The UK guidelines for management and surveillance of Tuberous Sclerosis Complex.

BACKGROUND: The severity of Tuberous Sclerosis Complex (TSC) can vary among affected individuals. Complications of TSC can be life threatening, with significant impact on patients' quality of life. Management may vary dependent on treating physician, local and national policies, and funding. There are no current UK guidelines. We conducted a Delphi consensus process to reach agreed guidance for the management of patients with TSC in the UK. METHODS: We performed a literature search and reviewed the 2012/13 international guideline for TSC management. Based on these, a Delphi questionnaire was formed. We invited 86 clinicians and medical researchers to complete an online survey in two rounds. All the people surveyed were based in the UK. Clinicians were identified through the regional TSC clinics, and researchers were identified through publications. In round one, 55 questions were asked. In round two, 18 questions were asked in order to obtain consensus on the outstanding points that had been contentious in round one. The data was analysed by a core committee and subcommittees, which consisted of UK experts in different aspects of TSC. The Tuberous Sclerosis Association was consulted. RESULTS: About 51 TSC experts took part in this survey. Two rounds were required to achieve consensus. The responders were neurologists, nephrologists, psychiatrist, psychologists, oncologists, general paediatricians, dermatologist, urologists, radiologists, clinical geneticists, neurosurgeons, respiratory and neurodisability clinicians. CONCLUSIONS: These new UK guidelines for the management and surveillance of TSC patients provide consensus guidance for delivery of best clinical care to individuals with TSC in the UK.

Sirolimus Ointment for Facial Angiofibromas in Individuals with Tuberous Sclerosis Complex.

Background. Facial angiofibromas affect most patients with tuberous sclerosis complex. They tend to progress, can cause recurrent bleeding and facial disfigurement, and have significant psychological effects. We reviewed the effectiveness and safety of topical sirolimus ointment 0.1%. We also assessed the effect of treatment on quality of life. Methods. We report our experience in using sirolimus ointment in 14 patients with TSC (9 children and 5 adults). The impact of sirolimus ointment was monitored with digital photography, dermatological review using a validated Facial Angiofibroma Severity Index (FASI), and quality of life assessments using the questionnaires PedsQL for children and SF36 for adults. Results. The FASI scores were improved in 12/14 cases after six months' treatment, and improvement was more likely in children (median FASI scores of improvement after treatment were 3 points for children and 1 for adults). Proxy-reported PedsQL scores for the total psychosocial domain improved significantly in the children in the cohort with treatment. Conclusions. Sirolimus ointment 0.1% administered once a day was effective in treating facial angiofibromas. It appears to be safe and well tolerated and to have a positive impact on patients' quality of life. It appeared to be most beneficial when started in childhood.

External hydrocephalus and subdural bleeding in infancy associated with transplacental anti-Ro antibodies.

BACKGROUND: The isolated finding of an unexplained chronic subdural haematoma in an infant may suggest non-accidental head injury (NAHI). The authors report a previously undescribed cause of multifocal chronic subdural haematoma in infancy which could result in a misdiagnosis of previous NAHI. METHODS: Two infants, aged 3 and 4 months of age, presented with progressively increasing head circumference measurements from birth. There was no history of encephalopathy. Retinal haemorrhages were not present. CT and MRI demonstrated bilateral subdural fluid collections over the frontal regions that were consistent with either chronic subdural haematomas or haemorrhagic subdural effusions. In view of the possibility of NAHI, child protection investigations were initiated. FINDINGS: In neither case did the child protection investigations raise concerns. Comprehensive investigations for known haematological and metabolic disorders associated with subdural haematomas or effusions in infants were all normal. In both cases the infant's mother had a history of Sjögren's syndrome and both infants had positive anti-Ro antibody at presentation. CONCLUSIONS: Transplacental acquisition of anti-Ro antibodies has been associated with external hydrocephalus. External hydrocephalus has been recognised as a predisposing factor for subdural haemorrhage. These are the first reported cases linking the presence of anti-Ro antibodies and external hydrocephalus with subdural fluid collections in infancy.

Mortality from childhood stroke in England and Wales, 1921-2000.

OBJECTIVE: Stroke is an important but under-recognised cause of childhood mortality. The authors aimed to describe the trends in mortality from childhood stroke in England and Wales between 1921 and 2000. DESIGN: The study searched the Office for National Statistics mortality database for the years 1921-2000 using appropriate, previously validated International Classification of Diseases codes. Mortality rates were analysed by period of death, gender, age at death, birth cohort and stroke subtype. RESULTS: 6029 deaths from childhood stroke were found between 1921 and 2000. Analysis by period of death demonstrated an initial decline in mortality followed by a steep rise in the 1940s. Subsequently, rates declined from the late 1960s onwards. At all time points males had a higher mortality rate than females. Infants had a relatively high mortality rate (24.5 per million person years) but rates fell steeply in early childhood (2.5 per million person years at age 5-9 years) before rising again in late adolescence (7.5 per million person years at age 15-19 years). An increased rate was found for males at all ages (RR = 1.24, p<0.0001) but was greatest in infancy (RR = 1.45, p<0.0001). Haemorrhagic stroke accounted for 71% of stroke deaths. Birth cohort analysis showed a trend of declining mortality with each successive generation since the 1950s. CONCLUSIONS: This study describes characteristics and temporal changes in childhood stroke mortality in the 20(th) century. In particular, the higher mortality rates in males and infants, the importance of deaths from haemorrhagic stroke and the finding of a decline in birth cohort mortality since the 1950s provide aetiological insights.

Running an international paediatric non-commercial clinical trial.

The current regulations for conducting non-commercial clinical trials in Europe are many and complex. These are explored from the perspective of a UK based non-commercial international clinical trial. The reasons for the difficulties encountered are discussed and suggestions made as to how best to overcome them. Improvements are suggested for our law makers and competent authorities. It is argued that the current regulatory environment could be considered unethical as it inhibits and delays research.

Cerebral venous sinus thrombosis: a case series including thrombolysis.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) in children is associated with a high incidence of serious morbidity and mortality. The presenting features are variable. It can be diagnostically challenging and the optimal treatment is uncertain. AIM: To describe the features of a series of children with CVST treated in a single paediatric neurology centre and to discuss the role of local thrombolysis. METHODS: Electronic databases were searched using diagnostic labels and International Classification of Diseases (ICD) codes to identify children aged 1 month to under 17 years with CVST. Their records were reviewed. RESULTS: 21 children were identified over a period of 8.25 years with a median age of 7.1 years. The presenting symptoms included headache (15 children), vomiting (14 children) and visual disturbance (eight children). Signs found included papilloedema (16 children), fever (six children) and sixth nerve palsy (six children). The most common underlying condition was middle ear infection (13 children). All cases received unfractionated heparin and four severe cases received local pharmacological thrombolysis. 48% of cases had an adverse outcome (death, chronic intracranial hypertension, residual hemiparesis or sixth nerve palsy). DISCUSSION: CVST has non-specific presenting features and a high risk of significant morbidity. CVST is typically found in association with a predisposing condition. Although heparin is the mainstay of treatment, thrombolysis may reverse deterioration as seen in three cases in this series. However, there is insufficient evidence to recommend the routine use of thrombolysis at present.

Subependymal nodules, giant cell astrocytomas and the tuberous sclerosis complex: a population-based study.

OBJECTIVES: (1) In a population-based study of tuberous sclerosis (TSC), to identify the number of patients presenting with symptomatic giant cell astrocytomas (GCAs); (2) within a subset of this population, to identify the number who would be diagnosed with GCAs on predetermined radiological criteria. METHODS: Patients with TSC in Wessex (a geographical region of England) were identified, and their medical history determined. A subset were invited to have a cranial MRI if they did not have a history of a symptomatic GCA and if they were likely to tolerate cranial imaging without a general anaesthetic. Scans were performed according to a standard protocol on a single scanner and were reported blindly by a neuroradiologist. RESULTS: 179 people were identified with TSC. Ten of these had a history of treatment for a symptomatic GCA. Forty-one of the remainder had a cranial MRI. Thirty-nine of these had subependymal nodules, of whom 24 (59%) had at least one (maximum 11) that showed enhancement with gadolinium. In seven (17%), the lesion was >1 cm, and all of these lesions showed gadolinium enhancement. CONCLUSIONS: In this study, the proportion of patients with TSC who had a history of symptomatic GCA was 5.6%. In the subset without such a history, who underwent imaging, the number diagnosed as having a GCA on radiological criteria was much higher (59% gadolinium enhancement and 17% >1 cm in size). Screening for GCAs (performing scans on asymptomatic patients with TSC) would therefore identify large numbers of patients who had not presented with symptoms. This finding leads us to recommend that screening should not be undertaken.

Oily fish intake during pregnancy--association with lower hyperactivity but not with higher full-scale IQ in offspring.

BACKGROUND: Long-chain omega-3 polyunsaturated fatty acids are thought to be important for fetal neurodevelopment. Animal studies suggest that a deficiency of omega-3 fatty acids may lead to behavioural or cognitive deficits. As oily fish is a major dietary source of omega-3 fatty acids, it is possible that low intake of fish during pregnancy may have adverse effects on the developing fetal brain. METHODS: We used the Strengths and Difficulties Questionnaire and the Wechsler Abbreviated Scale of Intelligence to assess behavioural problems and intelligence in 217 nine-year-old children. The mothers of these children had participated in a study of nutrition during pregnancy during which fish intake was assessed in early and late gestation. RESULTS: Children whose mothers had eaten oily fish in early pregnancy had a reduced risk of hyperactivity compared to those whose mothers did not eat oily fish: OR .34, 95% CI .15 to .78, after adjustment for potential confounding factors. Children whose mothers had eaten fish (whether oily or non-oily) in late pregnancy had a verbal IQ that was 7.55 points higher (95% CI .75 to 14.4) than those whose mothers did not eat fish. There were, however, no significant associations between fish intake in pregnancy and other behavioural problems or full-scale and performance intelligence, after adjustment for potential confounding factors. CONCLUSIONS: Although maternal fish intake in pregnancy was associated with hyperactivity scores and verbal IQ in children, in general, how much fish women ate during pregnancy appeared to have little long-term relation with neurodevelopmental outcomes in their child.

Psychopathology in tuberous sclerosis: an overview and findings in a population-based sample of adults with tuberous sclerosis.

BACKGROUND: Tuberous sclerosis (TS) is a multi- system disorder with complex genetics. The neurodevelopmental manifestations of TS are responsible for considerable morbidity. The prevalence of epilepsy and intellectual disabilities among individuals with TS have been well described. Ours is the first study that explores the prevalence and pattern of psychopathology in a population-based sample of adults with TS. METHODS: Sixty subjects were identified through a capture-recapture analysis of TS. Information was gathered as to seizure history, cognitive functioning (WISC-III) and psychopathology (SADS-L, SAPPA). Lifetime psychopathology was categorized according to Research Diagnostic Criteria. The overall pattern of mental illness (MI) was examined as well as how this varied with IQ and seizure history. RESULTS: Twenty-four (40.0%) subjects had a history of MI. The most common diagnosis was that of an affective disorder [18 (30.0%)], the majority of which were major depressive episodes. Alcoholism [4 (6.7%)] and anxiety disorders [3 (5.0%)] were the next most common diagnoses. Two (3.3%) subjects had had a tic disorder. Only one individual had a diagnosis of schizophrenia. MI was found in 75.0% of those with a history of epilepsy and 37.5% of those without epilepsy. MI was significantly more prevalent in those with a full-scale IQ above 70. CONCLUSIONS: A significant proportion of adult with TS experience MI. MI was significantly more [corrected] prevalent in subjects with a full-scale IQ above 70. Reasons for such a finding are explored, and related methodological considerations for future research outlined.

CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.

OBJECTIVE: To determine the frequency of mutations in CDKL5 in both male and female patients with infantile spasms or early onset epilepsy of unknown cause, and to consider whether the breadth of the reported phenotype would be extended by studying a different patient group. METHODS: Two groups of patients were investigated for CDKL5 mutations. Group 1 comprised 73 patients (57 female, 16 male) referred to Cardiff for CDKL5 analysis, of whom 49 (42 female, 7 male) had epileptic seizure onset in the first six months of life. Group 2 comprised 26 patients (11 female, 15 male) with infantile spasms previously recruited to a clinical trial, the UK Infantile Spasms Study. Where a likely pathogenic mutation was identified, further clinical data were reviewed. RESULTS: Seven likely pathogenic mutations were found among female patients from group 1 with epileptic seizure onset in the first six months of life, accounting for seven of the 42 in this group (17%). No mutations other than the already published mutation were found in female patients from group 2, or in any male patient from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information was available for six patients: autistic features and tactile hypersensitivity were common but only one had suggestive Rett-like features. All had a severe epileptic seizure disorder, all but one of whom had myoclonic jerks. The EEG showed focal or generalised changes and in those with infantile spasms, hypsarrhythmia. Slow frequencies were seen frequently with a frontal or fronto-temporal predominance and high amplitudes. CONCLUSIONS: The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported. CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder, irrespective of whether they have suspected Rett syndrome. Analysis should be considered in these patients in the clinical setting.

The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex.

BACKGROUND: The aetiology of the learning difficulty in tuberous sclerosis is debated. It may be related to the amount of tubers in the brain or caused by the infantile spasms that occur in early life. AIMS: To examine the relative contributions to final intelligence (IQ) made by both cerebral tubers and infantile spasms. METHODS: As part of an epidemiological study of tuberous sclerosis in the south of England, patients were recruited who were able to undergo magnetic resonance imaging (MRI) without the need for an anaesthetic. Epilepsy history was determined by interview and review of clinical records. IQ was assessed using either Wechsler intelligence scales or Raven's matrices. RESULTS: A total of 41 patients consented to have an MRI scan. IQ scores were normally distributed about a mean of 91. Twenty six patients had a positive history of epilepsy, and 11 had suffered from infantile spasms. There was a significant relation between the number of tubers and IQ. Infantile spasm status partly confounded the relation between tubers and IQ, but did not render the relation statistically insignificant. The relation between infantile spasms and learning difficulty remained strong even when controlling for the number of tubers.

Postmodern values, attitudes and the use of complementary medicine.

OBJECTIVES: To examine the relationship between postmodern values, demographic variables and people's attitudes towards and use of acupuncture, aromatherapy and naturopathy. DESIGN: One hundred and seventy-one adults completed a survey measuring postmodern values about health, attitudes towards and use of complementary and alternative medicine (CAM), age, gender, education, and current and recent health. SETTING: Griffith University, Gold Coast, Australia. MAIN OUTCOME MEASURES: Attitudes to CAM and use of CAM. RESULTS: Postmodern values significantly predicted attitudes to CAM and actual use of CAM. Age also significantly predicted attitudes to CAM. CONCLUSIONS: The results highlight the importance of patients' belief in natural remedies and in their active involvement in the healing process.

Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex.

BACKGROUND: Intellectual impairments are a recognized feature of tuberous sclerosis complex (TSC), but the frequency and degree of intellectual impairments has not been systematically studied in large epidemiological samples using standardized measures. As such, the form of the IQ distribution (uni- or bi-modal) has not been established and the relationship between IQ and other features (e.g. epilepsy history) is poorly delineated. To address these shortcomings, we assessed the intellectual abilities of a large epidemiological sample of individuals with TSC, drawn from the 'Wessex' area of SW England and compared them with the abilities of their unaffected siblings. METHOD: Standardized tests were used to estimate the abilities of 108 (56 males, 52 females, median age = 25, range = 4-75) individuals with TSC and 29 unaffected siblings (14 males, 15 females, median age = 18, range = 6-55). Seizure history was obtained from informants and medical records. RESULTS: Estimated IQ was bi-modally distributed: 55.5% had an IQ in the normal range; 14% had mild to severe impairments: and 30.5% had profound disability (IQ < 21). Forty-four per cent of the individuals with TSC had an IQ < 70. In the subset of normally intelligent individuals with TSC, IQ was normally distributed with a mean of 93.6. This mean was significantly lower than the mean IQ of unaffected siblings (IQ = 105.6). All individuals with learning disability had a history of seizures that usually commenced before 12 months of age and that often presented as infantile spasms. Multivariate analyses indicated that a history of seizures as well as a history of infantile spasms was predictive of the degree of intellectual impairment. CONCLUSIONS: Intellectual abilities were bi-modally distributed in a representative sample of individuals with TSC. The likelihood of impairment was associated with a history of seizures, particularly infantile spasms. The genetic and brain basis of these findings requires further investigation.

Ophthalmic manifestations of tuberous sclerosis: a population based study.

BACKGROUND/AIMS: Tuberous sclerosis complex (TSC) has retinal and non-retinal ophthalmic manifestations. This study was designed to determine the prevalence of the ophthalmic manifestations and of refractive errors in a population of patients with TSC. METHODS: 179 patients identified were in a prevalence study of TSC in the south of England and 107 of these agreed to full ophthalmic examination which was successful in 100. Ophthalmic examination included examination of the eyelids, cover test, examination of the irides, dilation funduscopy using both direct and indirect ophthalmoscopy, and refraction using retinoscopy. Myopia was defined as a spherical equivalent <-0.5D and hyperopia as a spherical equivalent >+0.5D. RESULTS: Retinal hamartomas were seen in 44 of the 100 patients. The commonest morphological type of hamartoma seen was the flat, translucent lesion in 31 of the 44 patients (70%). The multinodular "mulberry" lesion was seen in 24 of the 44 patients (55%) and the transitional type lesion was seen in four of the 44 patients (9%). Punched out areas of retinal depigmentation were seen in 39 of the 100 patients but only six of 100 controls. 27% of eyes were myopic, 22% were hyperopic, and 27% had astigmatism >0.75D. Of the non-retinal findings, 39 patients had angiofibromas of the eyelids, five had non-paralytic strabismus, and three had colobomas. CONCLUSION: Apart from the higher prevalence of flat retinal hamartomas, the findings of this study compare closely with previous large clinic based series of TSC patients. Refractive findings were similar to previous studies of a similarly aged non-TSC population. This is the first series to document the statistically significant association of punched out chorioretinal depigmentation with TSC and the authors believe that it should be looked for as an aid to diagnosis.