Safety and feasibility of regenerative therapy using autologous cord blood cells in neonates with hypoxic ischemic encephalopathy

Background:
A major cause of cerebral palsy is considered to be a hypoxic ischemic encephalopathy in newborn infants with moderate or severe asphyxia. To date, therapeutic hypothermia has been the only effective treatment for hypoxic ischemic encephalopathy to prevent the development of cerebral palsy. However, even if infants are treated with therapeutic hypothermia, nearly half of them die or left with moderate to severe neurological impairments as yet. A recent regenerative medicine indicated benefits of autologous umbilical cord blood stem cell transplantation combined with therapeutic hypothermia for hypoxic ischemic encephalopathy (Cotten et al. JP 2014). Umbilical cord blood stem cells which combines the action of suppressing early inflammation and the action of promoting regeneration is expected as a remarkable excellent therapeutic method as a treatment for hypoxic ischemic encephalopathy.
Methods:
Umbilical cord blood stem cells was collected aseptically and prepared by using SEPAX which need more than 40ml of umbilical cord blood. Infants admitted to the NICU of 6 hospitals in our research group will be eligible if they are ≥36 weeks’ gestational age and birth weight ≥1800 g with hypoxic ischemic encephalopathy and meet the cooling criteria.
Results:
Autologous umbilical cord blood stem cells therapy for neonatal hypoxic ischemic encephalopathy in addition to therapeutic hypothermia was performed in 6 newborn patients. All of them have discharged NICU without support of ventilator and survived from 18 months to 4 years.
Conclusions:
Autologous umbilical cord blood stem cells for newborn hypoxic ischemic encephalopathy is safe and feasible, and warrants a larger and controlled phase II study.

Efficacy of Modified Atkins diet (MAD) as treatment of intractable epilepsy in children – A randomized controlled trial

Purpose: To determine the efficacy, adverse effects and tolerability of MAD in intractable epilepsy of children of different types in our country.

Method: This was a randomized controlled trial done from July 2016 to December 2017. This study was carried out in the OPD of Paediatric Neurology, National Institute of Neurosciences, (NINS) Dhaka, BSMMU, Dhaka, Dhaka Shishu Hospital. At each of the study sites intractable epilepsy cases aged 3 to 18 years having at least 3 seizures per week who intended to be enrolled were randomized either as in study group (MAD treatment group) and control group (getting normal family diet). Children were evaluated thereafter through detail history and clinical examination, lab test were obtained. Subsequently cases were randomized by lottery method. The standard anticonvulsant medications were continued to both the group as per requirement. After one month observation period MAD was given to the study group and 3 follow up visit at an interval of one month was made. Parents checked urine ketones by reagent test sticks daily throughout 3 month.

Results: Age and sex of both the group is comparable.Phenytoin,valproate,Carbamazepine were the common AED for study group whereas valproate,levitiracetum,carbamazepine and phenobarbitone were the common AED for the control group to treat intractable epilepsy in present study. The primary outcome of this study at the endpoint of 3rd follow-up, 71 % children had at least 50% or more seizure reduction and 25.7 % children had a ≥ 90% seizure reduction. 8 children in MAD group developed constipation,and other adverse effects were vomiting, skin rash, abdominal pain and abdominal distention.

Conclusion: Results of the study documented that MAD was found to be effective in reducing seizure burden in children with refractory epilepsy, well tolerated in the studied children and only few adverse effects were observed during study period

The referral features of autistic children in a tertiary Medical Center of Southern China: a Chinese cohort

Objectives: To study the referral recognition features of autistic children in a tertiary Women and Children’s Medical Center.

Methods: The diagnostic autistic children in the past four years in Guangzhou Women and Children’s Medical Center were reviewed. The five groups were classified based on different ways of referral: (1) Parent/Guardian (PG); (2) Medical institutions’ personnel (MIP); (3) Educational services (kindergarten/Early Education Institutes); (4) Relatives or friends or others around (RFO); (5) Media (TV, Internet, We Media). The other 15 groups were classified according to the first noticed symptoms (1) Language developmental abnormalities (LDB) (Non-verbal/delay/idiosyncratic); (2) Name is ignored; (3) Don’t play with other children (DBWOC)/asocial/Live in own world (LOW); (4) Poor eye contact (PEC); (5) Hyperactivity; (6) Repetitive motor mannerisms (RMM) (Body rotation/Walk on tiptoe/Weird Hand Style/Look sideways/Upturn of eyes); (7) Don’t listen to instructions (DLI); (8) Motor developmental delay (MDD); (9) Regression; (10) Stereotyped behaviors (SB) (Turn things around/Playing with toy wheels/Repeat a road); (11) Emotional disorders (ED) (Hasty temper/cry and scream/Beat somebody); (12) Stay delay/Poor understanding/Can’t teach); (13) Inappropriate facial expressions (IFE) (Gelastic/Farewell without expression/Can’t make him/her laugh/No smile); (14) No pointing; (15) Others (Poor self-care ability/Sleep disorders/Fear of strangers/Fear of banyan whiskers). The age of PG first noticed were recorded.

Results: The total 716 autistic cases were included (mean diagnostic age 3.28 years, M/F: 639/77). The referral rates of different groups were as follows: (1) PG (82%); (2) MIP (7.3%); (3) Educational services (6.8%); (4) RFO (2.8%) and Media (1.1%). The referral rates of first noticed symptoms were as follows: LDB (46.4%), Name is ignored (10.2%), DBWOC/asocial/LOW (9.8%), Poor eye contact (4.3%), Stay delay/poor understanding/Can’t teach) (4.3%), MDD (4.1%), SB (3.9%), Hyperactivity (3.1%), ED (2.9%), DLI (2.8%), Regression (2.5%), Others (2.5%), IFE (0.7%), and the No pointing (0.3%). The mean age of PG first noticed was 2.13 years, with the more than one year later than the diagnostic age.

Conclusions: The most common referral method is by PG, while the most common symptom of first noticed is language retardation. Exploiting the potential of medical/educational institutions, or even media referrals, is a concern in the future.

The international DEM-CHILD Database: From Disease Database to Evaluation Tools for Experimental Therapies – the CLN2 Experience.

Background: NCLs (Neuronal Ceroid Lipofuscinoses) are neurodegenerative diseases, characterized by dementia, motor decline, vision loss and epilepsy. All except one are without any approved treatment option. Early diagnosis and exact knowledge of the natural history are important for evaluation of urgently needed experimental therapies. Since only few expert centers across the world follow NCL patients regularly, an international effort is necessary to describe the progression of disease, leading to the development of an evaluation tool for current and future experimental therapy studies.

Aims: (1) Collecting the world’s largest, clinically and genetically best characterized set of CLN2 patients. (2) Analyzing disease prevalence, time of onset and character of first symptoms and providing quantitative longitudinal data on disease progression using an established clinical rating scale (Steinfeld et al., 2002).

Results: 74 CLN2 patients were analyzed longitudinally. (1) Mean age at symptom onset and diagnosis were 35 and 54 months, respectively, indicating diagnosis occurred on average 19 months after onset of first symptoms, reported as seizures (70%), loss of language (57%) or motor abilities (41%). However, a systematic review of early language development in 36 patients revealed that 83% had a significant delay in language development preceding the onset of other symptoms. (2) Our cohort showed a highly homogeneous, rapid decline in motor-language summary scores from normal (score 6) to no function (score 0), which occurred over approximately 36 months with a mean rate of decline of −1.8 units per year.

Conclusions: This international collaboration represents the largest set of quantitative longitudinal data on the natural history of CLN2 disease to date. Delayed language acquisition frequently precedes the onset of more typical symptoms. The course of disease is highly predictable. These data served as historical controls for the evaluation of treatment efficacy in clinical trials of intraventricular enzyme replacement therapy for CLN2 and were successfully audited and approved by US and European Medical Agencies (FDA, EMA).

Development and Adaptive function of pediatric patients with neurological disorders on ketogenic diet and Caregivers’ psychological stress

Background:
Family members should bear caregiving responsibility with its accompanying stress. This study aimed to investigate function of pediatric patients with neurological disorders on Ketogenic Diet (KD) and their caregivers’s psychological stress.

Methods :
The assessments for 40 caregivers and pediatric patients with neurological disorders including epilepsy were administered and analyzed, between 2015 and 2018 at the pediatric clinics of the Severance Children’s Hospital in South Korea. The neurodevelopmental data of pediatric patients were including developmental quotient/ intellectual quotient, the level of adaptive function and clinical variables such seizure-related as age of onset, lead time to KD start. Additionally the caregivers were administered psychological assessment rated Minnesota Multiphasic Personality Inventory-2, Beck Depression Index-II, State-Trait Anxiety Inventory, Parenting Stress Index .

Results:
A review on clinical variables such KD-related and seizure-related. The pediatric patients’ age at onset of symptoms was 1.98±1.6 years and the duration of illness was 2.52±2.37 years, lead time to KD start was 2.55±2.41 years. Their function were intellectual disability level on 60% of social quotient and 67% intellectual quotient. Caregivers’s were negative emotion such as clinical level of depression (64%), anxiety (74%), and 40% of the Caregivers’ parenting stress were increased to clinical level particularly in parent-child dysfunctional interaction. Moreover, higher parenting stress were related their negative emotion.

Conclusions:
Adequate, well-designed KD program in pediatric patients with neurological disorders showed benefits in their caregivers’ psychological well-being. The importance of caregivers’ emotional distress and parenting stress for pediatric epilepsy with KD were considered. Moreover, the essential role of medical professionals including pediatrician and pediatric neurologists was highlighted for and comprehensive intervention & total care planning as well as diagnosis of comorbid condition.

Acknowledgements: This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI18C1166).

The clinical significance of erythema of BCG inoculation site in Kawasaki Disease

Background: Erythema and induration of the Bacillus Calmette-Guerin (BCG) inoculation site has been recognised as a significant sign in aiding diagnosing Kawasaki disease (KD). The study aims to evaluate the clinical significance of BCG site erythema.
Methods: A retrospective observational study of patients discharged with a diagnosis of KD from 01.01.2018 to 31.12.2018 was conducted. The proportion of patients with BCG site erythema was identified in either complete or incomplete KD and were statistically analysed in terms of age, race, gender and coronary artery outcomes. Multiple logistic regression model was used to identify if BCG site erythema was significantly correlated with any of the other clinical signs of KD.

Results: Of the 27 patients identified during the study period, 2 were excluded as their BCG inoculation site status was unknown with 1 of patient presented with myocardial infarction suspected of past KD in view of dilated coronary artery aneurysms with thrombosis. Ten patients (40%) had BCG site erythema, and all were below 30 months of age (p=0.015). Statistically, BCG erythema was not significant in terms of race, gender or coronary outcomes but the presence of BCG erythema in complete KD was significant (p= 0.046). There is significant correlation between BCG site erythema and erythema of extremities (p=0.004), and perianal erythema (p=0.014).
Conclusion: BCG site erythema is common in children below 30 months of age. It is significantly correlated with erythema of extremities and perianal erythema, and should be considered a diagnostic clinical sign in diagnosing KD.

Prevalence of electroencephalography abnormality in children with complex febrile seizures and multiple episodes of febrile seizures

Introduction: Febrile seizures are the most common seizure disorder in childhood. Although most febrile seizures are benign and self-limited, there are high risk of epilepsy and abnormal electroencephalography findings in patients with complex febrile seizures and multiple episodes of febrile seizure. There has been no prior study about the prevalence of abnormal electroencephalography findings in complex febrile seizures and multiple episodes of febrile seizures in Thailand.
Objective: To study the prevalence of electroencephalography abnormality in children with complex febrile seizures and multiple episodes of febrile seizures.
Methods: This is a cross-sectional study. Patients aged between 6 months to 5 years old who were diagnosed with complex febrile seizures or multiple episodes of febrile seizures were enrolled in this study from July 1, 2017 to June 30, 2018 at Faculty of Medicine Vajira Hospital, Navamindradhiraj University. After initial history taking and physical examination, electroencephalography (EEG) were performed within 1 week. EEG results were interpreted by a pediatric neurologist. The data was recorded and then analyzed.
Results 100 patients (62 males, 38 females) were enrolled in this study. 18 cases were diagnosed with complex febrile seizure, while 82 cases had multiple episodes of febrile seizure. Abnormal EEG findings were seen in 4 cases of complex febrile seizures (22.2%) and 6 cases of multiple episodes of febrile seizures (7.3%). Patients with complex febrile seizures were more likely to have EEG abnormalities than multiple episodes of febrile seizures (OR 8.15, p-value <0.001). At 6-month follow up, 18 patients (18%) in this study were diagnosed with epilepsy.
Conclusions The prevalence of electroencephalography abnormality was 10% in children with complex febrile seizures and multiple febrile seizure. EEG abnormalities were 8.51 times more common in patients with complex febrile seizures than the patients with multiple episodes of febrile seizures. The risk of developing epilepsy at 6 months is 18% in our study.
Keywords Complex febrile seizures, Multiple episodes febrile seizures, electroencephalography, epilepsy, prevalence

Cerebral Sinus Venous Thrombosis as the Initial Presentation in a Child with Homocystinuria : Case Report .

Background: Inherited homocystinuria is a rare autosomal recessive metabolic disorder affecting several organs including the CNS resulting in a neurologic and vascular abnormalities through toxic effect of homocysteine. Neurologic involvement includes progressive mental retardation, seizure, dystonia, behavioral and personality disorder, while the vascular one include stroke due to thromboembolic syndromes.
Case report: A 6-year-old boy with learning disability, skeletal abnormalities,myopia,frequent fractures , and previous febrile convulsion presented with sudden onset of worsening headache ,left sided frequent seizures with generalization, and behavioral changes for 48 hours followed by abnormal gait, and deterioration in his mental status.Preceded by febrile illness.His parents were consanguineous with no neurologic disorder or epilepsy in the family. Examination revealed mental subnormality,poor social interaction, slurred speech, general hypotonia left > right,DTR+1 , extensor planter response bilaterally,and unsteady gait. Brain MRI and MRV showed extensive superior sagittal sinus thrombosis,localized cortical right parieto-occipital infarction,and abnormal white matter of both hemispheres,sparing subcortical fibers with diffusion restriction suggestive of metabolic white matter disease. Laboratory evaluation revealed, high serum methionine, homocysteine level,and presence of cysteine in the urine.Marked improvement was noted after intravenous anticoagulant therapy.He was maintained on lamotrigine ,aspirin, high dose of oral pyridoxine,folate ,betaine, and methionine-restricted diet. Genetic study revealed a nonsense homozygous mutation in CBS gene
( C969G>A P.Trp323Ter (W323X) ) . Afollow-up brain MRI showed a significant recanalization of all sinuses with reduction of thrombosis within the superficial cortical veins.
Conclusion:Although homocystinuria is a vanishing disease, physician should keep high index of suspicion among patients with mental disabilities and seizure disorders as early detection and treatment can prevent future neurologic and vascular complications.

Key words: Homocysteine, Cerebrovascular disease, Metabolic disorders, Seizure disorder

Vici syndrome: Experience at tertiary care center

Background:Vici syndrome (OMIM:242840) is a rare autosomal recessive congenital multisystem disorder characterized by oculocutaneous hypopigmentation , agenesis of corpus callosum, cataract, combined immunodeficiency, hypertrophic cardiomyopathy, and psychomotor retardation. It is caused by mutations in the EPG5gene (18q12.3). Approximately 30 patients have been reported in the world. Reports of patients from the Arabian Peninsula are rare due to lack of awareness among physicians.
Method:A retrospective chart review of seven children diagnosed with Vici syndrome at a University Hospital, in Riyadh.
Results:There was female sex preponderance (71.4%).All patients were failing to thrive (85.7%)except for one.Developmental delay and hypotonia were found in all, while seizure disorder was found in 3(42.9%).Ocular albinism was detected in 2 (28.6%).Facial dysmorphism was found in all (high arched palate and micrognathia) Five (71.4%)patients had optic atrophy,and 4(57%) patients had retinal hypoplasia while only one had cataract.Brain MRI revealed hypoplasia of corpus callosum in 5 (71.4%) patients while agenesis of corpus callosum was found in one.Hypoplasia of cerebellar hemisphere was found in all while of the vermis was found in all except one.All had delayed myelination of white matter,and only 4(57 %) had gyral abnormalities.Muscle biopsy was done in 3 (42.9%) patients and showed myopathy. One patient had cardiac hypertrophy, 2 (28.6%) patients had kidney abnormalities, and lymphopenia with lymophocytes subsets abnormalities were detected in 3(42.9%) patients.
Conclusion:Vici syndrome should be suspected in children presented with developmental delay, hypotonia,and abnormalities of corpus callosum or cerebellum .Awareness may help in improving the quality of life and survival of these patients.

Further delineation of phenotypic and genotypic features of MICU1 gene mutations in two Saudi families of Arab Descent.

Background:The mitochondrial calcium uptake protein 1(MICU1) is a newly discovered gene (2010).It is a subunit of the mitochondrial uniporter, a multisubunit calcium channel of the mitochondrial inner membrane. It regulates channel opening in response to intracellular calcium content and calcium transients. It`s mutation result in an early childhood onset of proximal muscle weakness, progressive extrapyramidal signs, and learning disabilities.Only 30 cases have been described in the literature. Objective: To describe the clinical characteristics, neuroloradiolgical , laboratory profiles of four cases diagnosed with MICU1 mutation from two Saudi consanguineous families .
Method: A retrospective chart review study of four cases diagnosed with MICU1mutation at a tertiary university center in Saudi Arabia.
Results: The phenotype associated with MICU1gene mutations in our patients is fairly consistent, although our case series is unique in that all the affected patients are a product of consanguineous marriages ,severity of the disease varies within the same family, extrapyramidal signs were not the major symptom initially, congenital heart disease and Arnold – Chiari malformation were additional clinical features . Early encephalopathic changes (slow background) with epileptiform discharges on EEG were seen in two patients, and evidence of mitochondrial disorder was detected on liver and muscle biopsy of one patient. A novel nonsense homozygous mutation c.547C>T (p. Gln 183*) was detected in one family, while a previously reported c.553C >T (p. Gln185*) was detected in the other family.
In conclusion, our findings expand the phenotypic and genotypic manifestations of MICU1 gene mutations.

Key Words: Mitochondrial calcium uptake protein 1, MICU1, Muscle weakness, Extrapyramidal signs, learning disabilities, MRI .