The importance of acknowledging diagnostic uncertainty in patients with new-onset paroxysmal spells.

OBJECTIVE: The aims of this study were to evaluate the frequency of paroxysmal spells of indeterminate nature (PSIN) in a large cohort of children and adults with suspected new-onset seizures, to evaluate the reasons for including patients in this category, and to calculate the rate of erroneous diagnoses if the epileptologists were compelled to label those events as epileptic seizures or nonepileptic paroxysmal spells. METHODS: Patients identified for this study participated in a prospective study evaluating patients with suspected new-onset unprovoked seizures. The workup included a detailed history and a thorough description of the spells, a 3-hour video EEG recording, and an epilepsy protocol brain MRI. Based exclusively on a detailed description of the ictal events, two epileptologists were asked to independently classify each patient into those with a definite diagnosis of unprovoked seizures or a definite diagnosis of a nonepileptic paroxysmal spells (group 1) and those with PSIN (group 2). RESULTS: A total of 1880 consecutive patients were enrolled with 255 (13.6%) included in the PSIN group. Patients with PSIN were significantly younger than those with a definite diagnosis, and PSIN were significantly more frequent in children with developmental delay. The most common reason for including patients in the PSIN group was the inability to categorically discriminate between a seizure and a nonepileptic mimicker. When the raters were compelled to classify the spells in the PSIN group, the frequencies of erroneous diagnoses ranged between 32% and 38%. The final diagnoses on those patients were made based on the results of the EEG, MRI, and follow-up visits. SIGNIFICANCE: Our data indicate that a diagnostic category of PSIN should be recognized and ought to be used in clinical practice. Acknowledging this uncertainty will result in lower frequencies of erroneous diagnoses, possible stigma, and potential exposure to unnecessary antiseizure medications.

Contribution of copy number variants (CNVs) to congenital, unexplained intellectual and developmental disabilities in Lebanese patients.

BACKGROUND: Chromosomal microarray analysis (CMA) is currently the most widely adopted clinical test for patients with unexplained intellectual disability (ID), developmental delay (DD), and congenital anomalies. Its use has revealed the capacity to detect copy number variants (CNVs), as well as regions of homozygosity, that, based on their distribution on chromosomes, indicate uniparental disomy or parental consanguinity that is suggestive of an increased probability of recessive disease. RESULTS: We screened 149 Lebanese probands with ID/DD and 99 healthy controls using the Affymetrix Cyto 2.7 M and SNP6.0 arrays. We report all identified CNVs, which we divided into groups. Pathogenic CNVs were identified in 12.1% of the patients. We review the genotype/phenotype correlation in a patient with a 1q44 microdeletion and refine the minimal critical regions responsible for the 10q26 and 16q monosomy syndromes. Several likely causative CNVs were also detected, including new homozygous microdeletions (9p23p24.1, 10q25.2, and 8p23.1) in 3 patients born to consanguineous parents, involving potential candidate genes. However, the clinical interpretation of several other CNVs remains uncertain, including a microdeletion affecting ATRNL1. This CNV of unknown significance was inherited from the patient's unaffected-mother; therefore, additional ethnically matched controls must be screened to obtain enough evidence for classification of this CNV. CONCLUSION: This study has provided supporting evidence that whole-genome analysis is a powerful method for uncovering chromosomal imbalances, regardless of consanguinity in the parents of patients and despite the challenge presented by analyzing some CNVs.

Behavioral problems, cognitive difficulties and quality of life in children with epilepsy: an analysis of parental concerns.

In cognitively impaired or young children with epilepsy, only proxy-report can be used for the assessment of Quality of Life (QOL) and behavior. The present study aims to propose proxy QOL tools applicable in all children with epilepsy and to examine the impact of epilepsy characteristics (e.g., age of onset of epilepsy, epilepsy syndrome) and child's age and situation (in mainstream school or in special institution). We studied 219 children with various types of epilepsy with and without cognitive impairment. The study adapted published QOL scales and used a new parental QOL questionnaire. Selected items concerned 6 "domains" of QOL: global QOL, illness impact, depression/anxiety, hyperactivity/disrupting behavior, sociability, and parental QOL. School situation, epilepsy syndrome, and age were significantly and differentially related to the QOL domains. The proposed QOL tools are applicable to all children with epilepsy independently of comorbid conditions and can be used in a clinical context and for research studies of QOL in children with epilepsy. Epilepsy syndromes in children and their associated factors have a crucial impact on parental concerns and QOL.

Ambiguous genitalia, microcephaly, seizures, bone malformations, and early death: a distinct MCA/MR syndrome.

We report on two siblings with hypotonia, ambiguous genitalia, microcephaly, ptosis, microretrognathia, thin lips, seizures, absent ossification of pubic rami, and brain abnormalities at the MRI. The two siblings died at 5 and 8 months, respectively. Molecular analysis indicated that SOX9, ARX, and DHCR7 genes were normal. Comparative genomic hybridization (CGH)-array analysis performed on the younger boy indicated two notable deletions, one on paternally inherited chromosome 4, and one on maternally inherited chromosome 5. The same deletions were found in a normal sister. Differential diagnoses and the possibility of a hitherto unreported syndrome are discussed.

Epileptic phenotypes in children with respiratory chain disorders.

PURPOSE: Epilepsy is a commonly reported but rarely described clinical hallmark of mitochondrial respiratory chain defects (RCDs) with encephalopathy. METHODS: From 1990-2006 we collected data about 56 children with RCD (single, n = 24 or multiple, n = 20 mitochondrial complex deficiencies; mtDNA mutation, n = 11; mtDNA depletion n = 10 of 21; and nuclear gene mutation n = 11). Epileptic features were reviewed retrospectively. RESULTS: First seizures were frequently (47 patients, 82.5%) preceded by failure to thrive, psychomotor delay, ataxia, or multisystemic dysfunction. Sixty percent of the patients had several seizure types. Six age-related epilepsy phenotypes could be identified: status epilepticus complicating neonatal multivisceral deficiency (2 patients), neonatal myoclonic encephalopathy (3 patients), infantile spasms (8 patients), refractory or recurrent status epilepticus (21 patients), epilepsia partialis continua (4 patients), and myoclonic epilepsy (18 patients). Except for infantile spasms, epilepsy was difficult to control in most patients (95%). Valproate was administered to 25 patients, one of whom developed acute liver failure 6 days later. Twenty-two patients (45%) died, half of them within 9 months from the onset of epilepsy. DISCUSSION: In RCD, epilepsy is not only difficult to control but its occurrence often indicates a severe turn in the course of the disease. For one-third of the patients, classical biochemical measures failed to reveal any abnormality and RCD could be detected in the liver only.

Parental report of cognitive difficulties, quality of life and rehabilitation in children with epilepsy or treated for brain tumour.

PURPOSE: Paediatric neurological chronic conditions are often associated with physical, cognitive, psychological and behavioural difficulties that may affect quality of life (QOL) of children and their families. In this study, we compare parental report of difficulties and rehabilitation in children with various epileptic syndromes or treated for a benign or malignant brain tumour. METHOD: One hundred fifty-three children aged between 6 and 12 years were included, 119 with epilepsy (non-idiopathic generalized 31, non-idiopathic partial 62, idiopathic 26) and 34 treated for a brain tumour. Parents answered a multidimensional questionnaire on child's autonomy and cognitive or behavioural difficulties, impact of the illness on their own everyday life, and rehabilitation. RESULTS: Learning difficulties were reported by a majority of parents in all groups. Behavioural and autonomy problems were more often reported in the non-idiopathic generalized epilepsy group. Report of tiredness was more frequent and of disrupting behaviour less frequent in the tumour group than in epilepsy. Impact of the child's illness on parents' QOL was strong in all groups, and stronger in case of severe forms of epilepsy. CONCLUSIONS: Parental concerns are important to consider for rehabilitation programmes adapted to each child with these neurological conditions.

Myoclonic absence epilepsy with photosensitivity and a gain of function mutation in glutamate dehydrogenase.

Activating mutations in glutamate dehydrogenase (GDH), de novo or dominantly inherited, are responsible for the hyperinsulinism/hyperammonemia (HI/HA) syndrome. Epilepsy has been frequently reported in association with mutations in GDH, but the epilepsy phenotype has not been clearly determined. Here, we describe a family with a dominantly inherited mutation in GDH. The mother, brother and both sisters had myoclonic absence seizures, but only the mother and one sister had the complete HI/HA pattern. For the two sisters with myoclonic absences, epilepsy started during the second year of life while the brother, it started at 6 years. All 3 children showed the same EEG pattern characterized by photosensitive generalized and irregular spike-wave discharges and runs of multiple spikes. The mother's EEG recordings were normal without photosensitivity. Magnetic resonance imaging (MRI) and spectroscopy (MRS) were normal. A direct effect of the GDH mutation, perhaps in combination with recurrent hypoglycemia and chronic hyperammonemia could provide a pathophysiological explanation for the epilepsy observed in this syndrome and these are discussed.

Quality of life in children with epilepsy and cognitive impairment: a review and a pilot study.

Various methods have recently been proposed to assess the physical, psychological or social dimensions of quality of life (QoL) in children with epilepsy (CwE) and their families. Some methods are based exclusively on parental report and others emphasize the importance of an interview with the patient himself. In children with epilepsy and severe cognitive deficit only parental report is possible in practice; however, some parental based methods to evaluate QoL in CwE have excluded children with cognitive deficit. The present pilot study explores which items are suitable for a parental-based QoL evaluation in CwE and special educational needs, and the most frequently reported parental concerns in this special population of children.