The response patterns of infantile spasms to treatments in 156 patients: Hormonal therapy with intravenous synthetic ACTH appears promising.

OBJECTIVES: To report the efficacy of intravenous (IV) synthetic ACTH (Tetracosactide) in the treatment of infantile spasms. METHODS: This is a retrospective chart review of patients with a diagnosis of infantile spasms conducted at the Pediatric Department of King Abdulaziz Medical City (KAMC) in Riyadh, Saudi Arabia, from 01-01-2005 to 31-12-2019. RESULTS: Of the 156 cases, 141 were treated initially with vigabatrin (VGB) with a complete response seen in 42(30%). Synthetic ACTH (Tetracosactide) IV injections were used in a total of 52 cases with response in 25(48%). Of the 35 cases which initially failed with VGB, 20(57%) responded to synthetic ACTH. The injections were used as a first line in 8 cases with response in 6(75%). The response to oral steroids was seen in 4/14(29%) cases. A relapse was seen in 2/42(5%) of patients treated with VGB and in 5/25(20%) of those who were treated with synthetic ACTH. The response was highest in the idiopathic group with 7/7(100%). Epilepsy at 2 years was seen in 26/50(52%) and 50/57(88%) of the responders and non-responders, respectively (p=0.000). Only 14/156(9%) of cases had a fair neurological outcome. All of them were from the responder group CONCLUSION: The response to VGB is suboptimal, while the response to synthetic ACTH is encouraging making it a good alternative for natural ACTH as a potential first line therapy in infantile spasms.

The comorbidity of headaches in pediatric epilepsy patients: How common and what types?

OBJECTIVE: To estimate the prevalence and characteristics of headache in pediatric epileptic patients. METHODS: This cross-sectional study was performed over 6 months period from January 2018 to June 2018 at King Abdullah Specialist Children Hospital, King Abdulaziz Medical City, Riyadh, Kingdom of Saudi Arabia using a structured questionnaire in pediatric patients with epilepsy. RESULTS: There were 142 patients enrolled (males, 57.7%; average age, 10.7+/-3.1 years) with idiopathic epilepsy (n=115, 81%) or symptomatic epilepsy (n=27, 19%). Additionally, patients had focal epilepsy (n=102, 72%) or generalized epilepsy (n=40, 28%), and among them, 11 had absence epilepsy. Overall, 65 (45.7%) patients had headaches compared with 3/153 (2%) in the control group (p<0.0001). Among the 65 patients with headaches, 29 (44.6%) had migraine-type, 12 (18.4%) had tension-type, and 24 (36.9%) had unclassified headache. There was no significant difference in age, gender, type of epilepsy syndrome, and antiepileptic used except in patients with or without headache. For migraine patients, there was a lower headache prevalence in the subgroup treated with valproic acid compared with other treatments. CONCLUSION: Headache, predominantly migraine, is a common problem in pediatric epileptic patients and choosing valproic acid when possible can be important in preventing migraine in these patients.

Clinical Presentation and outcome of acute disseminated encephalomyelitis in Saudi Arabia. Tertiary Center Experience.

OBJECTIVE: To evaluate the clinical presenation of acute disseminated Encephalomyelitis (ADEM) in pediatric age group, treatments, and to asses the outcome at King Abdulaziz Medical City, Riyadh, Kingdom of Saudia Arabia. METHODS: The medical records of all patients younger than 18 years of age with a diagnosis of ADEM and treated at King Abdulaziz Medical City from January 1996 to Decemeber 2016 were collected. A total of 20 patients were included. RESULTS: Of 20 patients enrolled in our study, 13 (65%) were female. Autumn and summer were the most common seasons in which ADEM presented (60%); 19 (95%) patients had a history of preceding viral illnesses. The most common neurological deficits on presentation were weakness (85%), ataxia (45%), and nystagmus (45%). Cortical and subcortical lesions (60%) were the most common finding on cranial magnetic resonance imaging. Seventeen patients (85%) received steroid only. Only 16 patients continued with follow-up, with a mean duration of 7 months. All 16 patients improved: 11 patients were recovered and 5 patients still had a neurological deficit at the clinic visits. No patient had relapsed. CONCLUSION: Most of the patients in this case series have an excellent outcome and attended follow-up visits and no disease relapses were identified. Further exploration of the disease is recommended.

Extending the ophthalmological phenotype of Galloway-Mowat syndrome with distinct retinal dysfunction: a report and review of ocular findings.

BACKGROUND: Galloway-Mowat syndrome (GMS) is a rare autosomal recessive condition first described in 1968 and characterized by microcephaly and infantile onset of central nervous system (CNS) abnormalities resulting in severely delayed psychomotor development, cerebellar atrophy, epilepsy, and ataxia, as well as renal abnormalities such as nephrotic syndrome, proteinuria, end-stage renal disease (ESRD), and hiatal hernia. CASE PRESENTATION: We describe a GMS case diagnosed with homozygous missense mutation in the WDR73 gene, with absence of renal abnormalities. We expanded the clinical phenotype of GMS with WDR73 gene defect to include retinal dysfunction with missense mutation and developmental dysplasia of the hip. We compared eye findings of our case to previously reported cases, and we present an electroretinogram (ERG) picture for the first time in the literature. CONCLUSION: We recommend that clinicians screen patients with GM syndrome for retinal dysfunction and that a skeletal survey should be done to detect developmental dysplasia of the hip (DDH) so as to provide for early intervention.

ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies.

We describe a previously unreported syndrome characterized by secondary (post-natal) microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract in a highly consanguineous family with six affected children. Homozygosity mapping and exome sequencing revealed a novel homozygous frameshift mutation in the basic helix-loop-helix transcription factor gene ARNT2 (c.1373_1374dupTC) in affected individuals. This mutation results in absence of detectable levels of ARNT2 transcript and protein from patient fibroblasts compared with controls, consistent with nonsense-mediated decay of the mutant transcript and loss of ARNT2 function. We also show expression of ARNT2 within the central nervous system, including the hypothalamus, as well as the renal tract during human embryonic development. The progressive neurological abnormalities, congenital hypopituitarism and post-retinal visual pathway dysfunction in affected individuals demonstrates for the first time the essential role of ARNT2 in the development of the hypothalamo-pituitary axis, post-natal brain growth, and visual and renal function in humans.

The Response of Synthetic Adrenocorticotropic Hormone (ACTH) Treatment in Pediatric Drug-Resistant Epilepsy Other Than Infantile Epileptic Spasms Syndrome: A Retrospective Observational Study.

INTRODUCTION:  Adrenocorticotropic hormone (ACTH) is a tropic hormone naturally secreted by the anterior pituitary gland to stimulate the secretion of cortisol and androgens. ACTH is used in non-tuberous sclerosis infantile epileptic spasms syndrome (IESS), and it has shown significant, promising results in epilepsy syndromes with possible inflammatory processes. However, many studies have also demonstrated a promising potential even in other types of drug-resistant epilepsy.  Material and method: This study is a retrospective observational study that follows the clinical characteristics and outcomes of nine pediatric patients with drug-resistant epilepsy treated with short-term synthetic ACTH in Saudi Arabia. The response was assessed during the ACTH infusion and after three months. RESULTS: During infusion, six of the nine (66%) patients had a short-term (within two weeks) favorable response, with a more than 50% reduction in seizure frequency. Four of the nine (44%) patients had complete responses with seizure freedom. After three months, four patients (44%) had a three-month seizure frequency reduction of more than 30% attributed to ACTH, including one patient with an IESS history who had a 70% reduction in seizure frequency. Of the four patients who had a complete response, three (75%) had a seizure relapse after tapering in the following three months.  Conclusion: This case series adds to the literature to suggest ACTH treatment of drug-resistant epilepsies other than IESS might benefit some patients in the acute setting but they are less likely to maintain a sustained treatment response. Randomized and large sample size studies are necessary to assess treatment response and accurately aid in appropriate patient selection.

Phenotype and Genotype of Saudi Pediatric Patients With Neurofibromatosis Type 1: A Seven-Year Multicenter Experience From Saudi Arabia.

Background Neurofibromatosis type 1 (NF1) is a complex disorder. Genetics and environment might be attributed as the leading cause of NF1, which is characterized by multisystemic involvement. We aim to elaborate on Saudi children's NF1 phenotypes and genotypes. Methods This study was conducted in the Ministry of National Guard Health Affairs (MNGHA), Saudi Arabia including three tertiary hospitals, using a retrospective cohort method. Electronic charts were reviewed to extract the variables. All Saudi pediatric patients aged less than 18 with NF1 were included. Consecutive sampling was used due to the limited number of patients. Results The study included 160 patients (81 males) with an average age of 8.08 years. Also, 33 (20.6%) patients had cutaneous neurofibroma while 31 (19.4%) patients had plexiform neurofibromas. Iris lisch nodules were seen in 33.75%. Optic pathway glioma was seen in 29 (18%) cases while non-optic pathway glioma was seen in 27 (17%) cases. Skeletal abnormalities were seen in 27 (17%) of cases. A first-degree relative with NF1 was seen in 83 (52%) of cases. Epilepsy was the presenting feature of 27 (17%) cases. Cognitive impairment was found in 15 (9.4%) patients. Genetic mutation was seen in 82/100 cases, the rest were negative. The types of mutations were as follows: nonsense 30 (36.6%); missense 20 (24.4%); splicing site mutation 12 (14.6%); frameshift 10 (12.2%); microdeletion 7 (8.5%); and whole gene deletion 3 (3.75%) patients. No phenotype-genotype correlation was seen. Conclusion In this cohort of Saudi pediatric patients with NF1, optic pathway glioma and other brain tumors were prevalent. The most common mutation is the nonsense mutation.

Phenotype and genotype of 15 Saudi patients with achromatopsia: A case series.

PURPOSE: Achromatopsia is a rare stationary retinal disorder that primarily affects the cone photoreceptors. Individuals with achromatopsia present with photophobia, nystagmus, reduced visual acuity (VA), and color blindness. Multiple genes responsible for achromatopsia have been identified (e.g. cyclic nucleotide-gated channel subunit alpha 3 [CNGA3] and activating transcription factor 6). Studies have assessed the role of gene therapy in achromatopsia. Therefore, for treatment and prevention, the identification of phenotypes and genotypes is crucial. Here, we described the clinical manifestations and genetic mutations associated with achromatopsia in patients from Saudi Arabia. METHODS: This case series study included 15 patients with clinical presentations, suggestive of achromatopsia, who underwent ophthalmological and systemic evaluations. Patients with typical achromatopsia phenotype underwent genetic evaluation using whole-exome testing. RESULTS: All patients had nystagmus (n = 15) and 93.3% had photophobia (n = 14). In addition, all patients (n = 15) had poor VA. Hyperopia with astigmatism was observed in 93.3% (n = 14) and complete color blindness in 93.3% of the patients (n = 14). In the context of family history, both parents of all patients (n = 15) were genetic carriers, with a high consanguinity rate (82%, n = 9 families). Electroretinography showed cone dysfunction with normal rods in 66.7% (n = 10) and both cone-rod dysfunction in 33.3% (n = 5) patients. Regarding the genotypic features, 93% of patients had variants in CNGA3 (n = 14) categorized as pathogenic Class 1 (86.7%, n = 13). Further, 66.7% (n = 10) of patients also harbored the c.661C>T DNA variant. Further, the patients were homozygous for these mutations. Three other variants were also identified: c.1768G>A (13.3%, n = 2), c.830G>A (6.6%, n = 1), and c. 822G >T (6.6%, n = 1). CONCLUSION: Consanguinity and belonging to the same tribe are major risk factors for disease inheritance. The most common genotype was CNGA3 with the c.661C>T DNA variant. We recommend raising awareness among families and providing genetic counseling for this highly debilitating disease.

What Is the Effect of Topiramate Use on Growth in Children With Epilepsy?

Objective The literature related to weight loss as a side effect of using topiramate (TPM) in pediatric patients is inconsistent. The aim of this study was to assess the effect of TPM on the growth of pediatric epileptic patients. Methods The electronic medical files of 50 pediatric epileptic patients who were prescribed TPM over 5 years were retrospectively reviewed. Cases treated with other antiepileptic drugs were the control group (n=60). Results Height growth was similar in both groups. At the 6-12-month follow-up, there was a decrease in the average BMI in the TPM group of -0.81 kg/m2 (p=0.019) and an increase in the control group of +0.46 kg/m2 (p=0.023). Weight loss was noted in 21/50 (42%) of the TPM group as compared with 13/60 (22%) in the control group (p=0.02). More weight loss was observed in the overweight TPM group in 7/16 (44%) compared to none in the nine cases in the control group (p=0.03). After the one-year follow-up, the average change in weight was +1.73 kg (p=0.0001) and +3.53 kg (p=0.0001) in the TPM and control groups, respectively. In patients with normal initial BMI, the weight increased by +1.3 kg on average, compared to the group with a high initial BMI, which decreased by -2.55 kg. Conclusion Topiramate use has no negative effect on height growth in pediatric patients with epilepsy. While mild weight loss occurs frequently in the first year of treatment, weight gain resumes after the first year except in patients with a high initial BMI.

Prevalence and outcomes of Guillain-Barré syndrome among pediatrics in Saudi Arabia: a 10-year retrospective study.

BACKGROUND: Guillain-Barré syndrome (GBS) is a progressive acute form of paralysis most probably secondary to an immune-mediated process. GBS among Saudis has been seldom investigated, which leaves both clinicians and researchers with scarcity in knowledge. Therefore, this study aims to assess the prevalence and clinical prognosis of GBS among pediatrics admitted with acute paralysis at a large healthcare facility in Riyadh, Saudi Arabia. METHODS: This retrospective study reviewed patients' medical records between 2005 and 2015. Eligible cases were children (<14 years old) admitted to the hospital complaining of acute paralysis and later diagnosed with one form or variant of GBS. Pearson's chi-square, Fisher's exact test, and binary logistic regression were employed to analyze the collected data. RESULTS: The prevalence of GBS was 49%. The male-to-female ratio was 1.45:1. The mean ± standard deviation age was 7±3.7 years. There were 34 (69.4%) cases with progression to maximum paralysis in ≤2 weeks, while 15 (30.6%) cases occurred beyond 2 weeks. Males (n=24, 82.8%) were more likely to endure progression to maximum paralysis in ≤2 weeks after the disease onset, compared to females (n=10, 50%), P=0.014. All cases complaining of respiratory problems exhibited a progression to maximum paralysis in ≤2 weeks, compared to those with no respiratory problems, P=0.027. Residual paralysis at 60 days post disease onset was highly associated with GBS patients of age 8-14 years (n=15, 65.2%), compared to younger patients (n=8, 30.8%), P=0.016. Patients admitted in colder seasons (n=14, 63.6%) were more likely to suffer residual paralysis too, compared to those in warmer seasons (n=9, 33.3%), P=0.035. GBS cases who complained of facial weakness (n=9, 75%) and ocular abnormalities (n=10, 71.4%) were also more likely to endure residual paralysis at 60 days post disease onset, P=0.025 and P=0.03, respectively. CONCLUSION: Male gender could be a determinant of rapid progression to maximum paralysis, while the older age group in pediatrics is expected to endure residual paralysis at 60 days post disease onset. GBS can be accounted as a rare disease, especially in pediatrics, so confirmed cases should be investigated comprehensively for research purposes.

Targeted SLC19A3 gene sequencing of 3000 Saudi newborn: a pilot study toward newborn screening.

BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder mostly presented in children. The disorder is described as having subacute encephalopathy with confusion, dystonia, and dysarthria triggered by febrile illness that leads to neuroregression and death if untreated. Using biotin and thiamine at an early stage of the disease can lead to significant improvement. METHODS: BTBGD is a treatable disease if diagnosed at an early age and has been frequently reported in Saudi population. Keeping this in mind, the current study screened 3000 Saudi newborns for the SLC19A3 gene mutations using target sequencing, aiming to determine the carrier frequency in Saudi Population and whether BTBGD is a good candidate to be included in the newborn-screened disorders. RESULTS: Using targeted gene sequencing, DNA from 3000 newborns Saudi was screened for the SLC19A3 gene mutations using standard methods. Screening of the SLC19A3 gene revealed a previously reported heterozygous missense mutation (c.1264A>G (p.Thr422Ala) in six unrelated newborns. No probands having homozygous pathogenic mutations were found in the studied cohort. The variant has been frequently reported previously in homozygous state in Saudi population, making it a hot spot mutation. The current study showed that the carrier frequency of SLC19A3 gene mutation is 1 of 500 in Saudi newborns. CONCLUSION: For the first time in the literature, we determined the carrier frequency of SLC19A3 gene mutation in Saudi population. The estimated prevalence is too rare in Saudi population (at least one in million); therefore, the data are not in favor of including such very rare disorders in newborn screening program at population level. However, a larger cohort is needed for a more accurate estimate.

X-linked ichthyosis associated with psychosis and behavioral abnormalities: a case report.

BACKGROUND: X-linked ichthyosis is a dermatological condition caused by deficiency for the enzyme steroid sulfatase. Previously, X-linked ichthyosis/steroid sulfatase deficiency has been associated with developmental and neurological phenotypes. Here, we show for the first time, that X-linked ichthyosis may be comorbid with an additional psychiatric phenotype (psychosis). CASE PRESENTATION: We report the case of an 11-year-old Saudi Arabian boy with X-linked ichthyosis associated with psychosis, mental retardation, autism spectrum disorder, inattentive attention deficit hyperactivity disorder, and epilepsy. Genetic analysis revealed a 1.68 Mb deletion encompassing STS in 95% of cells while biochemical analysis revealed correspondingly low steroid sulfatase activity consistent with a diagnosis of X-linked ichthyosis. The psychotic symptoms could be reasonably well controlled by administration of an atypical antipsychotic. CONCLUSIONS: This report describes a case of comorbid X-linked ichthyosis and psychosis (most closely corresponding to early-onset schizophrenia) for the first time, and suggests that deficiency for steroid sulfatase and contiguous genes may increase vulnerability to psychosis as well as other psychological disorders.