 ± 3.1 years, 54% were male, and 50% had migraine without aura. Migraine attacks were common (1-3 attacks/week in 38%). Mean age at onset was 7 years and 4 months (±3 years). In 2009, migraine prevalence was 39/84 (46% [95% confidence interval 36-56]), 12 patients (14%) were headache-free, and 62 patients (74%) had tension-type headaches that were isolated headaches in 33 (39%) patients. The rate of patients with at least one migraine attack per week fell from 37% to 8% (P = 0.001) over the 10-year period. Age at the first visit to the center was significantly higher in 2009 migraine sufferers than nonsufferers (12.5 ± 3.0 versus 10.9 ± 3.1 years (P = 0.02)). In multivariate analysis, age ≥12 years at the time of first presentation was the only significant factor associated with long-term chronic migraine (odds ratio = 3.0 [1.1-8.0]). CONCLUSIONS: Ten years after first presentation, 46% of patients had migraine but the frequency of attacks had diminished. The only factor associated with chronic migraine was age ≥12 years at first presentation.

Anxiety, depression and school absenteeism in youth with chronic or episodic headache.

BACKGROUND: Chronic daily headache (CDH) in children has been documented in general and clinical populations. Comorbid psychological conditions, risk factors and functional outcomes of CDH in children are not well understood. OBJECTIVES: To examine anxiety and depression, associated risk factors and school outcomes in a clinical population of youth with CDH compared with youth with episodic headache (EH). METHODS: Data regarding headache characteristics, anxiety, depression and missed school days were collected from 368 consecutive patients eight to 17 years of age, who presented with primary headache at a specialized pediatric headache centre. RESULTS: A total of 297 patients (81%) were diagnosed with EH and 71 were diagnosed with CDH. Among those with CDH, 78.9% presented with chronic tension-type headache and 21.1% with chronic migraine (CM). Children with CDH had a higher depression score than the standardized reference population. No difference was observed for anxiety or depression scores between children with CDH and those with EH. However, children with CM were more anxious and more depressed than those with chronic tension-type headache. Youth experiencing migraine with aura were three times as likely to have clinically significant anxiety scores. Headache frequency and history were not associated with psychopathological symptoms. Children with CDH missed school more often and for longer periods of time. CONCLUSIONS: These findings document the prevalence of anxiety, depression and school absenteeism in youth with CDH or EH. The present research also extends recent studies examining the impact of aura on psychiatric comorbidity and the debate on CM criteria.

Pain management in newborns: from prevention to treatment.

All neonates in the Neonatal Intensive Care Unit (NICU) or during the first days of life undergo painful and stressful procedures. Epidemiologic studies have shown that pain induced by these procedures is not effectively prevented or is inadequately treated. Pain experienced during the neonatal period may lead to negative outcomes, especially in preterm neonates. Prevention is the first step of pain management, and practical guidelines should be used in the NICU. Assessment must be done with adequate tools that take into account the infant's pathology and gestational age. Distinguishing between acute and prolonged pain is important for both assessment and treatment. The most common drugs that have been studied for the treatment of pain and stress are opioids, hypnosedatives, and NMDA receptor antagonists. Morphine and fentanyl are most frequently used for acute or prolonged pain in the NICU. They have potent analgesic effects and few immediate or long-term adverse effects. Midazolam is a commonly used hypnosedative, but its adverse effects limit its use. Drugs such as propofol and ketamine have been used for acute painful procedures; however, further research is needed to assess their long-term effects. Use of non-pharmacologic pain management techniques has increased in recent years. These methods are easy, inexpensive, and effective in helping newborns recover from painful procedures. Sweet solutions and non-nutritive sucking, breastfeeding, skin-to-skin mother care, swaddling, and facilitated tucking are the most commonly employed and evaluated non-pharmacologic methods. Hospitals should promote and improve parent involvement in pain management. In-service education and well organized hospital teams are crucial for successful implementation of pain protocols in newborns.

[The CNRD, a commitment to managing acute procedural pain]. / Le CNRD, un engagement contre la douleur aiguë liée aux soins.

Created in 2002 in the framework of the 2nd national plan for pain, the Centre of national resources for pain management (CNRD) is devoted to procedural pain prevention and management. It works with professionals providing information and training, logistical and methodological assistance, support with research and the development of new practices.

EMLA cream and nitrous oxide to alleviate pain induced by palivizumab (Synagis) intramuscular injections in infants and young children.

OBJECTIVE: Palivizumab (Synagis [Abbot Laboratories, Kent, United Kingdom]) is recommended for the prevention of severe lower respiratory tract infections caused by respiratory syncytial virus in infants at high risk. These injections are very painful, and currently the use of analgesics is not systematic. The objective of this study was to compare the efficacy of EMLA with premixed 50% nitrous oxide/oxygen, used alone or combined with EMLA, for pain alleviation during palivizumab injections. METHODS: This randomized, double-blind, multicenter study included children who were younger than 24 months. Each child randomly received during the first 3 monthly injections 3 different analgesic interventions: (1) EMLA: application of EMLA plus air inhalation; (2) nitrous oxide/oxygen: inhalation of 50/50 nitrous oxide/oxygen plus application of a placebo cream; and (3) nitrous oxide/oxygen plus EMLA: inhalation of 50/50 nitrous oxide/oxygen plus application of EMLA. Each child was his or her own control. Procedural pain was assessed through videotapes with the Modified Behavioral Pain Scale. The procedure itself was subdivided in 2 periods: (1) injection and (2) recovery (first 30 seconds after the removal of the needle). Modified Behavioral Pain Scale scores over time (injection and recovery periods) and among treatments were compared by repeated-measures analysis of variance. RESULTS: Fifty-five children were included. Mean +/- SD Modified Behavioral Pain Scale pain scores for EMLA, nitrous oxide/oxygen, and nitrous oxide/oxygen plus EMLA were, respectively, 9.3 +/- 1.0, 8.8 +/- 1.2, and 8.2 +/- 1.8 during the injection and 7.8 +/- 1.7, 7.4 +/- 1.9, and 6.9 +/- 2.4 during the recovery period. A significant time and treatment effect in favor of the combined nitrous oxide/oxygen plus EMLA was observed. CONCLUSIONS: The administration of 50/50 nitrous oxide/oxygen to infants and young children is effective in decreasing the pain associated with palivizumab intramuscular injections. The combined nitrous oxide/oxygen plus EMLA cream was more effective than either EMLA cream or nitrous oxide/oxygen alone.