ABSTRACTS

Invited speakers for the Sixth European PaediatricNeurology Society, EPNS Congress

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Pathogenesis of pediatric brain damageJohnston, MichaelKennedy Krieger Johns Hopkins, Neurology andPediatrics, Baltimore, USA

Hypoxia-ischemia, trauma, infection and geneticmetabolic disorders can damage the developingbrain. These insults damage the brain by activatingendogenous molecular cascades within neurons,glia, and white matter. For example, the periven-tricular white matter is selectively vulnerable toinjury in fetuses or premature infants prior to 34weeks gestation, while neurons are more heavilytargeted in full term infants. Injury at both ages ismediated by accumulation of the excitatory aminoacid neurotransmitter glutamate. However, NMDAtype glutamate receptors play a greater role inneuronal injury while white matter injury is morelikely to be mediated by non-NMDA receptors.Immature white matter is also vulnerable toinfection, which activates cascades of inflammatorysignaling in the immature oligodendroglia. Magneticresonance imaging reveals distinctive patterns ofinjury in premature compared to term infants as wellas patterns associated with other forms of injury inolder children. Study of experimental hypoxia-ischemia in neonatal models has uncovered down-stream molecular steps that determine the finaloutcome of injury, including production of nitricoxide, injury to mitochondria, activation of caspasesand calpains, changes in gene expression, andexecution of apoptosis and/or necrosis. Activationof the DNA repair enzyme poly (ADP-ribose) poly-merase (Parp-1) also contributes to injury. How-ever, we found that the effect of knocking out Parp-1in neonatal mice is strongly dependent on the sex of

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the animals: males are protected but females arenot (Hagberg, et al, J Neurochem 90:1068–1075,2004). This raises the issue of whether there is also asex difference in the mechanisms of injury in humaninfants. Several other neuroprotective strategies,including erythropoietin and hypothermia, areunder investigation for brain injuries in these modelsand in clinical trials. These studies may lead tobetter therapies to salvage brain tissue.

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Acquired brain injury, managementin emergency casesRydenhag, BertilSahlgrenska University Hospital, Neurosurgery,Goteborg, Sweden

Background: Severe traumatic brain injury will givelife-lasting neurological deficits at least to someextent in those children who survive. Previousmortality reports have been as high as 30–50%depending on the inclusion criteria. The last15 years, a tremendous develoment has takenplace in the understanding and treatment of severetraumatic brain injury, specialised neurointensivecare units have been developed the last 20 years.From some centers specific neurointensive treat-ment protocols have been described, such as the“Lund concept” from Sweden. These protocols areoften combined with aggressive surgical treatmentsuch as decompressive craniectomy. Specific pae-diatric guidelines for traumatic brain injury has alsobeen published.Methods: In the presentation an overview will begiven of the managent of severe traumatic braininjury from the perspective of a neurosurgeon and

European Journal of Paediatric Neurology (2005) 9, 129–134

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the neurointensive care. Some historical commentswill be given and selected published treatment andoutcome studies will be presented. Features specialfor the paediatric population will be higlighted andsome of the problems that may be connected withsurvival after severe brain injury regarding therehabilitation and long-time outcome.Results and conclusions: The incidence of severetraumatic brain injuries in children are decreasingin Sweden, but figures are different for differentparts of the world. The modern treatment protocolsand specialised neurointensive departments havesubstantially increased the survival rates forchildren after severe brain injury. Mortality ratesas low as 5–10% are reported. Over 60% goodoutcome is also reported in some studies. Optimaltiming and resourses for rehabilitation programmesfor the children surviving after severe traumaticbrain injury are of great importance.

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I Children with severe epilepsyCross, HelenUK

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II Severe epilepsy in childrenTuxhorn, IngridGermany

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Lysosomal storage diseases: currenttreatment prospectsPercy, AlanUniversity of Alabama at Birmingham, Birming-ham, USA

Following remarkable advances over the last halfcentury in moving from clinicopathologic descrip-tions of the lysosomal storage diseases to under-standing their biochemical and molecular bases,effective treatment is now available for many. Thefuture holds promise that still others will beamenable to therapeutic interventions. Treatmentmethodologies first emerged for Gaucher diseasewith the harvesting of sufficient quantities ofreplacement enzyme, glucosylceramidea-glucosidase, from human placenta. The develop-ment of recombinant technologies has allowed theexpansion of enzyme production for this and otherlysosomal hydrolases including the acid hydrolasesassociated with Fabry, Pompe, and Hurler diseases.Implementation of enzyme replacement therapy

(ERT) has raised important issues related to enzymetargeting to affected tissues, implementation ofmeaningful outcome measures, and a clear under-standing of the natural history of each disease, thevariability of clinical expression within each disease,and the role of environmental and other geneticfactors in modifying disease expression. Initialsuccess has been achieved in the treatment ofdiseases generally sparing the central nervoussystem (CNS). Recent efforts have explored diseaseswith significant CNS involvement including neurono-pathic forms of Gaucher disease and the mucopoly-saccharidoses. Additional strategies in combinationwith ERT are being increasingly evaluated includingsubstrate reduction and bone marrow transplan-tation. The ultimate goal remains insertion of therespective gene for the missing or defectiveenzymes. Progress in this area is being made inanimal models. Until this modality becomes avail-able, effective therapy will rely on ERT and relatedstrategies. Regardless of the mode of therapy, amultidisciplinary approach involving the expertiseof many individuals including basic scientists,physicians, counselors, therapists, nutritionists,and social service is essential.

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Mitochondrial disorders: current treat-ment and managementPihko, HelenaFinland

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I The prevalence of paediatric movementdisordersFernandez-Alvarez, EmilioSpain

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II Paediatric movement disorders quizGrattan-Smith, PadraicAustralia

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Congenital muscular dystrophies: musclemeets its matrixBonnemann, CarstenThe Children’s Hospital of Philadelphia, andPennsylvania School of Med., Div of Neurology,Philadelphia, USA

Invited speakers for the Sixth European Paediatric Neurology Society, EPNS Congress 131

The group of congenital muscular dystrophies (CMDs)is quite heterogenous clinically. Patients usuallypresent at birth or in infancy with weakness as wellas histological evidence for a dystrophic process thatcan be of variable severity. Two major pathophysio-logical groups that can be recognized so far includeon the one hand conditions that are caused bymutations in genes that are involved in theO-mannose linked glycosylation of the matrixreceptor alpha-dystroglycan as well as mutations inthe alpha2 chain of its ligand laminin-2 (merosin),and on the other hand mutations in the three genesconstituting collagen VI, a ubiquitous microfibrillarcomponent of the muscle extracellular matrix. Thus,a common theme of disturbed muscle/matrixinteractions seems to emerge for CMD. Mutations inlaminin-2 (merosin) cause a relatively common formof CMD with evidence of abnormal white mattersignal on T2 weighted MR images of the brain. Thedisorders affecting alpha-dystroglycan glycosylationrange in spectrum from Walker Warburg syndrome,via Muscle eye brain disease, Fukuyama congenitalmuscular dystrophy, congenital muscular dystrophywith mental retardation, to pure congenital muscu-lar dystrophy without evidence of CNS involvement,merging with a spectrum towards even milder limb-girdle muscular dystrophy (for FKRP mutations).Genes incolved include POMT1, POMGnT1, LARGE,Fukutin, and FKRP, with considerable phenotypicheterogeneity for most of these genes. In contrast,the collagen VI related disorders CMD types Ullrichand Bethlem are characterized by a notable connec-tive tissue component manifesting as joint laxity andcontractures in addidition to the muscle involve-ment, but without central nervous system involve-ment. Again a very broad spectrum of phenotypicseverity is apparent for the collagen VI disorders. Themechanisms of disease causation for the two majortypes of mechanism outlined are still insufficientlyknown but may in fact be quite different. Finally, anincreasing number of clinical CMD phenotypes but asyet unknown genetic defects are being recognized.

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Treatment of neuromuscular disorders:facts and fictionsMuntoni, FrancescoImperial College, Pediatrics, London, UK

Neuromuscular disorders (NMD) have traditionallybeen considered as untreatable disorders. In therecent years however it became clear that the useof pharmacological approaches can improvemuscle strength and outcome in individual

conditions. This is best exemplified by the recentdata related to the use of corticosteroids to slowdown muscle weakness and Ace inhibitors toimprove cardiac function in Duchenne musculardystrophy (DMD). Clearly these approaches havetheir own limitations and considerable preclinicalresearch is focused on gene and stem celltherapies of NMD. However, significant technicalchallenges remain regarding their use in thehuman and it is anticipated that these approacheswill take several more years before they could bewidely available in the clinical settings. However,the improved understanding of the molecularpathogenesis of several neuromuscular conditionsis allowing to devise therapeutic approaches thatare likely to result in benefit to patients affectedby NMD. As far as DMD is concerned for example,a shortcut to the great technical challenge ofreplacing the entire dystrophin gene has beendevised by using antisense oligonucleotides whichfunction as molecular patches partially “repair-ing” the genetic defect induced by the deletionswhich characterize most DMD patients. Earlyphase I-II clinical trials are underway using thisapproach. Similarly in spinal muscular atrophy(SMA), therapeutic trials using drugs capable ofincreasing the production of functional SMNprotein from the SMN2 gene are underway orplanned. The increasing recognition of moleculartargets in NMD is likely to result in an increase inthe diversity of the therapeutic approachesavailable for patients with NMD in the years tocome. The hopes and challenges for both thepatients and treating physicians raised by thesenovel approaches will be presented.

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Brain development and learning abilityP AndersonDept Physiology, Inst Basic Medical Science,University of Oslo, Norway

Recently, we have witnessed great advance inunderstanding the principles guiding the develop-ment of the central nervous system. A number ofthe instructive and controlling genetic factors havebeen identified and some of the interactingmechanisms between genes and cellular signalingcascades have been defined. The publication of theannotated and corrected form of the HumanGenome in March 2003 was a major landmark. Ithas already led to significant understanding ofgenetic influences on normal behaviour and diseasestates.

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Of the roughly 25,000 human genes just over 50per cent is engaged in the construction of the brainand spinal cord. Once constructed, roughly 30 percent of the genes are played upon in the dailyoperation of our nervous system.

Fortunately, the genetic make-up of variousorganisms show a remarkable homology, not onlybetween various vertebrates, but also between manand insects and worms. The many general patternshave facilitated the analysis of the early part ofbrain development and raise the hope for correc-tive procedures for certain processes underlyingmalformations.

For child neurology, psychiatry, psychology andpedagogy a particularly important discovery hasbeen the finding that cortical development has itsmost intense phases relatively late in pregnancyand that important cellular and connectionistdevelopmental stages carry on in the first fewyears after birth.

A number of examples are now known of therelation between specific genes and the suscepti-bility for diseases or specific behavioural traits.These co-operative mechanisms have demon-strated a complex interplay of genetic and epige-netic signals. Nature and Nurture certainly interact.

More opportunities do seem to exist for plasticchanges in the construction and operation of short-distance connections, a fact of intense interest forpatients in need of rehabilitation.

Technical developments has given a long list ofprocedures for recording developmental steps andfor detection of aberrations of the normalsequence. Some of these procedures may beapplicable for improved diagnosis and therapeuticapproaches.

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Pontocerebellar hypoplasias—an updateBarth, PeterEmma Children’s Hospital /University of Amster-dam, Pediatric Neurology, Amsterdam,Netherlands

The MR image showing a flat profile of the ventralpons in combination with hypoplasia or atrophy ofthe cerebellum is found in a variety of non-relatedgenetic disorders including CDG type 1a, Brain-Muscle-Eye disease, and Walker-Warburg syn-drome. A separate group of fetal onset neurode-generations known as pontocerebellar hypoplasiasis characterized by autosomal-recessive inheri-tance, cerebellar atrophy/hypoplasia, mainlyaffecting the hemispheres, subtotal loss of ventral

pontine neurons and progressive microcephaly.These disorders are known collectively as pontocer-ebellar hypoplasias with type I affecting spinalanterior horn cells, and type II having clinicalinvolvement of the extrapyramidal system leadingto dystonia/dyskinesia. A third type links to chr.7q11-21 and does not feature dystonia (Rajab et al2003). The focus of this lecture will be on type II.New findings from a large affected family cluster inthe Netherlands confirm that some patients havespasticity without dystonia. Cerebellar atrophy maybe more prominent than (fetal) hypoplasia in somecases. A severe variant or separate disorder withpolyhydramnios, and impressive neonatal (myo)-clonus exists. Neuropathological evidence supportsa relationship to PCH-2. Growth of the cerebellumin PCH-2 during pregnancy tends to level off notearlier than the third trimester, making ultrasoundunreliable for antenatal diagnosis. A cooperativePCH-2 mapping project by the University ofAmsterdam and the Gene Mapping Center (MDC)Berlin, so far has resulted in a single locus onchromosome 17q (lod score 5.07, extent ofcandidate region 3.04 Mb). Present efforts aredirected at sequence analysis of candidate genesin this region.

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Aspects on treatment in Attention-defi-cit/hyperactivity disorder (ADHD)Christopher GillbergSweden

Attention-deficit/hyperactivity disorder (ADHD) is acommon condition, affecting several per cent ofschool age children and at least a few per cent ofadults. It is more common in boys than in girls, butmany girls, even with major ADHD problems, arecurrently missed. ADHD is very often associatedwith other conditions, including oppositional andconduct problems, depression and anxiety, tics andautistic features, and a variety of learning difficul-ties. It predisposes to or is the forerunner of amultitude of adult psychiatric disorders. Theheritability of ADHD has been well established anda majority of affected individuals have closerelatives with similar and overlapping types ofproblems. All of these issues need to be taken intoaccount when discussing “treatments”. The highprevalence of the disorder calls for simple inter-ventions that can be applied to large groups ofchildren without the need for highly specializedtreatment in all cases. Psychoeducational interven-tions in society, including in the school setting

Invited speakers for the Sixth European Paediatric Neurology Society, EPNS Congress 133

(such as education of teachers regarding ADHD andrelated issues, raised public awareness, handbookson the benefits of understanding rather thanrejecting attitudes, structure and predictability inthe environment, and the application of a long-term, indeed often life-time, perspective) arecrucially important. The overlap with other typesof conditions warrants screening for such problemsas soon as a diagnosis of ADHD has been made.

Specific treatment (including medication in somecases) should target attentional, hyperactive andimpulsive symptoms in severely affected individ-uals, and take into account the need for focusedinterventions depending on types and degree ofassociated “comorbidity”. Professional teams mustnot be so overly focused on ADHD that they cannotdiagnose and intervene when there are otherproblems. The high rate of ADHD in families,suggests that it is important for professionalteams to be aware of the need for additional helpto members of the extended family once a child hasbeen diagnosed as suffering from ADHD. Only whenthe whole family receives state-of-the-are help,will children with severe ADHD benefit fully fromthe interventions directed at him/her.

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Treatment in autismRapin, IsabelleAlbert Einstein College of Medicine, Bronx NY, USA

There is no curative treatment for autism, abehaviorally complex consequence of aberrantstructure and function of the immature brain withmany, mostly genetic, etiologies. The goal ofindividualized intervention is to enable children tofunction optimally within the limitations of theirbiologic constraints.

Intensive specialized education of children andtheir parents is the most effective interventionavailable to mitigate core symptoms and shapebrain development and function. Operant con-ditioning powerfully trains joint attention andfosters compliance, skills essential for educationalprogress. Education must address both communi-cation and social issues, help children developmore effective play and adaptive skills, andattempt to extinguish undesirable behaviors. Thepsychic health of the family needs attention.Educators need to teach parents optimally effec-tive parenting skills so they can adapt to homesome powerful behavioral techniques research hasdeveloped. Older more able children can betaught social skills in interactive dyadic or triadic

groups given specific tasks requiring cooperation.Visual organizers are a useful for teachingeffective communication, planning, and organiz-ation skills.

The role of pharmacotherapy is to targettroublesome behaviors, considering the safetyprofile and potential side-effects of medications.The goal is the smallest dose for the shortest timepossible. Some children require no medication,whereas others benefit from stimulants, neurolep-tics, or anticonvulsants. There is no consensus on aneffective treatment for autistic/languageregression. Surgery is limited to the rare childwith intractable epilepsy. Many other interventionslike special diets, vitamins, discredited drugs likesecretin, and behavioral therapies like sensorystimulation, hippotherapy, and others have onlyanecdotal evidence of efficacy and are notrecommended.

Empirical evidence regarding the efficacy edu-cational and pharmacologic interventions is neededbecause escalating amounts of public and privatemonies are being spent without scientific infor-mation regarding their effects on the developingbrain, long term safety and efficacy.

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Cerebral palsy—aetiology, morphologyand functionKrageloh-Mann, IngeborgUniversity Children’s Hospital, Department ofPediatric Neurology, Tuebingen, Germany

Cerebral Palsy (CP) is considered a group ofdisorders with different aetiologies, constituting,however, a useful socio-medical framework forcertain motor disabled children with special needs.Many countries run registers, which are importantfor service planning and for monitoring trends in CPrate. However, it was difficult to compare resultsfrom these registers due to the lack of consensus ondefinition and sub classification. Therefore, anetwork funded by the EU, the SCPE (Surveillanceof Cerebral Palsy in Europe), has worked on thestandardisation and harmonization of definitions.CP is described on a neurological and functional/-behavioural level. The neurological subtypesinclude spastic CP (bilateral and unilateral types),dyskinetic (further sub classified into dystonic andchoreoathetotic) and ataxic CP. The functionalseverity is further characterized with the help ofstandardized functional scores.

Another major progress in CP research comesfrom neuroimaging. Pathogenic events affecting

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the developing brain cause abnormalities/lesions,the pattern of which depend on the state of braindevelopment. Identifying these patterns by meansof MRI helps to time the major period for CPpathogenesis. There is increasing evidence, thatthe majority of CP cases, e.g. 70–75%, show clearlesional patterns of different timing. Maldevelop-ments are rare. In spastic CP, topography of thelesion determines unilateral or bilateral involve-ment; preterm born children show lesional patternscorresponding to their gestational age and termborn children show in about 2/3 clearly prenatalpathology (mainly early 3rd trimester) and in about

1/3 lesions arising around birth. Dyskinetic CP isdominated by basalganglia/thalamus-lesions,which explains its main prevalence in term bornchildren. Ataxic CP is mainly non-lesional inpathology.

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Genes and development: from patient topathwayDonnai, DianUK