Intellectual abilities in tuberous sclerosis complex: risk factors and correlates from the Tuberous Sclerosis 2000 Study.

BACKGROUND: Tuberous sclerosis complex (TSC) is associated with intellectual disability, but the risk pathways are poorly understood. METHOD: The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of the natural history of TSC. One hundred and twenty-five UK children age 0-16 years with TSC and born between January 2001 and December 2006 were studied. Intelligence was assessed using standardized measures at ≥2 years of age. The age of onset of epilepsy, the type of seizure disorder, the frequency and duration of seizures, as well as the response to treatment was assessed at interview and by review of medical records. The severity of epilepsy in the early years was estimated using the E-Chess score. Genetic studies identified the mutations and the number of cortical tubers was determined from brain scans. RESULTS: TSC2 mutations were associated with significantly higher cortical tuber count than TSC1 mutations. The extent of brain involvement, as indexed by cortical tuber count, was associated with an earlier age of onset and severity of epilepsy. In turn, the severity of epilepsy was strongly associated with the degree of intellectual impairment. Structural equation modelling supported a causal pathway from genetic abnormality to cortical tuber count to epilepsy severity to intellectual outcome. Infantile spasms and status epilepticus were important contributors to seizure severity. CONCLUSIONS: The findings support the proposition that severe, early onset epilepsy may impair intellectual development in TSC and highlight the potential importance of early, prompt and effective treatment or prevention of epilepsy in tuberous sclerosis.

Prevalence, incidence and risk factors of epilepsy in older children in rural Kenya.

BACKGROUND: There is little data on the burden or causes of epilepsy in developing countries, particularly in children living in sub-Saharan Africa. METHODS: We conducted two surveys to estimate the prevalence, incidence and risk factors of epilepsy in children in a rural district of Kenya. All children born between 1991 and 1995 were screened with a questionnaire in 2001 and 2003, and those with a positive response were then assessed for epilepsy by a clinician. Active epilepsy was defined as two or more unprovoked seizures with one in the last year. RESULTS: In the first survey 10,218 children were identified from a census, of whom 110 had epilepsy. The adjusted prevalence estimates of lifetime and active epilepsy were 41/1000 (95% CI: 31-51) and 11/1000 (95% CI: 5-15), respectively. Overall two-thirds of children had either generalized tonic-clonic and/or secondary generalized seizures. A positive history of febrile seizures (OR=3.01; 95% CI: 1.50-6.01) and family history of epilepsy (OR=2.55; 95% CI: 1.19-5.46) were important risk factors for active epilepsy. After the second survey, 39 children from the same birth cohort with previously undiagnosed epilepsy were identified, thus the incidence rate of active epilepsy is 187 per 100,000 per year (95% CI: 133-256) in children aged 6-12 years. CONCLUSIONS: There is a considerable burden of epilepsy in older children living in this area of rural Kenya, with a family history of seizures and a history of febrile seizures identified as risk factors for developing epilepsy.

Childhood convulsive status epilepticus: epidemiology, management and outcome.

Convulsive status epilepticus (CSE) in childhood is a medical emergency and its aetiology and outcome mean that it should be studied separately from adult CSE. The incidence in developed countries is between 17 and 23/100,000 with a higher incidence in younger children. Febrile CSE is the commonest single group with a good prognosis in sharp distinction to CSE related to central nervous system infections which have a high mortality. The aim of treatment is to intervene at 5 min and studies indicate that intravenous (i.v.) lorazepam may be a better first-line treatment than rectal diazepam and i.v. phenytoin a better second-line treatment than rectal paraldehyde. An epidemiological study strongly supports the development of prehospital treatment with buccal midazolam becoming a widely used but unlicensed option in the community. More than two doses of benzodiazepines increase the rate of respiratory depression without obvious benefit. The 1 year recurrence rate is 17% and the hospital mortality is about 3%.

Childhood convulsive status epilepticus: epidemiology, management and outcome.

Convulsive status epilepticus (CSE) in childhood is a medical emergency and its aetiology and outcome mean that it should be studied separately from adult CSE. The incidence in developed countries is between 17 and 23/100,000 with a higher incidence in younger children. Febrile CSE is the commonest single group with a good prognosis in sharp distinction to CSE related to central nervous system infections which have a high mortality. The aim of treatment is to intervene at 5 min and studies indicate that intravenous (i.v.) lorazepam may be a better first-line treatment than rectal diazepam and i.v. phenytoin a better second-line treatment than rectal paraldehyde. An epidemiological study strongly supports the development of prehospital treatment with buccal midazolam becoming a widely used but unlicensed option in the community. More than two doses of benzodiazepines increase the rate of respiratory depression without obvious benefit. The 1 year recurrence rate is 17% and the hospital mortality is about 3%.

Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder.

This study presents the clinical findings on seven children from Malta (population 385,000). All of them had early motor delay and a significant degree of cognitive impairment. Diurnal variation of the motor impairments was clear in six out of seven of the subjects and oculogyric crises occurred from an early stage also in six out of the seven. Five out of seven had clear evidence of dystonia but the early picture was dominated by hypotonia in five. Two had early Parkinsonian tremor and chorea was seen in four, although in two this was attributable to the use of L-dopa. Three had early bulbar involvement. In all, although minor motor problems persisted, the response to L-dopa was dramatic and there was a need to balance improvement in dystonia against aggravation of chorea. The majority were not able to walk until they were treated. Increased doses of L-dopa were required in hot weather, to which they were sensitive. Despite a good response of improved motor ability and abolition of oculogyric crises, there was no obvious change in cognitive function with learning remaining in the moderate impairment range. This report widens the phenotype of dopa-responsive motor disorders and the range of young children with primary motor delay (cerebral palsy) who need a clinical trial of L-dopa. All of the subjects had the same novel mutation in the tetrahydrobiopterin pathway involving sepiapterin reductase, and no abnormality in the gene encoding guanosine triphosphate cyclohydrolase 1. Clinically and molecularly the condition shows autosomal recessive inheritance.

Obesity in childhood craniopharyngioma: relation to post-operative hypothalamic damage shown by magnetic resonance imaging.

OBJECTIVE: To quantify the extent of hypothalamic damage after surgery for craniopharyngioma using magnetic resonance imaging (MRI) and to relate the findings to changes in body mass index (BMI). PATIENTS: Sixty-three survivors (36 males, 27 females) of childhood cramopharyngioma were treated surgically between 1973 and early 1994. METHODS: Cranial MRI was performed at a structured follow-up assessment 1.5-19.2 yr after the initial surgery. Hypothalamic damage was scored as 0 (no visible damage), 1 (intermediate), or 2 (severe). RESULTS: After surgery there was an increase in BMI standard deviation (SD) from diagnosis to study assessment in all but 7 patients. However, patients with MRI scores of 2 (n = 17) had a significantly greater increase in median BMI SD score at follow-up (+5.5 SD score), compared with +2.5 SD score and +1.1 SD score for patients with MRI scores of 1 or 0, respectively. Of the 17 cases with MRI scores of 2, 10 had a history of extreme weight loss or weight gain at presentation; preoperative neuroimaging demonstrated extensive hypothalamic infiltration by tumor in these cases. CONCLUSION: MRI gives sufficient anatomical definition to allow assessment of the extent of hypothalamic damage and, thereby, prediction of the patients most at risk for severe post-operative weight gain.

Lateralization of brain function in childhood revealed by magnetic resonance spectroscopy.

We used proton magnetic resonance spectroscopy (1H MRS) for the assessment of focal brain pathology in 22 right-handed children with a diagnosis of intractable temporal lobe epilepsy, and we related this pathology to cognitive dysfunction. Cognitive assessment was based on measurements of verbal IQ, performance IQ, and the Paired Associate Learning subtest of the Wechsler Memory Scale. Five of the 22 children showed no abnormalities of the temporal lobes on 1H MRS, seven showed unilateral pathology, and 10 showed bilateral abnormalities. We found that left-sided pathology is associated with a loss of verbal cognitive functions, whereas right-sided pathology is associated with a loss of nonverbal functions. These findings are consistent with the pattern of lateralization of brain function that has been observed in adults.

Quantitative magnetic resonance characterization of mesial temporal sclerosis in childhood.

OBJECTIVE: To investigate whether quantitative MR techniques can be used to distinguish between mesial temporal sclerosis in patients with a history of prolonged febrile convulsion and in patients without such a history. METHODS: Quantitative hippocampal T2 relaxometry, hippocampal volumetry, and single voxel (1)H-MRS data were acquired from 16 children who subsequently underwent temporal lobe resections for intractable temporal lobe epilepsy and histologically were shown to have sclerosis of the horn of Ammon. Eight children had a history of prolonged febrile convulsion in early childhood and eight children had other or no associations. RESULTS: Patients with a history of prolonged febrile convulsion had smaller hippocampi (p = 0.02) and prolonged T2 relaxation time (p = 0.03) ipsilateral to the seizure focus when compared with patients without such a history. There was also more side-to-side asymmetry of T2 relaxation time (p = 0.004) and hippocampal volume (p = 0.02) in the patients with a history of prolonged febrile convulsion than in those with other or no associations. No differences between the groups were identified using (1)H-MRS. CONCLUSIONS: These data support the view that there are at least two types of mesial temporal sclerosis. There may be several pathogenetic pathways from initial insult to later mesial temporal sclerosis, and these pathways are, at least in part, dependent on the initial insult.

Epileptic seizure-induced hypoxemia in infants with apparent life-threatening events.

OBJECTIVE: To describe the physiologic changes that occur during epileptic seizure (ES)-induced apparent life-threatening events (ALTE) and to provide an explanation for the mechanism whereby the hypoxemia characterizing these events occurred. PATIENTS AND DESIGN: Six infants were retrospectively selected from a group of 17 because they had ALTE documented on physiologic recordings where the first change in signals was in the electroencephalogram (EEG). The 17 infants had clinical features suggestive of partial seizures (but normal standard EEGs) and were from a sample of 172 infants with recurrent ALTE. All 17 infants underwent continuous recordings of breathing, electrocardiogram (ECG), oxygenation, and EEG, but only in 6 was an ES-induced ALTE recorded and the physiologic changes described. RESULTS: Twenty-three ALTE were documented in six infants. Events commenced with an abnormality in the EEG, followed by a decrease in SaO2 after a median interval of 27 seconds (range 2 to 147). Despite resuscitation, the median duration of severe hypoxemia (SaO2 < or = 60%) was 40 seconds (range 8 to 74). In 18 events (five infants) there was a median of four apneic pauses (range 1 to 9) preceding the decrease in SaO2 by a median duration of 24 seconds (range 3 to 48). The longest apneic pause per event lasted a median of 19 seconds (range 8 to 47). Breathing movements continued in five events (four infants), and expiratory airflow in one. Sinus tachycardia was found in 19 of the 23 events (six infants), but there were no cardiac arrhythmias. CONCLUSIONS: ES in infants can manifest as ALTE and be accompanied by potentially life-threatening episodes of severe hypoxemia and apnea, despite a normal EEG between events.

Epileptic nystagmus in infancy.

Epileptic nystagmus (EN) is a rare form of nystagmus that occurs only during epileptic seizures. We report an infantile case in which EN was first noted at 10 days of age. Electronystagmography showed a right-beating nystagmus with predominantly linear slow phases that traversed the midline. Neuro-imaging revealed dysplasia of the left middle temporal gyrus extending posteriorly into the parieto-occipital cortex. The right hemisphere and subcortical structures appeared normal. Perfusion studies demonstrated interictal hypoperfusion with ictal hyperperfusion in the left temporal lobe. Electrocorticography demonstrated spiking over the left temporal-parieto-occipital region. Following extensive surgical resection of this area and weaning of anti-convulsants, the child has remained seizure-free without nystagmus. This case demonstrates the cortical origin of EN, and shows that infant cortex has functioning efferent connections to brainstem oculomotor centres from 10 days of age.

Management of childhood craniopharyngioma: can the morbidity of radical surgery be predicted?

Seventy-five children treated for craniopharyngioma between 1973 and 1994 were studied to demonstrate which pre- and intraoperative factors were indicative of a poor outcome as defined by a quantitative assessment of morbidity. This involved a retrospective review of 65 patients and a prospective study of 10 patients focused on clinical details and cranial imaging and a follow-up "study assessment" of 66 survivors performed over the last 2 years. As part of the assessment, 63 patients underwent magnetic resonance imaging with a three-dimensional volume acquisition sequence 1.5 to 19.2 years after initial surgery. Predictors of high morbidity included severe hydrocephalus, intraoperative adverse events, and young age ( < or = 5 years) at presentation. Predictors of increased hypothalamic morbidity included symptoms of hypothalamic disturbance already established at diagnosis, greater height ( > or = 3.5 cm) of the tumor in the midline, and attempts to remove adherent tumor from the region of the hypothalamus at operation. Large tumor size, young age, and severe hydrocephalus were predictors of tumor recurrence, whereas complete tumor resection (as determined by postoperative neuroimaging) and radiotherapy given electively after subtotal excision were less likely to be associated with recurrent disease. Based on these findings, the authors propose an individualized, more flexible treatment approach whereby surgical strategies may be modified to provide long-term tumor control with the lowest morbidity.

Reversible disability associated with epilepsy.

Epilepsy is a syndrome complex in which the impairments include seizures, cognitive arrest and regression, psychiatric illness, and motor and visual disorders. In both lesional and non-lesional epilepsy there is evidence of reversibility of these impairments in some patients which provides compelling evidence that there is a dynamic pathogenetic mechanism which can 'take-out' discreet or global cortical functions. The best evidence that we have suggests that seizures themselves particularly sub-clinical seizure activity are the major factor. Numerous examples of partial and even complete recoveries as a result of medical and surgical treatments are now available. These support the notion that in addition to direct seizure activity there is a pervasive element to the syndromes of epilepsy which causes anything from mild attention deficit or difficulties with language processing to catastrophic loss of cognitive and social functioning. The malignant seizure syndromes are mostly defined by the high risk of these impairments. The challenge of the developmental epilepsies is to explore the pathogenesis and develop new treatments. Perhaps the most difficult aspect of this work is to understand the critical periods for recovery and thus how to avoid irreparable damage.

Surgical treatment of severe autistic regression in childhood epilepsy.

We report 2 children with partial epilepsy who manifested social and language regression and partial recovery after surgical treatment. One child had seizures since the first 2 weeks of life, caused by a right temporal dysembryoplastic neuroepithelial tumor and regression in the latter part of the first year; seizures were relieved and some functions were recovered after temporal lobe resection at 12 months of age. The second child developed epilepsy at 3 years 3 months, and between 5 years 9 months and 6 years 1 month he became aphasic (Landau-Kleffner syndrome) and lost social functioning, manifesting a very severe behavior disorder. He exhibited a significant improvement in communication, social functioning, and behavior after left multiple subpial transections. Both children manifested evidence of subclinical seizure activity in both temporal lobes. Their clinical picture was one of combined language and autistic regression, and the autistic features demonstrated a clear response to surgical treatment. We suggest that in pediatric epilepsy surgical programs, autistic regression should prompt urgent investigation if drug treatment is not effective.

Growth arrest despite growth hormone replacement, post-craniopharyngioma surgery.

Children with growth failure, whether secondary to an endocrinopathy such as growth hormone deficiency or secondary to neurological handicap with poor nutrient intake, grow at a subnormal rate but it is most unusual for a child to have complete growth arrest.