Safety,tolerability, and effectiveness of oral zonisamide therapy in comparison with intramuscular adrenocorticotropic hormone therapy in infants with West syndrome

West syndrome is a distinct, infantile onset, epileptic encephalopathy, associated with poor neurodevelopmental outcome. The present study was designed as a randomized, open-label, pilot study to evaluate the safety, feasibility, and effectiveness of oral zonisamide therapy in comparison with adrenocorticotropic hormone therapy in infants with West syndrome. Thirty infants with West syndrome were randomized to receive treatment with either synthetic, intramuscular adrenocorticotropic hormone (30–60 IU) or oral zonisamide (4–25 mg/kg/day). The study participants had a long treatment lag and preponderance of male sex (90%). The primary effectiveness outcome measure was the cessation of epileptic spasms at 2 weeks of initiation of therapy and persistent till 6 weeks as per West Delphi consensus statement recommendations. Comparison of efficacies of zonisamide versus adrenocorticotropic hormone was as following: the cessation of epileptic spasms (27% vs. 40%, p = 0.70), resolution of hypsarrhythmia at 14 days (20% vs. 33%, p = 0.68) and resolution of hypsarrhythmia at 6 weeks (36% vs. 71%, p = 0.14). Overall, the study observed a poor efficacy of both adrenocorticotropic hormone and zonisamide therapy, which is probably due to long treatment lag and a high proportion of structural aetiology. However, oral zonisamide appeared to be safe and tolerable in the study.     

Vitamin D deficiency in childhood — A review of current guidelines on diagnosis and management

Vitamin D deficiency has emerged as a significant public health problem throughout the world. Even in the Indian context,it has been reported to be present in majority of children in spite of wide availability of sunlight. Recent guidelines have defined vitamin D status as severe deficiency, deficiency, sufficiency and risk for toxicity as 25(OH)D levels <5, <15, >20 and >50ng/mL, respectively.The manifestations of deficiency may vary from hypocalcemic seizures, tetany in infancy and adolescence to florid rickets in toddlers. Treatment is necessary for all individuals with deficiency whether symptomatic or not and consists of vitamin D supplementation as Stoss therapy or daily or weekly oral regimens with equal efficacy and safety, combined with calcium supplements. Routine supplementation starting from newborn period is being increasingly endorsed by various international organizations. Prevention by sensible sunlight exposure, food fortification and routine supplementation are the currently available options for tackling this nutritional deficiency.     

Central brain herniation in shunted Dandy walker cyst

Introduction

Dandy–Walker Syndrome (DWS) is a constellation of congenital anomalies of the central nervous system consisting of cerebellar vermis hypoplasia or agenesis, cystic dilatation of the fourth ventricle, enlarged posterior fossa, and a high tentorium. Hydrocephalus is a common occurrence in DWS and its treatment varies between shunting-ventriculoperitoneal or cystoperitoneal or both, endoscopic cyst fenestration, and third ventriculostomy. Chronic cerebral herniation is a known complication of treatment in DWS; however, we present an unusual case of central brain herniation.

Case report

A 2 year old boy with shunted DWS presented with status epilepticus. Initial CT brain scan showed no increase in ventricle or cyst size; however, tapping the shunt reservoir did not yield any CSF prompting a shunt revision. Postoperatively, he was very slow to wake and subsequently experienced an episode of fixed pupils and extensor posturing. MRI brain demonstrated severe herniation of both thalami through the tentorium.

Conclusion

This child had chronic central brain herniation (CCBH) secondary to the shunting of his cyst. To our knowledge, this is the first case of CCBH following treatment of DW cyst     

From the Cover: Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

Viruses must evade the host innate defenses for replication and dengue is no exception. During secondary infection with a heterologous dengue virus (DENV) serotype, DENV is opsonized with sub- or nonneutralizing antibodies that enhance infection of monocytes, macrophages, and dendritic cells via the Fc-gamma receptor (FcγR), a process termed antibody-dependent enhancement of DENV infection. However, this enhancement of DENV infection is curious as cross-linking of activating FcγRs signals an early antiviral response by inducing the type-I IFN-stimulated genes (ISGs). Entry through activating FcγR would thus place DENV in an intracellular environment unfavorable for enhanced replication. Here we demonstrate that, to escape this antiviral response, antibody-opsonized DENV coligates leukocyte Ig-like receptor-B1 (LILRB1) to inhibit FcγR signaling for ISG expression. This immunoreceptor tyrosine-based inhibition motif-bearing receptor recruits Src homology phosphatase-1 to dephosphorylate spleen tyrosine kinase (Syk). As Syk is a key intermediate of FcγR signaling, LILRB1 coligation resulted in reduced ISG expression for enhanced DENV replication. Our findings suggest a unique mechanism for DENV to evade an early antiviral response for enhanced infection.Despite long-lived serotype-specific immunity upon initial infection, predicted global prevalence of dengue now surpasses World Health Organization estimates by more than threefold with 390 million cases annually (1). Furthermore, the risk of severe disease is augmented by cross-reactive or subneutralizing levels of antibody (2, 3), which opsonize dengue virus (DENV) to ligate Fc-gamma receptor (FcγR) for entry into monocytes, macrophages, and dendritic cells, a phenomenon known as antibody-dependent enhancement (ADE) of DENV infection (4, 5). The resultant greater viral burden leads to increased systemic inflammation that precipitates plasma leakage, a hallmark of dengue hemorrhagic fever (6). However, ligation of the activating FcγRs by immune complexes has been shown to induce type-I IFN stimulated genes (ISGs), independent of autocrine or paracrine IFN activity, unless the inhibitory FcγRIIB is coligated (7). We and others reported recently that coligation of FcγRIIB by DENV immune complexes requires high antibody concentration, and such coligation inhibited the entry of DENV immune complexes into monocytes (8, 9). At low antibody concentrations where ADE occurs, the inhibitory FcγRIIB is not coligated (9). Ligation of the activating FcγRs by DENV opsonized with subneutralizing levels of antibody would thus induce the expression of ISGs and hinder DENV replication (10). Here, we demonstrate that DENV employs a unique evasive mechanism by coligating LILRB1 to down-regulate the early antiviral responses triggered by activating FcγRs for ADE.     

Glaucoma and optical coherence tomography changes in migraine: A comparative cross-sectional study

Purpose:To study the prevalence of glaucoma among adults with migraine and the effect of migraine on peripapillary retinal nerve fiber layer (pRNFL) and central macular thickness (CMT) using optical coherence tomography (OCT) compared to those without migraine headache, i.e. in tension-type headache (TTH) and normal group.Methods:One hundred and eleven patients (222 eyes) were recruited in three groups. migraine, TTH, and normal subjects visiting hospital outpatient services. After noting demographic details and pertinent history, ophthalmological evaluation including optic disc for glaucomatous changes along with computerized visual field testing and OCT for pRNFL thickness and CMT was performed in all eyes. Continuous variables were compared using ANOVA or Kruskal–Wallis test, while categorical variables including the association of glaucoma with migraine were analyzed using Chi-square or Fisher’s exact test.Results:Prevalence of glaucoma in migraine group (12.2%) was more than in comparison groups (6.8% in TTH, 4.1% in normal) which was however not significant (Fisher’s exact P = 0.207). Average pRNFL thickness (103.59 ± 12.82 μm) and thickness in nasal (90.49 ± 19.19 μm) and temporal quadrants (70.58 ± 16.13 μm) and CMT (213.78 ± 19.81 μm) were significantly reduced (ANOVA P < 0.05) in migraine patients when compared to the other groups and this was independent of the presence of glaucoma.Conclusion:Prevalence of glaucoma is not significantly higher in migraine patients. However, migraine causes thinning of retinal layers on OCT that is statistically significant.     

Disseminated and disfiguring molluscum contagiosum in a child

We report widely disseminated and disfiguring lesions of molluscum contagiosum occurring in a 4-year-old girl secondary to a primary immunodeficiency disorder. The child, born of consanguineous parents, had multiple, asymptomatic, raised, skin-colored and whitish lesions since 2 years of age. On physical examination she had growth retardation features with grade II protein energy malnutrition. Cutaneous examination revealed numerous, widespread, skin-colored to translucent, firm, umbilicated papules of varying sizes (pinpoint to larger than 10 mm). They were distributed bilaterally over all four limbs, including the dorsum of the hands and feet, trunk, face (including lips), eyelids, auriculae, and perineal and gluteal areas. In places, they were linearly disposed and had coalesced to form plaques. A biopsy specimen from a representative skin lesion (arm) demonstrated lobulated epidermal growth consisting of keratinocytes with large intracytoplasmic eosinophilic inclusion bodies and a central crater. These findings were consistent with the diagnosis of molluscum contagiosum. Topical therapies with phenol and trichloroacetic acid were ineffective The child succumbed to a fulminant systemic infection at home, 2 months after discharge from the hospital. The extent and distribution of molluscum contagiosum in our patient was remarkably vivid and has been hitherto reported only rarely.     

Pattern of pediatric dermatoses in a referral center in South India

This study was undertaken to determine the pattern of dermatoses in children in south India. All children <14 years presenting to us between May 2001 and June 2002 were recruited. A total of 2100 children (males -995; females- 1105) with 2144 dermatoses were recorded. Infections and infestations were the most common dermatoses (54.5%) followed by dermatitis and eczema (8.6%), pigmentary disorders (5.7%), insect bite reaction (5.27%), hair and nail disorders (5.2%), miliaria (4.1%), nutritional deficiency disorders (2.8%), urticaria (2.5%), genetic disorders (2.1%), psoriasis (1.4%), collagen vascular disorders (0.5%), hemangiomas (0.5%), drug eruptions (0.3%), pityriasis rosea (0.2%) and others (5.8%). Pyodermas were the most common dermatoses (47.13%) followed by scabies (30.6%) amongst infections and infestations. Atopic dermatitis was noticed only in 3 patients. Insect bite reactions (papular urticaria) (5.27%) and miliaria (4.1%) were attributed to the tropical weather conditions in this coastal area. Genetic disorders including ichthyosis and palmoplantar keratoderma contributed to 2.1% of cases and could be due to the high incidence of consanguinous marriages in this society.     

Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3

Dietary intake of many fruits and vegetables has been shown to be associated with reduced risk of cancer. We investigated the in vivo efficacy of grape seed extract (GSE, patented as Traconol) against prostate cancer (PCA) and associated molecular events. Athymic nude mice were implanted with hormone-refractory human prostate carcinoma DU145 cells and fed with 100 and 200 mg/kg/day (5 days/week) doses of GSE for 7 weeks. At the end of experiment, tumors were immunohistochemically analyzed for cell proliferation, apoptosis and angiogenesis. Our data show that GSE feeding strongly inhibited tumor growth that accounted for 59-73% (p < 0.001) inhibition in tumor volume and 37-47% (p < 0.05) decrease in tumor weight at the end of the experiment. It did not show any significant change in body weight gain profile and diet consumption. Immunohistochemical analysis of tumors showed that GSE decreases proliferation index by 51-66% (p < 0.001) and increases apoptotic index by 3-4-fold (p < 0.001). CD31 staining for endothelial cells, showed decrease in intratumoral microvasculature in GSE-fed group of mice. Control tumors showed 64.0 +/- 1.6 CD31 positive cells/400x field compared to 23.2 +/- 0.9 and 15.7 +/- 0.08 (p < 0.001) CD31 positive cells in 100 and 200 mg/kg doses of GSE-treated tumors, respectively. GSE strongly inhibited (47-70%, p < 0.05) vascular endothelial growth factor (VEGF) secretion in conditioned medium by DU145 cells. Recently, the circulating level of insulin-like growth factor binding protein (IGFBP)-3 is shown to inversely related with PCA risk, growth and prognosis. Consistent with this, we observed 6-7-fold (p < 0.001) increase in tumor-secreted levels of IGFBP-3 after GSE feeding. In other immunohistochemical studies, compared to controls, tumor xenografts from GSE-fed groups of mice showed a moderate decrease in VEGF but an increase in IGFBP-3 levels. These findings suggest that GSE possesses in vivo anticancer efficacy against hormone-refractory human PCA, which is associated with its antiproliferative, proapoptotic and antiangiogenic activities together with upregulation of IGFBP-3.