Colin Kennedy

The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial

BACKGROUND Infantile spasms is a severe infantile seizure disorder that is difficult to treat and has a high morbidity. Absence of spasms on days 13 and 14 after randomisation is more common in infants allocated hormone treatments than in those allocated vigabatrin. We sought to assess whether early control of spasms is associated with improved developmental or epilepsy outcomes. METHODS Infants enrolled in the United Kingdom Infantile Spasms Study (UKISS) were randomly assigned hormone treatment (n=55) or vigabatrin (n=52) and were followed up until clinical assessment at 12-14 months of age. We assessed neurodevelopment with the Vineland adaptive behaviour scales (VABS) at 14 months of age on an intention to treat basis. FINDINGS Of 107 infants enrolled, five died and 101 survivors reached both follow-up assessments. Absence of spasms at final clinical assessment (hormone 41/55 [75%] vs vigabatrin 39/51 [76%]) was similar in each treatment group (difference 1.9%, 95% CI -18.3% to 14.4%; chi(2)=0.05; p=0.82). Mean VABS score did not differ significantly (hormone 78.6 [SD 16.8] vs vigabatrin 77.5 [SD 12.7]; difference 1.0, 95% CI -4.9 to 7.0; t(99)=0.35, p=0.73). In infants with no identified underlying aetiology, the mean VABS score was higher in those allocated hormone treatment than in those allocated vigabatrin (88.2 [17.3] vs 78.9 [14.3]; difference 9.3, 95% CI 1.2 to 17.3; t(95)=2.28, p=0.025). INTERPRETATION Hormone treatment controls spasms better than does vigabatrin initially, but not at 12-14 months of age. Better initial control of spasms by hormone treatment in those with no identified underlying aetiology may lead to improved developmental outcome.

The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial

BACKGROUND Infantile spasms, which comprise a severe infantile seizure disorder, have a high morbidity and are difficult to treat. Hormonal treatments (adrenocorticotropic hormone and prednisolone) have been the main therapy for decades, although little evidence supports their use. Vigabatrin has been recorded to have a beneficial effect in this disorder. We aimed to compare the effects of vigabatrin with those of prednisolone and tetracosactide in the treatment of infantile spasms. METHODS The United Kingdom Infantile Spasms Study assessed these treatments in a multicentre, randomised controlled trial in 150 hospitals in the UK. The primary outcome was cessation of spasms on days 13 and 14. Minimum doses were vigabatrin 100 mg/kg per day, oral prednisolone 40 mg per day, or intramuscular tetracosactide depot 0.5 mg (40 IU) on alternate days. Analysis was by intention to treat. FINDINGS Of 208 infants screened and assessed, 107 were randomly assigned to vigabatrin (n=52) or hormonal treatments (prednisolone n=30, tetracosactide n=25). None was lost to follow-up. Proportions with no spasms on days 13 and 14 were: 40 (73%) of 55 infants assigned hormonal treatments (prednisolone 21/30 [70%], tetracosactide 19/25 [76%]) and 28 (54%) of 52 infants assigned vigabatrin (difference 19%, 95% CI 1%-36%, p=0.043). Two infants allocated tetracosactide and one allocated vigabatrin received prednisolone. Adverse events were reported in 30 (55%) of 55 infants on hormonal treatments and 28 (54%) of 52 infants on vigabatrin. No deaths were recorded. INTERPRETATION Cessation of spasms was more likely in infants given hormonal treatments than those given vigabatrin. Adverse events were common with both treatments.

Presentation of childhood CNS tumours: a systematic review and meta-analysis

BACKGROUND Suspicion of a CNS tumour is classically raised by symptoms of raised intracranial pressure, focal deficits (including seizures), or papilloedema. Development of guidelines is needed for the identification and referral of children who might have a CNS tumour. We did a systematic literature review and meta-analysis to identify the clinical presentation of childhood CNS tumours to provide evidence to support the development of guidelines to assist with the identification and referral for imaging of children who might have a central nervous system tumour. METHODS Medline, Embase, and PubMed were searched for cohort studies and case series in children, published between January, 1991, and August, 2005, detailing the symptoms and signs at diagnosis of a CNS tumour. FINDINGS 74 papers (n=4171) met the inclusion criteria. 56 symptoms and signs at diagnosis were identified, ranked by frequency, and clustered according to age, anatomical criteria, and genetic criteria. The most frequent symptoms and signs at diagnosis were: headache (33%), nausea and vomiting (32%), abnormalities of gait and coordination (27%), and papilloedema (13%) for intracranial tumours; macrocephaly (41%), nausea and vomiting (30%), irritability (24%), and lethargy (21%) for children aged under 4 years with intracranial tumours; reduced visual acuity (41%), exophthalmia (16%), and optic atrophy (15%) for children with an intracranial tumour and neurofibromatosis; nausea and vomiting (75%), headache (67%), abnormal gait and coordination (60%), and papilloedema (34%) for posterior fossa tumours; unspecified symptoms and signs of raised intracranial pressure (47%), seizures (38%), and papilloedema (21%) for supratentorial tumours; headache (49%), abnormal eye movements (21%), squint (21%), and nausea and vomiting (19%) for central brain tumours; abnormal gait and coordination (78%), cranial nerve palsies (52%), pyramidal signs (33%), headache (23%), and squint (19%) for brainstem tumours; and back pain (67%), abnormalities of gait and coordination (42%), spinal deformity (39%), focal weakness (21%), and sphincter disturbance (20%) for spinal-cord tumours. Other features noted were weight loss, growth failure, and precocious puberty. Symptoms of raised intracranial pressure were absent in more than half of children with brain tumours. Other neurological features were heterogeneous and related to tumour location. INTERPRETATION Apart from raised intracranial pressure, motor and visual system abnormalities, weight loss, macrocephaly, growth failure, and precocious puberty also suggest presence of an intracranial tumour. Children with signs and symptoms that could result from a CNS tumour need a thorough visual and motor system examination and an assessment of growth and pubertal status. Occurrence of multiple symptoms and signs should alert clinicians to possible CNS tumours.

Controlled trial of universal neonatal screening for early identification of permanent childhood hearing impairment

Summary Background Congenital permanent childhood hearing impairment (PCHI) impairs communication skills and, possibly, mental health and employment prospects. Management within 1 year of birth can alleviate most of its adverse effects. Neonatal screening for this disorder is feasible but its benefit for all babies is disputed. We investigated whether neonatal screening of all babies born in hospital, in addition to the standard health visitor distraction test, would increase the rates of early referral, confirmation, and management. Methods Between 1993 and 1996, two teams of four parttime testers and equipment moved between two pairs of hospitals to achieve four periods with neonatal screening and four without neonatal screening, each of 4–6 months’ duration. Babies did or did not undergo neonatal screening dependent on during which periods they were born. We used a transient evoked otoacoustic emissions test and, in babies who failed this test, an automated auditory brainstem response test on the same day. We referred babies with positive results for audiological assessment. Findings 53 781 babies were included in the trial, and 25 609 were born during periods with neonatal screening. Neonatal screening achieved 87% coverage of births, with a false-alarm rate of 1·5%, and an overall yield of 90 cases of bilateral PCHI of 40 dB or more relative to hearing threshold level per 100 000 target population, equivalent to 80% of the expected prevalence of the disorder in the population. 71 more babies with moderate or severe PCHI per 100 000 target population were referred before age 6 months during periods with neonatal screening than during periods without. Early confirmation and management of PCHI were significantly increased. The rate of falsenegative results from neonatal screening was significantly lower than that for the distraction test (4 vs 27% p=0·041). Interpretation Neonatal screening is effective in identification of congenital PCHI early and may be particularly useful for babies with moderate and severe PCHI for whom early management may have the most benefit.

Universal newborn screening for permanent childhood hearing impairment: an 8-year follow-up of a controlled trial

An 8-year follow-up study of the birth cohort of babies enrolled in the Wessex controlled trial of universal newborn screening (UNS) for permanent childhood hearing impairment (PCHI) was undertaken to establish whether UNS would increase the proportion of all true cases of PCHI in children aged 7-9 years who are referred early. The proportion referred before 6 months of age increased from 11 of 35 (31%) children with true PCHI born during periods without UNS to 23 of 31 (74%) born during periods with UNS (difference 43%, 95% CI 19-60). UNS leads to early referral of PCHI.

The underlying etiology of infantile spasms (West syndrome): Information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification

Purpose:  To examine the underlying etiology of infantile spasms from the United Kingdom Infantile Spasms Study (UKISS), using the pediatric adaptation of ICD 10.

The presenting features of brain tumours: a review of 200 cases

Objective: To determine the presenting features of brain tumours in children. Design: Retrospective case note review. Setting: Paediatric and neurosurgical services at the Wessex Neurology Centre and Southampton General Hospital, UK. Patients: 200 patients presenting with a CNS tumour between 1988 and 2001. Results: The commonest first presenting symptoms were headache (41%), vomiting (12%), unsteadiness (11%), visual difficulties (10%), educational or behavioural problems (10%), and seizures (9%). The commonest symptoms occurring at any time were headache (56%), vomiting (51%), educational or behavioural problems (44%), unsteadiness (40%), and visual difficulties (38%). Neurological signs were present at diagnosis in 88%: 38% had papilloedema, 49% cranial nerve abnormalities, 48% cerebellar signs, 27% long tract signs, 11% somatosensory abnormalities, and 12% a reduced level of consciousness. The median symptom interval was 2.5 months (range 1 day to 120 months). A short symptom interval was significantly associated with high grade tumours and patient age of 3 years or younger. Conclusions: The well known predominance of headache in children with CNS tumours is confirmed. Visual, behavioural, and educational symptoms were also prominent. With the exception of seizures, every initial symptom was accompanied by other symptoms or signs by the time of diagnosis. Questions about visual symptoms and educational or behavioural difficulties, as well as the more widely recognised symptoms of raised intracranial pressure and motor dysfunction, are important in the diagnosis of brain tumours, as are vision assessment and the appropriate plotting of growth and head size.

Otoacoustic emissions and auditory brainstem responses in the newborn.

The auditory function of 370 infants, drawn from both low and high risk groups, was tested before postnatal discharge using three tests: standard auditory brain stem responses (ABR), automated analysis of ABR, and automated analysis of evoked otoacoustic emissions (OAE). All infants failing any neonatal test had further audiological evaluation. Follow up information was also available on those who passed neonatal tests. Automated OAE testing of both ears was quickest (median 12.5 minutes) and least invasive (no scalp electrodes). Bilateral failure rates (and upper 95% confidence limits) with a stimulus 35-36 dB above normal hearing threshold level (nHL) were 3.0% (4.6) with automated OAE, 3.2% (5.1) with ABR, and 2.7% (4.4) with automated ABR. Automated OAE was the test most sensitive for subsequently confirmed hearing impairment. Sequential testing with automated OAE followed, in those failing this test, by automated ABR would have provided a screening test for substantial hearing impairment with a specificity greater than 99% in this population. Possible application as a universal screen is discussed.

The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: Evidence from the United Kingdom Infantile Spasms Study

Purpose:  Infantile spasms is a severe infantile seizure disorder. Several factors affect developmental outcome, especially the underlying etiology of the spasms. Treatment also affects outcome. Both age at onset of spasms and lead time to treatment (the time from onset of spasms to start of treatment) may be important. We investigated these factors.

Disability and quality of life in spina bifida and hydrocephalus

This study examined the impact of severity and type of condition and family resources on quality of life in children with spina bifida and hydrocephalus. A national UK sample of children aged between 6 and 13 years with spina bifida (n=62), hydrocephalus (n=354), and spina bifida plus hydrocephalus (n=128) were identified via the register of the Association for Spina Bifida and Hydrocephalus (ASBAH). Parents completed standardized measures of Child Health Related Quality Of Life (CQOL), family needs survey (FNS), and caregiving self-efficacy scale (CSES) as well as questions on childrens health and physical ability. Results showed there were no significant differences in the overall quality of life for the three disability conditions. The overall CQOL was over 1 SD lower for those with spina bifida and hydrocephalus than for children with other physical conditions. Sex and age were not related to overall CQOL. Specific aspects of CQOL differentiated the three groups. Children with spina bifida had poorer CQOL scores on self-care, continence, and mobility/activities whilst those with hydrocephalus had poorer scores on school activities, worries, sight, and communication. Severity of condition and family resources, i.e. CSES and FNS, predicted 32% of the variance in CQOL. Associations were also found between overall CQOL and problems discernible at birth as well as epilepsy. Other factors, including those related to shunts, were not significantly related to CQOL. It was concluded that hydrocephalus is just as great a threat to CQOL as spina bifida. Beyond the general effect of condition severity on CQOL, family resources (as measured by the CSES and FNS) represent an additional influence on CQOL.