Factors associated with outcomes of severe acute necrotizing encephalopathy: A multicentre experience in Malaysia.

This case series compared clinical variables and various combinations of immunotherapy received with outcomes of patients with severe acute necrotizing encephalopathy (ANE). We performed a retrospective review of clinical variables, immunotherapy received, and outcomes (based on the modified Rankin Scale) in Malaysia between February 2019 and January 2020. Twenty-seven children (12 male), aged 7 months to 14 years (mean 4 years) at diagnosis were included. Of these, 23 had an ANE severity score of 5 to 9 out of 9 (high risk). Eleven patients received tocilizumab (four in combination with methylprednisolone [MTP], seven with MTP + intravenous immunoglobulin [IVIG]) and 16 did not (two received MTP alone, 14 received MTP + IVIG). Nine died. Among the survivors, six had good outcomes (modified Rankin Score 0-2) at 6 months follow-up. All patients who received tocilizumab in combination with MTP + IVIG survived. Twenty children received first immunotherapy within 48 hours of admission. No significant association was found between the timing of first immunotherapy with outcomes. Those with brainstem dysfunction (p = 0.016) were observed to have poorer outcomes. This study showed a trend towards better survival when those with severe ANE were treated with tocilizumab in combination with MTP + IVIG. However, larger studies will be needed to determine the effect of this regime on the long-term outcomes.

Glycemic biomarkers in children with drug-resistant epilepsy on various types of ketogenic diet therapies: A cross-sectional study.

OBJECTIVE: This study was undertaken to determine the hemoglobin A1c (HbA1c) and modified glucose-ketone index (mGKI) in children on different types of ketogenic diet (KD) for treatment of drug-resistant epilepsy, with attempts to evaluate their relationships with components of diet regime and other biomarkers. METHODS: We conducted a cross-sectional study in children with drug resistant epilepsy aged between 6 months and 18 years, who were on various types of KD therapies without any change in regime for at least 3 months. Parental interview, review of medical records, and a single measurement for blood ketone, HbA1c, and plasma carnitine were performed. mGKI was the ratio of an average plasma glucose estimated from HbA1c to blood ß-hydroxybutyrate level. RESULTS: Thirty-four patients were recruited with a median blood ketone of 2.90 mmol·L-1 and median HbA1c of 4.55%. Those on classical KD (cKD) had higher blood ketone (p = .031) and lower HbA1c (p = .010) and mGKI (p = .021) than those receiving modified Atkins diet, although both shared similar percentages of calories from carbohydrate (p = .211). The cKD and medium-chain triglyceride (MCT) KD groups had similar HbA1c (p = .252) and mGKI (p = .510). Blood ketone (p = .045) and the percentage of calories from MCT (p = .037) were the two main independent variables, inversely correlating with HbA1c. Other than plasma acylcarnitine (p = .047), neither blood ketone (p = .188) nor HbA1c (p = .170) could predict seizure reduction reliably. Both plasma acylcarnitine ≥ 6 µmol·L-1 (p = .013) and mGKI ≤ 2.2 (p = .013) were significantly associated with good seizure control. SIGNIFICANCE: HbA1c could potentially be useful for monitoring KD adherence or, indirectly, systemic ketosis in nondiabetic children on KD for drug-resistant epilepsy. Plasma acylcarnitine and mGKI could be important biomarkers in the management of KD therapy.

Medication self-management among parents of children with epilepsy at a tertiary care center in Malaysia.

PURPOSE: Self-management is crucial in the management of chronic diseases. However, information is limited on medication self-management among parents of children with epilepsy. This study aimed to assess medication self-management among parents of children with epilepsy and its association with sociodemographic data, clinical characteristics, antiepileptic drug (AED) regimen complexity, and parent self-reported AED adherence. METHOD: A cross-sectional survey was conducted at a tertiary care center in Malaysia from February 2019 to June 2019. Parents of children with epilepsy who were on AED for at least 3 months and aged ≤18 years old were recruited. Medication self-management was assessed using a validated Pediatric Epilepsy Medication Self-Management Questionnaire (PEMSQ). A higher total score reflects better medication self-management. RESULTS: A total of 166 patients were recruited. The mean ±â€¯standard deviation (SD) age of patients was 8.20 ±â€¯5.21 years, and 51.8% and 36.7% of patients have generalized seizure and focal seizure, respectively. The mean ±â€¯SD PEMSQ score was 116.2 ±â€¯11.28 from a total score of 135. Among the four domains of PEMSQ, the barriers to treatment contributed to the lowest mean scores. Univariate analysis showed that the following were significantly associated with poorer medication self-management: differences in ethnicity, religion; higher number of medications; presence of comorbidities; inability to swallow tablets; and a more complex AED regimen. Other variables were not significant. Multivariate analysis showed that only ethnicity and presence of comorbidity remained independently significant (R2 = 0.14; F [4, 161] = 6.28; p < 0.001). Poorer medication self-management was observed in the Malaysian Chinese population than in the Malaysian Malay population (b = -8.52; p < 0.001) and in children with comorbidities than in those without comorbidities (b = -5.04, p = 0.01). CONCLUSION: The overall medication self-management was satisfactory. Barriers to treatment should be addressed to empower parents to achieve better medication self-management. Furthermore, medication self-management should be reinforced among Malaysian Chinese patients and children with comorbidities.

Vitamin D deficiency and insufficiency in Malaysian children with spina bifida.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To determine the prevalence and potential risk factors of vitamin D deficiency and insufficiency among Malaysian children with spina bifida. SETTING: Four Malaysian tertiary hospitals. METHODS: Children with spina bifida were assessed for potential demographic, disease severity and lifestyle risk factors for vitamin D deficiency and insufficiency. Blood for 25-hydroxy vitamin D (25(OH)D) was taken. Vitamin D deficiency was defined as 25(OH)D levels ≤ 37.5 nmol/L and insufficiency as 37.6-50 nmol/L. RESULTS: Eighty children aged 2-18 years (42 males) participated in the study. Vitamin D levels ranged from 14 to 105 nmol/L (mean 52.8, SD 19.1). Vitamin D deficiency was identified in 18 (22.5%) and insufficiency in 26 (32.5%) children. Logistic regression analysis showed that skin exposure to sunlight ≤ 21% body surface area (OR: 6.2, CI 1.7-22.9) and duration of sun exposure ≤ 35 min/day (OR: 4.0, CI 1.2-14.1) were significant risk factors for vitamin D deficiency and insufficiency, respectively. CONCLUSIONS: Over half (55%) of Malaysian children with spina bifida seen in urban tertiary hospitals have vitamin D insufficiency and deficiency. Lifestyle sun exposure behaviours were risk factors for vitamin D deficiency and insufficiency.

A novel homozygous truncating variant of NECAP1 in early infantile epileptic encephalopathy: the second case report of EIEE21.

We report the second case of early infantile epileptic encephalopathy (EIEE) arising from a homozygous truncating variant of NECAP1. The boy developed infantile-onset tonic-clonic and tonic seizures, then spasms in clusters. His electroencephalogram (EEG) showed a burst suppression pattern, leading to the diagnosis of Ohtahara syndrome. Whole-exome sequencing revealed the canonical splice-site variant (c.301 + 1 G > A) in NECAP1. In rodents, Necap1 protein is enriched in neuronal clathrin-coated vesicles and modulates synaptic vesicle recycling. cDNA analysis confirmed abnormal splicing that produced early truncating mRNA. There has been only one previous report of a mutation in NECAP1 in a family with EIEE; this was a nonsense mutation (p.R48*) that was cited as EIEE21. Decreased mRNA levels and the loss of the WXXF motif in both the families suggests that loss of NECAP1 function is a common pathomechanism for EIEE21. This study provided additional support that synaptic vesicle recycling plays a key role in epileptogenesis.

Quality of life in Malaysian children with epilepsy.

BACKGROUND: Children with epilepsy (CWE) are at risk of impaired quality of life (QOL), and achieving a good QOL is an important treatment goal among CWE. To date, there are no published multiethnic QOL studies in Asia. Our study aimed to: i) investigate the QOL of multiethnic CWE in Malaysia as reported by both the child and parent; ii) determine the level of agreement between child-self report and parent-proxy report QOL; and iii) explore potential correlates of sociodemographic, epilepsy characteristics, and family functioning with QOL in CWE. METHODS: Cross-sectional study of all CWE aged 8-18years old with at least 6months' duration of epilepsy, minimum reading level of primary school education Year 1, and attending mainstream education. Quality of life was measured using the parent-proxy and child self-report of Quality of Life Measurement for Children with Epilepsy (CHEQOL-25) questionnaire. Total and subscale CHEQOL-25 scores were obtained. The levels of parent-child agreement were determined using intraclass correlation coefficients (ICC). Family functioning was assessed using the General functioning subscale (GF-12). RESULTS: A total of 115 CWE and their parents participated in the study. In general, Malaysian parents rated children's total CHEQOL-25 scores poorer than the children themselves [mean total parent score: 68.56 (SD: 10.86); mean total child score: 71.82 (SD: 9.55)]. Agreement between child and parent on the CHEQOL-25 was poor to moderate (ICC ranged from 0.31-0.54), with greatest discordance in the epilepsy secrecy domain (ICC=0.31, p=0.026). Parent and child were more likely to agree on more external domains: intrapersonal/social (ICC=0.54, p<0.001) and interpersonal/emotional (ICC=0.50, p<0.001). Malay ethnicity, focal seizure and high seizure frequency (≥1 seizure per month) were associated with lower CHEQOL-25 scores. There was a significant but weak correlation between GF-12 and parent-proxy CHEQOL-25 Total Scores (r=-0.186, p=0.046). CONCLUSION: Our results emphasize the importance to have the child's perspective of their QOL as the level of agreement between the parent and child reported scores were poor to moderate. Malaysian CWE of Malay ethnicity, those with focal seizures or high seizure frequency are at risk of poorer QOL.

Vitamin D deficiency and its risk factors in Malaysian children with epilepsy.

OBJECTIVE: Long-term use of antiepileptic drugs (AEDs) is a significant risk factor for vitamin D deficiency in children with epilepsy. The aims of our study were to evaluate the prevalence and risk factors for vitamin D deficiency among Malaysian children with epilepsy. METHODS: Cross-sectional study of ambulant children with epilepsy on long-term AEDs for >1 year seen in three tertiary hospitals in Malaysia from April 2014 to April 2015. Detailed assessment of pubertal status, skin pigmentation, sunshine exposure behavior, physical activity, dietary vitamin D and calcium intake, anthropometric measurements and bone health blood tests (vitamin D, alkaline phosphatase, calcium, phosphate, and parathyroid hormone levels) were obtained on all patients. Vitamin D deficiency was defined as 25-hydroxy vitamin D [25(OH)D] levels ≤35 nmol/L and insufficiency as 25(OH)D levels of 36-50 nmol/L. RESULTS: A total of 244 children (146 male) participated in the study. Ages ranged between 3.7 and 18.8 years (mean 12.3 years). 25(OH)D levels ranged between 7.5 and 140.9 nmol/L (mean 53.9 nmol/L). Vitamin D deficiency was identified in 55 patients (22.5%), and a further 48 (19.7%) had vitamin D insufficiency. Multivariate logistic regression analysis identified polytherapy >1 AED (odds ratio [OR] 2.16, 95% confidence interval [CI] 1.07-4.36), age >12 years (OR 4.16, 95% CI 1.13-15.30), Indian ethnicity (OR 6.97, 95% CI 2.48-19.55), sun exposure time 30-60 min/day (OR 2.44, 95% CI 1.05-5.67), sun exposure time <30 min/day (OR 3.83, 95% CI 1.61-9.09), and female (OR 2.61, 95% CI 1.31-5.20) as statistically significant (p < 0.05) risk factors for vitamin D deficiency. SIGNIFICANCE: Despite living in the tropics, a high proportion of Malaysian children with epilepsy are at risk of vitamin D deficiency. Targeted strategies including vitamin D supplementation and lifestyle advice of healthy sunlight exposure behavior should be implemented among children with epilepsy, particularly for those at high risk of having vitamin D deficiency.

Barriers to Education for Children With Neurodisabilities in a Developing Country.

Despite having equal rights to education, children with neurodisability (CWND) continue to face a myriad of barriers to education. This cross-sectional survey aimed to investigate the barriers to education among CWND who attended follow-up at a Malaysian tertiary hospital. Sixty-two caregivers of CWND completed a questionnaire which included the 'Washington Group/United Nations Children's Fund (UNICEF) Child Functioning Module', type of schooling and open-ended questions for barriers to education. The out-of-school rate was 16/62 (26%). The level of schooling (i.e. not in school, special education or mainstream class) was strongly associated with difficulties in mobility, self-care, communication, controlling behaviour and getting along with other children. Five themes identified by caregivers as barriers to education were 'school infrastructure', 'inclusive opportunity, staffing and teacher's training', 'social environment', 'child's intrinsic factor' and 'practical limitations'. Practical solutions to overcome the significant barriers to education are required to address the unmet educational needs of CWND.

Severe and rare neurological manifestations following COVID-19 infection in children: A Malaysian tertiary centre experience.

INTRODUCTION: Since the emergence of COVID-19, we have experienced potent variants and sub-variants of the virus with non-specific neurological manifestations. We observed a surge of the Omicron variant of COVID-19 patients with neurological manifestations where less cases of multisystem inflammatory syndrome in children (MIS-C) were reported. This article describes our experience of children with severe and rare neurological manifestations following COVID-19 infection. METHODS: This is a retrospective observational case series of patients under 18 years old who fulfilled the WHO COVID-19 case definition and were referred to our paediatric neurology unit at Hospital Tunku Azizah Kuala Lumpur. Their demographic data, neurological symptoms, laboratory and supporting investigations, neuroimaging, treatment and outcomes were collected and analysed. RESULTS: There were eleven patients with neurological manifestations who fulfilled the WHO COVID-19 case definition. Nine patients presented with seizures and/or encephalopathy, one patient with eye opsoclonus and another patient with persistent limbs myokymia. Based on the history, clinical, electrophysiological and radiological findings, two of them had febrile infection-related epilepsy syndrome, two had acute disseminated encephalomyelitis, two had acute necrotising encephalopathy of childhood, one each had hemiconvulsion-hemiplegia-epilepsy syndrome, acute encephalopathy with bilateral striatal necrosis, hemi-acute encephalopathy with biphasic seizures and reduced diffusion, infection-associated opsoclonus and myokymia. CONCLUSIONS: This case series highlighted a wide spectrum of neurological manifestations of COVID-19 infection. Early recognition and prompt investigations are important to provide appropriate interventions. It is essential that these investigations should take place in a timely fashion and COVID-19 quarantine period should not hinder the confirmation of various presenting clinical syndromes.

Clonic seizures, continuous spikes-and-waves during slow sleep, choreoathetosis and response to sulthiame in a child with FRRS1L encephalopathy.

BACKGROUND: Ferric chelate reductase 1 like (FRRS1L) encephalopathy is a rare cause of developmental and epileptic encephalopathy. Only a few cases have been reported thus far and seizures tend to be drug refractory. We report an additional case to highlight the good seizure response to sulthiame. CASE REPORT: A boy from non-consanguineous parents presented with history of 'abnormal movements' from 7 months of age. At one year of age, video electroencephalogram (EEG) monitoring demonstrated the 'abnormal movements' to be clonic seizures. Valproate, lamotrigine and clobazam combination were only partially effective at reducing the seizures. Repeat EEG at 1 year 8 months old revealed a continuous spikes-and-waves during slow sleep (CSWS) pattern, prompting a trial of sulthiame. After 2 weeks of sulthiame, seizures ceased completely. The clonic seizures recurred at age 4 years when sulthiame supply was interrupted, but the seizures promptly remitted following sulthiame's resumption. Subtle choreiform movements appeared from age one year and later became more prominent. Whole exome sequencing (WES) identified a homozygous novel variant (nonsense) in the FRRS1L gene (NM_014334.3: c.670C>T:p.Gln224*). He has been seizure free since 4 years of age but remained profoundly delayed. CONCLUSION: Sulthiame may have a role in the early treatment of seizures in children with refractory epilepsy due to FRRS1L mutation.

Geniospasm: A systematic review on natural history, prognosis, and treatment.

BACKGROUND: Geniospasm is a rare and generally benign movement disorder of the chin yet with potentially debilitating complications. Due to its rarity, previous literature was limited to only case reports or series with critical knowledge gap on its natural history, prognosis, and management. We aimed to establish the natural history, prognosis, and treatment for geniospasm. METHODS: A systematic review on case reports or series was performed with literature search on PubMed and Google Scholar, from inception through December 2021. The quality of the reports was assessed with low-quality articles excluded for analyses other than demographics. RESULTS: Forty-one articles were included for demographic analysis (n = 489) while forty articles for other analyses (n = 451). There was only slight male preponderance of this disease in our cohort (Male:Female = 1.2:1) with 98.6% having family history of geniospasm, 68.1% having onset below 1 year of age, 91.4% having emotional triggers of the symptoms, 25.7% having geniospasm in sleep, 100% involving mentalis muscles, 4.9% involving muscles adjacent to mentalis, 55.2% having regular paroxysms (≥1/week, but brief in 56.3% of the cases) and only 11.1% having complications. The paroxysms reduced with age, but complete remission only happened in 9.9%. Females (p = 0.010) and those without geniospasm in sleep (p = 0.048) were associated with good outcome of the disease. Geniospasm was usually refractory to treatment except for regular botulinum toxin injections. CONCLUSION: Generally, geniospasm improved with age but complete remission was rare. Considering our review limitations, our findings should be interpreted with caution. Future studies of higher evidence level are crucial.

Association of common genetic variants with vitamin D status in Malaysian children with epilepsy.

PURPOSE: Children with epilepsy (CWE) are at risk of vitamin D deficiency. Single nucleotide polymorphisms (SNPs) affecting the vitamin D pathway are potentially important risk factors for serum 25-hydroxyvitamin D [25(OH)D] concentration. The aims of our study were to evaluate the association of vitamin d-related SNPs to serum 25(OH)D concentrations in Malaysian CWE. METHODS: Cross-sectional study of Malaysian ambulant CWE on antiseizure medication for >1 year. Sixteen SNPs in 8 genes (GC, VDR, CYP2R1, CYP24A1, CYP27B1, CYP27A1, CYP3A4, NADSYN1/DHCR7) were genotyped. Linear and logistic regression models and co-variates adjusted analyses were used. SNPs with significant associations were further analysed in a group of ethnically-matched healthy Malaysian children. RESULTS: 239 CWE were recruited (52.7% Malay, 24.3% Chinese and 23.0% Indian) with mean serum 25(OH)D of 58.8 nmol/L (SD 25.7). Prevalence of vitamin D deficiency (≤37.5 nmol/L) was 23.0%. Minor allele of GC-rs4588-A was associated with lower serum 25(OH)D in the meta-analysis of both CWE (ß -8.11, P = 0.002) and Malaysian healthy children (ß -5.08, P < 0.001), while VDR-rs7975232-A was significantly associated with reduced odds of vitamin D deficiency in Malay subgroup of CWE (OR: 0.16; 95% CI: 0.06-0.49; P = 0.001) and this association was not found in the healthy children group. CONCLUSIONS: Our results suggest that GC-rs4588 is associated with lower serum 25(OH)D concentration in both Malaysian CWE and healthy children, while VDR-rs7975232A is associated with lower risk of vitamin D deficiency in Malaysian CWE of Malay ethnicity. Our findings may assist in the genetic risk stratification of low vitamin D status among CWE.

Prevalence and impact of physical disability on Malaysian school-aged children: a population-based survey.

PURPOSE: To determine the magnitude and impact of physical disability on Malaysian school-aged children between 7 and less than 18 years old. METHOD: Cross-sectional population-based household interview with two-stage stratified sampling design. SETTING: The Malaysian Third National Health of Morbidity Survey, 2006. RESULTS: Overall prevalence of physical disability was 2.8 per 1000 population among children aged between 7 and less than 18 years old. The commonest cause was congenital, in 61.5% of the affected children. Slightly more than a third of these children with physical disability were partially or totally dependent on their caregivers in the various areas of self care (37.4%) and mobility (34.9%). We also found that the more severe the physical disability, the more adverse impact it had on the functional independence and community participation of these children. Among these children, almost 40% of them had no verbal communication, 31.5% had not attended formal education and 21% were housebound. CONCLUSION: This population-based survey on physical disability among school-aged children highlighted the key areas where physical disability can greatly impact on the child's function. It has identified the areas of needs that require multisectoral involvement and commitment from the government, non-government and private agencies.

Unusual case of cerebral demyelination and bilateral optic neuritis in an infant with suppurative BCG lymphadenitis.

Cerebral demyelination and optic neuritis are often seen in children with acute disseminated encephalomyelitis following various infections and immunisations. An eight month old girl presented with a left axillary lymph node swelling and an erythematous lace-like rash over her cheeks and trunk. She then developed acute encephalopathy, bilateral nystagmus, right hemiparesis and left facial nerve palsy. Her electroencephalogram showed an encephalopathic process and visual evoked response study were grossly abnormal. Her MRI brain showed hyperintensities in the midbrain, pons and bilateral cerebellar peduncles. She was treated as postinfectious cerebral demyelination with intravenous antibiotics, methylprednisolone and immunoglobulin. Left axillary lymph node excision biopsy and GeneXpert test detected Mycobacterium tuberculosis complex that prompted initiation of antituberculous therapy. Her chest X-ray and cerebrospinal fluid examinations for tuberculosis were normal. She showed significant recovery after 2 weeks. This case illustrates a rare presentation of cerebral demyelination and bilateral optic neuritis following suppurative BCG lymphadenitis.

Flaccid paralysis in an infant associated with a dirty wound and application of honey.

An infant, who was born preterm at 36 weeks, presented with fever and ulcer at umbilical region which progressed to necrotising fasciitis of anterior abdominal wall. He was treated with intravenous penicillin, intravenous cloxacillin and local application of medicated honey. Subsequently, he required wound debridement. Postoperatively, he required prolonged invasive ventilation due to poor respiratory effort which was associated with hypotonia and areflexia. Nerve conduction study revealed absent responses. The diagnosis of infant botulism was made based on the clinical presentation, nerve conduction study and his clinical progress. Botulinum immunoglobulin was not available. He was treated with intravenous immunoglobulin and oral pyridostigmine. He was successfully extubated after 37 days, and currently the patient is doing well.

Paediatric in-patient prescribing errors in Malaysia: a cross-sectional multicentre study.

Background There is a lack of large comprehensive studies in developing countries on paediatric in-patient prescribing errors in different settings. Objectives To determine the characteristics of in-patient prescribing errors among paediatric patients. Setting General paediatric wards, neonatal intensive care units and paediatric intensive care units in government hospitals in Malaysia. Methods This is a cross-sectional multicentre study involving 17 participating hospitals. Drug charts were reviewed in each ward to identify the prescribing errors. All prescribing errors identified were further assessed for their potential clinical consequences, likely causes and contributing factors. Main outcome measures Incidence, types, potential clinical consequences, causes and contributing factors of the prescribing errors. Results The overall prescribing error rate was 9.2% out of 17,889 prescribed medications. There was no significant difference in the prescribing error rates between different types of hospitals or wards. The use of electronic prescribing had a higher prescribing error rate than manual prescribing (16.9 vs 8.2%, p < 0.05). Twenty eight (1.7%) prescribing errors were deemed to have serious potential clinical consequences and 2 (0.1%) were judged to be potentially fatal. Most of the errors were attributed to human factors, i.e. performance or knowledge deficit. The most common contributing factors were due to lack of supervision or of knowledge. Conclusions Although electronic prescribing may potentially improve safety, it may conversely cause prescribing errors due to suboptimal interfaces and cumbersome work processes. Junior doctors need specific training in paediatric prescribing and close supervision to reduce prescribing errors in paediatric in-patients.

Classification of childhood epilepsies in a tertiary pediatric neurology clinic using a customized classification scheme from the international league against epilepsy 2010 report.

In its 2010 report, the International League Against Epilepsy Commission on Classification and Terminology had made a number of changes to the organization, terminology, and classification of seizures and epilepsies. This study aims to test the usefulness of this revised classification scheme on children with epilepsies aged between 0 and 18 years old. Of 527 patients, 75.1% only had 1 type of seizure and the commonest was focal seizure (61.9%). A specific electroclinical syndrome diagnosis could be made in 27.5%. Only 2.1% had a distinctive constellation. In this cohort, 46.9% had an underlying structural, metabolic, or genetic etiology. Among the important causes were pre-/perinatal insults, malformation of cortical development, intracranial infections, and neurocutaneous syndromes. However, 23.5% of the patients in our cohort were classified as having "epilepsies of unknown cause." The revised classification scheme is generally useful for pediatric patients. To make it more inclusive and clinically meaningful, some local customizations are required.