Cardiac dysfunctions in children with drug-resistant epilepsy.

Objective: There were reports of cardiac dysfunction that led to sudden unexpected death in epilepsy (SUDEP) in patients with epilepsy. Early detection of cardiac dysfunction can lead to early management to prevent sudden cardiac death in these patients. The objective of our study is to assess cardiac functions in children with drug-resistant epilepsy (DRE) compared with the normal population by using a standard echocardiogram (SE), tissue Doppler imaging (TDI) and myocardial strain evaluations (MSE). Method: Twenty-seven children who have been diagnosed with DRE based on the International League against Epilepsy (ILAE) were included in the study, along with 27 children whose ages match those of the normal control group. Results: Seventeen children, median age 12 years old, were using more than four anti-seizure medications. Structural brain lesions were the most common cause of epilepsy, 55.6% (15). Generalized tonic-clonic seizures were the most common seizure type, 55.6% (15). Children with DRE had a lower early mitral valve E wave inflow velocity compared with the control group (p < 0.05). They also had lowered early diastolic velocities (e') and myocardial performance index (MPI) when compared with the control group (p < 0.05). There was a statistically significant difference in left ventricular myocardial strain in children with DRE, with an average of -21.1 (IQR -23.5 and -19.4) and control, -25.5 (IQR -27.3 and -24.2). Significance: Children with DRE have an impairment of left ventricular diastolic function and myocardial strain, which could indicate decreased myocardial deformation and contraction compared with controls. These cardiological assessments can be used to evaluate children with DRE for early diagnosis and management of their cardiac dysfunction.

Clinical and Genetic Studies of the First Monozygotic Twins with Pfeiffer Syndrome.

Objective: To report the clinical and radiographic findings and molecular etiology of the first monozygotic twins affected with Pfeiffer syndrome. Methods: Clinical and radiographic examination and whole exome sequencing were performed on two monozygotic twins with Pfeiffer syndrome. Results: An acceptor splice site mutation in FGFR2 (c.940-2A>G) was detected in both twins. The father and both twins shared the same haplotype, indicating that the mutant allele was from their father's chromosome who suffered severe upper airway obstruction and subsequent obstructive sleep apnea. Hypertrophy of nasal turbinates appears to be a newly recognized finding of Pfeiffer syndrome. Increased intracranial pressure in both twins were corrected early by fronto-orbital advancement with skull expansion and open osteotomy, in order to prevent the more severe consequences of increased intracranial pressure, including hydrocephalus, the bulging of the anterior fontanelle, and the diastasis of suture. Conclusions: Both twins carried a FGFR2 mutation and were discordant for lambdoid synostosis. Midface hypoplasia, narrow nasal cavities, and hypertrophic nasal turbinates resulted in severe upper airway obstruction and subsequent obstructive sleep apnea in both twins. Hypertrophy of the nasal turbinates appears to be a newly recognized finding of Pfeiffer syndrome. Fronto-orbital advancement with skull expansion and open osteotomy was performed to treat increased intracranial pressure in both twins. This is the first report of monozygotic twins with Pfeiffer syndrome.

Comparison of Clinical Manifestations, Laboratory, Neuroimaging Findings, and Outcomes in Children With Posterior Reversible Encephalopathy Syndrome (PRES) in Children With and Without Renal Disease.

BACKGROUND: To demonstrate and compare the clinical manifestations, laboratory findings, and neuroimaging findings of posterior reversible encephalopathy syndrome (PRES) in children with and without underlying renal disease. METHODS: The study included 23 children with a diagnosis of PRES from January 2009 to March 2019. All data, including clinical manifestations, laboratory findings, underlying medical illness, and neuroimaging results, were obtained. RESULTS: Sixteen had underlying renal disease. The median age of PRES onset was 10.3 years in children with renal disease and 9.8 years in children without renal disease. Higher blood pressure at the baseline, on admission, and at the onset of PRES was found in the renal disease group more than in the nonrenal disease group (P < 0.05). Seizures were likely seen in the renal disease group compared with the nonrenal disease group (P = 0.03). Generalized tonic-clonic seizures were the most common seizure type in both groups. An initial CT scan revealed vasogenic edema in 75% of the renal group and 85.7% of the nonrenal group. During a long-term follow-up, all children recovered without significant neurological deficits or subsequent epilepsy. CONCLUSIONS: Hypertension and higher baseline blood pressure are more common in children with renal disease who develop PRES compared with nonrenal disease. Seizures are more common in the renal disease group. A computed tomographic (CT) scan can help with PRES diagnosis when magnetic resonance imaging is not available. All children with PRES recovered without significant neurological deficits or subsequent epilepsy.

Diffuse neonatal hemangiomatosis with a single atypical cutaneous hemangioma.

Diffuse neonatal hemangiomatosis (DNH) is an extremely rare but deadly neonatal condition which presents as multiple cutaneous hemangiomas and hemangiomas in 3 or more visceral organs. DNH is usually suspected when multiple hemangiomas are found on the skin of the baby. We hereby present an interesting case in a newborn whose diagnosis was made from multiple intracranial, hepatic, and intramuscular hemangiomas, but with a single and unusual cutaneous manifestation over the right ankle. The patient was asymptomatic at the time of diagnosis. Due to the solitary nature of skin lesion, this report might contribute to a redefining of the term DNH.

Comparison of Arterial Ischemic and Hemorrhagic Pediatric Stroke in Etiology, Risk Factors, Clinical Manifestations, and Prognosis.

BACKGROUND: Stroke is relatively rare in children but has a significant impact on long-term morbidity and mortality. There are limited data regarding the etiology, clinical manifestation, and prognosis of arterial ischemic stroke (AIS) and hemorrhagic stroke (HS) in children. OBJECTIVE: The aim of this study is to identify and compare etiology, risk factors, clinical manifestations, and prognostic outcomes between arterial ischemic and hemorrhagic pediatric stroke. METHODS: We retrospectively reviewed all hospital medical records and pediatric neurology database of 83 children who were first diagnosed with AIS and HS at the Pediatric Department, Chiang Mai University Hospital, Chiang Mai, Thailand between January 1, 2009, and December 31, 2018. All children were from 1 month to 18 years old. RESULTS: Fifty-one AIS (56%) and 32 (35.2%) HS were identified. The median age of onset was 6.9 years for AIS and 5.3 years for HS. Moyamoya disease/syndrome was the most common cause in AIS (21.6%). Rupture of cerebral arteriovenous malformation was the most common cause in HS (21.9%). More than one-third (39%) of children had multiple risk factors associated with stroke. Iron deficiency anemia was commonly found in children with AIS (39.2%). The majority of clinical presentations were hemiparesis (80.4%) for AIS and alteration of consciousness (68.8%) for HS. The median time to diagnosis exceeded 6 hours in both AIS and HS. The overall mortality rate of acute stroke was 5.1 per 100 person-years (95% confidence interval [CI], 2.9-9). The mortality rate was higher in HS compared with that in AIS with statistical significance (16.6; 95% CI, 8.9-30.8 vs 1.1%; 95% CI, 0.3-4.6 per 100 person-years). Thirty children (36.1%) developed epilepsy during the follow-up (median duration, 26 months). Recurrent stroke occurred in 1 child with AIS and 1 child with HS. CONCLUSIONS: Moyamoya disease/syndrome and arteriovenous malformation rapture are the most common cause of AIS and HS, respectively. Iron deficiency anemia was commonly found in childhood AIS. The time to diagnosis in both AIS and HS was delayed. The mortality rate in HS was higher than in AIS. Neurological deficits are seen in 70% of childhood AIS during the follow-up. One-third of the children in our study developed epilepsy, which generally responds to a single antiseizure medication. The recurrence rate of childhood stroke was low compared with adult stroke.

Risk factors of epilepsy in children with complex febrile seizures: A retrospective cohort study.

BACKGROUND: Febrile seizures are the most common seizures in children. Children with complex febrile seizures have a higher risk of subsequent epilepsy compared with children with simple febrile seizures. Multiple risks factors for epilepsy, including focal status epilepticus, family history of epilepsy, neurodevelopmental abnormalities and abnormal electroencephalogram findings, have been found with inconsistent results. The aim of this study is to identify risk factors for developing epilepsy in children with complex febrile seizures. METHODS: The study included 248 children aged 3-72-months, diagnosed with complex febrile seizures at Chiang Mai University Hospital. Demographic data, seizure characteristics, electroencephalogram and neuroimaging findings were identified, and assessed to establish whether they were risk factors for subsequent epilepsy. RESULTS: Fifty-five patients (22.1%) had subsequent epilepsy. Using Cox regression-survival analysis, factors associated with epilepsy were prolonged seizures >15 min (P = 0.006; Hazard Ratio (HR): 2.475; 95% Confidence Interval (CI): 1.294-4.735), developmental delay (P = 0.019; HR: 4.476; 95% CI: 2.280-15.646), epileptiform discharges on electroencephalogram (P = 0.023; HR: 1.391; 95%CI: 1.174-1.876), and abnormal neuroimaging (computed tomography or magnetic resonance imaging; P = 0.028; HR: 1.355; 95% CI: 1.034-1.776). Age at onset, peak febrile temperature, duration between the onset of fever and the occurrence of seizure, recurrent seizures within 24 h, focal seizures, abnormal neurological exams and family history of febrile seizure or epilepsy were not associated with increased risk of subsequent epilepsy in this study. CONCLUSIONS: Risk factors associated with increased risk of epilepsy in children with complex febrile seizures are prolonged seizures or febrile status epilepticus, developmental delay, electroencephalogram epileptiform discharges, and abnormal neuroimaging. Their presence would merit close clinical monitoring.

Dental Anomalies in Ciliopathies: Lessons from Patients with BBS2, BBS7, and EVC2 Mutations.

Objective: To investigate dental anomalies and the molecular etiology of a patient with Ellis−van Creveld syndrome and two patients with Bardet−Biedl syndrome, two examples of ciliopathies. Patients and Methods: Clinical examination, radiographic evaluation, whole exome sequencing, and Sanger direct sequencing were performed. Results: Patient 1 had Ellis−van Creveld syndrome with delayed dental development or tooth agenesis, and multiple frenula, the feature found only in patients with mutations in ciliary genes. A novel homozygous mutation in EVC2 (c.703G>C; p.Ala235Pro) was identified. Patient 2 had Bardet−Biedl syndrome with a homozygous frameshift mutation (c.389_390delAC; p.Asn130ThrfsTer4) in BBS7. Patient 3 had Bardet−Biedl syndrome and carried a heterozygous mutation (c.389_390delAC; p.Asn130ThrfsTer4) in BBS7 and a homozygous mutation in BBS2 (c.209G>A; p.Ser70Asn). Her clinical findings included global developmental delay, disproportionate short stature, myopia, retinitis pigmentosa, obesity, pyometra with vaginal atresia, bilateral hydronephrosis with ureteropelvic junction obstruction, bilateral genu valgus, post-axial polydactyly feet, and small and thin fingernails and toenails, tooth agenesis, microdontia, taurodontism, and impaired dentin formation. Conclusions: EVC2, BBS2, and BBS7 mutations found in our patients were implicated in malformation syndromes with dental anomalies including tooth agenesis, microdontia, taurodontism, and impaired dentin formation.

Short-term outcome of perinatal hypoxic-ischaemic encephalopathy at Chiang Mai University Hospital, Thailand: a 15-year retrospective study.

BACKGROUND: The outcome of perinatal hypoxic-ischaemic encephalopathy (HIE) in middle-to-low-income countries varies between regions. OBJECTIVES: To determine the mortality and morbidity, and factors influencing the deaths of infants with perinatal HIE. METHODS: A retrospective study was conducted at Chiang Mai University Hospital, Thailand. Perinatal HIE infants of >35 weeks gestation, birthweight ≥2000 g and admitted during 2005-2019 were reviewed. Baseline Characteristics, clinical course and outcome at discharge were compared between the period before and after initiation of therapeutic hypothermia (TH). Risk of death in HIE infants who underwent TH was identified. RESULTS: A total of 162 HIE infants were included. Compared to the period before TH initiation, the mortality rate was significantly decreased in the TH period. (27% vs. 12.8%, p=0.04) Among 100 HIE infants who underwent TH, the mortality rates was 14%(14/100), of whom 2.5% (2/76) and 50% (12/24) were in the moderate and severe HIE groups. Apgar score at 5 mins ≤1, severe HIE, seizures, hypoglycaemia, organ involvement ≥ five sites, ammonia ≥100 umol/L, lactate ≥14 mmol/L, and requirement for two or more inotropic drugs were risks of death. Multivariate analysis demonstrated that severe HIE (aOR 732.8, 95% CI 4.7-114643, p=0.01) and a need for two or more inotropic drugs (aOR 45.7, 95% CI 1.5-1040, p=0.029) were significant factors for mortality. CONCLUSION: In the period of TH, perinatal HIE infants had decreased mortality. Severe HIE and a need for two or more inotropic drugs were associated with death in the infant with HIE who underwent TH.Abbreviations: AED: anti-epileptic drug; BW, birthweight; CI: confidence interval; CMU: Chiang Mai University; EEG: electro-encephalogram; GA: gestational age; HIE: hypoxic-ischaemic encephalopathy; IQR: interquartile range; NICU: neonatal intensive care unit; SD: standard deviation; TH: therapeutic hypothermia.

Infantile onset Sandhoff disease: clinical manifestation and a novel common mutation in Thai patients.

BACKGROUND: Sandhoff disease (SD) is an autosomal recessive lysosomal storage disorder, resulting in accumulation of GM2 ganglioside, particular in neuronal cells. The disorder is caused by deficiency of ß-hexosaminidase B (HEX-B), due to pathogenic variant of human HEXB gene. METHOD: This study describes clinical features, biochemical, and genetic defects among Thai patients with infantile SD during 2008-2019. RESULTS: Five unrelated Thai patients presenting with developmental regression, axial hypotonia, seizures, exaggerated startle response to noise, and macular cherry red spot were confirmed to have infantile SD based on deficient HEX enzyme activities and biallelic variants of the HEXB gene. In addition, an uncommon presenting feature, cardiac defect, was observed in one patient. All the patients died in their early childhood. Plasma total HEX and HEX-B activities were severely deficient. Sequencing analysis of HEXB gene identified two variants including c.1652G>A (p.Cys551Tyr) and a novel variant of c.761T>C (p.Leu254Ser), in 90 and 10% of the mutant alleles found, respectively. The results from in silico analysis using multiple bioinformatics tools were in agreement that the p.Cys551Tyr and the p.Leu254Ser are likely pathogenic variants. Molecular modelling suggested that the Cys551Tyr disrupt disulfide bond, leading to protein destabilization while the Leu254Ser resulted in change of secondary structure from helix to coil and disturbing conformation of the active site of the enzyme. Genome-wide SNP array analysis showed no significant relatedness between the five affected individuals. These two variants were not present in control individuals. The prevalence of infantile SD in Thai population is estimated 1 in 1,458,521 and carrier frequency at 1 in 604. CONCLUSION: The study suggests that SD likely represents the most common subtype of rare infantile GM2 gangliosidosis identified among Thai patients. We firstly described a potential common variant in HEXB in Thai patients with infantile onset SD. The data can aid a rapid molecular confirmation of infantile SD starting with the hotspot variant and the use of expanded carrier testing.

Pericardial effusion and cardiac tamponade after ventriculoperitoneal shunt placement: a case report.

Insertion of a ventriculoperitoneal shunt is a common neurosurgical procedure in both adult and paediatric patients. It is one of the most important treatments in cases of hydrocephalus; however, there is a wide range of complications: the most common complication being a shunt infection, and examples of rare complications are shunt migrations and cardiac tamponade. Several reports of distal ventriculoperitoneal shunt migration in different sites, including chest, right ventricle, pulmonary artery, bowel and scrotum were published. But pericardial effusion with cardiac tamponade and its relationship to distal ventriculoperitoneal shunt migration into the pericardial sac has never been reported.

Clinical Prediction Rule of Drug Resistant Epilepsy in Children.

BACKGROUND AND PURPOSE: Clinical prediction rules (CPR) are clinical decision-making tools containing variables such as history, physical examination, diagnostic tests by developing scoring model from potential risk factors. This study is to establish clinical prediction scoring of drug-resistant epilepsy (DRE) in children using clinical manifestationa and only basic electroencephalography (EEG). METHODS: Retrospective cohort study was conducted. A total of 308 children with diagnosed epilepsy were recruited. Primary outcome was the incidence of DRE. Independent determinants were patient characteristics, clinical manifestations and electroencephalography. CPR was performed based on multiple logistic regression. RESULTS: The incidence of DRE was 42%. Risk factors were age onset, prior neurological deficits, and abnormal EEG. CPR can be established and stratified the prediction using scores into 3 levels such as low risk (score<6), moderate risk (score 6-12) and high risk (score>12) with positive likelihood ratio of 0.5, 1.8 and 12.5 respectively. CONCLUSIONS: CPR with scoring risks were stratified into 3 levels. The strongest risk is prior global neurological deficits.

Vincristine-induced polyneuropathy in a child with stage I Wilms' tumour presenting with unilateral abducens nerve palsy.

A 4-year-old boy presented with right esotropia while receiving vincristine and dactinomycin for stage I Wilms' tumour according to the National Wilms Tumour Study-5 protocol. On examination, he had isolated limitation of his right lateral gaze. CT of the brain and cerebrospinal fluid examination were normal. A nerve conduction velocity study which was performed on the peripheral nerves revealed predominant motor polyneuropathy compatible with axonal loss involving the upper limbs. The patient had received a cumulative vincristine dose of 17 mg/m(2) before developing esotropia. Vincristine-induced abducens nerve mononeuropathy and subclinical motor polyneuropathy was suspected. Unilateral esotropia markedly improved after the discontinuation of vincristine and a short course of oral pyridoxine treatment.

Case series: the paradox of epilepsy surgery and psychiatric disorder.

De novo psychiatric disorder following epilepsy surgery is an infrequent but very interesting phenomenon. The authors described 4 distinct cases with medically intractable epilepsy who had epilepsy surgery and developed postsurgical psychiatric disorder. The onset of psychiatric disorder was during dramatic improvement of their epilepsy after surgery. There was no history of psychiatric disorder in their familial members or in the patients prior to the surgery. Since three patients also had mental retardation, presurgical cognitive impairment may be one of the risk factors for developing postsurgical psychiatric disorder. Potential mechanisms include volume reduction of gray matter in frontal, temporal and parietal cortexes secondary to epilepsy surgery as well as forced normalization. Several other mechanisms may also play important role for this phenomenon and further studies will be required which may reveal the connection between these two aspects.

Long-term follow-up of febrile infection-related epilepsy syndrome.

PURPOSE: Febrile infection-related epilepsy syndrome (FIRES) is an increasingly recognized epileptic syndrome that presents with multifocal refractory status epilepticus in previously normal children and evolves into a chronic, refractory, focal epilepsy with associated cognitive and behavioral difficulties. Herein we describe the features of the chronic epilepsy and critically review evidence for the etiology of this syndrome. METHODS: Seven patients with FIRES were studied. The duration of follow-up in six survivors was 5-17 years. Clinical, electroencephalography (EEG), neuroimaging, and other investigative findings during the acute and chronic phases were reviewed. KEY FINDINGS: These previously normal children presented with a febrile illness and status epilepticus that was refractory to antiepileptic medications in all children, to immunotherapies (including immunoglobulin, corticosteroids, plasma exchange, and rituximab) in four, and to acute vagus nerve stimulation in one. Markers of cerebral inflammation were few and response to antiepileptic and immunomodulatory therapies was poor. Evolution to chronic epilepsy occurred without a silent period. Seizure characteristics in the chronic phase were strikingly stereotyped and similar to the acute phase, with head and eye version, unilateral facial jerking, asymmetric tonic posturing, and unilateral limb jerking in all patients. Electrographic ictal onset was lateralized in all recorded seizures, unilateral in one patient, and independent bilateral in three. Seizures were refractory to multiple antiepileptic medications in all patients and partly responsive to chronic vagus nerve stimulation in two patients. Moderate to severe intellectual impairment was noted in four patients, and borderline intellectual abilities were noted in two. Magnetic resonance imaging (MRI) in the chronic phase was normal in three patients and showed mild diffuse cortical atrophy and/or mild hippocampal atrophy or sclerosis in three. SIGNIFICANCE: The similar perirolandic and perisylvian features of acute and chronic seizures, the lack of a silent period, the absence of evidence of cerebral inflammation, and the poor response to immunotherapies suggest FIRES is best conceptualized as a chronic epilepsy with explosive onset, not a remote-symptomatic epilepsy with an acute inflammatory antecedent.

Outcome of medulloblastoma in children treated with reduced-dose radiation therapy plus adjuvant chemotherapy.

Medulloblastoma is the most common malignant brain tumor in children. Post-surgical craniospinal irradiation (CSI; 30-36 Gy) plus local boost radiation therapy (RT; 54-56 Gy) is a standard treatment for children with medulloblastoma who are over 3 years old, resulting in a 5-year overall survival (OS) rate of 46% to 65% in average-risk patients and 50% in high-risk patients. The addition of chemotherapy has the benefit of reducing complications from radiation and improving the OS rate. Using this approach, the estimated 5-year OS rates for patients with average- and high-risk medulloblastomas treated with different protocols are 65% to 85% and 16% to 70%, respectively. In this study, we determined the outcome of patients with average- and high-risk medulloblastomas treated with reduced dosage CSI and chemotherapy with an oral etoposide-based regimen. The study included 49 patients, with a mean age of 7.7 ± 3.4 years. Twenty-six patients (53%) were classified as average-risk and 23 patients (47%) as high-risk. In the average-risk group, the 5-year progression free survival (PFS) rate was 62.9% ± 10% and the 5-year OS rate was 70.4% ± 9.5%. In the high-risk group the 5-year PFS rate was 48.9% ± 13% and the 5-year OS rate was 49.7% ± 13%. In the average-risk group, patients who received CSI of either 24 Gy (n=20) or 36 Gy (n=9) showed no difference in their 5-year PFS and OS rates. We found that patients who were ≤ 10 years old and patients who were female had a significantly better 5-year PFS rate.

Progressive Multifocal Leukoencephalopathy in HIV-Infected Children: A Case Report and Literature Review.

We report a case of a perinatally HIV-infected patient aged 9 years, who presented with right-sided hemiplegia. His initial CD4 T-cell was of 0.21% (4 cells/muL) and plasma HIV RNA virus of 185 976 copies/mL (log 5.27). Plasma and CSF samples were subsequently positive for JCV. Twelve days after the initiation of highly active antiretroviral therapy (HAART), the MRI showed progressive white matter lesions with asymmetrical deep and subcortical white matter lesions over the left frontotemporoparietal region and the right frontal lobe. Immune Reconstitution Inflammatory Syndrome (IRIS) was suspected, and the patient was treated with methylprednisolone. His clinical symptoms worsened and despite therapy the patient deteriorated.

Primary hypomagnesemia in Thai infants: a case report with 7 years follow-up and review of literature.

A female Thai baby born to non-consanguineous parents, presented with primary hypomagnesemia at 10 weeks of age, and suffered recurrent convulsions that responded to magnesium supplementation. She was found to have hypomagnesemia (Mg 0.35-1.02 mEq/L) and a low urinary magnesium excretion of less than 10 mg per day, or urinary Mg/Cr that ranged from 0.005-0.01 mg/mg. Intermittent hypomagnesemia and one episode of hypocalcemia with occasional convulsions developed, due to irregular consumption of oral magnesium sulfate, which had a bitter taste, caused frequent loose stools and black staining of the teeth. Better compliance after switching from magnesium sulfate to magnesium oxide resulted in an increased level of serum magnesium and the gradual disappearance of the black staining of the teeth and frequent loose stools. The patient required an oral elemental magnesium dosage of 15-30 mg/kg/day to maintain the serum magnesium level at between 1.02-1.33 mEq/L and keep her free from convulsions. The follow-up period was 7 years during which the patient showed normal physical growth and a mild degree of mental retardation.