Rapid exome sequencing for children with severe acute encephalopathy - A case series.

Increasingly, next-generation sequencing (NGS) is becoming an invaluable tool in the diagnosis of unexplained acute neurological disorders, such as acute encephalopathy/encephalitis. Here, we describe a brief series of pediatric patients who presented at the pediatric intensive care unit with severe acute encephalopathy, initially suspected as infectious or inflammatory but subsequently diagnosed with a monogenic disorder. Rapid exome sequencing was performed during the initial hospitalization of three unrelated patients, and results were delivered within 7-21 days. All patients were previously healthy, 1.5-3 years old, of Muslim Arab descent, with consanguineous parents. One patient presenting with acute necrotizing encephalopathy (ANEC). Her sister presented with ANEC one year prior. Exome sequencing was diagnostic in all three patients. All were homozygous for pathogenic and likely-pathogenic variants associated with recessive disorders; MOCS2, NDUFS8 and DBR1. Surprisingly, the initial workup was not suggestive of the final diagnosis. This case series demonstrates that the use of rapid exome sequencing is shifting the paradigm of diagnostics even in critical care situations and should be considered early on in children with acute encephalopathy. A timely diagnosis can direct initial treatment as well as inform decisions regarding long-term care.

Bariatric Surgery-Associated Myelopathy.

Bariatric surgery is gaining acceptance as an efficient treatment modality for adults and adolescents with morbid obesity. The early postbariatric period has the potential to induce an immunomodulatory imbalance due to the development or worsening of nutritional deficiencies, changes in hormonal balance (specifically after sleeve gastrectomy), and a shift in the proinflammatory cytokine profile along with a major change in the gut microbiome and permeability. These changes may induce encephalomyelitic T cell activity, change neural barrier permeability, and induce gut dysbioisis, favoring a proinflammatory metabolic profile. Such changes, in genetically prone individuals or those with additional risk factors, may lead to the development of myelopathy, particularly MS. Key Message: Postbariatric myelopathy is rare but should be considered in bariatric patients with relevant complaints in the postoperative period.

A new approach for assessing executive functions in everyday life, among adolescents with Genetic Generalised Epilepsies.

Studies have characterised relationships between cognitive status and a variety of clinical epilepsy factors. The aim of this study was to describe a new approach for assessing executive functions in everyday life and its unique expression in adolescents with Genetic Generalised Epilepsies (GGEs) compared with typical peers. Twenty adolescents with a diagnosis of GGEs and 20 typical healthy peers, matched by age and gender, were studied. Assessment of everyday executive function was carried out using: (1) the Weekly Calendar Planning Activity (WCPA), a direct performance based and outcome measure of strategy use and cognitive performance; and (2) Behavior Rating Inventory of Executive Function (BRIEF) parental report. Adolescents with GGEs demonstrated significantly less accuracy, less efficiency and fewer strategies used, as measured by the WCPA. Parents of adolescents with GGEs rated their child's daily performance as less efficient compared with typical peers. Better ratings of executive function (low BRIEF score) were associated with greater WCPA accuracy in the entered appointments. The WCPA provides a useful evaluation of cognitive performance for adolescents with GGEs and a functionally relevant information on task efficiency, self-monitoring and effective strategy use. Direct observation of performance supplements parental ratings and has strong potential to guide intervention and measure outcomes.

Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course.

Ohtahara syndrome, early infantile epileptic encephalopathy with a suppression burst EEG pattern, is an aetiologically heterogeneous condition starting in the first weeks or months of life with intractable seizures and profound developmental disability. Using whole exome sequencing, we identified biallelic DMXL2 mutations in three sibling pairs with Ohtahara syndrome, belonging to three unrelated families. Siblings in Family 1 were compound heterozygous for the c.5135C>T (p.Ala1712Val) missense substitution and the c.4478C>G (p.Ser1493*) nonsense substitution; in Family 2 were homozygous for the c.4478C>A (p.Ser1493*) nonsense substitution and in Family 3 were homozygous for the c.7518-1G>A (p.Trp2507Argfs*4) substitution. The severe developmental and epileptic encephalopathy manifested from the first day of life and was associated with deafness, mild peripheral polyneuropathy and dysmorphic features. Early brain MRI investigations in the first months of life revealed thin corpus callosum with brain hypomyelination in all. Follow-up MRI scans in three patients revealed progressive moderate brain shrinkage with leukoencephalopathy. Five patients died within the first 9 years of life and none achieved developmental, communicative or motor skills following birth. These clinical findings are consistent with a developmental brain disorder that begins in the prenatal brain, prevents neural connections from reaching the expected stages at birth, and follows a progressive course. DMXL2 is highly expressed in the brain and at synaptic terminals, regulates v-ATPase assembly and activity and participates in intracellular signalling pathways; however, its functional role is far from complete elucidation. Expression analysis in patient-derived skin fibroblasts demonstrated absence of the DMXL2 protein, revealing a loss of function phenotype. Patients' fibroblasts also exhibited an increased LysoTracker® signal associated with decreased endolysosomal markers and degradative processes. Defective endolysosomal homeostasis was accompanied by impaired autophagy, revealed by lower LC3II signal, accumulation of polyubiquitinated proteins, and autophagy receptor p62, with morphological alterations of the autolysosomal structures on electron microscopy. Altered lysosomal homeostasis and defective autophagy were recapitulated in Dmxl2-silenced mouse hippocampal neurons, which exhibited impaired neurite elongation and synaptic loss. Impaired lysosomal function and autophagy caused by biallelic DMXL2 mutations affect neuronal development and synapse formation and result in Ohtahara syndrome with profound developmental impairment and reduced life expectancy.

Acute ataxia in children: Common causes and yield of diagnostic work-up in the era of varicella vaccination.

We aimed to identify the most common causes of acute ataxia in children in the era of widespread varicella vaccination and the yield of commonly used diagnostic work-up. This retrospective study reviewed the medical records of children who presented with ataxia of less than 72 h duration, over the last 12 years. Associated signs and symptoms, laboratory, EEG and neuroimaging studies, final diagnosis and clinical findings at discharge and during follow-up were studied. A total of 58 patients (35 boys, 23 girls), mean age 4.9 ±â€¯3.8 years, were enrolled. The most common etiology of acute ataxia in our study was post-infectious acute cerebellar ataxia (50%). Children diagnosed with post-infectious acute cerebellar ataxia were significantly younger (3.48 ±â€¯2.23 vs. 6.5 ±â€¯3.1 years, p = 0.01), as compared with children diagnosed with infection and acute disseminated encephalomyelitis. 86% of children with post-infectious cerebellar ataxia were younger than 5 years of age. The abnormality yield of work-up studies performed in our cohort was 39% for lumbar puncture, 36% for EEG, 7% for CT scan. MRI was done in children who showed extra cerebellar signs, when vascular or demyelinating diseases were suspected and in children with prolonged symptoms and was abnormal in 8 (14%) children. We conclude that post-infectious acute cerebellar ataxia remains the most common cause of acute ataxia in children. Although lumbar puncture and neuroimaging should be considered in all children with acute cerebellar ataxia, younger children with a history of previous viral illness and no extra cerebellar signs and symptoms may benefit from watchful waiting.

Highly Selective Eating in Autism Spectrum Disorder Leading to Scurvy: A Series of Three Patients.

BACKGROUND: Some children with autism spectrum disorder (ASD) have highly specific food selectivity and therefore are prone to nutritional deficiencies of different kinds. PATIENTS: We document three children with ASD who presented with refusal to walk and gingivitis who underwent comprehensive evaluations before establishing the diagnosis of vitamin C deficiency (scurvy). The symptoms resolved after treatment with vitamin C. CONCLUSIONS: Prevention of nutritional deficiencies in children with ASD is essential, and providing multivitamin supplementation whenever high food selectivity is noted may prevent significant morbidity.

Severe infantile epileptic encephalopathy associated with D-glyceric aciduria: report of a novel case and review.

D-glycerate 2 kinase (DGK) is an enzyme that mediates the conversion of D-glycerate, an intermediate metabolite of serine and fructose metabolism, to 2-phosphoglycerate. Deficiency of DGK leads to accumulation of D-glycerate in various tissues and its massive excretion in urine. D-glyceric aciduria (DGA) is an autosomal recessive metabolic disorder caused by mutations in the GLYCTK gene. The clinical spectrum of DGA is highly variable, ranging from severe progressive infantile encephalopathy to a practically asymptomatic condition. We describe a male patient from a consanguineous Arab family with infantile onset of DGA, characterized by profound psychomotor retardation, progressive microcephaly, intractable seizures, cortical blindness and deafness. Consecutive brain MR imaging showed an evolving brain atrophy, thinning of the corpus callosum and diffuse abnormal white matter signals. Whole exome sequencing identified the homozygous missense variant in the GLYCTK gene [c.455 T > C, NM_145262.3], which affected a highly conserved leucine residue located at a domain of yet unknown function of the enzyme [p.Leu152Pro, NP_660305]. In silico analysis of the variant supported its pathogenicity. A review of the 15 previously reported patients, together with the current one, confirms a clear association between DGA and severe neurological impairment. Yet, future studies of additional patients with DGA are required to better understand the clinical phenotype and pathogenesis.

Legionella pneumophila Pneumonia in Two Infants Treated with Adrenocorticotropic Hormone.

Patients with infantile spasms, an intractable epileptic disorder, often are treated with adrenocorticotropic hormone. Legionella pneumophila is a rare cause of pneumonia in children. We describe 2 infants with Legionella pneumonia whose infection occurred within 1 month after starting adrenocorticotropic hormone.

A novel homozygous splice site mutation in NALCN identified in siblings with cachexia, strabismus, severe intellectual disability, epilepsy and abnormal respiratory rhythm.

We studied three siblings, born to consanguineous parents who presented with severe intellectual disability, cachexia, strabismus, seizures and episodes of abnormal respiratory rhythm. Whole exome sequencing led to identification of a novel homozygous splice site mutation, IVS29-1G > A in the NALCN gene, that resulted in aberrant transcript in the patients. NALCN encodes a voltage-independent cation channel, involved in regulation of neuronal excitability. Three homozygous mutations in the NALCN gene were previously identified in only eight patients with severe hypotonia, speech impairment, cognitive delay, constipation and Infantile-Neuroaxonal-dystrophy- like symptoms. Our patients broaden the clinical spectrum associated with recessive mutations in NALCN, featuring also disrupted respiratory rhythm mimicking homozygous Nalcn knockout mice.

Long-term motor, cognitive and behavioral outcome of acute disseminated encephalomyelitis.

OBJECTIVE: The purpose of this study was to evaluate the long-term motor and neurocognitive outcome of children with acute disseminated encephalomyelitis and to identify prognostic risk factors. METHODS: The study included 43 children who were hospitalized due to acute disseminated encephalomyelitis during the years 2002-2012. The children underwent full neurological examinations, along with comprehensive neurocognitive and behavioral assessments. RESULTS: Twenty-six (61%) children had different degrees of neurological sequelae after a mean follow-up of 5.5 ± 3.5 years. The most common residual impairment included attention-deficit hyperactivity disorder (44%), behavioral problems (32%), and learning disabilities (21%). Five (12%) children had a full-scale IQ of 70 or less, compared to 2.2% in the general population. CONCLUSIONS: Neurocognitive sequelae were found even in children who were considered as fully recovered at the time of discharge. Risk factors for severe neurological sequelae were older age at diagnosis and male gender. We suggest neuropsychological testing and long-term follow-up for all children with acute disseminated encephalomyelitis, even in the absence of neurological deficits at discharge.

Clival Syndrome Secondary to Anaerobic Mastoiditis in A 2-Year-Old Child.

Complications of acute mastoiditis can occur in about 10-20% of cases. Clival syndrome is a rare complication of mastoiditis, involving the 6th and 12th cranial nerves. We describe a case of a child with mastoiditis and presumed Lemierre syndrome complicated by clival syndrome.

Visual Outcome and Recurrence Rate in Children With Idiopathic Intracranial Hypertension.

The purpose of this retrospective study was to evaluate the visual outcome and recurrence rate of idiopathic intracranial hypertension in children. The study included 68 patients who were diagnosed with idiopathic intracranial hypertension according to the modified Dandy criteria. Permanent visual impairment was rare. Three percent remained with mild visual impairment, 4% with minimal visual field defects, and only 1 patient had severe visual impairment. However, 26% had either a prolonged course of disease or a recurring condition. Higher cerebrospinal fluid opening pressure was the only clinical predictor at presentation (P = .04). Recurrence rate was 18%, and in most cases, the second episode occurred during the first year after remission. There was no significant difference between the group of patients with only 1 episode and the group of patients with more than 1 episode. We suggest long-term follow-up after remission, for at least a year, for all children with idiopathic intracranial hypertension.

Migraine & paediatric obesity: a plausible link?

Obesity and migraine are both highly prevalent disorders in the general population, influenced by genetic and environmental risk factors. In recent studies, obesity was found to be a strong risk factor for transformed migraine and, among migraineurs, obesity was associated with frequent headaches and higher disability scores. Suggested mechanisms included: (i) obesity as a pro-inflammatory state may be associated with neurovascular inflammation in patients with migraine; (ii) elevated levels of plasma calcitonin gene-related peptide (CGRP) in obese individuals may play a role as an important post-synaptic mediator of trigeminovascular inflammation in migraine; (iii) dismodulation in the hypothalamic neuropeptide, orexin, in obese persons may be associated with increased susceptibility to neurogenic inflammation causing migraine attacks; and (iv) leptin and adiponectin can activate proinflammatory cytokine release that is involved in the pathogenesis of migraine. In addition, both conditions are associated with psychiatric co-morbidities, such as depression and anxiety, that can further increase headache frequency and disability. Therefore, the effect of obesity on migraine outcome is important. Weight and BMI should be measured and calculated in all children presenting with migraine, and weight control should be a part of the treatment.

Childhood-onset primary generalized epilepsy--impacts on children's preferences for participation in out-of-school activities.

The purpose of this study was to compare preferences for participation in out-of-school activities between children with childhood-onset primary generalized epilepsy and their healthy peers. Overall, participants were 56 children aged 6-11 years. The study group included 26 children with childhood-onset primary generalized epilepsy. The controls were 30 healthy children. Parents of all participants completed a demographic and health status questionnaire. All children completed the Preference Assessment of Children (PAC) that profiles the out-of-school activities the child wishes to participate in. Scores are calculated for five activity types, namely, recreational, active physical, social, skill-based, and self-improvement and for two domains of formal and informal activities. Children with generalized epilepsy showed a similar preference for participation in out-of-school activities as did their healthy peers. The study group showed a lower preference for participation in social activities but showed a higher preference for participation in self-improvement activities. In both groups, younger children (aged 6-8 years) showed a lower preference for participation in most PAC scales. Older children (aged 9-11 years) showed a higher preference for participation in social activities. Difference between genders was close to being statistically significant in the skill-based activities (F(1,21)=3.84, p=.06), where girls showed a higher preference compared with boys. Intervention policies need to be undertaken in order to encourage children with epilepsy to participate in activities together with their healthy peers, aiming to enhance the well-being of children with primary generalized epilepsy.

Long-term motor and cognitive outcome of acute encephalitis.

OBJECTIVES: To examine the long-term motor and neurocognitive outcome of children with acute encephalitis and to look at possible prognostic factors. METHODS: Children who were treated for acute encephalitis in 2000-2010 were reevaluated. All children and their parents were interviewed by using structured questionnaires, and the children underwent full neurologic examinations, along with comprehensive neurocognitive, attention, and behavioral assessments. RESULTS: Of the 47 children enrolled, 1 died and 29 had neurologic sequelae, including motor impairment, mental retardation, epilepsy, and attention and learning disorders. Children with encephalitis had a significantly higher prevalence of attention-deficit/hyperactivity disorder (50%) and learning disabilities (20%) compared with the reported rate (5%-10%) in the general population of Israel (P < .05) and lower IQ scores. Lower intelligence scores and significantly impaired attention and learning were found even in children who were considered fully recovered at the time of discharge. Risk factors for long-term severe neurologic sequelae were focal signs in the neurologic examination and abnormal neuroimaging on admission, confirmed infectious cause, and long hospital stay. CONCLUSIONS: Encephalitis in children may be associated with significant long-term neurologic sequelae. Significant cognitive impairment, attention-deficit/hyperactivity disorder, and learning disabilities are common, and even children who were considered fully recovered at discharge may be significantly affected. Neuropsychological testing should be recommended for survivors of childhood encephalitis.

Double-blind placebo and active (caffeine) controlled study to examine the effects of the herbal nutritional supplement beverage "Wake up" on vigilance and function after lunch.

BACKGROUND: Post-lunch dip is a well-known phenomenon that results in a substantial deterioration in function and productivity after lunch. OBJECTIVES: To assess whether a new herbal-based potentially wake-promoting beverage is effective in counteracting somnolence and reduced post-lunch performance. METHODS: Thirty healthy volunteers were studied on three different days at the sleep clinic. On each visit they ate a standard lunch at noontime, followed by a drink of "Wake up," 50 mg caffeine, or a placebo in a cross-over double-blind regimen. At 30 and 120 minutes post-drinking, they underwent a battery of tests to determine the effects of the beverage. These included: a) a subjective assessment of alertness and performance based on a visual analog scale, and b) objective function tests: the immediate word recall test, the digit symbol substitution test (DSST), and hemodynamic measurements. The results of the three visits were compared using one-way analysis of variance, with P < 0.05 considered statistically significant. RESULTS: In all performance tests, subjective vigilance and effectiveness assessment, both Wake up and caffeine were significantly superior to placebo 30 minutes after lunch. However, at 2 hours after lunch, performance had deteriorated in those who drank the caffeine-containing drink, while Wake up was superior to both caffeine and placebo. Blood pressure and pulse were higher 2 hours after caffeine ingestion, compared to both Wake up and placebo. CONCLUSIONS: These results suggest that a single dose of Wake up is effective in counteracting the somnolence and reduced performance during the post-lunch hours. In the current study it had no adverse hemodynamic consequences.

Viral-induced intracranial hypertension mimicking pseudotumor cerebri.

BACKGROUND: Pseudotumor cerebri or idiopathic intracranial hypertension is characterized by normal spinal fluid composition and increased intracranial pressure in the absence of a space-occupying lesion. METHODS: This study describes a subgroup of 10 patients with the same typical presenting symptoms (headache, vomiting, and papilledema) but without nuchal rigidity, meningeal signs, or change in mental status. Patients had normal neuroimaging studies and intracranial hypertension but also pleocytosis in the cerebrospinal fluid, suggesting central nervous system infection. From the results it can be hypothesized that those children represent a unique subgroup of viral-induced intracranial hypertension when comparing their risk factors, clinical course, treatment, and outcome with 58 patients who had idiopathic intracranial hypertension. RESULTS: All patients with viral-induced intracranial hypertension presented with papilledema but none had reduced visual acuity or abnormal visual fields, compared with 20.7% of patients who had idiopathic intracranial hypertension. They also responded better to treatment with acetazolamide, needed a shorter duration of treatment (7.7 ± 2.6 months vs 12.2 ± 6.3 months, P = 0.03), and had no recurrences. CONCLUSIONS: The results suggest that children who fulfill the typical presenting signs and symptoms and all diagnostic criteria for pseudotumor cerebri other than the normal cerebrospinal fluid component may represent a unique subgroup of viral-induced intracranial hypertension and should be managed accordingly. The overall prognosis is excellent.

Primary headaches, attention deficit disorder and learning disabilities in children and adolescents.

BACKGROUND: Primary headaches and Learning difficulties are both common in the pediatric population. The goal of our study was to assess the prevalence of learning disabilities and attention deficit disorder in children and adolescents with migraine and tension type headaches. METHODS: Retrospective review of medical records of children and adolescents who presented with headache to the outpatient pediatric neurology clinics of Bnai-Zion Medical Center and Meyer Children's Hospital, Haifa, during the years 2009-2010. Demographics, Headache type, attention deficit disorder (ADHD), learning disabilities and academic achievements were assessed. RESULTS: 243 patients met the inclusion criteria and were assessed: 135 (55.6%) females and 108 (44.4%) males. 44% were diagnosed with migraine (35.8% of the males, 64.2% of the females, p = 0.04), 47.7% were diagnosed with tension type headache (50.4% of the males, 49.6% of the females). Among patients presenting with headache for the first time, 24% were formerly diagnosed with learning disabilities and 28% were diagnosed with attention deficit disorder (ADHD). ADHD was more prevalent among patients with tension type headache when compared with patients with migraine (36.5% vs. 19.8%, p = 0.006). Poor to average school academic performance was more prevalent among children with tension type headache, whereas good to excellent academic performance was more prevalent among those with migraine. CONCLUSIONS: Learning disabilities and ADHD are more common in children and adolescents who are referred for neurological assessment due to primary headaches than is described in the general pediatric population. There is an association between headache diagnosis and school achievements.

Obesity in children with headaches: association with headache type, frequency, and disability.

OBJECTIVE: To examine the association between obesity and the different types of primary headaches, and the relation to headache frequency and disability BACKGROUND: The association between obesity and headache has been well established in adults, but only a few studies have examined this association in children, in particular, the relationship between obesity and different types of primary headaches. METHODS: The authors retrospectively evaluated 181 children evaluated for headaches as their primary complaint between 2006 and 2007 in their Pediatric Neurology Clinic. Data regarding age, gender, headache type, frequency, and disability, along with height and weight were collected. Body mass index was calculated, and percentiles were determined for age and sex. Headache type and features were compared among normal weight, at risk for overweight, and overweight children. RESULTS: A higher prevalence (39.8%) of obesity was found in our study group compared with the general population. The diagnosis of migraine, but not of tension-type headache, was significantly associated with being at risk for overweight (odds ratio [OR] = 2.37, 95% confidence interval 1.21-4.67, P = .01) or overweight (OR = 2.29, 95% confidence interval 0.95-5.56, P = .04). A significant independent risk for overweight was present in females with migraine (OR = 4.93, 1.46-8.61, P = .006). Regardless of headache type, a high body mass index percentile was associated with increased headache frequency and disability, but not with duration of attack. CONCLUSIONS: Obesity and primary headaches in children are associated. Although obesity seems to be a risk factor for migraine more than for tension-type headache, it is associated with increased headache frequency and disability regardless of headache type.

Headache in children: young age at onset does not imply a harmful etiology or predict a harsh headache disability.

The purpose of this retrospective study was to compare headache etiology, type, and burden and the learning and behavioral profile in children with early-onset (under 6 years) and late-onset (8-12 years) headaches. The study included 133 patients, 35 in the early-onset group and 98 in the late-onset group. Headache diagnosis was based on International Classification of Headache Disorders -II (ICHD-II) criteria. Learning profile and behavioral problems were assessed by parental reports. Tension headache was the most common diagnosis in the early-onset headache group (51.4%). No significant differences were found between the age groups with regard to headache etiology, disability, abnormal neuroimaging results, school performance, or attention problems. Nevertheless, the early-onset group patients had a significantly higher prevalence of behavioral problems: 25.7% versus 11.2% (P < .02). The authors suggest that early age of headache onset does not imply a harmful etiology or a relentless headache disability or burden.