18
Hippocampal neuronal loss following experimental traumatic brain injury in the rat is predominantly due to necrosis rather than apop tosis BA WEEDA, P GRUNDP, M HARBUZB, S LIGHTMAN’, PM SHARPLESA aDepartments of Paediatric Neurology C Neurosurgery, Frenchay Hospital, Bristol; bUniversityResearch Centre for Neuroendocrinology, University of Bristol, Erenchay Hospital, Bristol, UK Background: Traumatic Brain Injury (TBI) is the most com- mon cause of death and acquired disability in children and young adults in the developed world. The hippocampus is selectively vulnerable to TBI and hippocampal damage is believed to underlie the high incidence of memory problems following head injury. Following TBI the injured hippocam- pal neurons demonstrate, besides necrosis, cell loss by apop- toticmechanisms (Rink, Funget al. 1995;Yakovlev, Knoblachet al. 1997; Newcomb, Zhao et al. 1999) suggesting that anti- apoptotic treatments may improve outcome. However, much uncertainty exists concerning the relative roles of apoptosis versus necrosis in the production of hippocampal neuronal loss after TBI. Aim: The aim was to define the relative contributions of apoptosis and necrosis to neuronal loss in the hippocampus in an experimental head injury model. Method: Using the rat fluid percussion injury (FPI) model of TBI, characteristics of hippocampal neuronal loss were com- pared between head injured and control rat brains using (1) basic histology, (2) dUTP nick end labeling (TUNEL) histo- chemistry, and (3) immunocytochemical identification of caspase (CASP3/p89) activation. Results: The proportion of necrotic neurones in the hip- pocampal dentate hilar regions was significantly higher in animals undergoing FPI on both the ipsilateral (sham mean 10.1, SD 2.4%; FPI mean 26.3, SD 3.7%,p=0.0017) and con- tralateral sides (sham mean 9.5, SD 2.3%;FPI mean 18.8, SD 3.3%,p=0.0380). Very few apoptotic neurones were observed in haematoxylin and eosin sections in the hippocampal den- tate gyrus and cornu ammonis (CS) 3 & 2 regions following FPI. Strong TUNEL & cAsPYp89 immunopositivity was observed in the injured cortical and sub-cortical white mat- ter ipsilaterally, whereas other regions of the hippocampus demonstrated very few TUNEL, cAsP3 & p89 immunoposi- tive cells. Conclusion: Hippocampal neuronal death following experi- mental TBI occurs by predominantly non-apoptotic process- es. Anti-apoptotic therapies are hence unlikely to be helpful in preventing memory deficits secondary to hippocampal damage, although they may have a role in reducing cortical and subcortical damage following cerebral contusion. Session 2: Thursday, 12.00pm-1.00pm mere will be oralpresentations of Posters 1 to 10 1. Natural history of subdural haemorrhage in infants: imaging and pathological correlations W SOUlEe Radcliffe Injirmary, Oxford, UK Objective: To review the natural history of subdural haemor- rhage (SDH) in infants and to correlate published imaging data with pathological observations. SDH is common in the first year of life. Trauma (accidental and inflicted) is considered the most frequent cause of SDH. Recent MRI studies have shown an 8% incidence in asympto- matic infants after birth;’ these haemorrhages were all said to disappear by 4 weeks of age. Methods: The locations of SDH due to birth injury or ‘shak- ing’, as assessed from MRI data, were compared with the sites of draining veins thought to be damaged in the genesis of traumatic SDH. Four cases of SDH in children were available for pathological study and the evolution and distribution of SDH was documented. Results: The majority of birth related SDH is found in the pos- terior fossa and SDH said to be due to ‘shaking’is predomi- nantly in the posterior interhemispheric fissure or the posterior fossa.* These are not the sites of the major draining veins, bringing into question the mechanism of these haem- orrhage s . Microscopical study of infant SDH shows that they evolve by development of an extensive, thin, highly vascular membrane with evidence of repeated rebleeding. This membrane may persist for many months with a continuing capacityto rebleed. Conclusions: An extensive but thin, vascular subdural mem- brane will not be identified by routine MRI and yet may per- sist as a potential site for further bleeding. It may be unwise to assume that failure to demonstrate chronic SDH by MRI means that it has fully resolved. Further, the assumption that ‘shaking’causes the SDH associated with ‘shaken baby syn- drome’ is brought into question when the distribution of the SDH is considered. References 1. Whitby EH, Griffiths PD, Rutter S, Smith MF, SpriggA, Ohadike P: Davies NI: Rigby AS, Paley MN. (2004) Frequency and natural his- tory of subdural haemorrhages in babies and relation to obstetric factors. Lancet 383: 84-51. 2:Griffiths I! (2004) Can we diagnose that a baby has been shaken? &perpresented at tbe Brftfsb Paedfatrfc NeurologyAssociation Annual Conference, Shefield, January 23-25tb, 2004. 6 BPNA Abstracts 2005

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Page 1: Session 2: Thursday, 12.00pm-1.00pm

Hippocampal neuronal loss following experimental traumatic brain injury in the rat is predominantly due to necrosis rather than ap op tosis BA W E E D A , P GRUNDP, M HARBUZB, S LIGHTMAN’, PM SHARPLESA

aDepartments of Paediatric Neurology C Neurosurgery, Frenchay Hospital, Bristol; bUniversity Research Centre for Neuroendocrinology, University of Bristol, Erenchay Hospital, Bristol, UK

Background: Traumatic Brain Injury (TBI) is the most com- mon cause of death and acquired disability in children and young adults in the developed world. The hippocampus is selectively vulnerable to TBI and hippocampal damage is believed to underlie the high incidence of memory problems following head injury. Following TBI the injured hippocam- pal neurons demonstrate, besides necrosis, cell loss by apop- toticmechanisms (Rink, Funget al. 1995;Yakovlev, Knoblachet al. 1997; Newcomb, Zhao et al. 1999) suggesting that anti- apoptotic treatments may improve outcome. However, much uncertainty exists concerning the relative roles of apoptosis versus necrosis in the production of hippocampal neuronal loss after TBI. Aim: The aim was to define the relative contributions of apoptosis and necrosis to neuronal loss in the hippocampus in an experimental head injury model. Method: Using the rat fluid percussion injury (FPI) model of TBI, characteristics of hippocampal neuronal loss were com- pared between head injured and control rat brains using (1) basic histology, (2) dUTP nick end labeling (TUNEL) histo- chemistry, and (3) immunocytochemical identification of caspase (CASP3/p89) activation. Results: The proportion of necrotic neurones in the hip- pocampal dentate hilar regions was significantly higher in animals undergoing FPI on both the ipsilateral (sham mean 10.1, SD 2.4%; FPI mean 26.3, SD 3.7%,p=0.0017) and con- tralateral sides (sham mean 9.5, SD 2.3%; FPI mean 18.8, SD 3.3%,p=0.0380). Very few apoptotic neurones were observed in haematoxylin and eosin sections in the hippocampal den- tate gyrus and cornu ammonis (CS) 3 & 2 regions following FPI. Strong TUNEL & cAsPYp89 immunopositivity was observed in the injured cortical and sub-cortical white mat- ter ipsilaterally, whereas other regions of the hippocampus demonstrated very few TUNEL, cAsP3 & p89 immunoposi- tive cells. Conclusion: Hippocampal neuronal death following experi- mental TBI occurs by predominantly non-apoptotic process- es. Anti-apoptotic therapies are hence unlikely to be helpful in preventing memory deficits secondary to hippocampal damage, although they may have a role in reducing cortical and subcortical damage following cerebral contusion.

Session 2: Thursday, 12.00pm-1.00pm mere will be oralpresentations of Posters 1 to 10

1. Natural history of subdural haemorrhage in infants: imaging and pathological correlations W SOUlEe

Radcliffe Injirmary, Oxford, UK

Objective: To review the natural history of subdural haemor- rhage (SDH) in infants and to correlate published imaging data with pathological observations.

SDH is common in the first year of life. Trauma (accidental and inflicted) is considered the most frequent cause of SDH. Recent MRI studies have shown an 8% incidence in asympto- matic infants after birth;’ these haemorrhages were all said to disappear by 4 weeks of age. Methods: The locations of SDH due to birth injury or ‘shak- ing’, as assessed from MRI data, were compared with the sites of draining veins thought to be damaged in the genesis of traumatic SDH. Four cases of SDH in children were available for pathological study and the evolution and distribution of SDH was documented. Results: The majority of birth related SDH is found in the pos- terior fossa and SDH said to be due to ‘shaking’ is predomi- nantly in the posterior interhemispheric fissure or the posterior fossa.* These are not the sites of the major draining veins, bringing into question the mechanism of these haem- orrhage s .

Microscopical study of infant SDH shows that they evolve by development of an extensive, thin, highly vascular membrane with evidence of repeated rebleeding. This membrane may persist for many months with a continuing capacity to rebleed. Conclusions: An extensive but thin, vascular subdural mem- brane will not be identified by routine MRI and yet may per- sist as a potential site for further bleeding. It may be unwise to assume that failure to demonstrate chronic SDH by MRI means that it has fully resolved. Further, the assumption that ‘shaking’ causes the SDH associated with ‘shaken baby syn- drome’ is brought into question when the distribution of the SDH is considered.

References 1. Whitby EH, Griffiths PD, Rutter S, Smith MF, SpriggA, Ohadike P:

Davies NI: Rigby AS, Paley MN. (2004) Frequency and natural his- tory of subdural haemorrhages in babies and relation to obstetric factors. Lancet 383: 84-51.

2:Griffiths I! (2004) Can we diagnose that a baby has been shaken? &perpresented at tbe Brftfsb Paedfatrfc Neurology Association Annual Conference, Shefield, January 23-25tb, 2004.

6 BPNA Abstracts 2005

Page 2: Session 2: Thursday, 12.00pm-1.00pm

2. An analysis of first and second line agents for the treatment of convulsive status epilepticus in childhood RFM CHIN MRCPCH, BGR NEVILLE FRCP, C PECKHAM FRCP, H

BEDFORD PHD, A WADE PHD, RC scolr PHD MRCPCH FOR THE

Institute of Child Health, UCL Medical School, London

Objective: Although rectal diazepam is an appropriate pre- hospital treatment for convulsive status epilepticus (CSE), it is uncertain whether seizure termination inA&E is more like- ly with intravenous lorazepam than with rectal diazepam. It is also unclear whether seizure termination is more likely with phenytoin than paraldehyde when administered as a second line agent. From a prospective population-based study, we report on the safety and efficacy of rectal diazepam compared with intravenous lorazepam, and rectal paralde- hyde compared with intravenous phenytoin in the treatment of childhood CSE . Metbods: The methods for ascertainment of cases and data collection have been previously described.' In children with CSE not treated in the prehospital setting, seizure termina- tion and risk of respiratory depression were compared between those receiving different therapies. Differences are presented with confidence intervals which were estimated using StatXact (v4 .O. 1) . Results: Initial treatment with intravenous lorazepam was associated with a greater likelihood of seizure termination compared with those given rectal diazepam (16136 vs 6/49 respectively, 95% CI for difference 11.0-53.9%, p=0.005) without an increased risk of respiratory depression (7B6 vs 8/49, 95% CI for difference 16.7-27.3%, p=0.79). Second line treatment with intravenous phenytoin was associated with a greater likelihood of seizure termination compared to treatment with rectal paraldehyde (10/11 vs 9/22,95% CI for difference 12 .0-78.7%, p = 0.0 1). Conclusions: In A&E, intravenous lorazepam should be pre- ferred to rectal diazepam as first-line rescue therapy for chil- dren that have not received prehospital treatment. When first-line therapy has failed, intravenous phenytoin is more likely to be associated with seizure termination than rectal paraldehyde. Therefore, paraldehyde should not be given as rescue therapy in children with intravenous access.

NLSTEPSS COLLABORATIVE GROUP

Reference 1. Chinet al. (2004) The epidemiology ofconvulsive status epilepticus in childhood. DevMedCbildNeuml48 (Suppl. 98): 20. (Abstract)

3. A national view of neurodegenerative disease: findings of the PIND study after more than seven years of surveillance CM VERITY F R C P C H ~ , L STELLITANO~, AM WINSTONE R G N / R M ~ , A

NICOLL F R C P C H ~ , RG W I L L FRCPC

aAddenbrookes Hospital, Cambridge; bCommunicable Disease Surveillance Centre, Colindale; CNational CJD Surveillance Unit, Edinburgh, UK

Objective: To report on children with diagnosed neurode- generative disease in the national study of progressive intel- lectual and neurological deterioration (PIND) .

Methods: Surveillance for childhood variant Creutzfeldt-Jakob disease (VCJD) commenced in May 1997 via the PIND Study. Children with PIND are identified using the British Paediatric Surveillance Unit monthly surveillance card. Clinical informa- tion about notified cases is obtained by telephone question- naire or hospital visit. The anonymized cases are classified by an expert group. Results: By July 2004, UK paediatricians had notified 989 children who met the criteria for PIND. Among them were six with probable or definite KJD. There were 734 children with other confirmed diagnoses and in these children there were 114 known neurodegenerative conditions, which illus- trates the complexity of classifying children with PIND.

The six most common diagnostic groups were: neuronal ceroid lipofuscinoses (NCL; n =85), mucopolysaccharidoses (MPS; n=71), mitochondrial cytopathies (n=71), gangliosi- doses (n=68), adrenoleukodystrophy (n=44), and Rett syn- drome (n=41).

Within the NCL group the distribution was: late infantile (n=36), juvenile (n=29), infantile (n=15), andvariant late infantile (n=5). The most common MPS diagnosis was type IIIa (Sanfilippo). The most common mitochondrial cytopathies were: Leigh syndrome (n= 13), cytochrome oxidase deficien- cy (n=9), pyruvate dehydrogenase deficiency (n=5), NARP (n= 5) , and complex Ndeficiency (n =3). The gangliosidoses consisted ofGm2 (n=51) and Gml (n= 17).

As expected the distribution of disorders varied according to age. Conclusions: Paediatricians are asked to report all children with PIND, even if they have a known diagnosis. However we do not have full ascertainment of cases. For instance, not all children with a particular diagnosis (eg Rett syndrome) fullill the criteria for PIND. We cannot use these data to calculate incidence figures. Nevertheless, they give a useful guide to the differential diagnosis ofchildren with PIND at different ages.

Acknowledgments: Many thanks to all who report cases to the PIND study and to members of the Expert Group.

4. Clinical guidelines for the diagnosis and management of childhood stroke VIJEYA GANESAN O N BEHALF OF THE PAEDIATRlC STROKE WORKING

GROUP

Objective: To highlight recently developed evidence-based guidelines for the diagnosis, investigation, and management of childhood arterial ischaemic stroke beyond the neonatal period. Methods: These guidelines were developed by a multidisci- plinary group in accordance with Appraisal of Guidelines Research and Evaluation (AGREE) principles and in collabo- ration with the Royal College of Physicians (RCP). They have been subsequently appraised and approved by the RCPCH Quality of Practice Committee and have been circulated for peer review. The views of affected children and their parents were sought in a workshop. Evidence was evaluated using the Scottish Intercollegiate Guidelines Network (SIGN) scheme in order to formulate recommendations. Where research evi- dence relating to childhood stroke was unavailable, recom- mendations were formulated by extrapolation from other conditions, from reports and consensus statements based on

Posters witb OralPresentations 7

Page 3: Session 2: Thursday, 12.00pm-1.00pm

clinical experience of the working party Results: Key recommendations relevant to paediatric neurol- ogists are (1) all affected children should be referred to or discussed with a paediatric neurologist (GPP: good practice point*). Acute investigations: all affected children should have (2) cross sectional brain imagingwithin 48 hours (GPP) (3) brain MRI (B) (4) cerebral arterial imaging from aortic arch to circle of Willis (C) (4) transthoracic echocardiogram within 48 hours of presentation (GPP) (5) prothrombotic evaluation (C). Acute medical management: (1) exchange transfusion for sickle cell disease (GPP) (2) aspirin if there is no haemorrhage (GPP) (3) consider anticoagulation for dis- section (GPP) and cerebral venous thrombosis (C). Secondary prevention: (1) aspirin for cerebral arteriopathy (GPP) (2) blood transfusion for sickle cell disease (C) (3) anticoagula- tion for dissection, cardiac source of embolism, cerebral venous thrombosis, recurrence on aspirin (all GPP) (4) con- sider revascularisation in moyamoya (D). Recommendations regarding both acute and longer term rehabilitation may also be relevant to management of children with other acquired neurological disorders. Conclusions: The full document is available through the RCP Publications unit (020 7935 1174x358) and http:/M.rcplon- don.ac.uk/pubshooktmke/.

*Letters in brackets relate to strength of the recommendation using the SIGN scheme. Recommendations are graded A-D, and good practice point, with 'A' being the strongest grade of recommendation.

5. Succinate improves clinical symptoms and whole cell oxidation in a patient with complex-1 deficiency E WASSMER, N MACKAY, B ROBINSON, I TEIN

7be Hospital for Sick Children, University of Toronto, C a d

Introduction: Succinate has been used as an adjuvant treat- ment in complex-1 deficiency (C-1-D). We present a boywith C-1-D, who had a dramatic clinical response to succinate. Objective: The aim was to study the effect of succinate on res- piratory chain function in fibroblasts. We hypothesized that in C-1-D the underlying mechanisms for the clinical response to succinate may be due to (1) a succinate transporter defect, (2) a succinate utilization disorder, or (3) that succinate bypasses the complex-1 defect. Methods: As a marker for respiratory chain function we stud- ied whole cell oxidation (WCO) in cultured fibroblasts of our patient with C-1-D and in normal controls. Succinate was added to tissue culture medium for 1 hour. We compared WCO with and without succinate.

To study succinate utilization we compared succinate oxida- tioninthe fibroblastsofthe patientwithc-1-D tothat ofcontrols.

Succinate transport was studied by measuring succinate uptake across the cell membrane of fibroblasts in the patient with C-1-D and in controls. Results: WCO of the patient with C-1-D was reduced at 0.6 (normal 2-4 nm/mg/hr) and improved in the presence of suc- cinate to 3.9. There was no change in the controls (2.9-3.9).

There was no difference in succinate oxidation between the patient with C-1-D and in six controls. Succinate oxida- tion ranged from 15-34 nm/mg/hr.

There was no difference in succinate uptake at 5 and 15

min between the patient with C-1-D and 5 controls. Conclusions: Succinate markedly improved clinical symp toms and normalized WCO in the fibroblasts of the patient with C-1-D. Succinate utilization and transport across the cell membrane appeared to be normal. We hypothesize that succinate bypasses the complex-1 defect and stimulates the Krebs cycle thereby generating ATI! We further suggest that this patient may have a defect in succinate transport across the mitochondria1 membrane.

6. Atypical presentation of ataxia-oculomotor apraxia type 1 ( AOAl) A SHAHWAN MRCPCH", A M TAYLOR', T NEST0RA, MD KING FRCPl

F R C P C H ~

aDepartment of Paediatric Neurology, The Children's University Hospital, Dublin, Ireland; bInstitute for Cancer Studies, The University of Birmingham, Birmingham, UK

Objective: To describe an atypical presentation of ataxia-ocu- lomotor apraxia type 1 (AOA1). Design: Case report. Patient: An Irish, 10-year-old male of non-consanguineous parents with unremarkable family and past medical history presented at 3.5 years with ataxia, poor oromotor function, and dysarthria.

Investigations included an extensive biochemical analysis of blood, CSF, and urine, genetic testingfor Friedreich's atax- ia and ataxia telangectasia, muscle biopsy, EEG, EMG, and brain MRI, which were all normal.

The illness was static from presentation to 8 years but became progressive thereafter. He was a full-time wheelchair user with worsening symptoms including bouts of tonic up- gaze, grimacing, and episodes of incontinence, marked atax- ia, axial hypotonia, muscle wasting, abnormal vertical saccades, brisk deep tendon reflexes, and abnormal choreic move- ments. There was no cognitive decline.

Investigations at 8 years, showed cerebellar atrophy on brain MRI, mild impairment of sural and ulnar sensory nerve conduction. Aprataxin protein was completely absent from lymphocytes. Furthermore, the patient was homozygous for the G837A (W279X) mutation in the aprataxin (-1) gene. Discussion: Ataxia-oculomotor apraxia 1 (AOA1) is a rare form of autosomal recessive ataxia. The manifestations of AOAl are: early onset ataxia, choreic movements, oculomotor apraxia (OMA), marked peripheral neuropathy with cognitive decline in most patients, cerebellar atrophy, hypoalbumine- mia and hypercholesterolemia.

Our patient is atypical in his presentation in that he did not have choreic movements or OMA at presentation, had very mild evidence of neuropathy, absence of cognitive decline, and absence of early MRI changes. Conclusion: AOAl has been rarely reported in the paediatric literature. Diagnosis of AOAl should be considered in early onset cerebellar ataxia, even in absence of marked neuropa- thy, OMA, choreic movements, or cerebellar atrophy on MRI at presentation.

References 1. Le Ber I, Moreira MC, Rivaud-Pechoux Set al. (2003) Cerebellar

ataxiawith oculomotor apraxia type 1: clinical and genetic stud- ies. Brain 126 2761-2772.

8 BPNA Abstracts 2005

Page 4: Session 2: Thursday, 12.00pm-1.00pm

7. Central nervous system tumours in childhood, in England and Wales from 1971- 1990. An epidemiological analysis of mortality experience NlV CORDEIRO"'R, L WOODS", B RACHEIH

aFraser of Allander Neurosciences Unit, RHSC-Yorkhill, Glasgow; bLondon School of Hygiene and nopica1 Medicine, London, UK

Objective: To explore the additional role of geographical and social variables in explaining mortality in children with pri- mary tumours of the central nervous system. Methods: Cox regression, using a dataset' of 4404 children with central nervous system tumours, diagnosed in England and Wales between 1971 and 1990. Results: After adjustment for age at diagnosis, the effect of cancer registry remained significant in the model (likelihood ratio test excluding cancer registryp=0.0012), in addition to significant effects of tumour morphology and site. A protec- tive effect over each 5 year time period since 1971-75 was also noted.

Current NHS region (as organised in 1998), was not sig- nificant, nor was the scale for social deprivation (Carstairs deprivation index), although the effect of original NHS region (as organized in 1990) remained significant. Conclusion: The model is in keeping with patterns of risk associated with site and morphology The effect for cancer registry remains significant where adjustment for age at diag- nosis is made in the timescale of the model. The effect oforig- inal NHS region is difficult to separate from this, as the organization of the NHS and cancer registration has changed substantially since 1990.

The possibility of an effect due to differential recording by independent cancer registries cannot be excluded. It rein- forces the need for the ongoing maintenance of registers as a vital part of the information infrastructure available to us in planning for the health needs of children.

References 1. Coleman ME Babb E Damiecki I! Grosclaude P: Honjo S, Jones J,

Knerer G , Pitard A, Quinn M, Sloggett A, De Stavola 6. (1999) Chapter 54: Brain and Spinal Cord: Children. In: Cancer Survival Pends in England and Wales, 1971-1995: Deprivation and NHS Region. Studies in Medical and Population Subjects No . 61. London: The Stationery Office.

8. Polymicrogyria and 22qll deletion syndrome: a window to understanding a common cortical malformation? CJ HILL", N KATZ", M SPLITT',, SN MOHAMMED', R F M A S S E Y ~ ,

N STOODLEY', R GIJERRINI' , RJ LEVENTER R J ~ , I n PILP aInstitute of Medical Genetics, IJniversity Hospital of Wales, Card# VK; 'Department of Paediatrics, Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Australia; cSouth East Barnes Regional Genetics Service, Guy's Hospital, London; dDepartment of Paediatrics, Hull Royal Infirmaty, Hull; eDepartment of Neurology, Guy's Hospital, London, UK; fistituto Neurologico, C Besta, ItaIy; Whildren S Hospital at Westmead, Sydney,

WE, KJ COLLINS', T GRANATA", D GILL", TISCHKOWI'I'Z'',

Australia; 'Department of Clinical Genetics Unit, Institute of Child Health, London; 'Department of Neuroradiology, Frencbay Hospital, Bristol, UK; JDivision of Child Neurology and Psycbiatry, University of Pisa G IRCCS Fondazione Stella Maris, Calambrone Pisa, Italy; 'Department of Neurology, Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Australia

Background: The association of polymicrogyria (PMG) and 22ql l deletion syndrome (22qllDS) is being increasingly recognised, and so far 11 cases have been reported in the lit- erature. PMG is a heterogeneous cortical malformation, and a 22ql l deletion appears to be the most common cytogenet- ic cause of this disorder, thus providing the possibility of new insights into aetiology of PMG. The 22ql l DS is usually char- acterized by congenital heart disease, cleft palate, hypocal- caemia, and immune dysfunction. Methods: We reviewed the clinical and cranial MRI findings of a further 10 patients with PMG and a 22ql l deletion, and com- pared these with the 11 patients reported in the literature. Results: Half of all patients had unilateral PMG, while the oth- ers had bilateral PMG. The perisylvian region was usually affected. Interestingly, in unilateral cases the PMG was almost always right sided. Congenital heart disease was reported in 12/21 patients, but there was no apparent correlation with its presence or the severity of the PMG. Discussion: The reason for the greater than expected occur- rence of PMG in the 22ql IDS is unknown. The genes within the common 3 Mb 22ql l deletion have been sequenced, but no obvious candidates for PMG have been proposed. Furthermore, so far there have been no reports of cortical malformations in the 22ql l mouse models. PMG may result as a secondary consequence of abnormal extracerebral or intracerebral vasculature, resulting in hypoperfusion to the developing cerebral cortex. Anomalous internal carotid arteries have been reported in 22ql IDS, and might suggest wider vascular pathology.

9. Mutation screening of the s&ne/threonine kinase 7 gene in a UK Rett syndrome population JC EVANS P H D ~ , H L ARCHER MB BCH", J GECZ PHD",

J CHRISTODOULOU MD' , A W.RR OBE FRCP RFRCP AND CH",

R BUTLER BSC", S D W H A l L E Y PHD", A CLARKE MD FRCPCH"

aInstitute of Medical Genetics, Cardiff University, CardifJf ff& bWomen's and Children's Hospital, Adelaide, Australia; fChildren's Hospital at Westmead, Sydney, Australia; dGlasgow University Department of Psychological Medicine, Gartnavel Royal Hospital, Glasgow, UK

Objective: The STK9 gene (also known as CDKL5) has recent- ly been implicated in infantile spasms (West syndrome) in two females with X;autosome translocations. More recently, we described S7K9 mutations in two families with a Rett syn- drome (RTT)-like phenotype who had tested negative for mutations in the MECP2 gene. We are currently screening a population with a RTT or RTT-like phenotype, without an MECP2 mutation, for mutations in STK9. Methods: Patients were recruited from those referred to

Posters witb OralPresentations 9

Page 5: Session 2: Thursday, 12.00pm-1.00pm

Cardiff for MECP2 mutation analysis, the British Isles Rett Survey, and through direct RTT family contacts. The pheno- type was initially assessed by clinical questionnaire. So far, the coding region of STK9 has been screened by DHPLC and direct sequencing in 64 patients with suspected R’IT who have tested negative forMECP2 mutations. Those with muta- tions in S7K9 were clinically assessed by HA. Results: We identified SX9 mutations in two females with the early onset seizure variant of RTT. STK9 mutations account for the early onset seizure variant of RTT in 3 / 1 4 patients in our population. There are eight patients from both the literature and our own experience: seven females and one male, from 6 families with S77Z9 mutations. Of these: six patients developed epileptic seizures in the first 3 months, five developed a severe mixed seizure disorder, and five had hypsarrhythmia on EEG. Conclusions: This study reinforces the observation that the S77Z9 phenotype overlaps with RTT. However RTT patients with an MECP2 mutation rarely present with epileptic seizures in the first year of life. Mutation screening of SX9 is indicated in patients with severe epilepsy with onset in the first year of life and a RTT-like phenotype. Mutation screen- ing in selected patients is ongoing.

Ackmwledgements: The families and clinicians, particularly DrJardine, and The Health Foundation, a health care charity, for funding this work. Financial support for the Australian research was provided by the Rett Syndrome Association of NSVC: the Rett Syndrome Australian Research Fund, the National Health and Medical Research Council ofAustralia, and the Country Women’s Association of NSW

10. Hypoglycemia and combined hypoxia- hypoglycemia in term newborns: comparison of neuroimaging patterns SN BASHEER MB MRCPP, EH ROLAND MD F R C P C ~ , KA POSHTT MD

F R C P C ~ , M SARGENT MD F R C P C ~ , A HILL M D PHD F R C P C ~

Divisions of aNeurology and bNeuroradiology, Department of Pediatrics, British Columbia’s Children ’s Hospital, University of British Columbia, Vancouvet; Canada

Background: Hypoglycemia may result in brain injury in the newborn infant and there may be a synergistic effect with hypoxic-ischemic insult (HII). However, there is limited information concerning the topography and evolution of cerebral injury seen on neuroimaging following transient neonatal hypoglycemia (TNH) . Objectives: This study compares the abnormalities observed on early and follow-up neuroimaging in term newborns with: (1) symptomatic TNH alone and (2) TNH with con- comitant HII. Methods: The study population comprised 25 term neonates admitted to a tertiary centre between 1986-2004 who had symptomatic TNH alone or in combination with HII. Abnormalities on early neonatal CT and follow-up MRI (> 2 years) were reviewed. Results: Nine infants had symptomatic TNH alone; 16 had combined TNH and HII. All had CT in the neonatal period which demonstrated decreased attenuation in cortex and

white matter, predominantly in parieto-occipital regions. Hypodensity in thalamihasal ganglia occurred in only two infants (22%) with TNH alone who also had the most severe cortical injury. In contrast, 12 newborns with concomitant TNH and HI1 (75%) had thalamichasal ganglia abnormalities ( p C 0 . 0 2 ) . In seven infants with TNH alone, there were signal abnormalities in parieto-occipital cortexhvhite matter and normal thalami on follow-up MRI. In nine infants with both TNH and HII, late MRI demonstrated marked, diffuse signal abnormalities or cystic encephalomalacia in conexiwhite matter in addition to persistent, albeit less severe, altered sig nal in the thalami in eight infants ( p < O . O O l ) . Conclusions: These observations suggest there is a distinct pattern of selective neuronal vulnerability to hypoglycemic injury involving the parieto-occipital cortexhhite matter in the term newborn. Despite the high rate of metabolic activity in thalamihasal ganglia in the newborn brain, these regions appear to be relatively resistant to hypoglycemic injury unless there is superimposed HII.

11. Epilepsy: how much do primary school children really understand? GL W H I L E S ~ , C P WHITE^ aUniversity of Wales College of Medicine; ‘Department of Child Health, Morriston, SuJansea, Wales, IJK

Objective: The aim of this study was to establish the level of knowledge and understanding that five- to eleven-year-old children with epilepsy have about their condition. Methods: Convenience sampling was used to select children from paediatric epilepsy clinics over a two month period. ’Rventy-six children were approached at the clinics and twen- ty-one children were included in the study.

A questionnaire was used to assess four areas of knowl- edge as well as the feelings of the children. Results: One third of the children had little or no knowledge about the nature of their condition. None of the children attempted to give a biological explanation of their condition. None of the children had known anything about epilepsy before they themselves were diagnosed. Over one third of the children had not disclosed their diagnosis to friends although, when questioned, over half of the children wished that their friends knew more about epilepsy. Children with epilepsy are keen to reassure other children with the condi- tion that it should not be a cause for concern. However, the majority of children (86%) expressed either neutral or nega- tive emotions regarding their epilepsy. One third of the chil- dren would ask their doctor if they wished to find out more about their condition, over half would ask a parentm and six of the children would ask a teacher. Conclusions: There appears to be a poverty of knowledge among children with epilepsy. The results of the question- naire suggest that children are reluctant to disclose their diagnosis to their peers. However, this may reflect the fact that they themselves are unable to explain the condition due to their own lack of understanding. The results suggest that patient education needs to be increased and the children need to be made aware of the resources available to them.

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12. Intravenous immunoglobulin therapy in childhood narcolepsy SM ZUBERI" FRCP, E M I G N O T ~ MD, c F E R R I E ~ FRCP, L L I N ~ MD,

aRzediatrlc Sleep Service, Eraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, UK bStanford Center for Narcolepsy, Stanford University Medical School, Pa10 Alto, CA, USA; Cyorkshire Regional hediatric Neurology Service, lBe General Infirmary at Leeds, Leeds, UK

Objective: Recent studies suggest that the pathology underly- ing most human narcolepsy is autoimmune in nature with damage to hypocretin secreting neurons in the hypothalamus. k c e n d r e a d reported a case of recent onset narcolepsy responsive to intravenous immunoglobulin (MG) therapy. We describe our experience of M G therapy in four children. Methods: An 8-year-old male and two 7-year-old females with severe recent onset symptoms and one 15-year-old female with chronic narcolepsy were selected for M G treatment. Pretreatment investigations included magnetic resonance imaging (MRI) ofthe brain with gadolinium enhancement and fine cuts through the hypothalamus and cerebrospinal fluid (CSF) hypocretin assay; 2gkg of M G was given over two days. Wenty-four hour diaries recorded sleep status hourly for sev- eral weeks pre- and posttreatment. Results: AU patients had normal brain MRI. Three CSF samples had undetectable hypocretin. In three recent onset cases, sleep diaries and parental and child interview confirmed a sig- nificant treatment response following MG. This began within 1 week but took 4 weeks before maximum improvement. Excessive daytime sleepiness improved with children main- taining wakefulness through the school day. Cataplexy did not reduce significantly Frightening hypnagogic hallucinations were abolished in two children. Repeat CSF hypocretin remained undetectable when measured in one child. Six to eight weeks following M G treatment, symptoms of narcolepsy began to increase. Repeat doses have been given with positive effect but not as dramatic as the first dose. The child with chronic narcolepsy showed no improvement in symptoms. Conclusion: M G can be an effective therapy for recent onset narcolepsy in childhood. Its efficacy supports an autoimmune aetiology. Early diagnosis in childhood may allow disease modifying therapy for this disabling, lifelong neurological sleep disorder.

References 1. Lecendreaux M, Maret S, Bassetti C, Mouren MC, Tafti M. (2003)

I MCARTHUR" BSC

Clinical efficacy of highdose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy. JSfeepRes 12: 347-348.

13. Efficacy of the Oxford Modified Ketogenic Diet for intractable epilepsy in children T NAKAZAWA~J:, J LAMBERT~, z WIWALLA~

yohn Radcliffe Hospital, Oxj-ord; bRark Hospital for Children, Oxj-ord, UK CJuntendo University School of Medicine, Tokyo, Japan

Objective: To look at the efficacy and acceptability of the Oxford Modified Ketogenic Diet (OmKdiet) in children with intractable epilepsy.

Methods: Medical records were retrospectively reviewed of al l children attending the Park Hospital epilepsy service who were offered the OmKdiet between 1992 and 2001. Comparison was made of seizure frequency at 1 year between those who continued the diet for more than 3 months (group A), came off in less than 3 months (group B), or refused the diet (group C). Results: Forty-eight children were offered the diet (group A n= 18; group B n= 14; group C n= 16). Age at seizure onset, start of the diet, and epilepsy syndrome distribution were similar in the three groups: mean seizure onset 32 months (<5 years in 40 children). Epilepsy syndromes included Lennox Gastaut Syndrome (n= 14) and multifocal lesional or cryptogenic epilepsy (n= 13); 41 children had daily seizures, and 31 were on 2-4 anticonvulsants. Duration on diet for group A ranged from 4 months to 6 years (median ly).

At 1 year, 10/18 (55.5%) in group A had responded with > 50% seizure reduction (6/10 >90%), and included 5/7 with the Lennox Gastaut syndrome while 4 out of 10 children had abnormal neuroimaging. Anticonvulsant reduction was pos- sible in four children. N o child in group B and only 2/16 in group C responded to anticonvulsant manipulation.

In group B, 6/14 stopped the diet because of side effects (vomiting, diarrhoea, abdominal pain, worsening seizures). The others withdrew because compliance was difficult. Conclusions: Of children with severe intractable epilepsy 55.5% showed sustained seizure improvement on the OmKdiet compared with 6.6% in control groups with a similar clinical profile, with no serious adverse events. However, the diet can be daunting for some children and families with a 25% drop- off rate and 1/3 refusing the diet.

14. Auditing outcomes of new referrals to a paediatric epilepsy clinic in a district general hospital R I FAWCETT", CR SHARP, M ALWAIDH~ MBCHB MRCP MRCPCH

aUniversity of Liverpool; bWhiston Hospital, Prescot, Liverpool, UK

Objective: The establishment of a new paediatric epilepsy clin- ic run by a general consultant paediatrician in a district general hospital (DGH) created the need to audit the outcomes of the clinic. The aim was to calculate the number of new referrals and from that, deduce the percentage of those given the final diagnosis of epilepsy, indicating that they had been correctly referred. As there is no previous similar study, a standard of 50% of correctly diagnosed referrals was deemed acceptable. Method: Outcomes of referral to a paediatric epilepsy clinic were studied using a retrospective audit for the previous 30 months at the DGH. AU patients who had been newly referred within the designated time period were selected using the health trust computer record system. Results: The total number of patients selected for the study was 99. After the application of exclusion criteria this was reduced to 67. Patients were excluded because: (1) they already had an established diagnosis by a paediatric neurologist (n=23); (2) they had unobtainable notes or on-going diagnosis (n=5); or (3) due to continuous non-attendance (n=4). Our audit revealed that an overwhelming majority of the referrals came from GPs (52 patients [78%]), with an additional 12 patients (18% of referrals) coming from other consultant clinics, and

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only a minority from Accident and Emergency (3 patients [4%]). It also showed an over referral of non-epileptic children to the specialist clinic with only 23 patients (34%) being given a final diagnosis of epilepsy (standard 50%). Ten patients (15%) had a final diagnosis of syncope; 6 patients (9%) were diag- nosed with febrile convulsions, and 28 patients (42%) had a mixture of 'other' final diagnoses. Conclusion: Less than 50% of referrals were diagnosed with epilepsy. This indicates the need for guidelines and support material for GPs due to the distressing implications that an epilepsy referral has on the child and family.

15. Childhood narcolepsy: a quantitative study of psychosocial and intellectual outcomes L D O R R I S " ~ ~ DCLINPSYCH, c MOFFAT~ BSC, I MCARTHLIR" BSC,

akediatric Sleep Service, Baser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow; bDepartment of Psycbological Medicine, University of Glasgow, Glasgow, UK

Objective: This study is the first to use standardized and vali- dated empirical measures to describe the neuropsychologi- cal and psychosocial profiles of children with narcolepsy. Methods: The participants were seven children aged between seven and 16 years (mean age lOy, SD 3y), diagnosed and assessed within a multi-disciplinary regional paediatric neu- rosciences unit. The children were assessed using the Wechsler Intelligence Scale for Children411 (WISC-III) and the Achen- bach Child Behaviour Checklist (CBCL). Results: Despite difficulties in maintainingvigilance and wake- fulness, the group as a whole had IQs in the average range (mean 100, SD 11, range 84-116). Significant individual vari- ability was found between the Verbal IQ and Performance IQ scales, with 4/7 of the participants showing > 1SD difference between these factors. The group obtained a mean CBCL Total (7) score of 66 (SD lo), falling within the clinically significant range (T-critical value 64; 92nd centile). However, the princi- pal finding within this group concerned the high level of inter- nalizing symptoms (T score=65, SD 8; 93rd centile) with clinically significant levels in: Withdrawing (Tscore 65, SD 9; 93rd centile) and Somatic (Tscore 66, SD 8; 94th centile) com- ponents and with levels of AnxietyDepression approaching significance (T score 58, SD 7; 81st centile). The group showed levels of externalizing behaviours falling within the normal range (Tscore 56, SD 8; 72nd centile). Highly signifi- cant difficulties were also found in Thought Problems and Attention Problems subscales (Tscores 71, SD 13; >98th cen- tile), whilst the Social Problems subscale score also fell within the borderline clinical range (Tscore 62, SD 12; 88th centile). The Competence subscales fell within the borderline clinical rangewithaTscoreof33 (Tcriticalvalue <30; B98thcentile). Conclusions: These findings suggest first, that children with narcolepsy have normal cognitive abilities. Second, that they adopt an internalizing coping style leading to difficulties in acknowledging and communicating distressinn g physical and psychological symptoms to parents and others. Several narcolepsy-specific concerns resulted in social withdrawal and feelings of isolation.

SM ZUBERI" FRCP

16. Identification of a second locus for Aicardi- Goutihres syndrome LORNA I HICHET" MRCPCH, M ALI" PHD, AP JACKSON".B P H D ,

P LEBON' P H D , MS VAN IXR KNAAP" P H D , MD KING^ FRCP,

D LAC OM BE^ MD, u TACKE" MD, YJ CROW^^^ PHI)

aMolecular Medicine Unit, University of Leeds, St James's University Hospital, Leeds; bDepartment of Clinical Genetics, University of Leeds, St James's University Hospital, Leeds, UK; cService de Virologie, Hbpital Saint Vincent de Paul, Paris, France; dFree IJniversity Medical Center, Amsterdam, the Netherlands; rThe Children's Hospital, Dublin, Ireland; fGenetique Medicale-Hdpital Pellegrin-Enfants, Bordeaux, France; Wniversity of Freiburg, Freiburg, Germany

Objectives: Aicardi-Goutieres syndrome (AGS) is an auto- soma1 recessive, early-onset progressive encephalopathy bear- ing marked similarity to the sequelae of a congenital viral infection. The disorder is characterized by intracranial calcifica- tion, leukodystrophy, cerebrospinal fluid (CSF) lymphocyto- sis, and raised levels of interferon alpha in the CSF and serum. We have previously localized the AGSl gene to chromosome 3p21 and demonstrated locus heterogeneity. As part of our efforts to clone the genes responsible for AGS and to clarify the relationship of AGS with other disorders of intracranial calcifi- cation, we have sought to identify further AGS gene loci. Methods: We performed a genome-wide scan using 13 families incompatible with linkage to the AGSl critical interval. We sub- sequently undertook high density genotyping and heterogene- ity LOD score analysis using these data. Results: We have identified a second AGS locus at 13q14 - 13q21. Seven families, comprising 15 affected children, were compatible with linkage to this region. Our results indicate that further AGS loci exist. Conclusion: A second AGS-causing gene resides on chromo- some 13q. There appears to be no phenotypic difference between patients mapping to AGSI, AGS2, or as yet unidenti- fied loci. At the present time, locus heterogeneity precludes the possibility of prenatal diagnosis.

Acknowledgement We are grateful to all collaborating clinicians and are keen to receive further DNA samples.

17. The UK infantile spasms study comparing vigabatrin with predniiolone or tettracokctidk in a randomized controlled trial: developmental outcomes at age 14 months a"3F, SJ EDWARDS", E IIANCOCK", AL J O i l N S O N B , CR KENNEDY',

RW NEWTON^, FJK O'CAI .LAGHAN~,~ CM V E R I W , J P OSBORNE"

aRoyal United Hospital, Bath NHS Dust and School for Health, University of Bath; bMRC Biostatistics Unit, University of Cambridge Institute of Public Health, Cambrtkdge; ckediatrtc Neurology and Child Health, University of Southampton, Southampton; dDepartment of kediatric Neurology, Royal Manchester Children's Hospital, Manchester; eDepartment of Paediatrics, Addenbrooke's Hospital, Cambridge; fDepartment of kediatric Neurology, Frenchay Hospital and the Bristol Royal Hospital for Children, Bristol, UK

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Objective: By an intention to treat analysis, it was found that primary clinical response (absence of spasms on study days 13 and 14) was significantly more likelywith hormonal treatments (prednisolone or tetracosactide depot) than with vigabatrin. Our objective was to investigate whether these treatments were associated with differences in neurodevelopment. Methods: We randomly allocated treatment to 107 infants aged between 60 days and 1 year, stratlfying by sex, age categories, and a composite of known underlying aetiologies and develop mental delay preceding onset of spasms. Minimum doses were: vigabatrin 1OOmg'kg per day, oral prednisolone 40mg per day, or intramuscular tetracosactide depot 0.5mg (40iu) alternate days. Vineland Adaptive Behaviour scales were adm- inistered by telephone at 14 months of age. Results: There was no statistically significant difference in mean Vineland Composite scores comparing hormonal treat- ments against vigabatrin (mean [SD] 78.4 (16.6) vs 77.5 [ 1.81; F1,98=0.09, p=0.76); nor comparing prednisolone against tetracosactide (78.0 [ 15.81 vs 78.8 [ 17.81; F1,50=0.04, p=0.84). Ininfantswith no identifiedunderlyingcause, there was a statistically non-significant trend towards higher scores in those allocated hormonal treatments (mean [SD] 87.8 [ 17.11 vs 78.9 [ 14.31; two-sample t-test t=1.89,p=0.07; rank- sum test r=1.81, p=O.O7). Vineland Composite scores were significantly higher in primary clinical responders (mean [SD] 80.8 [14.8]vs72.7 [13.4];t=2.68,p=0.009) andininfantswith no identified underlying cause (83.7 [16.3] vs 73.3 [11.4]; t=3.70p<0.001). Conclusion: It is not surprising to find that neurodevelopment was better in infants with no identified underlying cause, and in infants with early clinical responses to treatment. Primary clinical response was more common with hormonal treat- ments, but hormonal treatments were not independently asso- ciated with better neurodevelopment overall. However, in infants with no identified underlying cause, in whom we might expect neurodevelopment to be more readily modified by treatment, there was a trend towards better outcomes with hormonal treatment that merits further investigation.

18. Value of polymerase chain reaction to detect viruses in patients with suspected central nervous system infection: a study of 787 cerebrospinal fluid samples NWS D A V I E S ~ MRCP, LJ BROWN" MSC, P M U I R ~ PHD MRCPATH,

R ROBINSON~J' FRCP

aGuy's, Kings, and St 7%omas' School of Medicine; &Guy's & St Thomas' NHS Foundation M t , London; =Health Protection Agency, Bristol; dEvelina Children's Hospital, London, UK

Background: In the UK, children with suspected central ner- vous system (CNS) viral infections are routinely investigated with polymerase chain reaction (PCR) to detect a virus in their cerebrospinal fluid (CSF). However, there is limited data to assist the use or interpretation of the results ofthese assays. Objectives: To ascertain the predictive value of detection or fail- ure to detect viral nucleic acid sequences in CSF and to identify factors that are associated with a positive PCR result. Methods: Over a 4-year period, CSF samples were tested for human herpes viruses types 1-6, Jacob Creutzfeld virus,

enteroviruses, and toxoplasma gondii. Details relating to the clinical episodes were obtained retrospectively. The likeli- hood of CNS infection in each episode was classified as likely, possible, or unlikely. Clinical findings were related to the PCR result using single, variable, and logistic regression analysis. Results: Seven hundred and eighty-seven samples from 735 patients were tested of which 97 (12%) were PCR positive for one or more viruses. One hundred and nine (15%) patients were infants and 189 (26%) aged between 1 and 16 years. Thirty per cent of episodes categorized as likely to be CNS viral infections were PCR positive compared with 5% of episodes categorized as unlikely. The most frequent positive findings were Epstein-Barr virus (EBV), enteroviruses and herpes sim- plex virus (HSV). Enteroviruses and HSV were found predomi- nantly in the likely CNS viral infection group, whereas EBVwas found mainly in the unlikely group. Positive PCR results were more likely when time between symptom onset and lumbar puncture was between 3 and 14 days, and when the CSF white cell count was abnormal. However, normal CSF did not exclude a viral infection. CSFs from three infants with pre- sumed bacterial infections showed an enterovirus, EBY and human herpes viruses type 6 respectively. Conclusions: The diagnostic value of PCR can be optimized through the use of sensitive assays to detect a range of pathogens in appropriately timed CSF samples. PCR results should be interpreted cautiously when symptoms cannot read- ily be attributed to the virus detected.

19. Simultaneous EEG and fMRJ in the pre- surgical evaluation of children with focal extratemporal epilepsy CJ R I N E Y ~ ~ ~ FRACP, D FLANAGAN" PHD, JH CROSS^.^ FRCP PHD,

A CONNELLY~ BSC (HONS) PHD

ahstitUte of Child Health (UCL), London; bGreat Ormond Street Hospital for Children NHS P u t , London, UK

Objective: Improved acquisition of good quality electroen- cephalograms (EEGs) during functional magnetic resonance imaging (tMRI) allows the localization of BOLD responses related to interictal epileptiform activity. In children with intractable symptomatic focal epilepsy, identification of the epileptogenic focus is often difficult, especially where conven- tional MRI is normal. Intractable seizures early in life can be associated with irreversible developmental regression. There- fore, we explore the role of EEG/fMRI in the presurgical evalua- tion of this group of children with difficult epilepsy. Methods: Patients were recruited from the Epilepsy Surgery Programme at Great Ormond Street Hospital, London if they (1) had intractable focal epilepsy, (2 ) had regular interictal epileptiform discharges, and (3) had either no visible lesion or a lesion confined to one lobe on MRI. MRI was performed on a Siemens 1.5T scanner with simultaneous EEG acquisition using lOMR compatible scalp electrodes positioned according to the location of interictal discharges. Statistical analysis of the acquired data was performed using Statistical Parametric Mapping (Wellcome Department of Cognitive Neurology). Results: Five patients have been included in this study to date. Significant activations and/or deactivations were identified in the BOLD responses for each of the five patients. Three patients had focal lesions (polymicrogyria in one and cortical dysplasia in two) on MRI and in two the locations of the BOLD

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responses were concordant with the visible lesion and with seizure semiology. W o patients had no obvious lesion on MRI. In one the BOLD responses were consistent with seizure semiology. In the other BOLD activations were not well local- ized and some clearly spurious deactivations were identified. Conclusfon: EEG/fMRI provided useful information in these patients, complementing data obtained h m other presurgical investigations. However, some care must be taken when ana- lyzing these data and further research will clarify the exact place that EEG and fMRI have in presurgical assessment of children with epilepsy.

20. Health related quality of life one month after diagnosis in children with brain tumours and its relationship to child and family variables A P E N N . ~ ~ ~ ~ ~ , s LOW IS^, R SHORT MAN^, RJ MCCARTER~, AL CUR RAN^, M ST EVENS^, PM S H A R P L E S ~ ~ ~

aFrenchay Hospital, Bristol; bBristol Royal Hospital for Children, Bristol, UK Wniversity of the Witwatersrand, Johannesburg, South Aj?tca

Introduction: Brain tumours are the second most common cause of childhood cancer. A major treatment aim is improved health related quality of life (HRQL), but few data exist con- cerning HRQL and its determinants early after diagnosis. Objective: To investigate HRQL in patients with brain tumours 1 month after diagnosis and relate HRQL to child and family variables. Methods: A longitudinal prospective study of children with brain tumours and normally developing matched controls. HRQLwas measured by the parental report Pediatric Quality of Life Inventory (PedsQL). Cognitive outcome was assessed by Wechsler Intelligence Scales for Children-111; psychological outcome was assessed by the Birleson Depression Scale (BDS), the Impact of Events Scale (IES), and Revised Children’s Manifest Anxiety Scale (RCMAS). Emotional health in the pri- mary carer was assessed by the Beck Depression Inventory I1 (BDI-II) and Beck Anxiety Inventory ; familial stress by the Impact on Family Scale (TFS); family functioning by the Family Assessment Device (FAD) and Coping Health Inventory for Parents (CHIP); and family support by the Family Support Scale (FSS) . Results: Wenty-three patients with tumours and 23 controls were recruited (mean age 9 . 4 ~ range 2-16.6~). Patients with tumours had a sigru!icantly reduced PedsQL total score com- pared with controls (p<O.OOl), with significant differences for all four domains (physical, p<O.OOl; emotional, p<O.OOl; social,p=O.O25; school,p=0.036). There was no relationship between PedsQL total score and age (r=-0.91,p=0.688), sex (p=0.78), Verbal IQ (r=0.41, p=O.lO), or Performance IQ (r=0.23, p=0.38). There was a significant relationship between PedsQL total score and BDS (r=-0.62,p=0.024) and IES (r=-0.63, p=0.004), between the physical domain and BDS (r=0-0.64,p=0.018) and the psychosocial score and IES (r=-0.49, p=0.033) and RCMAS (r=-0.60, p=0.02). There was a significant relationship between LFS and PedsQL total score (r=-0.63;p=0.004), PedsQL physical domain (r=-0.53; p=0.018), and PedsQL psychosocial score (r=-0.49, p=- 0.033). There was no correlation between PedsQL total score and BDI-11, BAI, FAD, CHII: and FSS (p>0.05 all comparisons).

Conclusion: Children newly diagnosed with brain tumours have simcantly reduced HRQL. Determinants include psy- chological status and family stress levels but not cognitive sta- tus, emotional health in the primary caregiver, or levels of family support.

21. Leigh syndrome with PDH deficiency due to an E2 subunit mutation dramatically responding to a ketogenic diet 2 ZOLKIPLI MRCPCH, G BROWN, P CLAYTON FRCP

Metabolic Unit, Great Ormond Street Hospital, London, UK

Defects in the pyruvate dehydrogenase (PDH) complex result in lactic acidosis, neuroanatomic defects, hypotonia, develop- mental delay, and early death. Our index case also had typical neuroradiological lesions of Leigh’s syndrome. Most cases of PDH responding to a ketogenic diet in the literature have the E l alpha subunit mutation.

Our index patient was a male born in Egypt to first cousin parents at term weighing 3.lkg. Initial concerns were at one month of age when he was started on phenobarbitone for a suspected seizure disorder. At 5 months, he developed nystag mus, jerky head movements, and episodic clenching of his hands. Multivitamins and monthly B,, injections were started and his parents described an overall improvement for a few months. He crawled at 13 months, walked with knee-foot orth- oses at 14 months, and had four words at 18 months. At 4 years he was ataxic with gross and fine motor delay. He also had involuntary twitching and drooled constantly.

Normal investigations included creatinine kinase, very long chain fatty acids, biotinidase, vacuolated lymphocytes, plasma AA, transferrin isoforms, white cell enzymes, chro- mosomes, organic acids, cerebrospinal fluid amino acids, amine metabolites, and neurotransmitters. Plasma lactate was 2.3 and the CSF lactate was 3.2mmol/L. Lactate pyruvate ratio was 19. Brain magnetic resonance imaging (MRI) at 1 yearwas normal but a repeat at 5 years revealed lesions in the globus pallidus with a low T-, signal and bright T-, signal. The magnetic resonance spectroscopy showed accumulation of lactic acid in the lentiform nuclei. Electromyogram, elec- troencephalogram, and echocardiogram were normal. Muscle biopsy revealed low PDH activity of 0.4nmoUmg proteidmins (normal 0.7-1.1). Respiratory chain enzymes were normal. There was no evidence of ragged red fibres or lipid deposi- tion. He has now been found to have a mutation in the gene for the E2 subunit of the PDH complex (in the lipoamide- binding region).

There was some improvement (eg. in drooling) follow- ing treatment with a ‘mitochondria1 cocktail’ that included thiamine, lipoic acid, and Coenzyme QvlO. However, his motor disability responded dramatically to a ketogenic diet. At the age of 10 he can walk independently with mild coordi- nation difficulties, mainly in his upper limbs. The nystagmus has been ameliorated. He is now able to hold conversations and is growing along the 0.4th centile. He continues on thi- amine and vitamin supplements.

The most common genetic defect for PDH is a mutation in the PDH E l alpha subunit. Our patient is one of two chil- dren so far found to have a mutation in the E2 subunit.

The clinical and biochemical abnormalities appear to be

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broadly similar but there was a particularly striking response to a ketogenic diet. Detection of an E2 defect might constitute an important indication for trying this form of treatment.

22. Pseudomyositic form of Emery-Dreifuss muscular dystrophy due to Lamins A/C gene mutation. Report of a new family DI WFEIRIOU" PHI) , SR B E N WOU' MD, E V A R G I A M I ~ M D , D

GIDARIS" MD, E TEFLIOUDI" MD, I. DEMAY' MD, P RICHARD' PHD,

"1st Department of Pediatrics, Aristotle University, nessaloniki, Greece; bINSEM U 582-Institut de Myologie, Groupe Hospltalier Pitie-SalpOtriere, Paris; 'LJF Cardioghetique et Myoghetique, Groupe Hospitalier Fiti&Sa&Ptri&re, Paris, France

C BONNE' P H D

Background: Mutations of the LMNA gene, encoding the nuclear envelope protein lamins A and C, have been associat- ed with autosomal forms of Emery-Dreifuss muscular dystro- phy (EDMD) as well as other conditions. Objective: To report two familial cases with autosomal-domi- nant EDMD carrying the LMNA gene mutation and histologi- cal abnormalities reminiscent of polymyostis. Design: Case report. Setting: A pediatric department in a tertiary general hospital. Results: The 40-year-old father initially noted trophic changes of his feet at age 15 years, followed by progressive onset of fasciculations, as well as muscle weakness and wast- ing in proximal muscles. Muscle biopsy showed an inflam- matory element, creatine phosphokinase (CPK) was about 800, while electroneuromyography was normal. Fifteen years after onset, he was finally diagnosed as having poly- myositis and put on corticosteroids and additionally cyclo- sporine for 2 years, without any effect. At this time, an electrocardiogram demonstrated supraventricular extrasys- toles. Twenty years after onset, a raised CPK level (-200) found in a routine examination in his 6-year-old twin daugh- ter led to her neurological examination which again demon- strated a very mild proximal muscle weakness without atrophy and normal cardiac function. Moreover, a rigid spine and mild elbow contractures were further noticed in the father. Thus, an autosomal dominant EDMD was suspected. Analysis of the LMNA gene identified a R335W lmna mutation in both father and daughter and analysis of emerin con- firmed normal size and quantity of emerin. Conclusion: These two familial cases illustrate further the spectrum of differential diagnosis of laminopathies, espe- cially in their skeletal muscle expressions. Moreover, the ini- tial misdiagnosis of an inflammatory myopathy, as reported in other neuromuscular conditions (dysferlinopathies, facioscapulohumeral muscular dystrophy), should be kept in mind, in order to reach the correct diagnosis. In the first decade of life, a raised CPK level and a very mild proximal muscular weakness without cardiac abnormali- ties can be the only manifestations of an autosomal domi- nant EDMD.

23. Memory deficits and their determinants early after paediatric traumatic brain injury HE MILLERA, RJ MCCARTER", Al. CURRAN", PM SHARPLES"'

"Kids' Head Injury Study Group, Frenchay Hospital, Brkitol; bBristol Royal Hospital for Children, Bristol; 'Royal Livetpool Children's Hospital, Livetpool, UK

Introduction: Traumatic brain injury (TBr) is a major cause of hospital admission in childhood. Memory deficits are recog- nized to be a major cause of disability following childhood TBI, yet few data exist concerning the nature and determinants of memory deficits early after injury. Objective: To define memory deficits in children with TBI one month after injury compared with normal non-injured con- trols and to investigate factors related to memory deficits. Methods: Prospective cohort study. TBI severity was classed by admission Glasgow Coma Score (GCS) as mild (GCS 13-15), moderate (GCS 9-12), and severe (GCS 3-8). Controls were matched for age, sex, and socioeconomic status. Memory was assessed by the Children's Memory Scale and intellectual func- tion was assessed by the Wechsler Intelligence Scales for Children-Ill. Psychological response was assessed by the Birl- eson Depression Scale (BDS) and Impact of Events Scale (IES). Results: Eighty patients with TBI (47, severe/moderate; 33, mild) and 34 controls were recruited. There was no significant difference in age between children with TBI and controls (mean 13.ly/13.2y; p=0.877). There was a significant differ- ence between children with TBI and controls with regard to the general memory scale (p =0.03). Verbal immediate and ver- bal delayed memory scores were significantly lower in the chil- dren with TBl than in controls (p=0.018;p=O.O06) but visual immediate and visual delayed memory scores did not differ sig- nificantly between the groups (p=0.085;p=0.117). Therewas a significant correlation between general memory scale and Performance IQ (PIQJ; between verbal immediate memory and PIQ (p<O.OOOl) and Verbal 1Q (VIQ;p<O.OOl); between verbal delayed memory and PIQ (p<O.OOOl) and VIQ (p<O.OOOl); between visual immediate memory and PIQ (p<O.OOl) and VIQ (p=0.002); and between visual delayed memory and PIQ (p<O.OOOl) and VIQ (p=0.004). There was no correlation between general memory, verbal immediate memoryorverbaldelayed memoryand BDS (p=0.23;p=0.53; p=0.49) or IES (p=0.84;p=0.78;p=0.76). Conclusion: TBI in children produces significant memory deficits. In contrast to adults, these appear to relate to verbal rather than visual memory. A strong relationship exists bet- ween memory and intellectual function but, in contrast to the situation in adults, there is no correlation between memory function and symptoms of depression and anxiety.

24. Mitochondrial DNA depletion associated with phenotypic variabiility ranging from fatal neonatal myoencephalopathy to slowly progressive bradykinetic extra pyramidal syndrome within a consanguineous family A MANZUR, R KNIGHT, F MLPJTONI, J POU13'0N

Dubowitx Neuromuscular Centre, Hammersmith Hospital, London, UK

Introduction: Mitochondrial DNA (mtDNA) depletion is caused by mutations in nuclear genes involved in mtDNA

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maintenance. There is a quantitative reduction in mtDNA relative to nuclear DNA in the affected tissue.

Objective: To report unusual intrafamilial phenotypic variability in association with mitochondria1 depletion. Methods: Case-note review and real-time-polymerase chain reaction for mtDNA copy number. Results: Five out of six children born to healthy first cousin parents were affected. Xvo elder daughters, now 2 1 and 19 years old, had delayed walking, mild learning difficulties, cognitive/motor decline in teenage years, slow gait with for- ward stoop, cog-wheel rigidity, and brisk deep tendon reflex- es. The eldest also had a tremor, myoclonus, and pigmentary retinopathy; her detailed metabolic investigations, including muscle respiratory chain enzymes, were normal.

Three siblings (two males) presented as newborns with decreased foetal movements, ventilator dependence from birth, severe muscle weakness, distal contractures, poor alert- ness, and no improvement over the neonatal period, leading to withdrawal of intensive care. Cerebrospinal fluid lactate was normal, and there was no definitive neuronal migrational or basal ganglia change on brain magnetic resonance imaging. Motor nerve conduction velocities were normal. Muscle biop- sies showed myopathic changes, with globally reduced respira- tory chain activity and mtDNA depletion (42%) in one child. MtDNAwas depleted to 30% in another. Investigation ofPOLG and "KLE, which are autosomal genes involved in mtDNA maintenance, are underway. Discussion: The clinical spectrum of defects in mtDNA mainte- nance includes all of the features seen in this family. In some cases, mtDNA copy number increases with time in skeletal muscle, and this may explain findings in the oldest child.

Real-time-PCR for diagnosing depletion in muscle is avail- able at one centre in the UK. Conclusion: We present a family with widely different neuro- IogicaVneuromuscular phenotype in siblings from a consan- guineous family. Initial studies suggest mtDNA depletion is the likely aetiology. Mitochondrial investigations will be complet- ed and presented.

25. Relationship between cerebral blood flow velocity as measured by transcranial Doppler and turbulence on magnetic resonance angiography in children with sickle cell disease K KOTECHA BSC MBBS MRCPCH, M PRENGLER MD, D SAUNDERS MB

MRCP FRCR, F KIRKHAM MB BCHIR FRCPCH

Institute of Child Health C Great Ormond Street Hospital, London, UK

Objective: To investigate whether blood flow velocity mea- sured by transcranial Doppler (TCD) is associated with severity of cerebrovascular disease measured as turbulence on magnetic resonance angiography (MRA), in order to determine the best method of selecting those children with an increased risk of stroke. Methods: Wenty-six children had both MRA and TCD per- formedwithin a month. Median age was 12.4years (interquar- tile range 8.46-15.47~) and the median number of days between both scans was 6.5 days (interquartile range 0-29.5~). Highest recorded average velocity on TCD was mea- sured on both sides of the internal carotid (ICA) and middle cerebral arteries (MU). MRAs were examined for evidence of

turbulence, in the terminal internal carotid (tICA) and in the A l , M1, M2, P1, and P2 segments of the basal vessels. Any tur- bulence was graded as 1 mild, 2, moderate, 3 severe, or 4 if occlusion was seen. Results: Comparing TCD velocity in both MCA and ICAon both sides with the corresponding areas on MRA, for vessels with turbulence (0 or l), TCD was normal. As the stenosis became moderate (grade 2), the velocity decreased. This continued until the stenosis became severe (grade 3) and there was reduced distal flow associated with increased TCD velocity. Finally, as the vessels became occluded (grade 4) the velocity decreased again. Results were the same for both right and left middle cerebral arteries and the right internal carotid artery (ANOVAp =0.002, Kruskal-Wallisp = 0.0 1 1). Conclusions: There was a significant association between TCD velocity and MRI turbulence. In contrast to previous studies, our scans were performed within a month of each other. There may be different mechanisms underlying the pathophysiology of stroke and silent infarction; the former is predicted by TCD while the latter is not.' Magnetic resonance aniography may have a role as an additional tool to identify high risk patients.

Reference 1. Kotecha K, Saundes DE. Kirkham FJ. (2004) Changeofcerebral

blood flow over time in children with sickle cell ciisease.ArchI1f.s Child89 [Suppl. 1):A19.

26. Fixation-off sensitivity in symptomatic focal epilepsy and epidermal naevus syndrome I IANKOVIC BA, S AYI.KlT MHCP, S BOYD FI<CP(.H

Great Ormond Street Hospital NHS Trust and The Institute of Child Health (UCL), London, IJK

Objectives: To report neurophysiological findings in a 7-year- old child with a facial epidermal naevus and focal symptomatic focal epilepsy. Methods: Case-note review and review of neurophysiology and magnetic resonance imaging. Results: An 8-month-old female presented with generalized, afebrile seizures. Further daily seizures continued but were subsequently controlled with the combination of sodium val- proate and lamotrigine. Electroencephalogram (EEG) showed almost continuous spike wave over the right parasaggital and posterior temporal regions, which generalized at times. There was global developmental delay, with poor concentration, hyperactivity, and impulsivity. Trials of vigabatrin, topiramate, and prednisolone did not improve the focal EEG activity, devel- opmental progress, or attention deficit-hyperactivity disorder. EEG at age 7 years showed 2Hz spike-slow wave activity over the right centro-tempodparietal area, appearing on eye clo- sure, interrupted on eye opening. This activity was also seen when fixation was prevented using + 10 dioptre and opaque goggles, and disappeared when they were removed ('fixation- off sensitivity').

Magnetic resonance imaging at age 3 years 5 months showed altered signal within the right temporal and occipital lobes and cerebellum with loss ofgreyhvhite matter diferentia- tion consistent with dysplasia. Bilateral signal change in the cerebral white matter was evident adjacent to the posterior aspects of the lateral ventricles. Skin biopsy showed changes consistent with an epidermal naevus.

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Conclusions: Fixation-off sensitivity was originally described in, and believed to be a feature of, idiopathic epilepsies, but has now been reported with posterior brain lesions. This is the first such report in a child with a symptomatic focal epilepsy.

2’7. Benign childhood epilepsy with centro- temporal spikes associated with sudden unexplained death in epilepsy K MARTIN MRCP, S AYLETT MHCP, S B O Y D , C GREENAWAY MRCP

Great Ormond Street Hospital NHS Rust and Tbe Institute of Child Health (UCL), London and East Surrey Hospital NHS Dust, Surrey, UK

Objective: To describe a child with benign childhood epilepsy with centrotemporal spikes (BCECTS) associated with sudden unexplained death in epilepsy (SUDEP). Methods: Case-note and electroencephalogram (EEG) review. Results: A 4-year-old male presented with a seizure during sleep characterized by grunting, upward eye deviation, and twitching of the right arm. Previous history and development were normal. Neurological examination and biochemistry investigations were normal. Awake EEG showed focal spikes and slowwave complexes arising from the left centro-temporal region. Adiagnosis ofBCECTS was made. He was reviewed reg- ularly in clinic and remained well. At the age of 8 years, after going to bed with no preceding illness, he was found unre- sponsive and cold in bed by his parents in the morning. Resuscitation was attempted, but he was confirmed dead. Post mortem showed evidence of enuresis and laceration to his lip and tongue, with no other positive findings. Death was asc- ribed to an epileptic seizure. Conclusion: BCECTS is not considered a risk factor for SUDEZ and this appears to be the first report of its occur- rence. This case suggests that BCECTS is not as benign as it may have been considered and adds to the discussion about the rationale for treating children with BCECTS with anti- epileptic drug treatment.

28. aneralized radiological abnormality associated with acute neurological presentations in sickle cell disease vs UPADHYAYA~ M D MRCPCH, M BYNEVELT~ M FRCR, T coxB FRCR,

K CHON&‘ MD FRLR, v G A N E S A N ~ . ‘ MD, M P R E N G L E R ~ MD,

F I KIRKHAM”.‘ M B B C H I R FRCPCH

“Southampton General Hospital, Southampton; bGreat Onnond Street Hospital, London; CInstitute of Child Health, London, UK

Introduction: Sickle cell disease (SCD) is the most common cause of stroke in childhood with a recurrence rate of lo%, despite regular prophylactic blood transfusions. Ninety per cent of patients have radiological or pathological evidence of large vessel disease, most of whom present with acute hemi- paresis and focal infarction on neuroimaging. However, patients presenting with neurological symptoms and signs after chest crisis have been reported to have generalized neuro- radiological abnormalities (posterior leukencephalopathy and acute demyelination). As few cases have been reported, the pathophysiology and natural history remain obscure. Methods: As part of a 10-year prospectively collected registry of

children with SCD, we report our experience with patients pre- senting acutely and found to have a generalized radiological abnormality. Results: Of 5 1 patients documented to have had an acute neu- rological presentation with focal signs, seizures, or coma, four (8%) had generalized rather than focal neuroradiological abnormality on imaging within 3 days of presentation. AU pre- sented with seizures and a reduced level of consciousness. Three (two after chest crisis and one after a facial infection) had generalized cerebral oedema, of whom two had bilateral bor- derzone infarction involving grey as well as white matter. These patients survived and were reintegrated into mainstream school without significant motor disability; none has had a recurrence after follow-up of 4-10 years. The fourth child, with nephrotic syndrome treated with cyclosporin, had posteri- or leukencephalopathy radiologically; he recovered con- sciousness but died of his renal disease. None of these patients had transcranial Doppler velocities > 200cdsec either before (n=2) orduring (n=4) the acute presentation. Conclusion: Our patients extend the neuroradiology associat- ed with acute seizures and coma in SCD to include generalized cerebral oedema and bilateral borderzone infarction, as well as posterior leukencephalopathy. Neurological outcome may be favourable if the patient survives the acute phase. The role of acute hypoxia and blood pressure abnormalities requires investigation.

29. Acquired transverse myelopathy in children in the UK - a pilot study for the British Paediatric Neurology Association Surveillance Unit CGEL DE G O E D E A MRCP MRCPC, MG PIKEB MA M D FRCPCH

“Royal Manchester Children s Hospital, Manchester; bJohn Radcliffe Hospital, Oxford, UK

Objectives: This is the first population based study of acquired transverse myelopathy (ATM) in childhood, which has now run for two years. The aim is to define the incidence, describe presentation, management and outcome, and identlfy factors of prognostic significance. Methods: This study is a pilot for the ‘British Paediatric Neurology Association Surveillance Unit’ (BPNASLJ). All paedi- atric neurologists in the UK are invited, and reminded on a quarterly basis, to report any child under 16 years of age pre- senting with ATM over a period of 2 years. Once a child is reported, the clinician is asked to complete a questionnaire. The study is largely descriptive. Results: Initial response rate was 82%, and 56 children were notified. Thirty completed questionnaires have been received and two cases were excluded. The incidence of ATM in chil- dren under 16 years on the basis of these data is 2.2 per million per year (confidence interval 1.7 to 2.9 per million). Clinical presentation will be discussed. Most children received high dose steroids. Fifteen patients were post-infectious, eight were cryptogenic, two demyelinating, and two post-traumatic. Recovery was described as ‘complete’ or ‘good’ in 15 children, and as ‘fair’ or ‘poor’ in four out of 19 patients. Significant pos- itive prognostic factors are start of recovery within a week and younger age. A significant negative predictor is preceding trau- ma. Other possible predictors are cerebrospinal fluid protein, post-infection, and sudden onset.

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Conclusion: The BPNASU is useful in the delineation of rare neurological disorders. This study has shown the incidence ofATM in children to be higher than expected, and has shed further light on the condition.

30. A survey of presentation, management, and outcomes of acute disseminated encephalomyelitis in children in the UK on behalf of the British Paediatric Neurology Association Surveillance Unit SR MORDEKAR MD MRCP (UK) MRCPCH, C D RITTEY FRCP FRCPCH

Ryegate Children’s Centre, Shefleld, UK

Objective: Acute disseminated encephalomyelitis (ADEM) in children is rare, often presenting as an acute polysymptomatic encephalopathy. The aim of this study was to define incidence, describe presentation, management and outcomes in children in the UK. Method: This study is a pilot for the British Paediatric Neu- rology Association Surveillance Unit. Ethical approval was acquired from the Metropolitan Multicentre Research Ethics Committee. Cases were collected by sending an anonymized confidential audit datasheet with a covering letter to all consul- tant paediatric neurologists working in tertiary centres in the UK and reminding them, on a quarterly basis, to report any child under sixteen years of age presenting with ADEM in the previous 3 months. Results: Preliminary results for the first six months are present- ed. Sixty-six paediatric neurologists in the UK were sent ques- tionnaires twice, at 3 months’ intervals. ’liventy-seven (41%) and 23 (35%) clinicians responded to the questionnaires. Fifteen children with completed questionnaires were notified. Weakness (73%), unsteadiness (47%), and preceding viral ill- ness (53%) were common presentingsymptoms. Cranial nerve involvement (66%), ataxia (66%), hypertonia (40%), and para- esthesia (27%) were the reported clinical features. Well- defined multifocal hyperintensities on T-2 weighted images on magnetic resonance imaging throughout the white matter, spinal cord, and grey matter were considered to be diagnostic of ADEM (100%). Lumbar puncture was performed in 66% of cases. Most children received high dose steroids. All patients were either post infectious or cryptogenic. Recovery was described as ‘too early to determine’ in seven children and ‘full recovery’ in eight children at 3 months’ follow-up. Conclusions: ADEM in children is rare with avaried clinical pre- sentation and no pathognomic investigation. Various treat- ment regimes of steroids are used. Most children seem to make excellent progress in the following days, weeks, or months, with no subsequent neurological impairment.

31. Aetiology, treatment and outcome of children admitted to paediatric intensive care with convulsive status epilepticus: a five year review N HUSSAIY MRCPCH MRCPI, R APPLETON MRCP, K THORBURN MRCP

Departments of Intensive Care Medicine and Neurology, Royal Liverpool Children’s NHS lfirst (Alder Hey), Liverpool, UK

Introduction: Convulsive status epilepticus (CSE) in chil-

dren is a relatively common medical emergency. Objective: To characterize the aetiology, treatment, and out- come of children with CSE. Method: Retrospective case-note review of all children admitted to a Regional Paediatric Intensive Care Unit (PICLJ) with CSE January 1999 to March 2004. CSE was defined as any child presenting to an Accident and Emergency depart- ment in having an acute tonic-clonic seizure, irrespective of the duration of the seizure. Results: One hundred and thirty-seven children (74 males) were admitted to the PICU with 147 episodes of status epilepti- cus. Aetiology included: remote symptomatic with a pre-exist- ing neurological abnormality including cerebral palsy or epilepsy (53 children, 39%); febrile CSE (47 children, 34%); acute symptomatic following meningitis, encephalitis, trauma or anoxia (24 children, 18%); a progressive encephalopathy (6 children, 4%); and cryptogenic (7 children, 5%). Mean age at presentationwas 2.5 years (range, lmo to 15y). Meanduration of CSE was 44 minutes (range, 30-120 minutes). Mean dura- tion of stay in PICU was 3.6 days (range, 1-27d). Thiopentone anaesthesia was used successfully in 42 children with persist- ing (refractory) CSE. N o child died in PICU and 64 of 70 (91%) children who were neurologically and developmentally nor- mal before presentation were normal a minimum of 6 months later on formal neurological assessment. Conclusion: Thiopentone anaesthesia successfully treated all children with refractory CSE. N o patient died and neurological sequelae were rare and appeared to relate more to the underly- ing cause than the duration or treatment of the CSE.

32. Role of azathioprine in Rasmussen’s syndrome S SHAH, S VARADKAR, J H CROSS

Institute of Child Health; Great Ormond Street Hospital NHS nust, London, UK

Objective: To describe experience of the use of azathioprine in the management of Rasmussen’s syndrome. Methods: Azathioprine therapy has been used in five patients in our unit to date. In each patient azathioprine was com- menced at a dose of 1.5m@g/day orally following initial use of high dose steroids. Disease characteristics, clinical course, and investigations were documented on regular review. Full blood counts and liver function tests were monitored for adverse drug effects. Results: Azathioprine has been used for a period of two months to seven years. In three of the five patients azathio- prine therapy allowed weaning-off of steroids (previously not possible) whilst maintaining improved seizure control. Improvement in school progress and neurological function was observed and treatment continues. All three had also shown a clinical response to steroids. Ttvo patients did not respond to azathioprine and indeed had also not shown clin- ical response to other medical treatments. N o patient experi- enced side effects of azathioprine at this dose. Conclusions: Azathioprine can be considered an alternative medical therapy in the treatment of Rasmussen’s syndrome. It has an important role as an immunosuppressive and steroid sparing agent. When used at a dose of 1.5mgkg/day o d y it is well tolerated.

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33. Measurement in Duchenne muscular dystrophy: developing and defining the protocol E SCOTT M P H I L MCSP, A MANZUR M D ~ , NORTH STAR PROJECT

c n o u P s c

uNorth Star Project, Muscular Dystrophy Campaign; bDubowitz Muscle Centre, Hammersmitb Hospital, London; =North Star Clinical Network for Paediatric Neuromuscular Disease Management, UK

Objective: To develop a protocol for clinical neuromuscular assessment to monitor disease progression in Duchenne muscular dystrophy (DMD) for use in the North Star Project. Methods: Possible measures were identified from a variety of sources: a review of those currently in use in specialist mus- cle centres across the UK, MEDLINE, and CINAHL databases, and recent recommendations from the international ENMC workshop on management of DMD. A paradigmatic approach was applied to evaluate possible choices of measure. Acritique of these measures was undertaken, addressing aspects of validity, reliability, responsiveness, and feasibility.

A report was produced from these sources and circulated to the North Star groups for comment. An expert group of physio- therapists met, and a nominal group consensus technique (NGT) was used to address best practice in measurement. ’helve core measures were identified, including functional scales, timed functional activities, muscle strength, respirato- ry capacity, and contractures. Group members anonymously ranked each measure on a Likert scale of 1-9. The degree of importance therapists gave to the individual measures (rnedi- an score), and to the level of agreement between the group members (range) were analyzed. Results: Seven items scored medians of 8 or 9, reflecting a high level of importance. All other items scored in the mid-range, indicating an equivocal response from the group. Strict agree- mentwas found for seven items (four of these showed one ‘out- lying’ score but a high median). The five other items showed relaxed or no agreement. Those measures which were designat- ed ‘high importance’ and a ‘strict’ level of agreement were rec- ommended for incorporation within the assessment protocol. Conclusions: A comprehensive review of existing practice, and the use of a nominal group consensus technique, identi- fied seven key measures for monitoring disease progression in DMD. These will be standardized to provide the basis of the North Star assessment protocol.

34. Audit of the acute reduction of antiepileptic drugs for video EEG/telemetry S S H A H , I TAKON, P NICOLAIDES, S BOYD, S WHITE, B NEVILLE,

R SCOTT, K DAS, S AYLETT, JH CROSS

Department of Neurosciences, Great Ormond Street Hospital, London, UK

Afm: To assess the practice of acute reduction of regular anti epileptic medication on admission for documentation of seizures. Methods: A retrospective case-note review of 50 consecutive patients admitted to the Epilepsy Unit over a period of 4 months for Video EEGKelemetry. In each patient, the decision to reduce or stop medication was made on the basis of seizure

frequency and proceeded careful discussion of the aims of the admission. Informed consent was obtained from patients. Results: Patients were aged between 1 year 5 months and 5 years (26 male, 24 female). Wenty-five out of 50 patients had no change made to their medication (group 1) while 25/50 patients’ medication was reduced and/or stopped (group 2). In group 1,825 patients were admitted for epilepsy surgery eval- uation, while in the remaining 17/25 the aim was to character- ize seizures or obtain an overnight EEG. Seizure frequency was at least l/day in 14 patients, and less than Ihveek in three patients. In four of them it was unpredictable and details were unobtainable in two notes. Typical seizures were observed in 18/25 patients; 14/18 on day 1 of admission. An ictal SPECTwas achieved in all three patients for whom it was the aim of the admission. In group 2, the seizure frequency was recorded as at least l/day in eight patients, and less than l/week in five patients. For six patients a record could not be found. w i c a l seizures were observed in 2 1/25 patients but only recorded in seven on day 1. An Ictal SPECT was obtained in 9/16 patients in whom it was the aim of the admission. Prolonged seizures requiring use of emergency medication were significantly more frequent where medication was reduced or stopped, occurring in five children in group 2, compared with no chil- dren in group l. One child in group 2, with pyridoxal phos- phate dependency, required PlCU admission for treatment of status epilepticus. Conclusion: Reduction or discontinuation of regular anti- epileptic medication in patients with epilepsy can be helpful to achieve characterization of seizures on admission for Video EECltelemetry. In 84% of patients, typical seizures were docu- mented; however, there is a risk of prolonged seizures occur- ring in such children. We feel that parents should be warned of the risk and measures taken to ensure ready access to emer- gency treatment at all times.

35. A behavioural and fMRI investigation of modified constraint-induced movement therapy for children with acquired hemiparesis A GORDON MSC”, A CONNELLY p m B , F VARGHA-KHADEM PHD‘-, B

NEVILLE F R C P C H ~ , v GANESAN M D ~

uNeurosciences Unit; bRadiology and Physics Unit; CDevelopmental Cognitive Neuroscience Unit; Institute of Child Health, University College London, London, UK

Introduction: Constraint-induced movement therapy (CIT) is an upper limb rehabilitation method that appears promis- ing in young children with cerebral palsy. There are limited data on older children which examine the optimal regime and mechanisms underlying functional changes. Objective: To undertake a pilot study exploring feasibility, tolerability, and effectiveness of modified CIT (mCIT) in chil- dren with acquired hemiparesis due to stroke. Methods: We aimed to study eight children and here we report data from the first patient. Children underwent four assess- ments - at 0,4,8, and 12 weeks - including measures of motor and sensory function, quality of upper limb movement, indi- vidualgoal setting, child and parent interviews, and functional magnetic resonance imaging (fMRI) studies using a passive hand movement paradigm. Home-based mCIT was delivered for 2 hours/day, 5 daysheek from weeks 4 to 8.

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Results: The first patient was an 11-year-old male with dystonic left hemiparesis and minimal hand function due to stroke at age 2 years. He was was receiving no regular therapy at the time of assessment. Although only small changes in motor, sensory, and hand function were evident following mCIT, he improved in three of four goals, and he and his parents report- ed improved spontaneous upper limb use.

On fMRI studies, despite the stroke-induced brain patholo- gy, the contralateral sensorimotor cortex was activated by pas- sive movement of the affected hand. This remained unchanged on serial imaging. Studies of other school-age children are ongoing, but have been challengingdue to intensity and practi- cality of the intervention and assessment in this age group. Conclusions: In this child mCIT was not associated with marked changes in sensorimotor function, but was followed by improvement in spontaneous use of the affected upper limb. Further studies are required to establish the effectiveness of mCIT relative to existing interventions, the optimal regime, and examining the mechanisms underlying functional change. Due to significant methodological issues, such studies will require substantial resources and commitment from the chil- dren and families.

36. Folic acid fortification of flour urgently required to prevent open spina bifida MA, C ROZETTE", D MAXWELL'

aPaediatric Neurosciences, 'Fetal Medicine Unit, Guy's and St Thomas' Foundation NHS nust, London, UK

Background: Health-care professionals realize the preventa- tive role that a daily dose of folic acid taken three months before, and for the first twelve weeks of pregnancy exerts in reducing the incidence of spina bifida. Despite the availabili- ty of such effective prevention, the incidence of spina bifida in Great Britain and Europe has remained unchanged since the 1992 recommendations to take folic acid supplements (Eurocat Report 2003). Aims: We wished to assess the level of knowledge that moth- ers had about the need to take folic acid and to explore some of the reasons behind the pattern of their medication intake in pregnancy. Methods: One hundred questionnaires were completed by randomly selected pregnant women attending for routine ultrasound in early pregnancy. Results: The majority of women (92%) knew that folic acid is recommended in early pregnancy and 73% of mothers knew that folic acid prevented neurological abnormality of the baby.

Although a majority of the women (60%) knew when folic acid should be taken, and the length of time they should take it, only one third of women had taken it preconceptionally. In two thirds of cases, failure to take preconceptional folic acid was due to an unplanned pregnancy. Only 40% were aware of the recommended dose. Discussion: Over 40 countries have adopted universal fortifi- cation of flour with folic acid, including the USA and Canada, leading to a halving in the incidence of spina bifida. By con- trast, the self-supplementation recommendation directed at women of child-bearing age is ineffective in reducing the incidence of spina bifida.

Conclusions: The UK government recommendation for pre- conceptional folic acid is that women at low risk of having a baby with spina bifida should take 400pg of folic acid daily and 5mg daily if they are at high risk. This study raises important issues around the practical implementation of this policy if it is to be effective in the population at large.

As the majority of pregnancies are unplanned, we strongly support mandatory fortification of flour with folic acid in the UK.

37. Spastic paraparesis associated with pseudohypoparathyroidism and pseudopseudohypoparathyroidism - a chance association? MA KLJRIAN M R C P C H ~ , s MURTHY MRCPCH", s JAYAWANT MRCP

aChild Development Centre, Upton Hospital, Slough; 'Department of Paediatric Neuroloa, John Radcliffe Hospital, Oxford, UK

Objective: To report on four children (within two families) with progressive spastic paraparesis associated with abnor- mal parathyroid hormone levels. Famfly 1: W o females, age 4 and 5 years. Both the parents and maternal grandparents are first cousins within a large consan- guineous pedigree. A maternal aunt and uncle presented in childhood with spastic paraparesis and pseudopseudohy- poparathyroidism (GNASI mutation negative). We describe the two youngest female siblings of seven children. Both chil- dren were born at term following unremarkable pregnancies. Initially they were hypotonic with global developmental delay. From 2 years, they both developed a progressive spastic para- paresis. On clinical examination, both children showed mild dysmorphism, increased lower limb tone, and hyperreflexia. Magnetic resonance imaging of the brain of the older sibling demonstrated decreased white matter and generalized delayed myelination. Investigations in both siblings revealed elevated parathyroid hormone levels but normal calcium, phosphate, alkaline phosphatase, and vitamin D levels, consistent with a diagnosis of pseudopseudohypoparathyroidism. Family 2: Female 3 years, male 9 years. The parents are first cousins. Both children were born at term following unre- markable pregnancies. The older male showed global devel- opmental delay. He developed epilepsy by one year of age. Investigations revealed hypocalcaemia, normal vitamin D, and high parathyroid hormone levels. A diagnosis of pseudohy- poparathyroidism was made. By 4 years of age he developed a progressive spastic paraparesis with increased lower limb tone and hyperreflexia. His younger female sibling also displayed global developmental delay. Her investigations at 2 years did not indicate pseudohypoparathyroidism but at 3 years she also started to develop a progressive spastic paraparesis. Conclusions: It is conceivable that two independent reces- sive conditions may coexist due to chance alone, especially within complex consanguineous families. Spastic parapare- sis may also be a presenting feature of disorders of parathy- roid hormone. The coexistence of spastic paraparesis and hypoparathyroidism may also indicate one recessive condi- tion which includes both phenotypes.

FRCPCHB

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38. Massive spinocerebellar ataxia type 7 expansion in an infant with hypotonia, cardiac failure, and renal dysfunction A WHITNEY MB CI-IB MRCP, M LIM BMBS BMED SCI MRCP, D

KANABAR MRCP FRCPCH, J P LIN MRCP(UK) P H D

Guy's Hospital, London, UK

Objective: Spinocerebellar ataxia type 7 (SCA7), an autosomal dominant inherited ataxia associated with pigmentary macu- lopathy, is a CAG trinucleotide repeat disorder with striking anticipation. Paternal inheritance is significantly more unsta- ble than maternal, and there is an inverse correlation between size of CAG repeats, age of onset of disease, and age at death. A severe infant form of SCA7 has been recognized, is rapidly pro- gressive and fatal, and may present with hypotonia, failure to thrive, and ataxia. Case History: We present a 7-month-old male infant with a massive CAG trinucleotide expansion who presented with cardiac and renal failure in addition to neurological disease.

Our patient was the only child of non-consanguineous par- ents of Afro-Caribbean origin. His father, paternal aunt, and grandfather all had a diagnosis of SCA7. He first presented at the age of 5 months with failure to thrive, signs of congestive heart failure, and hypotonia. A patent ductus arteriosus (PDA) was diagnosed using echocardiography but the heart failure continued to worsen despite closure of the PDA. At 7 months of age he had marked delay of gross motor skills, unsteady hand movements, and truncal and peripheral hypotonia with absent deep tendon reflexes. He had normal eye movements. Opthalmological examination detected pigment granularity. In addition to his cardiac dysfunction, with developing left ven- tricular hypertrophy, renal function was also significantly disor- dered. He developed marked proteinuria and renal failure of undetermined cause. Magnetic resonance imaging detected both cerebral and cerebellar atrophy DNA analysis confirmed an expanded trinucleotide repeat in the SCA7 loci of approxi- mately 240 repeats. He was exrensively investigated for failure to thrive, cardiomyopathy, and renal failure, the results of which were normal. He continued to deteriorate clinically and died aged eleven months of multiorgan failure. Conclusions: This patient demonstrates the wide phenotypic variation of the infantile form of SCA7 to include renal and cardiac involvement which have not been described in other case series.

39. Development of a young persons' epilepsies clinic: preliminary data B WALDRON MSC RSCN", c P I C ~ O N RSCN", J LANFEAR MA R S C N ~ ,

c HAYES M P H I L RSN", s WARDA, s JANES M B BS", c DUNKLEY M R C P

MRCPCH", J WILLIAMS MRCP F R C P C H ~ , W P WHITEHOUSE FRCP

F R C P C H " ' ~

"Queen's Medical Centre, Nottingham; hLeeds Metropolitan University, Leeds; cUniversity of Nottingharn, Nottingham, LrK

Objective: Last year we presented how we set up a young per- sons' epilepsies clinic (YPEC). Our aim here is to provide fur- ther data and an update. Methods: Young persons with epilepsies were opportunistical- ly interviewed by paediatric epilepsy clinical nurse specialists, using the standard questionnaire developed in-house, on their

views on service provision and knowledge of their epilepv. Some were also asked to complete a validated health related questionnaire ('Epilepsy Impact Scale'). Opportunities to engage youth-workers with this group of patients were sought. Results: We have preliminary data on the views and knowledge of 44 patients and results for the Epilepsy Impact Scale for 28 patients.

The group of 44 patients, who had not been previously to the YPEC, were aged between 11 and 17 years (54% female). Forty-four percent preferred an evening clinic, 32% a morning, and 16% an afternoon clinic. Fifty-six per cent wanted to be able to see a nurse and a doctor. Sixty-four per cent wanted the option to be seen with their parent or guardian present some- times and 28% wanted their parent or guardian with them at al l times. Seventy-six per cent wanted to attend without appoint- ment. Eighty-four per cent wanted career advice, 64% wanted to learn more about epilepsies, and 36% wanted information on sex and relationships. Thirty-six per cent reported that their activities were restricted by their epilepsy. Only 44% thought that they knew what type of epilepsy they had, yet 60% believed their current service provision was 'good' or better.

Funding has been secured for two youth workers to meet at the clinic and at other times, for social activities. Conclusions: We have confirmed some of the wishes and needs of this population and will measure changes in views, knowledge, and quality of life associated with the introduc- tion of the YPEC in the future. Further data and analysis will be available shortly.

40. The role of ketamine in the treatment of non-convulsive status epilepticus s MACLEOD, MT WILSON, SM ZUBERI, RC MCWILLIAM, M E O'REGAN

Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, UK

Introduction: Non-convulsive status epilepticus (NSCE) is a well recognized phenomenon in paediatric epilepsy syn- dromes such as Lennox Gastaut syndrome, rnyoclonic astatic epilepsy, and the progressive myoclonic epilepsies. It is charac- terized by cognitive and behavioural impairment, a lack of overt convulsive activity, and an EEG showing on-going seizure activity. Standard treatment includes benzodiazepines and steroids. Response to treatment is variable and side-effects are common. A recently published case series of five patients sug- gested Ketamine, a non-competitive NMDA receptor agonist, may have a role in the treatment of NSCE.' We report our pre- liminary findings in the use of oral ketamine. Patients and Methods: Subsequent to the recently published paper we are carrying out a prospective audit in our use of oral ketamine. Patients were selected on the basis of clinical and electrophysiological findings, all had an unequivocal diagnosis of NSCE before starting therapy Oral ketamine was prescribed (0.75mgkg twice daily), the first dose being administered in the department under supervision. A stan- dard course lasted 5 days. All patients had a clinical and elec- trophysiological re-evaluation on day 5 of treatment. Results: Eight patients (four male) were eligible for inclusion in the study. Two patients had Lennox Gastaut syndrome. The others had a variety of epilepsy diagnoses including severe myoclonic epilepsy of infancy, myoclonic astatic epilepsy,

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unclassified myoclonic epilepsy, and symptomatic epilepsy secondary to an acute ischaemic insult in early infancy. All eight had previous episodes of NCSE (range 1-8 previous episodes) and all had received steroids for these episodes with varying responses. Significant steroid related side-effects included a steroid myopathy in one patient and significant behavioural disturbance and altered mood in two patients. Four out of eight patients had an excellent clinical and EEG response fol- lowing ketamine administration with a rapid improvement in cognition and EEG findings. W o offour patients who respond- ed to ketamine relapsed back into NCSE soon after discontinu- ation of ketamine. Ketamine was reintroduced with a clinical and electrophysiological improvement. Four patients did not respond to ketamine. There was no reported adverse effect during or after ketamine administration, including two patients who have been on ketamine for more than 2 months. Summary: Ketamine was effective in 4/8 patients. It should be considered as an alternative to steroids and benzodi- azepines in the management of non-convulsive status epilep- ticus. Larger studies are required to assess its efficacy and safety compared with standard treatments.

Reference 1. Mewasingh LD, Sekhara T, Aeby A, Christiaens FJ, Dan B. (2003)

Oral ketamine in paediatric non-convulsive status. Sefzure 12: 483-489.

41. Cognitive function in children with temporal lobe epilepsy: impact of early onset seizures F CORMACK PHD, JH CROSS PHD FRCPCH, w HARKNESS FRCS, n

Institute of Child Health, University College London and Great Ormond Street Hospital NHS nust, London, UK

Objective: Temporal lobe pathology has long been associated with specific deficits in declarative memory. There is, howev- er, evidence that focal epilepsy can have a widespread effect on cognition, particularlywith onset in infancy. The extent to which this is seen in children with temporal lobe epilepsy (TLE) is largely unknown. This study sought to examine the full range of cognitive functioning in children with intractable TLE, and to relate this to clinical and seizure variables. Methods: Seventy-nine children with focal temporal lobe epilepsy (mean age at assessment l l y 6mo; 48% male) under- went a multidisciplinary evaluation, including magnetic reso- nance imaging, EEG, and psychiatric and neuropsychological assessment. AU went on to have temporal lobe resection. The latter included assessment with the Wechsler Intelligence Scale. Clinical variables, such as age at onset of epilepsy, acquisition of developmental milestones, and number of medications, were obtained from parental interview and review of clinical records. Results: The majority of patients in this sample were found to have clinically significant cognitive dysfunction: 14% of chil- dren could not be formally assessed (mostly due to communi- cation and behavioural difficulties), and 57% of those who could be assessed had an IQ of less than 70. Age at onset of epilepsywas the factorwhich best predicted the cognitive out- come of children, with younger age of onset associated with

NEVILLE FRCP FRCPCH, F VARGHA-KHADEM P H D , T BALDEWEG M D

lower IQ, with an additional contribution from number of medications. Those children with parental report of delayed or regressed milestones were at increased risk of cognitive impairment in later childhood. Conclusions: Early onset seizures are associated with poor cog- nitive outcome, even where seizure origin appears to be focal, as in surgically treatable temporal lobe epilepsy. Management strategies should strive for seizure relief, including early referral for surgical consideration. Longitudinal studies are required to clarify the possible impact of treatment.

42. Severe receptive language disorder: familial and clinical characteristics AE O'HARE", J S E C K L ~ , J WATSON~, A HODSON':, w C O H E N ~ , J

N A S I R ~ , H COWIE"

aUnlversity of Edinburgh; bWestern General Hospital; CQueen Margaret University College, Edinburgh; dUntversity of SbefleZd, ShefleZd, UK

Objective: To determine the clinical and familial characteris- tics of severe receptive language disorder for a Scottish cohort who were informative within the Specific Language Impairment consortium's highly significant linkage to chro- mosome l6and 19. Methods: Proband eligibility was determined by ICD-10 F80.2 criteria for severe receptive language disorder. This was done both retrospectively from clinical notes and cross-sectionally at the point of entry to the study Receptive and expressive lan- guage levels were determined from CELF-R for probands and siblings over the age of 5 years. Non-verbal IQ was determined from Raven's Progressive Matrices. A language learning impair- ment was determined from a structured interview and all fami- ly members over the age of 5 years completed a measure of auditory memory, which employed a non-word repetition test. Results: Fifty-eight probands and 274 family members partici- pated. Mean age (SD) of probands was 8;9 (33) years and they were a mean (SD) of 5;9 (2;8) years from initial multidiscipli- nary assessment of their educational needs following diagnosis of specific language impairment. The male to female ratio was 2.2 : 1. Only 4% of the probands had recovered expressive and receptive language to within 1SD of the mean for the normal population and 35% still met the 2SD deficit for ICD-I0 recep- tive disorder; expressive language correlated with receptive (p<O.OOOl) and was typically poorer and was not related to non-verbal IQ. Sixty-nine per cent of probands had a first degree relative with a language learning impairment. Auditory memory as measured by non-word repetition standard score was generally poor with a mean (SD) of 70 (16). This was inde- pendent of receptive language and age but correlated with both expressive language p=0.005 and non-verbal IQ. It was depressed in 'unaffected' family members. Conclusion: This study reports on the largest number of school-aged children with receptive language disorder as defined by ICD-10. This is a disorder, which frequently does not resolve, has a high familial incidence, and is related to poor phonological memory.

Acknowledgement: This study was funded by the Chief Scientist Office, Scotland, UK.

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43. Prospective evaluation of dancing eye syndrome ( opsoclonus-myoclonus ) management and outcome in UK paediatric neurology centres: provisional first year data KK PANG", B LANG", c DE SOUSA~, MG PIKE^

"John Radcliffe Hospital, Oxford; bGreat Ormond Street Hospital, London, UK

Objectives: Dancing eye syndrome (DES) is a rare but well described movement disorder associated with infectious or neoplastic disease. All previous studies have been retrospec- tive and there is limited information on which to base investi- gation and management. The aim of this study is, therefore, to collect data on all newly diagnosed patients seen by UK paediatric neurologists over a period of 2 years and to sug- gest a uniform approach to investigation and follow-up. Methods: Prompts to notify us of new patients are sent to the 19 participating UK paediatric neurology centres every sec- ond month. Newly-presenting patients, for whom informed consent is obtained, are assessed by questionnaire and pro- vide blood for a range of antibody assays. Quantitative neu- rodevelopmental assessments are obtained at 3-6, 18, and 30 months after presentation. Results: Preliminary results from the first year are presented. In the first 12 months (May 2003-April 2004) there have been 10 notifications of which parents of seven (five females) con- sented to take part in the study. This gives an approximate inci- dence of 0.25 new cases per million population per year. Age range was 5-42 months, with duration of symptoms at presen- tation varying from 1-42 days. Three had preexisting coryzal symptoms and neuroblastoma was identified in two patients. All were initially treated with steroids, except for one who had intravenous immunoglobulin because of a recent varicella contact. lbo had intravenous immunoglobulin as adjunctive therapy. Conclusion: The clinical presentations and developmental progress to date will be discussed.

44. Cluster headaches in children: a tertiary headache clinic experience A MAIUMDAR", s BENT ON^., PJ GO ADS BY^ aDepartment of Paediatric Neurology, Great Ormond Street Hospital for Children, Great Ormond Street; bInstitute of Neurology, Queens Square, London, UK

Introduction: Cluster headache is a well-defined form of pri- mary headache disorder with a distinctive periodicity and signature features of episodic severe unilateral pain with cra- nial autonomic features, such as lacrimation or conjunctival injection. The prevalence of cluster headaches is 0.1% of the adult population and with a male predominance. The inci- dence in children is thought to be 0 .0944%. The age of onset is usually in the second and third decade of life although onset in the first decade is recognized. We describe the experi- ence of cluster headache in children in a tertiary headache clinic setting and include a review of the literature. Methods: A case-note review was conducted of all children with suspected cluster headache seen at a tertiary headache clinic. Participant ascertainment was conducted using a per- forma and by telephone interviews with the parents.

Results: Ten children were identified (5 male). Median age of onset was 8 years 6 months (range 3-14y), while the median age of diagnosis was 11 years 6 months (range 7-17y). Eight had regular clusters. The average duration of a cluster attack was 72 minutes. Several children had circadian and circum- annual periodicity, and most displayed the other features of cluster headaches, e.g. agitation and cranial autonomic involvement. Oxygen, methysergide, verapamil, zolmitrip- tan, and dihydroergotamine were the drugswhich were effica- cious but paracetamol, ibuprofen, and co-codamol were not. Discussion: We describe our experience with cluster headache in 10 children who all presented before the age of 16 years. Although cluster headache is apparently rare in children, their attacks were typical for the condition. Given that the disorder is rare and the treatment specialized, it seems desirable to have such patients treated in specialty settings.

45. The use of stiripentol in childhood epilepsy M KINALI, P NICOLAIDES, SE AYLEIT, BGR NEVILLE, J H CROSS

Institute of Child Health and Great Ormond Street Hospital for Children NHS nust, London, UK

Objective: Studies have shown that stiripentol (STP), a cytochrome P450 inhibitor, has efficacy in severe myoclonic epilepsy of infancy (SMEI) when used concomitantly with other antiepileptic drugs (AEDs). The aim of our study was to assess the efficacy and tolerability of STP in childhood refrac- tory epilepsy. Methods: Stiripentol has been used to treat 15 children with refractory epilepsy at the Institute of Child Health, London, UK since November 2001. Case notes were reviewed with regard to seizure control and adverse effects. Results: Dataon 12/15 children (six females), aged 9.8years (range 1.4-15.1~) at onset of treatment, were available for analysis. Eleven children had symptomatic generalized epilep- sy (SGE; nine with SMEI) and one symptomatic focal epilepsy (SFE). The most common comedication was clobazam (1 1/12) with topiramate (6/12) or any combination with sodium Val- proate (4/12), lamotrigine (3/12), levetiracetam (3/12), pheno- barbitone (2/12), prednisolone (1/12), orethosuximide (1/12). One child did not receive clobazam but was on phenobarbi- tone, phenytoin, prednisolone, and oxcarbazepine. Median follow-up was 9 months (range 3mo-2.6~). Starting STP dose was 125mg/day(6y) or250mg/day(>by). Maximumdailydose of STP was 2 500mg (60mgkg). The earliest response observed was within two weeks of treatment onset. Generalized tonic- clonic (GTC) seizures were reduced by 50% in 10/12 children. -0 children (one with SMEI, one with SFE) became seizure free at 3 months. Seizure recurrence required readjustment of AEDs in 3/12 children treated for longer than 12 months. The most common adverse effects were drowsiness (8/12) fol- lowed by agitation that usuallyresolved with reduction ofAEDs or readjustment of STI! lbo patients discontinued treatment (one with SMEI due to adverse effects and one with SGE due to no real improvement). Conclusions: This audit has confirmed efficacy of STP in refrac- tory symptomatic epilepsy, particularly SMEI. Larger prospec- tive randomized studies in refractory epilepsies are needed to confirm these observations.

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