Startle Seizures and Diffuse Leukoencephalopathy After Resolution of Herpes Simplex Virus 1 Encephalitis in a Child.

We describe a unique clinical presentation of a child after the acute phase of herpes simplex virus 1 (HSV1) encephalitis. A 17-month-old boy first presented with HSV1 encephalitis and was promptly treated with antiviral medication. Seven months later, he was re-admitted for startle seizures. Magnetic Resonance Imaging of the brain showed diffuse confluent leukoencephalopathy. This constellation of symptoms has not been previously reported in HSV1 encephalitis. In conclusion, we showed that brain injury due to HSV1 encephalitis can be associated with the development of startle seizures and diffuse white matter injury in the post-acute phase.

Human Leukocyte Antigen Gene Testing and Carbamazepine-Induced Toxic Epidermal Necrolysis: A Study of Pediatric Practice.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening drug-induced dermatologic conditions. SJS/TEN occurs in 1-10 per 10 000 patients taking carbamazepine (CBZ) (Pratt VM, McLeod HL, Rubinstein WS et al. Medical Genetics Summaries. National Center for Biotechnology Information US; 2018: 1-527). The development of SJS/TEN is associated with variable drug metabolism and presence of an at-risk HLA haplotype. HLA-B*15:02 and HLA-A*31:01 haplotypes can produce a hyperimmune response in the setting of CBZ use in patients of Asian and European descent, respectively (Schneider JA, Cohen PR. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A concise review with a comprehensive summary of therapeutic interventions emphasizing supportive measures. Adv Ther. 2017; 34:1235-1244). OBJECTIVE: The US Food and Drug Administration (FDA) and the Canadian pharmacogenomics Network for Drug Safety (CPNDS) recommend that patients with high-risk ethnic backgrounds should be genetic tested before initiating CBZ (Sukasem C, Chaichan C, Nakkrut T et al. Association between HLA-B Alleles and Carbamazepine-induced maculopapular exanthema and severe cutaneous reactions in Thai patients. Journal of Immunology Research. 2018; 1-11).We sought out to assess the awareness of this in prescribing practitioners and their standard of practice. METHODS: We created a 15-question survey and distributed to pediatric neurologists and pediatricians at the University of Alberta. We hypothesized that there was a discordance between the standard of practice and the recommendation by the FDA and CPNDS. RESULTS: The survey results indicated a lack of awareness of the at-risk ethnicities for CBZ-induced SJS/TEN. HLA gene testing was rarely done prior to initiation of CBZ in high-risk patients. In addition, there was a lack of awareness for standard of care for genetic testing in Canada and worldwide. CONCLUSIONS: Our results demonstrate an evident gap between current prescriber practices and existing FDA and CPNDS recommendations to screen for HLA genotypes. We hope that this study captures the realistic potential to improve patient outcomes.

Healthcare professionals' perspective on the delivery of care to children with Acquired Brain Injury (ABI) and communication with their parents.

PURPOSE: The purpose of this study was to understand healthcare providers' perspective and responsivity to families' needs in rehabilitative care delivery for children with Acquired Brain Injury (ABI). METHODS: Three focus group sessions were conducted to explore and understand multidisciplinary healthcare professionals' (Hcps) perspectives about the care they deliver to parents of children with ABI. Convenience sampling was used to recruit healthcare providers (total sample size = 15) from a large rehabiliation centre of an urban setting in western Canada. Data was collected through semi-structured interviews and analysed thematically. RESULTS: Findings from this study revealed Hcps' perspectives on their day-to-day delivery of care and furthered our understanding of their challenges. It also increased our awareness about the rewards that Hcp gain as a result of their work. Five main themes emerged: (1) Getting back to normal; (2) Hsps' roles and perception; (3) Challenges in practices; (4) Practice rewards; (5) a focus on solutions/ideas for better healthcare delivery. CONCLUSION: Hcps' perspectives on their day-to-day delivery of care to families who have a child with ABI enhance our knowledge about the existing challenges and complexities. Findings from this study have significant implication for rehabilitation services in making rehabilitation goals more achievable for families of children with ABI.

Clinical clues for autoimmunity and neuroinflammation in patients with autistic regression.

AIM: Autistic regression is a unique variant within the autism spectrum disorders (ASDs), with recent reports raising the possibility of immune aetiology. This study explores clinical clues for an association between autistic regression and autoimmunity. METHOD: Single-centre charts of children diagnosed with ASD in 2014 were reviewed. We compared the rates of: (1) familial autoimmunity in first-degree and second-degree relatives; (2) febrile illness preceding initial parental concern, as a potential precipitant of immune activation; and (3) possible non-immune precipitants such as pregnancy and postnatal complications. RESULTS: The charts of 206 children with ASD and 33 diagnosed with autistic regression variant were reviewed. The incidence of febrile illness in the 6 months prior to initial parental concern was significantly higher in the children with autistic regression compared with those with ASD (30% vs 0%; p<0.001). The overall prevalence of familial autoimmunity was also higher in children with autistic regression compared with those with ASD (33% vs 12%; p<0.001). Type 1 diabetes and autoimmune thyroiditis were both more common in families with children with autistic regression. Other non-immune risk factors did not differ between the two groups. INTERPRETATION: Our findings suggest that predisposition to autoimmunity, and immune/inflammatory activation, may be associated with autistic regression.

After a child's acquired brain injury (ABI): An ethnographic study of being a parent.

PURPOSE: To explore the meanings associated with being a parent of a child with an aquired brain injury (ABI). METHODS: An ethnographic study was conducted with parents of children aged 3 to 10 years who had acquired a severe brain injury. Purposeful sampling was used to recruit parents from the Glenrose Rehabilitation Hospital in Edmonton, Alberta. Data collection involved participant observation, fieldwork and semi-structured interviews. Field notes and interviews transcriptions were analysed using a thematic analysis framework and informed by symbolic interactionism theory. RESULTS: Six parent dyads (mothers and fathers) and 4 mothers participated in the study.Parents' meanings of `parenting' a child with severe brain injury were shaped by the injury, wide range of familial dynamics, and interactions. Six main themes related to parental meanings emerged from our data: (1) Getting `back to normal'; (2) Relying on a support system; (3) Worrying something bad may happen after the injury; (4) Going through a range of emotions following the injury; (5) Changing family dynamics after the injury; and (6) Ongoing performativity. CONCLUSION: Parents' meanings of `parenting' a child are extensively impacted by their child's functioning after the ABI. Having a greater appreciation of these experiences may be beneficial for medical professionals.

Novel Method for Neuronal Nanosurgical Connection.

Neuronal injury may cause an irreversible damage to cellular, organ and organism function. While preventing neural injury is ideal, it is not always possible. There are multiple etiologies for neuronal injury including trauma, infection, inflammation, immune mediated disorders, toxins and hereditary conditions. We describe a novel laser application, utilizing femtosecond laser pulses, in order to connect neuronal axon to neuronal soma. We were able to maintain cellular viability, and demonstrate that this technique is universal as it is applicable to multiple cell types and media.

Social communication features in children following moderate to severe acquired brain injury: a cross-sectional pilot study.

We compared the social communication deficits of children with moderate to severe acquired brain injury or autism spectrum disorder, while accounting for the role of attention-deficit hyperactivity disorder (ADHD) symptoms. Parents of 20 children aged 6 to 10 years (10 acquired brain injury; 10 autism spectrum disorder) completed the Social Communication Questionnaire, and Conners 3 Parent Short. A multivariate analysis of covariance revealed significant differences between groups in Social Communication Questionnaire restricted repetitive behavior scores, but not reciprocal social interaction or social communication. Multiple linear regressions indicated diagnosis did not predict reciprocal social interaction or social communication scores and that Conners 3 Parent Short Form hyperactivity scores were the strongest predictor of Social Communication Questionnaire reciprocal social interaction scores after accounting for age and Intelligence Quotient. The lack of difference in social communication deficits between groups may help in understanding the pathophysiology underlying the behavioral consequences of acquired brain injury. The link between hyperactivity and reciprocal interaction suggests that targeting hyperactivity may improve social outcomes in children following acquired brain injury.

The impact of pediatric traumatic brain injury (TBI) on family functioning: a systematic review.

PURPOSE: To explore the impact moderate to severe traumatic brain injury (TBI) in a child has on family functioning. METHODS: The search was conducted using 9 bibliographic databases for articles published between 1980 and 2013. Two reviewers independently screened for inclusion and assessed study quality. Two reviewers extracted study data and a third checked for completeness and accuracy. Findings are presented by three domains: injury-related burden and stress, family adaptability, and family cohesion. RESULTS: Nine observational studies were included. Across the studies, differences between study groups for family functioning varied, but there was a trend for more dysfunction in families whose child had a severe TBI as compared to families whose child had a moderate TBI or orthopedic injury. In three studies, injury-associated burden was persistent post-injury and was highest in families whose child had a severe TBI followed by families with a child who had a moderate TBI. One study found fathers reported more family dysfunction caused by their child's injury compared to mothers. Two studies found that mothers' adaptability depended on social support and stress levels while fathers' adaptability was independent of these factors and injury severity. CONCLUSION: Moderate to severe TBI has a significant, long-standing impact on family functioning. Factors associated with family adaptability vary by parental role.

Femtosecond laser-induced cell-cell surgical attachment.

BACKGROUND AND OBJECTIVE: Laser-induced cell-cell surgical attachment using femtosecond laser pulses is reported. STUDY DESIGN/MATERIALS AND METHODS: We have demonstrated the ability to attach single cells using sub-10 femtosecond laser pulses, with 800 nm central wavelength delivered from a Ti:Sapphire laser. To check that the cells did not go through a cell-fusion process, a fluorescent dye Calcein AM was used to verify that the fluorescent dye did not migrate from a dyed cell to a non-dyed cell. The mechanical integrity of the attached joint was assessed using an optical tweezer. RESULTS: Attachment of cells was performed without the induction of cell-cell fusion, with attachment efficiency of 95%, and while preserving the cells' viability. Cell-cell attachment was achieved by delivery of one to two trains of femtosecond laser pulses lasting 15 ms each. CONCLUSIONS: Laser-induced ionization process led to an ultrafast reversible destabilization of the phospholipid layer of the cellular membrane. The inner cell membrane remained intact during the attachment procedure, and isolation of the cells' cytoplasm from the surrounding medium was obtained. A strong physical attachment between the cells was obtained due to the bonding of the membranes' ionized phospholipid molecules and the formation of a joint cellular membrane at the connection point. The cellular attachment technique, femtosecond laser-induced cell-cell surgical attachment, can potentially provide a platform for the creation of engineered tissue and cell cultures.

Global developmental delay, progressive relapsing-remitting parkinsonism, and spinal syrinx in a child with SOX6 mutation.

SOX6, a member of the SOX gene family, plays a key role in the development of several mammalian tissues and organs, including the central nervous system. Specifically, this gene modulates the differentiation and proliferation of interneurons in the medial ganglionic eminence, as well as oligodendrocytes in the spinal cord. We describe the case of a 4-year-old girl with global developmental delay and a spinal cord syrinx who presented with recurrent episodes of parkinsonian symptoms subsequent to febrile illnesses. The symptoms included gait instability, tremor, and dysarthria, with a progressive relapsing-remitting course over the span of 2 years. The patient was later found to have a large deletion-type mutation in the SOX6 gene. This case is the first report in humans implying a role for SOX6 in basal ganglia function, as well as spinal cord development.

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: an unusual cause of autistic regression in a toddler.

Anti N-methyl-d-aspartate (NMDA) receptor encephalitis in children is associated with psychiatric changes, seizures, and dyskinesias. We present the first report of autistic regression in a toddler caused by this entity. A 33-month-old boy presented with decreased appetite, irritability, and insomnia following an upper respiratory tract infection. Over the next few weeks he lost language and social skills, and abnormal movements of his hand developed. Within a month, this patient came to fit the diagnostic criteria for autistic spectrum disorder. Upon investigation, anti-NMDA receptor antibodies were found in the boy's cerebrospinal fluid. He was treated with intravenous immunoglobulins and steroids, resulting in reacquisition of language and social skills and resolution of movements. Our case emphasizes the significance of suspecting anti-NMDA receptor encephalitis as the cause of autistic regression, even in an age group where the diagnosis of autistic spectrum disorder is typically made, and especially when presentation follows a febrile illness.

Basal Ganglia Injury With Extrapyramidal Presentation: A Complication of Meningococcal Meningitis.

Basal ganglia injury, accompanied by extrapyramidal signs, has been described in the setting of chronic tuberculous meningitis; however, such injury rarely occurs in acute bacterial meningitis and has never been reported with meningococcal meningitis. We report the case of a boy who developed tongue bradykinesia and dysarthria 1 week following presentation with meningococcal meningitis. Magnetic resonance imaging revealed bilateral basal ganglia lesions, suspected to result from cytotoxic edema secondary to infection. The patient subsequently developed general bradykinesia, choreoathetosis, and ataxia, which had improved but not completely subsided by the time of discharge, 8 weeks following initial presentation. The purpose of this report is to present basal ganglia injury with extrapyramidal signs as a possible complication of meningococcal meningitis. Furthermore, we emphasize the importance of suspecting parkinsonian signs as early indicators of basal ganglia involvement in the setting of meningitis, which may later develop into a full-blown movement disorder.

Is the test of variables of attention reliable for the diagnosis of attention-deficit hyperactivity disorder (ADHD)?

The diagnosis of attention-deficit hyperactivity disorder (ADHD) is occasionally biased by the subjectivity of symptoms and reports of parents and teachers. The advent of continuous performance tests raised expectations that the diagnosis of ADHD will be more standardized and accurate. In this study, the authors looked for the validity of the ADHD scores obtained by the Test of Variables of Attention in 230 children who were referred to their ADHD clinic between 2005 and 2007. Based on clinical evaluations, 179 children were diagnosed with affirmed or suspected ADHD. Among the 179 children with ADHD, the Test of Variables of Attention was suggestive of ADHD in 163 participants (91.1% sensitivity), but it was also suggestive for ADHD in 78.4% of the children without ADHD. With a low specificity of 21.6%, the authors feel that the Test of Variables of Attention is not reliable enough to serve as a screening diagnostic tool for ADHD.

Using the test of variables of attention to determine the effectiveness of modafinil in children with attention-deficit hyperactivity disorder (ADHD): a prospective methylphenidate-controlled trial.

The efficacy of modafinil in comparison with methylphenidate in treatment of pediatric attention-deficit hyperactivity disorder (ADHD) has not been thoroughly investigated. This study compared the effect of modafinil versus methylphenidate on continuous attention task in children with ADHD, using the Test of Variables of Attention. Twenty-eight participants completed a baseline test followed by administration of a single dose of either methylphenidate or modafinil, after which the test was repeated. The test was performed a third time, after each subject received a dose of the medication not previously administered. Comparison of scores showed mean baseline, postmethylphenidate, and postmodafinil scores of -2.04, 0.017, and 0.09, respectively. No difference was found between improvements observed with either medication (P < .05). Adverse events for both agents were mild and self-limited, including abdominal pain, diarrhea, and hyposomnia. The authors conclude that modafinil is as effective as methylphenidate; however, a larger scale long-term study is required to confirm these results.

Three cases of cerebellar hypoplasia and vitamin a deficiency: a case report and a possible pathophysiology.

Studies in animal models have established that intra-uterine vitamin A deficiency can hinder hindbrain formation; however, reports of such a phenomenon in humans had not been published until recently, when our group presented the case of an infant diagnosed with pontocerebellar hypoplasia and vitamin A deficiency. We currently report the cases of 3 infants with cerebellar hypoplasia and hypovitaminosis A, whose vitamin A consumption was determined to be adequate, and whose mothers had no such deficiency. We suggest a possible pathophysiology whereby a mutation in the gene coding for cytoplasmic retinol-binding protein II, which is expressed both in the placenta and the yolk sac (during fetal development) and in the absorptive intestinal cells, can cause vitamin A deficiency, forming hindbrain anomalies. Validation of our hypothesis will require further research, including fetal vitamin A measurements and hindbrain examination in cytoplasmic retinol-binding protein II knockout animals.

Fetal exposure to alcohol, developmental brain anomaly, and vitamin a deficiency: a case report.

Prenatal alcohol exposure is a cause of congenital brain malformations such as hydrocephalus; however, a complete mechanism accounting for this phenomenon has yet to be discovered. We report a case of a newborn who was exposed to alcohol throughout pregnancy and presented with low serum vitamin A and hydrocephalus. To our knowledge, the connection between prenatal ethanol exposure, vitamin A deficiency, and a developmental brain anomaly has never been described in humans before. A possible mechanism may be mediated by disruption of the homeostasis of vitamin A, an important morphogen in the developing nervous system. This, in turn, compromises the activity of the floor plate, a structure in charge of polarization and midline formation in the neural tube. We conclude that vitamin A screening and supplementation might be recommended for newborns of mothers who ingested ethanol during pregnancy.

An unusual presentation of copper metabolism disorder and a possible connection with Niemann-Pick type C.

Abnormal copper metabolism has been linked with neurological disorders, such as Wilson and Menkes disease. Another disorder causing symptoms similar to copper metabolism disorder is Niemann-Pick type C. However, a definite pathophysiological connection between Niemann-Pick type C and copper metabolism disorders has never been established. The authors present an adolescent with an unusual presentation of copper deficiency-dysarthria, ataxia, and vertical gaze paresis, without significant cognitive degeneration or pathological magnetic resonance imaging (MRI). The patient was found to carry 2 mutations in the NPC1 gene. A possible link, explaining how copper deficiency might induce the Niemann-Pick phenotype might involve overproduction of cholesterol and inhibition of acid sphingomyelinase. We suggest that copper metabolism disorders be included in the differential diagnosis for ataxia and dysarthria, even in cases with unusual presentations. Moreover, should the connection between copper and Niemann-Pick be validated, screening for copper metabolism disorders may be advisable in Niemann-Pick type C patients and vice-versa.

Pontocerebellar hypoplasia type 3 with severe vitamin A deficiency.

Pontocerebellar hypoplasia consists of a rare heterogeneous group of congenital neurodevelopmental disorders. It is characterized by hypoplasia and atrophy of the cerebellar cortex, dentate nuclei, pontine nuclei, and inferior olives. We present an 18-month-old infant with pontocerebellar hypoplasia type 3 and severe vitamin A deficiency. This case emphasizes the significance of vitamin A in the proper formation of the hindbrain. The authors conclude that vitamin A screening should be considered in maternal and newborn metabolic screening.

Lingual dyskinesia and tics: a novel presentation of copper-metabolism disorder.

Copper is a trace element that is required for cellular respiration, neurotransmitter biosynthesis, pigment formation, antioxidant defense, peptide amidation, and formation of connective tissue. Abnormalities of copper metabolism have been linked with neurologic disorders that affect movement, such as Wilson disease and Menkes disease; however, the diagnosis of non-Wilson, non-Menkes-type copper-metabolism disorders has been more elusive, especially in cases with atypical characteristics. We present here the case of an adolescent with a novel presentation of copper-metabolism disorder who exhibited acute severe hemilingual dyskinesia and prominent tics, with ballismus of the upper limbs, but had normal brain and spinal MRI results and did not show any signs of dysarthria or dysphagia. His serum copper and ceruloplasmin levels were low, but his urinary copper level was elevated after penicillamine challenge. We conclude that copper-metabolism disorders should be included in the differential diagnosis for movement disorders, even in cases with highly unusual presentations, because many of them are treatable. Moreover, a connection between copper-metabolism disorders and tics is presented, to our knowledge, for the first time in humans; further investigation is needed to better establish this connection and understand its underlying pathophysiology.