Functional Benefit and Orthotic Effect of Dorsiflexion-FES in Children with Hemiplegic Cerebral Palsy.

Functional electrical stimulation of the ankle dorsiflexor (DF-FES) may have advantages over ankle foot orthoses (AFOs) in managing pediatric cerebral palsy (CP). This study assessed the functional benefit and orthotic effect of DF-FES in children with hemiplegic CP. We conducted an open-label prospective study on children with hemiplegic CP ≥ 6 years who used DF-FES for five months. The functional benefit was assessed by repeated motor function tests and the measurement of ankle biomechanical parameters. Kinematic and spatiotemporal parameters were assessed by gait analysis after one and five months. The orthotic effect was defined by dorsiflexion ≥ 0° with DF-FES at either the mid or terminal swing. Among 26 eligible patients, 15 (median age 8.2 years, range 6-15.6) completed the study. After five months of DF-FES use, the results on the Community Balance and Mobility Scale improved, and the distance in the Six-Minute Walk Test decreased (six-point median difference, 95% CI (1.89, 8.1), -30 m, 95% CI (-83.67, -2.6), respectively, p < 0.05) compared to baseline. No significant changes were seen in biomechanical and kinematic parameters. Twelve patients (80%) who showed an orthotic effect at the final gait analysis experienced more supported walking over time, with a trend toward slower walking. We conclude that the continuous use of DF-FES increases postural control and may cause slower but more controlled gait.

De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway.

CSNK2B encodes for casein kinase II subunit beta (CK2ß), the regulatory subunit of casein kinase II (CK2), which is known to mediate diverse cellular pathways. Variants in this gene have been recently identified as a cause of Poirier-Bienvenu neurodevelopmental syndrome (POBINDS), but functional evidence is sparse. Here, we report five unrelated individuals: two of them manifesting POBINDS, while three are identified to segregate a new intellectual disability-craniodigital syndrome (IDCS), distinct from POBINDS. The three IDCS individuals carried two different de novo missense variants affecting the same codon of CSNK2B. Both variants, NP_001311.3; p.Asp32His and NP_001311.3; p.Asp32Asn, lead to an upregulation of CSNK2B expression at transcript and protein level, along with global dysregulation of canonical Wnt signaling. We found impaired interaction of the two key players DVL3 and ß-catenin with mutated CK2ß. The variants compromise the kinase activity of CK2 as evident by a marked reduction of phosphorylated ß-catenin and consequent absence of active ß-catenin inside nuclei of the patient-derived lymphoblastoid cell lines (LCLs). In line with these findings, whole-transcriptome profiling of patient-derived LCLs harboring the NP_001311.3; p.Asp32His variant confirmed a marked difference in expression of genes involved in the Wnt signaling pathway. In addition, whole-phosphoproteome analysis of the LCLs of the same subject showed absence of phosphorylation for 313 putative CK2 substrates, enriched in the regulation of nuclear ß-catenin and transcription of the target genes. Our findings suggest that discrete variants in CSNK2B cause dominant-negative perturbation of the canonical Wnt signaling pathway, leading to a new craniodigital syndrome distinguishable from POBINDS.

The role of fundoscopy in pediatric seizures.

Fundoscopy can guide clinicians in the decision to perform neuroimaging. Our aim was to evaluate the rate of abnormal neuroimaging following fundoscopy in children presenting with seizures to the pediatric emergency department (PED). This was a retrospective single-center study. Patients with a discharge diagnosis of seizures were evaluated. Outcome measures were the rate of abnormal brain imaging following a finding of papilledema, and the rate of repeat fundoscopies due to an inconclusive initial examination. A total of 646 patients with seizures underwent fundoscopy. Out of 3 patients who were diagnosed initially with papilledema, only one patient had an abnormal brain CT. He was diagnosed with papilledema previously, and neuroimaging was previously recommended. A total of 7.6% (49/646) of patients underwent a second fundoscopic evaluation. In view of the limited yield and accuracy of fundoscopy in the PED, its role in the clinical decision making in children with seizures is questionable. What is Known: • Seizures are not described as an isolated presenting symptom of increased ICP. • Fundoscopy in children requires skill, time, cooperation. What is New: • Papilledema was found in only one patient who presented with seizures. • Fundoscopy in the PED has limited yield and accuracy in children with seizures.

Optic Nerve Drusen Is Highly Prevalent Among Children With Pseudotumor Cerebri Syndrome.

Introduction: The clinical presentation of pseudotumor cerebri syndrome (PTCS) usually includes headache, nausea, and vomiting with normal physical examination apart from papilledema and diplopia. However, pseudopapilledema, which can be caused by optic nerve drusen, may lead to misdiagnosis. The prevalence of optic nerve drusen in the general population is 0.5-2%. The purpose of our study was to evaluate the prevalence and risk factors of optic nerve drusen among patients with PTCS. Materials and Methods: Medical records of children evaluated in the pediatric department at Bnai Zion Medical Center due to PTCS between 2008 and 2020 were assessed. Inclusion criteria were children age under 18 years with a PTCS diagnosis and ophthalmic B-mode ultrasonography (US). Exclusion criteria were secondary intracranial hypertension. Results: Thirty-four children were included with a mean age 10.1 years which included 50% boys. A majority of the patients, 24 (72.4%), complained of headaches, while 15 (45.5%) complained of transient visual obscuration, and 9 (26.5%) of vomiting. Visual acuity on presentation was normal (20/20-20/30) in 23 of the children (67%), moderately diminished (20/40-20/80) in 9 (26%), and showing profound loss (20/200) in 2 (7%). Five patients (14.7%) were diagnosed with optic nerve drusen via B-mode ophthalmic ultrasonography (US). However, they still fulfilled the diagnostic criteria for PTCS, and disc swelling improved after treatment. There were no statistically significant differences between the group with optic nerve drusen and the rest of the patients. Conclusions: Optic nerve drusen are common among pediatric patients with PTCS. Diagnosis of optic nerve drusen should not rule out the presence of increased intracranial pressure.

Outcomes of Migraine and Tension-Type Headache in Children and Adolescents.

The aim of our study was to evaluate the long-term outcomes of pediatric migraine and TTH in a clinical setting. We conducted a cohort study. Pediatric patients who visited the pediatric neurology clinic due to diagnoses of migraine or TTH were contacted by phone 8-10 years after their initial diagnosis and interviewed about their outcomes. Of 147 children, we were able to reach 120 (81%) patients. Of these 120 patients, 59 were seen initially due to migraine and 61 due to TTH. For the migraine patients, headaches improved in 48 (81.4%) and worsened in four (6.8%). Regarding diagnosis at follow-up, 59% still had migraine, 17% had TTH, and 23% were headache-free. Aura and photophobia were significantly associated with persistence of a migraine diagnosis. For the TTH patients, headaches improved in 49 (81.7%) and worsened in nine (15.0%). Regarding diagnosis at follow-up, 36.7% still had TTH, 18.3% had migraine, and 45% were headache-free. Of the patients with TTH, 36.7% retained their initial diagnosis compared to 59.3% among the migraine patients. Most pediatric patients presenting with migraine or TTH will experience a favorable outcome over 10 years, with TTH patients having twice the chance of complete resolution.

Migraine and Tension-Type Headache Among Children and Adolescents: Application of International Headache Society Criteria in a Clinical Setting.

INTRODUCTION: The International Headache Society criteria were written in order to help physicians establish a headache diagnosis. However, sometimes children with headache do not seem to fit any diagnosis. The purpose of our study was to assess the application of the criteria in a clinical setting. METHODS: Medical records of children referred for primary headache to the pediatric neurology clinic at Bnai Zion Medical Center from 2008 to 2017 were assessed. RESULTS: A total of 989 patients (range 6-18 years; 53% female) were assessed at our neurology clinic. Twenty-four percent (n = 241) were diagnosed with tension-type headache, 26% (n = 256) with migraine, and 4.5% (45) with mixed headache. In 41.5% (410), we were unable to reach a specific diagnosis. No differences in gender or age were found between the groups. Children in the migraine group used more analgesic treatments to stop the headache attacks compared with the tension-type headache group (50% vs 38%, P = .001). Patients diagnosed with tension-type headache reported having more emotional difficulties (P = .001). No significant differences were found in headache characteristics (ie, location, sidedness, character), frequency, or intensity between the younger children (ages 6-11) and the adolescents (ages 12-18) within either the tension-type headache or migraine groups. CONCLUSIONS: Retrospective application of International Headache Society criteria in a large cohort of children with headaches failed to diagnose a specific type of headache in 41.5% of children. Migraine and tension-type headache were equally prevalent, and both constituted a major burden on our patients' everyday lives. We found no major differences in frequency, intensity, and characteristics of pain between younger children and adolescents.

Sensory processing patterns affect headache severity among adolescents with migraine.

OBJECTIVE: To evaluate the relationship between pain catastrophizing level, sensory processing patterns, and headache severity among adolescents with episodic migraine. BACKGROUND: Catastrophizing about pain is a critical variable in how we understand adjustment to pain and has a unique contribution in predicting pain intensity. Recent reports found that migraine is also related to enhanced sensory sensitivity. However, the relationship between pain severity, pain catastrophizing level and sensory sensitivity requires greater study especially among adolescents. METHODS: Participants were 92 adolescents aged 13-18 years, 40 with episodic migraine and 52 healthy controls. The migraine patients were prospectively recruited from outpatient pediatric neurology clinics. All participants completed the Adolescent/Adult Sensory Profile (AASP), and the Pain Catastrophizing Scale for children (PCS-ch). The migraine groups also completed the PedMIDAS, which measures Headache related disability. RESULTS: Adolescents with migraine had significantly lower tendency to seek sensory input than healthy controls. Elevated rumination and helplessness correlated with higher migraine pain severity. Tendency to avoid sensory input predicted the migraine related disability level. They also significantly higher pain catastrophizing level than healthy controls, as seen in enhanced rumination (p ≤ 0.001) and helplessness (p ≤ 0.05). CONCLUSIONS: Sensory processing difficulties are common among adolescents with episodic migraine. Sensory avoidance may be related to pain experience, and pain catastrophizing and disability level. TRIAL REGISTRATION: ISRCTN ISRCTN73824458. Registered 28 September 2014. retrospectively registered.

Sensory Processing Difficulties Correlate With Disease Severity and Quality of Life Among Children With Migraine.

Introduction: Headaches are common among children and about 80% of children reporting them. Migraine and tension type headaches are the most common primary headaches in children and the prevalence of migraine is about 8%. Accompanying sensory symptoms are common before, during and after migraine attacks. They may be a part of a wider symptom constellation called sensory processing disorder or difficulties (SPD). This includes both hyper or hypo sensitivity to sensations. However, the literature regarding sensory processing symptoms of children and youth with headaches as well as its interaction with child's emotional aspects and quality of life is scarce. Materials and Methods: One hundred and thirty-four children between the ages of 8 and 12 participated in this study. Fifty-four children (22 boys and 32 girls) with episodic migraine were prospectively recruited from pediatric neurological clinics during the years 2014-2017. The control group included 80 healthy children. Both groups completed a health and demographic questionnaire, headache assessment including Ped-MIDAS, Short Sensory Profile, State-Trait Anxiety Inventory (STAI) for children, and the Pediatric Quality of Life Inventory. Results: Children with migraine showed significantly higher prevalence of sensory processing difficulties and lower quality of life compared to healthy controls. Among children with migraine, sensory processing difficulties significantly correlated with lower quality of life. Headache-related disability and sensory processing difficulties predicted quality of life. Conclusion: The possible relationship between migraine and sensory processing disorder or difficulties stresses the need to screen for sensory processing difficulties among children with migraine and when found-refer to their impacts on children's daily function and quality of life.

Primary Coenzyme Q deficiency Due to Novel ADCK3 Variants, Studies in Fibroblasts and Review of Literature.

Primary deficiency of coenzyme Q10 (CoQ10 ubiquinone), is classified as a mitochondrial respiratory chain disorder with phenotypic variability. The clinical manifestation may involve one or multiple tissue with variable severity and presentation may range from infancy to late onset. ADCK3 gene mutations are responsible for the most frequent form of hereditary CoQ10 deficiency (Q10 deficiency-4 OMIM #612016) which is mainly associated with autosomal recessive spinocerebellar ataxia (ARCA2, SCAR9). Here we provide the clinical, biochemical and genetic investigation for unrelated three nuclear families presenting an autosomal form of Spino-Cerebellar Ataxia due to novel mutations in the ADCK3 gene. Using next generation sequence technology we identified a homozygous Gln343Ter mutation in one family with severe, early onset of the disease and compound heterozygous mutations of Gln343Ter and Ser608Phe in two other families with variable manifestations. Biochemical investigation in fibroblasts showed decreased activity of the CoQ dependent mitochondrial respiratory chain enzyme succinate cytochrome c reductase (complex II + III). Exogenous CoQ slightly improved enzymatic activity, ATP production and decreased oxygen free radicals in some of the patient's cells. Our results are presented in comparison to previously reported mutations and expanding the clinical, molecular and biochemical spectrum of ADCK3 related CoQ10 deficiencies.

Does Herpes 6 Infection Have a Role in Bell's Palsy Among Children and Adolescents?

BACKGROUND: Bell's palsy is a peripheral paralysis of the seventh cranial nerve, whose etiology is unknown. Using polymerase chain reaction technology, it is possible to sample accessible body fluids and identify possible viral factors. The purpose of this research is to investigate its connection to the herpes virus family by testing for the presence of the virus in the saliva and tear fluid of Bell's palsy patients. METHODS: Saliva and tears were collected from 42 children and adolescents suffering from idiopathic facial nerve paralysis. Polymerase chain reaction was used to test for the presence of the viruses Epstein-Barr virus, cytomegalovirus, herpes simplex virus 1 and 2, varicella zoster virus and human herpes virus 6 (HHV-6). Samples were also taken from a control group without paralysis. A second specimen was taken from patients who tested positive for HHV-6 several months after their recovery. RESULTS: Of the 42 patients in the study group, 71% (30 patients) tested positive for HHV-6, compared with only 37% of the control group (P = 0.001). The prevalence of the other 5 viruses tested was low-herpes simplex virus 1: 9.5%, Epstein-Barr virus: 9.5%, cytomegalovirus: 4.8%, varicella zoster virus: 2.3% and herpes simplex virus 2: 0%. Twenty-four of the 30 patients who were HHV-6-positive during their illness were reexamined following recovery. Only 13 patients (54.2%) excreted the virus after recovery from the paralysis. CONCLUSIONS: Herpes 6 virus appears to play some role in the etiology of facial nerve paralysis. The virus was detected in the saliva of children during acute illness and decreased with resolution. Our research opens new insights linking HHV-6 to the etiology of Bell's palsy in children.

Relationship Between Central Hypotonia and Motor Development in Infants Attending a High-Risk Neonatal Neurology Clinic.

PURPOSE: To study the relationship between central hypotonia and motor development, and to determine the relative contribution of nuchal, truncal, and appendicular hypotonia domains to motor development. METHODS: Appendicular, nuchal, and truncal tones of high-risk infants were assessed, as was their psychomotor developmental index (PDI). Infants with peripheral hypotonia were excluded. RESULTS: We included 164 infants (mean age 9.6 ± 4 months), 36 with normal tone in all 3 domains and 128 with central hypotonia. Twenty-six of the latter had hypotonia in 1 domain and 102 had multiple combinations of 3 domains. Hypotonia domains were distributed as follows: truncal (n = 115), appendicular (n = 93), and nuchal (n = 70). Each domain was significantly associated with PDI scores (P < .001) but not with a later diagnosis of cerebral palsy. On linear regression, nuchal hypotonia had the strongest contribution to PDI scores (ß = -0.6 [nuchal], -0.45 [appendicular], and -0.4 [truncal], P < .001). CONCLUSIONS: Central hypotonia, especially nuchal tone, is associated with lowered motor development scores.

Use of time from fever onset improves the diagnostic accuracy of C-reactive protein in identifying bacterial infections.

OBJECTIVE: To determine whether the input of time from fever onset will change the accuracy of C-reactive protein (CRP) in diagnosing bacterial infections in febrile children. STUDY DESIGN: We performed a prospective observational study on febrile children presenting to the emergency department. The diagnostic performance of CRP at different time points from fever onset was compared using a receiver operating characteristic (ROC) curve. RESULTS: Among 373 patients included, 103 (28%) had bacterial infection. The optimal cut-off for CRP suggesting bacterial infection changed with time from fever onset: 6 mg/dL for >12-24 h of fever; 10.7 and 12.6 mg/dL at >24-48 and >48 h of fever, respectively. The input of time from fever onset improved the area under the ROC curve from 0.83 (95% CI 0.78 to 0.88) for CRP overall to 0.87 (95% CI 0.77 to 0.96) and 0.90 (95% CI 0.84 to 0.97) at >24-48 and >48 h of fever, respectively. Duration of fever mostly affected the ability of CRP to correctly rule out bacterial infections. CRP level of 2 mg/dL obtained at ≤24 h of fever corresponds with a post-test probability for bacterial infection of 10%, whereas the same value obtained >24 h of fever reduces the risk to 2%. CONCLUSIONS: Clinicians should apply different CRP cut-off values depending on whether they are trying to rule in or rule out bacterial infection, but also depending on fever duration at the time of CRP testing.

The effect of antiepileptic drugs on mitochondrial activity: a pilot study.

Mitochondria are probably a target in antiepileptic drug-induced hepatotoxicity accompanied by oxidative stress. Most studies discuss valproic acid. The information regarding other antiepileptic drugs is scarce. Most studies used in vitro methods and animal models. In this study, the authors have investigated the effect of antiepileptic drugs, other than valproic acid, on the oxidative phosphorylation process in children, by measuring mitochondrial adenosine triphosphate (ATP) production and the enzymatic activities of respiratory chain complexes II-IV in peripheral white blood cells. The results demonstrate that several antiepileptic drugs can affect the mitochondrial oxidative phosphorylation. The authors have concluded that the effect of antiepileptic drugs on the mitochondria is not limited only to valproic acid, but can affect different mitochondrial pathways and can be performed in humans by relatively simple methods, using small samples of peripheral white blood cells.