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.

The treatment and management of alternating hemiplegia of childhood.

Alternating hemiplegia of childhood has many factors that make it difficult to manage. These include its rarity of about one case per million, the variability of the manifestations, with seven characteristic features, and the potential for disabilities and acute, often severe, episodes in a disease that is of uncertain cause and for which treatment evidence is sparse. An integrated multidisciplinary team and emergency availability are key medical requirements, as well as an educational setting that understands the variations in performance that occur. The mainstays of treatment have been flunarizine, antiepilepsy drugs for the 50% of patients with epilepsy, attempts to avoid trigger situations, and the rapid encouragement of sleep when attacks begin. The diagnostic and management predicament of child, parent, and paediatrician in complex rare disorders are well illustrated by this condition.

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%.

Transient exacerbation of hemiplegia following minor head trauma in Sturge-Weber syndrome.

Sturge-Weber syndrome (SWS) is a sporadic disorder characterized by naevus (port wine stain), a pial angioma, and glaucoma. The angioma comprises abnormal tortuous vessels on the leptomeninges with underlying brain gliosis, calcification, and atrophy. The cerebral angioma is commonly unilateral but may be bilateral. Hemiplegia usually follows recurrent hemiconvulsions and may be related to venous stasis. The hemiplegia can be static, progressive, or fluctuating. Transient worsening of the hemiplegia can be seen with seizures and episodes resembling hemiplegic migraine. We report five patients (four females, one male) with SWS who have had transient worsening of hemiplegia following minor head injuries, occurring between the ages of 10 months and 12 years (median age 4y 6mo). An additional pilot survey suggests that this may affect up to 20% of patients.

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%.

Risk factors for persisting neurological and cognitive impairments following cerebral malaria.

BACKGROUND: Persisting neurological and cognitive impairments are common after cerebral malaria. Although risk factors for gross deficits on discharge have been described, few studies have examined those associated with persistent impairments. METHODS: The risk factors for impairments following cerebral malaria were determined by examining hospital records of 143 children aged 6-9 years, previously admitted with cerebral malaria, who were assessed at least 20 months after discharge to detect motor, speech and language, and other cognitive (memory, attention, and non-verbal functioning) impairments. RESULTS: The median age on admission was 30 months (IQR 19-42) and the median time from discharge to assessment was 64 months (IQR 40-78). Thirty four children (23.8%) were defined as having impairments: 14 (9.8%) in motor, 16 (11.2%) in speech and language, and 20 (14.0%) in other cognitive functions. Previous seizures (OR 5.6, 95% CI 2.0 to 16.0), deep coma on admission (OR 28.8, 95% CI 3.0 to 280), focal neurological signs observed during admission (OR 4.6, 95% CI 1.1 to 19.6), and neurological deficits on discharge (OR 4.5, 95% CI 1.4 to 13.8) were independently associated with persisting impairments. In addition, multiple seizures were associated with motor impairment, age <3 years, severe malnutrition, features of intracranial hypertension, and hypoglycaemia with language impairments, while prolonged coma, severe malnutrition, and hypoglycaemia were associated with impairments in other cognitive functions. CONCLUSIONS: Risk factors for persisting neurological and cognitive impairments following cerebral malaria include multiple seizures, deep/prolonged coma, hypoglycaemia, and clinical features of intracranial hypertension. Although there are overlaps in impaired functions and risk factors, the differences in risk factors for specific functions may suggest separate mechanisms for neuronal damage. These factors could form the basis of future preventive strategies for persisting impairments.

Psychopathology in children with epilepsy before and after temporal lobe resection.

The aim of this study was to establish the rate and spectrum of psychiatric disorder among children before and after temporal lobe surgery for epilepsy. Data were examined for associations between psychopathology and seizure outcome following surgery, or association between psychopathology and other variables, such as laterality of lesion, sex, cognitive level, and underlying pathology. Participants were 60 children (35 males, 25 females) who had focal seizures of temporal lobe origin and who had undergone temporal lobe resection between 1992 and 1998; mean age at time of operation 10 y 7 mo, (SD 4 y 11 mo) range 7 mo to 17 y 11 mo. Mean length of follow-up was 5.1 years (SD 2.3, range 2 to 10 y). Twenty-eight (47%) children had undergone right temporal lobectomy. Diagnosis of a psychiatric disorder was present in 50/60 (83%) children at some point, with high rates of psychiatric comorbidity. Common childhood psychiatric disorders of attention-deficit-hyperactivity disorder, oppositional defiant disorder/conduct disorder, and emotional disorders were present in about 25% of children. Disorders rarely seen in the general child population were over-represented: disruptive behaviour disorder--not otherwise specified (30/60 [50%]), and pervasive developmental disorder (autistic spectrum disorder; 23/60 [38%]). there was no significant relationship between pathology, sex, seizure frequency, or postoperative seizure outcome and psychiatric disorder, other than for pervasive developmental disorder. The same proportion of children had psychiatric diagnoses pre- and postoperatively (43/60 [72%] and 41/57 [72%] respectively). Although mental health problems are common in children undergoing temporal lobe resection, there are few predictors of psychiatric outcome following epilepsy surgery. Parents require counselling on these issues in the preoperative work-up.

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.

Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children.

OBJECTIVES: There is little information on the characteristics of persisting impairments associated with severe forms of falciparum malaria. Previous work has suggested the existence of a group of children with particularly poor performance on neurocognitive assessments in the context of average group performance. The aim of this study was to provide a detailed characterisation of impairments in this subgroup. METHODS: Three groups of children were recruited: children admitted up to nine years earlier with cerebral malaria (CM) (n = 152), malaria and complicated seizures (M/S) (n = 156), or those unexposed to either condition (n = 179). Each child underwent a series of developmental assessments. Standard definitions were used to classify impairment. RESULTS: Twenty-four percent of the CM and M/S groups had at least one impairment in the major domains assessed in the study, compared with 10% of the unexposed group. CM was associated with a higher proportion of multiple impairments and an increased risk of mortality in the first year after recovery in those identified with impairments on discharge. CONCLUSIONS: After severe malaria, some children have neurocognitive impairments that are evident as long as nine years later. Impairments may become more evident as children progress and face more complex cognitive and linguistic demands, socially and educationally. The child's neurological status at discharge was not a good predictor of later neurocognitive impairment. This highlights the importance of follow up for children with severe malaria and the involvement of therapists and educators in the provision of services for this population.

Meningitis is a common cause of convulsive status epilepticus with fever.

AIMS: In children with convulsive status epilepticus (CSE) with fever, to determine the likelihood of acute bacterial meningitis (ABM), the proportion that are treated with antibiotics, and the proportion that have diagnostic CSF sampling. METHODS: Patients with an incident episode of CSE with fever were identified as part of an ongoing prospective population based study of CSE in childhood. RESULTS: There were 49 incident cases of CSE in the first six months. Ascertainment was 96%. Twenty four had CSE with fever, 16 had early parenteral antibiotics, nine had diagnostic CSF sampling, and four had ABM. The population risk of ABM in CSE with fever was significantly higher than that of short seizures with fever (17% v 1.2%). CONCLUSIONS: The classical symptoms and signs of ABM may be absent in CSE with fever. A high index of suspicion for ABM in the child with CSE with fever is paramount. The most appropriate management is suggested to be early parenteral antibiotics and a lumbar puncture when there are no contraindications.

Inappropriate emergency management of status epilepticus in children contributes to need for intensive care.

OBJECTIVES: To characterise the clinical features, emergency pre-paediatric intensive care (PIC) treatment, and course of status epilepticus (SE) in children admitted to PIC. This may provide insight into reasons for admission to PIC and provide a framework for the development of strategies that decrease the requirement for intensive care. DESIGN: Cross sectional, retrospective study. SETTING: A tertiary paediatric institution's intensive care unit. PARTICIPANTS: The admission database and all discharge summaries of each admission to a tertiary paediatric institution's PIC over a three year period were searched for children aged between 29 days and 15 years with a diagnosis of SE or related diagnoses. The case notes of potential cases of SE were systematically reviewed, and clinical and demographic data extracted using a standard data collection form. RESULTS: Most children with SE admitted to PIC are aged less than 5 years, male to female ratio 1:1, and most (77%) will have had no previous episodes of SE. Prolonged febrile convulsions, SE related to central nervous system infection, and SE associated with epilepsy occur in similar proportions. Contrary to the Advanced Paediatric Life Support guidelines many children admitted to PIC for SE receive over two doses, or inadequate doses, of benzodiazepine. There is a risk of respiratory depression following administration of over two doses of benzodiazepine (chi2 = 3.4, p = 0.066). Children with SE admitted to PIC who had prehospital emergency treatment are more likely to receive over two doses of benzodiazepines (chi2 = 11.5, p = 0.001), and to subsequently develop respiratory insufficiency (chi2 = 6.2, p = 0.01). Mortality is low. Further study is required to determine the morbidity associated with SE in childhood requiring intensive care. CONCLUSIONS: As the risk of respiratory depression is greater with more than two doses of benzodiazepines, clinicians should not disregard prehospital treatment of SE. As pre-PIC treatment of SE is inadequate in many cases, appropriate audit and modifications of standard guidelines are required.

Dyskinesias and associated psychiatric disorders following streptococcal infections.

BACKGROUND: The classical extrapyramidal movement disorder following beta haemolytic streptococcus (BHS) infection is Sydenham's chorea (SC). Recently, other post-streptococcal movement disorders have been described, including motor tics and dystonia. Associated emotional and behavioural alteration is characteristic. AIMS: To describe experience of post-streptococcal dyskinesias and associated co-morbid psychiatric features presenting to a tertiary referral centre 1999-2002. METHODS: In all patients, dyskinetic movement disorders followed BHS pharyngeal infection. BHS infection was defined by pharyngeal culture of the organism, or paired streptococcal serology. Movement disorders were classified according to international criteria, and validated by experienced child neurologists. Psychiatric complications were defined using ICD-10 criteria using a validated psychiatric interview. RESULTS: In the 40 patients, the following dyskinetic movement disorders were present: chorea (n = 20), motor tics (n = 16), dystonia (n = 5), tremor (n = 3), stereotypies (n = 2), opsoclonus (n = 2), and myoclonus (n = 1). Sixty five per cent of the chorea patients were female, whereas 69% of the tic patients were male. ICD-10 psychiatric diagnoses were made in 62.5%. Using the same psychiatric instrument, only 8.9% of UK children would be expected to have an ICD-10 psychiatric diagnosis. Emotional disorders occurred in 47.5%, including obsessive-compulsive disorder (27.5%), generalised anxiety (25%), and depressive episode (17.5%). Additional psychiatric morbidity included conduct disorders (27.5%) and hyperkinetic disorders (15%). Psychiatric, movement, and post-streptococcal autoimmune disorders were commonly observed in family members. At a mean follow up of 2.7 years, 72.5% had continuing movement and psychiatric disorders. CONCLUSION: Post-streptococcal dyskinesias occur with significant and disabling psychiatric co-morbidity and are potential autoimmune models of common "idiopathic" movement and psychiatric disorders in children. Multiple factors may be involved in disease expression including genetic predisposition, developmental status, and the patient's sex.

A systematic review of the epidemiology of status epilepticus.

Population-based data on the incidence, aetiology, and mortality associated with status epilepticus (SE) are required to develop preventative strategies for SE. Through a systematic review, we aimed to assess the methodological quality as well as similarities, and differences between available population based studies in order to arrive at conclusions on the epidemiology of SE. All population-based studies where primary outcome was incidence, aetiology or mortality of SE were identified through a systematic search and synthesized. Methodological quality of studies were independently rated by two examiners using a unique scoring system. Seven population-based projects on SE yielding nine published reports and five abstracts were reviewed. Quality scores were in the range of 19-34 with a possible maximum of 40 (kappa scores 0.67-1.0). The incidence of SE has a bimodal distribution with peaks in children aged less than a year and the elderly. Most SE were acute symptomatic. Short-term mortality was 7.6-22% and long-term mortality was 43%. Age and aetiology were the major determinants of mortality. There are few population-based studies on SE but most are of good quality. Most studies are primarily or exclusively based on adult populations. There is limited information on the association of ethnicity and socio-economic status and SE.

Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence.

Hemispherectomy has been performed in the treatment of epilepsy in association with hemiplegia for over 50 years. However, the optimal timing of surgery with respect to age at presentation and the influence of underlying pathology on outcome is only slowly emerging. This study reports on the clinical course and outcomes of 33 children who underwent hemispherectomy at Great Ormond Street Hospital, London, between 1991 and 1997. Age at surgery was 0.33-17 years (median 4.25) with 1-8 years follow-up (median 3.4). The underlying pathology was developmental in 16 (10 hemimegalencephaly, two polymicrogyria, two focal cortical dysplasia, one diffuse cortical dysplasia and one microdysgenesis), acquired in 11 (six middle cerebral artery infarct, three post encephalitis/trauma, and one each of hemiconvulsion-hemiplegia epilepsy and perinatal ischaemic insult) and progressive in six children (four Rasmussen encephalitis, two Sturge-Weber syndrome). At follow-up, 52% were seizure free, 9% experienced rare seizures, 30% showed >75% reduction in seizures and 9% showed <75% seizure reduction or no improvement. Seizure freedom was highest in those with acquired pathology (82%), followed by those with progressive pathology (50%) and those with developmental pathology (31%). However, seizure freedom, rare seizures or >75% reduction in seizures occurred in 100% of those with progressive pathology, 91% of those with acquired and 88% of those with developmental pathology, indicating a worthwhile seizure outcome in all groups. Hemiplegia remained unchanged following surgery in 22 out of 33 children, improved in five and was worse in six. No significant cognitive deterioration or loss of language occurred, and four children showed significant cognitive improvement. Behavioural improvement was reported in 92% of those who had behaviour problems pre-operatively.

Correlation of SPECT with pathology and seizure outcome in children undergoing epilepsy surgery.

SPECT can be used to image regional cerebral blood flow (rCBF) and has been shown to help localize the seizure focus in partial epilepsies as part of the presurgical evaluation. Few studies have explored the possible relation between preoperative SPECT and underlying pathology, or any relation to postsurgical outcome. In this study preoperative ictal and interictal rCBF in relation to the histopathological diagnosis and outcome in a series of 35 children (24 females, 11 males; mean age 9.6 years, age range 11 months to 18 years) who had undergone resective surgery for epilepsy were retrospectively evaluated. A correlation between ictal hyperperfusion and the underlying responsible pathology was shown, with a consistent ictal increase in perfusion in developmental pathologies and Rasmussen's encephalitis, and consistent interictal hypoperfusion in hippocampal sclerosis (HS). No rCBF study parameter appeared to relate to outcome but in the group with HS the best outcome was seen in those with localizing ictal rCBF. The varied group of pathologies from hemispherectomy had excellent outcome but the SPECT findings had little to contribute over the abnormalities detected on MRI. In conclusion, rCBF studies remain a useful presurgical investigation in children with partial epilepsy, especially where HS, cortical dysplasia, or inflammatory disease are the underlying pathology. However, rCBF studies add little to the investigation of children with seizures secondary to benign tumours or cerebral infarcts, or where hemispherectomy is the likely preferred surgical option.

Magnetic resonance imaging findings within 5 days of status epilepticus in childhood.

The nature of the relationships between status epilepticus, acute hippocampal injury, mesial temporal sclerosis (MTS) and temporal lobe epilepsy remains unclear. The aim of this study was to investigate whether generalized status epilepticus is associated with brain abnormalities, especially in the mesial temporal lobe, within 5 days of the acute event. Such changes may be the first part of a causative pathophysiological sequence relating status epilepticus and MTS. Thirty-five children with a history of status epilepticus, including 21 with a history of prolonged febrile convulsion (PFC), underwent qualitative and quantitative MRI investigations within 5 days of the acute episode. Quantitative assessments of the hippocampus included T(2) relaxometry and hippocampal volumetry. Hippocampal volumes were large in patients with PFC when compared with controls. In addition, T(2) relaxation time was elevated in patients with PFC compared with control subjects during the first 2 days of the acute event. No difference was observed in patients examined 3-5 days after the event. Patients with afebrile status epilepticus had a variety of imaging abnormalities including elevated hippocampal T(2) values, but no evidence of hippocampal enlargement. PFC is associated with hippocampal abnormalities, consistent with hippocampal oedema, whilst non-febrile status epilepticus is not. A systematic longitudinal study is required to characterize the evolution of these abnormalities and to determine whether any patient develops MTS.