Applicability of the International League Against Epilepsy (ILAE) 2022 diagnostic criteria for epilepsy syndromes in children: A retrospective review of 1550 children with epilepsy.

OBJECTIVE: Recently, the ILAE Nosology and Definitions Task Force defined diagnostic criteria for epilepsy syndromes. There is paucity of data on the use of these new diagnostic criteria in children with epilepsy, and how these criteria may lead to changes from previous practice. METHODS: This was a retrospective chart review of data of children attending the epilepsy clinic in a tertiary care children's hospital from January 2011 to January 2023. The clinical details such as age at onset, types of seizures, co-morbidities, and results of EEG, MRI and genetic testing were reviewed. Epilepsy syndrome diagnosis was made as per the ILAE 2022 criteria, and compared with the previous syndrome diagnosis as per records. RESULTS: Data from 1550 children (63 % boys) with epilepsy were analysed, and 55.4 % children were classified to have epilepsy syndromes as per the new ILAE 2022 diagnostic criteria. Application of the new 2022 ILAE diagnostic criteria was associated with a change in name alone in 676 (77.8 %) children. Hundred (11.5 %) children were newly classified under an epilepsy syndrome who had previously remained unclassified. Eleven (1.3 %) children who were previously classified into an epilepsy syndrome could not be classified using the new diagnostic criteria. Eight (0.9 %) were shifted to a new syndromic category. Overall, change in diagnosis occurred in 13.7 (11.5 + 1.3 + 0.9)%. No change in epilepsy syndrome classification/nomenclature occurred in 74 (8.5 %) children. SIGNIFICANCE: The new diagnostic criteria led to an overall change in diagnosis in 13.7 % of children with epilepsy. These criteria will hopefully lead to uniformity in diagnosis of epilepsy syndromes across diverse settings.

Familial hemiplegic migraine in Indian children-a tertiary center experience.

Familial hemiplegic migraine (FHM), an autosomal dominant subtype of hemiplegic migraine, is a channelopathy presenting with severe headache, visual field defect, paresthesia, unilateral motor deficit, encephalopathy, seizures and aphasia. This cross-sectional study was conducted over 10 months in children aged 1-18 years suspected of hemiplegic migraine at a tertiary care pediatric hospital. Fourteen children were screened and five children with genetically confirmed FHM were included. The symptoms in the study population were paroxysmal hemiparesis (5/5), headache (5/5) and focal seizures (1/5). The hemiplegia episodes lasted from 4 h to 7 days. The mean age at the onset of neurological symptoms was 6.8 ± 0.7 years and the mean age at diagnosis was 12.8 ± 1.7 years, with a mean delay of 6.1 ± 1.9 years for the diagnosis. Neuroimaging during acute episodes revealed accentuated gray, white differentiation in the contralateral cerebral hemisphere with mild effacement of sulcal spaces in T2/fluid-attenuated inversion recovery (FLAIR) images. Genetic testing revealed ATP1A2 mutations (FHM2) in 4/5 and SCN1A (FHM3) in 1/5 patients. All of them (5/5) were initiated on oral topiramate and had favorable treatment responses with a mean follow-up duration of 7 ± 1.4 months. Diagnosis of FHM is mainly clinical and can be confirmed by genetic analysis. Perfusion and diffusion-weighted MRI should be considered during acute headache episodes, as it is mostly normal in symptom-free periods. Routine MRI sequences like T1 weighted, T2 weighted, FLAIR and contrast remain normal even during acute attacks.

Teaching NeuroImage: Neuroimaging Features of Wilson Disease.

A 13-year-old boy of nonconsanguineous parents presented with abnormal body movements, gait difficulty, and slurring of speech for 2 years. On examination, he had rigidity, dystonia, dysarthria, and drooling. Ophthalmologic examination revealed bilateral Kayser-Fleischer rings. He had elevated serum "free" copper levels (41.2 µg/dL [range:10-15]), 24-hour urine copper levels (895.7 µg/d [range:<60]), and reduced serum ceruloplasmin levels (4.3 mg/dL (range:20-40]). MRI revealed "face of giant panda" appearance (Figure A), T2-fluid attenuated inversion recovery hyperintensities (Figure, B and C), and frontal cystic encephalomalacic changes (Figure D), suggestive of Wilson disease (WD). Face of giant panda in WD, first described by Hitoshi et al.,1 is due to high signal intensity in tegmentum with normal signals in red nuclei forming the eyes, normal signals of pars reticulata (lateral portion) of substantia nigra forming the ears, and hypointensity of superior colliculus forming the chin.2 Bilateral cystic changes are less commonly reported in WD.3 Recognizing diverse neuroimaging signatures beyond well-known findings in WD enhances diagnostic accuracy.

Primary Diffuse Leptomeningeal Melanomatosis in an Indian Child With Review of Literature.

BACKGROUND: Primary diffuse leptomeningeal melanomatosis (PDLM) is an extremely rare, aggressive malignant neoplasia of the central nervous system. We report the first case of pediatric PDLM from India. METHODS: A review of literature was done to describe the 15 pediatric cases reported so far. RESULTS: A 12-year-old male child presented with fever, vomiting, and headache for 2 months. Cerebrospinal fluid examination was normal. An MRI of the brain revealed hydrocephalus, for which antitubercular therapy was started and external ventricular drainage followed by ventriculoperitoneal shunt was done. Repeat MRI revealed a suprasellar lesion, nodular enhancement of cranial nerves along with dural enhancement of spinal cord with arachnoiditis, and long-segment myelomalacia. Repeat cerebrospinal fluid examination was negative for malignant cells. During biopsy, blackish dura with diffuse blackish deposits in ventricle were noted. Histopathological examination revealed tumor cells with intracytoplasmic coarse brown pigment melanoma, frequent mitotic figures, and immunohistochemistry testing was positive for human melanoma black-45 and MelanA, suggestive of PDLM. He expired 4 months after the diagnosis. CONCLUSION: Diagnosing PDLM can be daunting in light of its slow but malignant progression mimicking TBM leading to improper management. However, the absence of any supportive microbiological evidence and failure to respond to the standard antitubercular therapy with subsequent progression of the symptoms should prompt the need for finding an alternative diagnosis. A targeted molecular diagnosis and precision medicine may provide a favorable outcome in children with PDLM.

Mucocutaneous Manifestations in Children with Thalassemia: An Observational Study.

Thalassemia syndromes are a group of autosomal, recessively inherited, single-gene hemoglobinopathies with varied mucocutaneous manifestations. There is, however, a scarcity of these findings in the literature. This descriptive observational cross-sectional study was conducted to describe mucocutaneous manifestations in multi-transfused beta-thalassemia major children. The study comprised 68 thalassemia major children attending the thalassemia unit for blood transfusion at a tertiary care hospital in North India. A dermatologist conducted a detailed examination to look into the presence of any mucocutaneous manifestations, including disorders of the hair and nails. The age range of enrolled thalassemic children was 6 months-19 years, with an average age of 10.5 years; the boy versus girl ratio was 1.72:1. All enrolled children had at least one cutaneous manifestation. Common dermatologic manifestations observed in these patients included hyperpigmentation of the knuckles (60.2%), moderate pallor (42.6%), icterus (26.4%), lusterless hair (20.5%), leukonychia striata or horizontal white streaks on the nails (14.7%), and oral ulcers (10.2%). A careful evaluation of mucocutaneous manifestations, including disorders of the hair and nails, is required in multi-transfused thalassemic children to provide an early diagnosis of dermatologic manifestations.

Clinico-Etiologic Profile of Children and Adolescents with Drug-Resistant Epilepsy in a low-Resource Setting: 10 Years' Experience.

Purpose: Nearly 25% to 30% of children with epilepsy develop drug-resistant epilepsy. Etiology of epilepsy, including drug-resistant epilepsy, varies with geographical region. Identifying paucity of etiologic data on drug-resistant epilepsy from our region and similar low-resource settings, we aimed to describe the clinical and etiologic profile of children and adolescents with drug-resistant epilepsy, to better inform region-specific concerns. Methods: A chart-based retrospective review covering 10 years (January 2011-December 2020) was conducted. Participants between 1 months and 18 years of age who fulfilled International League Against Epilepsy (ILAE) definition of drug-resistant epilepsy were enrolled. Clinical details, perinatal history, electroencephalography (EEG), magnetic resonance imaging (MRI), and other evaluation-based data were analyzed. Results: Five hundred ninety-three children (52.3% males) were enrolled. The median age at presentation was 63 (interquartile range [IQR] 12-72) months and median age at onset was 12 (IQR 2-18) months. The most frequent seizure type was generalized (76.6%). Of these, epileptic spasms (48.1%) were most frequent. Focal seizures comprised 22.9%. The predominant contributor to etiology was perinatal adverse events, including perinatal asphyxia (37.9%), neonatal hypoglycemic brain injury (15.6%), and neonatal sepsis/meningitis. Electroclinical syndromes were observed in 361 (60.9%) children. Of these, the most frequent were West syndrome (48%) and Lennox-Gastaut syndrome (6.2%). Conclusion: Perinatal brain injury and brain infections were the most common causes of drug-resistant epilepsy identified. These findings indicate an opportunity for reducing the burden of pediatric drug-resistant epilepsy in our region by instituting preventive measures, including improved perinatal care, promotion of institutional deliveries, optimized obstetric and neonatal care, and immunization for vaccine-preventable infections such as bacterial meningitis and Japanese B encephalitis.

Recent Advances in Targeting the Urokinase Plasminogen Activator with Nanotherapeutics.

The aberrant proteolytic landscape of the tumor microenvironment is a key contributor of cancer progression. Overexpression of urokinase plasminogen activator (uPA) and/or its associated cell-surface receptor (uPAR) in tumor versus normal tissue is significantly associated with worse clinicopathological features and poorer patient survival across multiple cancer types. This is linked to mechanisms that facilitate tumor cell invasion and migration, via direct and downstream activation of various proteolytic processes that degrade the extracellular matrix─ultimately leading to metastasis. Targeting uPA has thus long been considered an attractive anticancer strategy. However, poor bioavailability of several uPA-selective small-molecule inhibitors has limited early clinical progress. Nanodelivery systems have emerged as an exciting method to enhance the pharmacokinetic (PK) profile of existing chemotherapeutics, allowing increased circulation time, improved bioavailability, and targeted delivery to tumor tissue. Combining uPA inhibitors with nanoparticle-based delivery systems thus offers a remarkable opportunity to overcome existing PK challenges associated with conventional uPA inhibitors, while leveraging potent candidates into novel targeted nanotherapeutics for an improved anticancer response in uPA positive tumors.

Spectrum of Movement Disorders Among Children With Subacute Sclerosing Panencephalitis: A Cross-Sectional Study.

Background: Subacute sclerosing panencephalitis is a progressive devastating condition due to persistence of mutant measles virus, affecting children and adolescents, characterised by myoclonus, seizures, and neuropsychiatric issues. Movement disorders apart from myoclonus are reportedly uncommon. We aimed to describe frequency and proportion of movement disorders among children with subacute sclerosing panencephalitis, hypothesizing that these occur more frequently than previously reported. Methods: In this cross-sectional study, we enrolled children with subacute sclerosing panencephalitis between 1 month and 18 years of age who fulfilled the diagnosis of subacute sclerosing panencephalitis as per modified Dyken criteria, and examined them for movement disorders. We also assessed their clinical profile and disease severity via Jabbour staging and modified Rankin Scale score. We compared demographic, clinical, and laboratory features of children with and without movement disorders. Results: We enrolled 50 children (36 males; 72%) (age range 1.5-14 years). Of these, 28 (56%) had movement disorders. Among movement disorders, the most frequent was myoclonus (92%), followed by ataxia (9; 18%), chorea-athetosis (7; 14%), dystonia (6; 12%), tremor (4; 8%), repetitive behavior (4; 8%), and parkinsonism (3; 6%). Movement disorders were the presenting feature of subacute sclerosing panencephalitis among 7 children. There were no significant differences in clinical or laboratory features among children with and without movement disorders. Conclusions: Movement disorders were frequent in subacute sclerosing panencephalitis. Hyperkinetic disorders were dominant. Dystonia and chorea-athetosis occurred more commonly among nonmyoclonus movement disorders. Movement disorders may manifest even in earlier stages of subacute sclerosing panencephalitis and may be the heralding feature. Recognition of these features is important to plan management and reduce morbidity.

The Urokinase Plasminogen Activation System in Pancreatic Cancer: Prospective Diagnostic and Therapeutic Targets.

Pancreatic cancer is a highly aggressive malignancy that features high recurrence rates and the poorest prognosis of all solid cancers. The urokinase plasminogen activation system (uPAS) is strongly implicated in the pathophysiology and clinical outcomes of patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic cancers. Overexpression of the urokinase-type plasminogen activator (uPA) or its cell surface receptor uPAR is a key step in the acquisition of a metastatic phenotype via multiple mechanisms, including the increased activation of cell surface localised plasminogen which generates the serine protease plasmin. This triggers multiple downstream processes that promote tumour cell migration and invasion. Increasing clinical evidence shows that the overexpression of uPA, uPAR, or of both is strongly associated with worse clinicopathological features and poor prognosis in PDAC patients. This review provides an overview of the current understanding of the uPAS in the pathogenesis and progression of pancreatic cancer, with a focus on PDAC, and summarises the substantial body of evidence that supports the role of uPAS components, including plasminogen receptors, in this disease. The review further outlines the clinical utility of uPAS components as prospective diagnostic and prognostic biomarkers for PDAC, as well as a rationale for the development of novel uPAS-targeted therapeutics.

Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors.

The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co-screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.