Cerebral Palsy - Early Diagnosis and Intervention Trial: protocol for the prospective multicentre CP-EDIT study with focus on diagnosis, prognostic factors, and intervention.

BACKGROUND: Early diagnosis of cerebral palsy (CP) is important to enable intervention at a time when neuroplasticity is at its highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that an early-diagnosis set-up can lower diagnostic age in high-risk infants. The aim of the current study is to lower diagnostic age of CP regardless of neonatal risk factors. Additionally, we want to investigate if an early intervention program added to standard care is superior to standard care alone. METHODS: The current multicentre study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing the feasibility of an early diagnosis set-up and the GO-PLAY early intervention. CP-EDIT is a prospective cohort study, consecutively assessing approximately 500 infants at risk of CP. We will systematically collect data at inclusion (age 3-11 months) and follow a subset of participants (n = 300) with CP or at high risk of CP until the age of two years. The GO-PLAY early intervention will be tested in 80 infants with CP or high risk of CP. Focus is on eight areas related to implementation and perspectives of the families: early cerebral magnetic resonance imaging (MRI), early genetic testing, implementation of the General Movements Assessment method, analysis of the GO-PLAY early intervention, parental perspective of early intervention and early diagnosis, early prediction of CP, and comparative analysis of the Hand Assessment for Infants, Hammersmith Infant Neurological Examination, MRI, and the General Movements method. DISCUSSION: Early screening for CP is increasingly possible and an interim diagnosis of "high risk of CP" is recommended but not currently used in clinical care in Denmark. Additionally, there is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. Most studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy. The current study aims at improving care of patients with CP even before they have an established diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov ID 22013292 (reg. date 31/MAR/2023) for the CP-EDIT cohort and ID 22041835 (reg. date 31/MAR/2023) for the GO-PLAY trial.

Acute flaccid rhombencephalomyelitis with radiculitis in a child with an enterovirus A71 infection seen for the first time in Denmark: a case report.

BACKGROUND: Acute flaccid myelitis is a serious condition of the spinal cord. More than 80% of patients experience a mild respiratory illness or fever consistent with a viral infection prior to acute flaccid myelitis development. Enterovirus A71 is known to circulate in Denmark, and has previously been associated with severe neurological symptoms. In this case report we describe acute flaccid rhombencephalomyelitis with radiculitis in an infant with an enterovirus infection. CASE PRESENTATION: The 8-month-old male of Asian origin presented with fever and gastrointestinal symptoms, followed by severe neurological deficits such as flaccid paralysis of the neck and upper extremities. An initial magnetic resonance imaging scan of the brain was normal, and the boy was treated for encephalitis. A follow-up magnetic resonance imaging scan of the brain and spinal cord 1 week later showed the development of pathological symmetrical gray matter hyperintensity lesions on T2-weighted images in the brainstem and upper medulla spinalis, and nerve enhancement in the terminal thread of the spinal cord and the cervical roots; findings consistent with rhombencephalomyelitis with radiculitis causing flaccid paralysis. Enterovirus A71 was detected in both nasopharyngeal and fecal specimens. Other differential diagnostic etiologies of viral and bacterial encephalitis, including poliovirus, were excluded. CONCLUSIONS: This is the first case in Denmark of a patient diagnosed with acute flaccid rhombencephalomyelitis strongly linked to an enterovirus A71 infection. This case emphasizes the diagnostic importance of combining a history of respiratory and/or gastrointestinal illness, fever, and delayed onset of varying degrees of paralysis with progressive characteristic spinal and brain lesions. Analysis of respiratory, fecal, and cerebrospinal samples for the presence of enterovirus, and eliminating other differential pathogens, is essential to confirm the diagnosis.

ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder.

ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children. New individuals were identified through GeneMatcher, ClinVar and the European Network for Therapies in Rare Epilepsy (NETRE). Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria. Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n = 8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n = 4); (iii) unclassified (n = 8). Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable. Dysmorphic features were variable. Variants were distributed across the gene and mostly de novo with no precise genotype-phenotype correlation. ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE. More detailed epilepsy descriptions of larger cohorts and functional studies might reveal genotype-phenotype correlation. The epileptogenic mechanism may be linked to interaction with histone H3.3.

Decline in gross motor skills in adult Rett syndrome; results from a Danish longitudinal study.

Longevity of individuals with neurodevelopmental diseases as Rett syndrome (RTT) has increased and many reach adulthood and old age. There is therefore a need to increase knowledge about the course of RTT in adults in order to improve medical care management and quality of life. We did a longitudinal study to address if a possible decline in motor skills in adults with RTT can be explained by the presence of common medical conditions as epilepsy, breathing disturbance, and scoliosis. Data from the Danish RTT database, medical files, and videos from visits at the national Center for Rett syndrome were reviewed. The study included 24 individuals aged 30-66 years at last visit after a follow-up period of 6-12 years. Results showed a clinically observable and significant decline in gross motor skills using the Rett syndrome Gross Motor Scale (RSGMS) with a tendency of less decline in the individuals with the best motor abilities. The frequencies of comorbidities were high. Decline in RSGMS score was associated with the presence of epilepsy and severe scoliosis that had been conservatively managed. The results emphasize that epilepsy plays a significant role in the adult RTT life and management of severe scoliosis in the younger years has impact on the motor abilities in adulthood.

Nonpharmacological Interventions Addressing Pain, Sleep, and Quality of Life in Children and Adolescents with Primary Headache: A Systematic Review.

PURPOSE: Children and adolescents with primary headache are at risk of persistent somatic symptoms and reduced quality of life (Qol) due to pain and pain-related behaviors, such as avoiding school and activities. Sleep is essential to health, and children and adolescents with primary headaches have more sleep complaints than do healthy controls. A treatment approach that addresses multifactorial causes is likely important. Nonpharmacological interventions seem promising. However, knowledge about effective strategies is limited. The objective of this review is to assess the effect of nonpharmacological interventions in randomized controlled trials (RCTs) among children and adolescents with primary headache in order to identify useful strategies. PATIENTS AND METHODS: Outcome measures are pain, sleep, Qol, and coping versus no intervention or control intervention. Medline, CINAHL, EMBASE, and PsycINFO were searched for eligible trials. ClinicalTrials.gov. was searched for ongoing trials. Initial searches yielded 2588 publications. After initial screening and subsequent full-text review and quality assessment, 13 RCTs reported in 15 articles were selected for review. All reviewers independently assessed study quality using the CONSORT criteria for nonpharmacological interventions. RESULTS: Cognitive behavioral therapy (CBT), including education on pain-related topics, sleep, coping, and stress management, is an effective strategy for reducing headache and pain within groups over time. Fifteen studies assessed pain, 3 studies assessed sleep, 6 studies assessed Qol, and 11 studies assessed coping. CONCLUSION: Strategies identified as useful were parts of CBT interventions. However, it was not possible to identify a single effective intervention addressing pain, sleep, Qol, and coping in children and adolescents with headache, primarily because sleep was infrequently addressed. Various aspects of Qol and coping strategies were assessed, rendering comparison difficult. Strategies for future interventions should include descriptions of theory-driven CBT interventions, depending on clinical setting and based on local resources, to promote a solid evidence base for nonpharmacological interventions.

Is it possible to diagnose Rett syndrome before classical symptoms become obvious? Review of 24 Danish cases born between 2003 and 2012.

BACKGROUND/PURPOSE: Rett syndrome (RTT) is a neurodevelopmental disorder that affects mainly females; it results in multiple disabilities and carries a risk of medical comorbidities. Early diagnosis is important to help establish the best treatment opportunities and preventive care in order to slow down the progression of symptoms. We wanted to test our hypothesis that it is possible to diagnose RTT before the classical symptoms become obvious. METHODS: We analysed development and symptoms before and at the time of the RTT diagnosis, as well as the symptoms that triggered MECP2 mutation analysis, in a cohort of girls with RTT born in Denmark between 2003 and 2012. RESULTS: Twenty-four girls were included, and 87.5% of these girls were diagnosed when the classical RTT symptoms were recognized. However, parents were concerned about their daughters between 3 and 58 months prior to the RTT diagnosis, and they felt that the professionals did not share their concern in the beginning. When reviewing medical files and questionnaires, we noted that the majority of girls did have combinations of concerning symptoms such as developmental delay and a collection of subtle signs such as autistic traits, placidity, floppiness with suspicion of muscular or mitochondrial diseases, hair pulling, teeth grinding, development of incontinence and problems with initiating movements. CONCLUSION: We conclude that many individuals with MECP2 mutation exhibit characteristics that should raise suspicion for RTT, prior to evolution of the core clinical criteria. As RTT is a rare disease, it is of importance to constantly educate clinicians for heightened awareness of RTT.

[Children with commotio cerebri at paediatric departments in Denmark]. / Børn med commotio cerebri varetages forskelligt på danske børneafdelinger.

INTRODUCTION: Commotio cerebri often occurs in children. The purpose of this study is to illustrate how children with commotio cerebri are treated at paediatric departments in Denmark MATERIALS AND METHODS: A questionnaire regarding visitation, admission, observation, discharge and follow-up of children with commotio cerebri as well as department guidelines was mailed to Danish paediatric departments in the period March-September 2006. RESULTS: Children are often initially treated in the emergency room and admitted to a paediatric department if there is a need for observation. The observation period varies within 24 hours. In most departments observation is standardized, for instance according to the Glasgow Coma Scale. Oral information at discharge is always given, whereas written information about symptoms of commotio cerebri and possible late complications are given by 58% of paediatric departments. Follow-up of the worse cases of commotio cerebri is scheduled by 68% of paediatric departments. Most departments have guidelines for the treatment of patients with commotio cerebri. CONCLUSION: There are differences regarding the period of observation for admitted children with commotio cerebri. Oral and written information for parents about deterioration symptoms and possible late complications is recommended along with a statement in the journal of each patient regarding the need for a follow-up. A broader dialogue between the different groups of doctors who treat children with commotio cerebri is recommended.