Pecas issue 6

Volume Two | Number Two | May 2007
Initial SANAD Findings Published
The recently published SANAD Study was a randomised ‘newer’ AEDs. Recruitment commenced in 1999 (although controlled trial of longer-term clinical outcomes and cost- oxcarbazepine was only included after 2001) and ended in effectiveness of Standard And New Antiepileptic Drugs 2004 and follow-up continued until 2005. The study (hence the title SANAD). The aim of the study was to achieved an extremely impressive follow-up rate of 98%.
compare most of the ‘new’ antiepileptic drugs (AEDs) Primary outcomes were similar to those commonly-used in (gabapentin, lamotrigine, oxcarbazepine, topiramate), with most antiepileptic drug studies and included ‘time to the older or ‘standard’ drugs, carbamazepine and sodium treatment failure’ and ‘time to 12-months remission’.
valproate, to find out whether the newer drugs are more Secondary outcomes included time to first seizure, time to effective in controlling seizures or have fewer side effects1,2 24-months remission and adverse events and a number of (the ‘genuinely’ new AEDs, levetiracetam and zonisamide quality of life measures such as the quality adjusted life year were not included as they were licensed for use in the UK after 2000, and it was not felt appropriate to includetiagabine). Because the new drugs are more expensive for the HealthService than the older drugs, it is important that any EDITORIAL ADVISORY BOARD
additional benefits from the new drugs are identified tojustify the additional costs. The National Institute for Clinical Excellence (NICE) suggested that this type of study might provide information that would allow evidence-based decisions to determine the first choice of treatment for epilepsy. The study was subsequently commissioned by the Health Technology Assessment (HTA) Programme of NHSResearch and Development (R&D). The study was a randomized yet highly pragmatic study recruiting over 2400 patients, approximately 350 of whom were children aged 5 years and above involving all types ofepilepsy. This represents the largest ever randomized study ofantiepileptic drugs and as well as providing efficacy and CONTENTS
toxicity data, also provides some related quality of life andhealth-economic data. The study was independently-fundedby the HTA NHS R&D with additional but considerably smaller contributions from the pharmaceutical industry. The studycomprised of two arms; Arm A, which was regarded as the The Excess Risk of Injury and Mortality in focal or partial epilepsy arm and Arm B, which was regarded as the generalized epilepsy arm. Drugs in Arm A were carbamazepine as the ‘standard’ AED with gabapentin,lamotrigine, oxcarbazepine and topiramate as the ‘newer’ 15. MSc Epilepsy Practice (by distance learning) AEDs; drugs in Arm B were sodium valproate as the ‘standard’ AED and lamotrigine and topiramate as the The study’s findings suggested two interpretations: The SANAD Study has provided a new genre of evidence in the Arm A: ‘Lamotrigine is clinically better than carbamazepine,
use of AEDs and has also demonstrated that extensive the standard drug treatment, for time to treatment failure (national) collaboration is possible using a randomized yet outcomes and is therefore a cost-effective alternative for pragmatic design which should facilitate patient recruitment.
patients diagnosed with partial onset seizures’1.
Specifically, this could encourage a greater recruitment ofchildren to national studies which should address one of the Arm B: ‘Valproate is better tolerated than topiramate and
more justifiable concerns of the SANAD Study, namely that the more efficacious than lamotrigine, and should remain the drug majority of the patients, particularly in Arm A, were adults. The of first choice for many patients with generalized and concept and methodological approaches adopted by SANAD unclassified epilepsies. However, because of known potential should serve as a good starting point for the design of future adverse effects of valproate during pregnancy, the benefits for studies, and particularly exclusive paediatric studies, along the seizure control in women of childbearing age should be lines of our Dutch paediatric neurology colleagues4 which has produced and will continue to produce a wealth of informativeand longitudinal, population-based papers on the epilepsies of It is important to understand that the study was not designed to answer many important and outstanding issues in not justadult epilepsy but the paediatric epilepsies and that furtherreports will be published in the near future, including assessments of drug efficacy and tolerability (ie: drugretention) by epilepsy syndrome. The study was not designedto identify one drug that would ‘fit all’ in terms of seizure typeand epilepsy syndrome. This would clearly be unrealistic and Reference
unachievable based on the heterogeneity of the epilepsy 1. Marson AG, Al Kharusi A, Alwaidh H, et al. The SANAD Study syndromes and underlying aetiologies and the enigmatic of efficacy of carbamazepine, gabapentin, lamotrigine, phenomenon of pharmacoresistance. It would also be naïve to oxcarbazepine or topiramate for treatment of partial epilepsy: an imply and wrong to expect that the findings of the SANAD unblinded randomised controlled trial. Lancet 2007; 369: 1000-15 Study would necessarily change the current prescribing 2. Marson AG, Al Kharusi A, Alwaidh H, et al. The SANAD study approach of paediatricians and paediatric neurologists. The of effectiveness of valproate, lamotrigine or topiramate for Lancet’s Editorial comment on the study (pages 970-1) raises generalised and unclassifiable epilepsy: an unblinded randomised this issue and suggests that the study, “In designating one controlled trial. Lancet 2007; 369: 1016-26.
drug as first choice may reduce the likelihood that a physician 3. French JA. First-choice drug for newly diagnosed epilepsy.
will make an effort to match the drug to the patient”3. Whilst in theory this may be correct, I consider that this is unlikely inpractice for the reasons stated earlier and particularly in 4. Brouwer OF, van Donselaar CA, Stroink H et al. The DutchStudy of Epilepsy in Childhood: design of the study. Epilepsia children where their management, including the initiation of an antiepileptic drug, is far more likely to be undertaken by apaediatric neurologist or paediatrician, and increasingly by apaediatrician with both an interest and expertise in epilepsy. Itis far more likely than not that the choice of antiepileptic drugwill (still) be tailored to the individual patient and the clinicalsituation.
The excess risk of injury and mortality in
childhood epilepsy
Dr Daniel Hindley, Consultant Paediatrician, Bolton PCT
Introduction
I have direct experience of the sometimes peculiar restrictions
5. Sherrard et al 20025. In 451 young people (age 5-29 years) that are applied blanket fashion to children with epilepsy; ‘you with intellectual disability injury risk was associated with can’t take your cycling proficiency’, ‘you can’t use a computer’, psychopathology (odds ratio [OR] 3.4), epilepsy (OR 2.4) and ‘you can’t use that electric nit-comb’ or ‘footbath’, ‘you can’t overly sociable temperament (OR 2.2).
have your belly-button pierced’. When challenged theserestrictions prove groundless but they do potentiate the stigma 6. Wirrell et al 19966. In a retrospective study of 59 young attached to the diagnosis of epilepsy and limit needlessly the adults with absence epilepsy 27% reported sustaining at least life experiences of children with the condition. They spring one injury and suffered more bicycle and car accidents than from ignorant perceptions about the risks of seizures and 7. Beghi 2002 & van den Broek 20047,8 A large prospective Health professionals too can be influenced by their perceptions European case control study of 951 people with epilepsy of the risks of epilepsy. We may feel a pressure to make a (including 233 children aged 5 – 15 years) showed a diagnosis of epilepsy sooner than we should, and reach for the cumulative risk of an accident of 17 and 27% by 12 and 24 prescription pad unnecessarily if we are concerned that there is months respectively (controls 12 and 17%, p<0.0001). Most a high risk of a child suffering injury or death if seizures accidents were not serious and the excess risk was caused by continue. Our confidence in this area can be easily shaken by seizure related events7. The risk compared to controls was anecdote; ‘did you hear about Dr X’s patient with benign highest for concussions, abrasions and wounds. Accidents rolandic epilepsy who died, wasn’t on treatment you know!’ were more likely in those with generalised and activeepilepsies8.
This paper attempts to summarise some of what is knownabout the excess risk of injury or death in childhood epilepsy so My own experience is that for most children the risk of injury that decisions can be based on our current state of knowledge due to seizures is small. Those who have suffered significant and repeated injuries have usually been independently mobile,had poorly controlled generalised tonic-clonic or a/tonic The excess risk of injury
seizures without warning and have had learning difficulties or There is limited published research about the risk of injury for challenging behaviours that make adequate supervision 1. Appleton 20021. This examined the risk of injury in 198 The International League Against Epilepsy (ILAE) have newly diagnosed and untreated children age 1-16 years with at published guidance on ‘Restrictions for children with least two unprovoked afebrile seizures of any type. 25 (12.6%) suffered an injury of whom 4 (2%) required medical attention.
Most injuries (17) followed generalised tonic-clonic seizures, 1. Decisions should balance the need to encourage the child’s continued self-development ……. against the need to protectthe child and others against physical and emotional injury.
2. Ziegler et al 19942. 198 children without motor or learning 2. Restrictions when necessary should be tempered by disability were followed for 10 years; 6 accidents without 3. Medical personnel should be facilitators and provide themeans for families to be creative in appropriately 3. Kirsch et al 20013. In 31 children with epilepsy and normal individualising limitations tailored to their child’s needs.
cognitive function the injury rate was identical to the matchedcontrol group without epilepsy.
To achieve this practitioners need an understanding themselvesof the risk of injury based on the child’s age; seizure type; 4. Deekollu et al 20054. 33 children requiring helmets because seizure frequency; timing, triggers and location of seizures; of severe epilepsy had 14,751 seizures and 59 injuries in 1 year.
compliance and other co-morbid diagnoses. In general for a Injuries occurred despite provision of helmets and suggestions child with well controlled seizures this means that very few were made on how to prevent injuries in this highly selected restrictions are required (advice about bathing), whereas for a child with frequent atonic seizures a personalised risk Dr Daniel Hindley,
Consultant Paediatrician,
Bolton PCT
assessment is required of his/her environment and activities to 3. Taking a balanced view of the degree of supervision,
keep him/her safe. Chappell and Brown10 have proposed 3 adaptation of the environment or adaptation of
equipment that might be necessary.
• 1. Obtaining an accurate description of the nature and If this stage is reached, it is perhaps reasonable for the person requirements of the activity in question.
to go fishing with a friend (extra supervision), who knowsabout the seizures and is capable of removing the person from • 2. Ensuring that appropriate essential information about the individual's seizure disorder is available. Are seizures predictable or unpredictable; predictable being aura always, It may be possible to fish in shallow water (up to four feet in pattern always, “trigger” always or no seizures for greater depth) (adaptation of the environment) if the friend is not a strong swimmer. It may also be possible to fish in places whereit is virtually impossible to fall into the water if a seizure occurs.
• 3. Taking a balanced view based on the above regarding the necessary degree of supervision, adaptation of the It may be possible to purchase equipment that secures the environment or adaptation of equipment, that might be person to the boat or river side (adaptation of equipment).
Using this model of assessment it is nearly always possible to They provide an interesting example for the activity of fishing make fishing or just about any activity ‘a safe activity’.
NICE guidance11 suggests that advice and information is 1. The nature and requirements of the activity
routinely given at diagnosis on safety issues and repeated at The perceived danger is standing in or being close to open follow up. A very helpful leaflet on Safety is produced by water for periods of time. As people with epilepsy are known to have an increased risk of fatal water-related accident thanthe general population, this is a reasonable perceived danger.
The excess risk of mortality
The overall standardised mortality ratio for children with
2. Providing essential information about the individual's
epilepsy is reported to be 7–13.213-16 (adults 2–317,18). As epilepsy seizures
in childhood is frequently associated with other life limiting The frequency of seizures might for example be low. If the neurological conditions this excess mortality does not equate person had none for the last year, then he or she would be to excess mortality caused by seizures. The latter results from legally entitled to hold an ordinary driving licence. The deaths due to injury caused by seizures, deaths due to status actuarial statistics on which decisions about eligibility for epilepticus and some sudden unexpected deaths due to driving licences are based suggest such a seizure-free interval carries a very low risk of recurrence in everyday life. The contribution of non-seizure related deaths to the excess If the person was still having seizures but there was an mortality found in children with epilepsy is demonstrated by established pattern where seizures only occurred while asleep, two large longitudinal studies from Holland15 and Canada16.
or on wakening, the risk of such seizures occurring while Combining the results 1162 children were enrolled. There were 35 deaths. 31 occurred due to underlying co-morbid CNSdisease, 2 were suicides and 1 each murder and SUDEP, i.e.
If seizures still occurred during waking hours but always in possibly one death directly attributable to a seizure (the SUDEP response to a specific “trigger” factor (precipitant) that was death was not witnessed). The standardised mortality ratio for not present during fishing, then the activity would still carry a children with idiopathic epilepsy and no cognitive/neurological deficit was 1; that for children with symptomatic epilepsy was22.
Even if seizures still occurred by day with no identifiable triggerfactor, the person might still have a useful subjective warning of an impending seizure and have time to remove from Apart from drowning there are very few published reports of proximity to water before the seizure started. deaths due to accidents caused by seizures in children. In theseven papers mentioned earlier six give no reports of deaths In circumstances such as those outlined above, the risk may be due to injury. The van den Broek8 paper does report 2 deaths, regarded as low. Of course the person may still prefer to have one in a car accident and another after inhalation of food someone else present for the duration of the activity, and this during a seizure; the ages of the individuals are not given. One may depend on seizure type and severity.
review18 states that deaths due to accidents in people with If none of the above factors apply, then the seizures should be epilepsy are ‘not rare’ but most of the references concern regarded as unpredictable, and risk assessment must move to studies in adults – even these suggest that deaths due to accidents caused by seizures are infrequent. Again deaths mayoccur more commonly in people with epilepsy because of concomitant neurological impairment rather than due to cannot provide accurate incidence figures and risk factors for SUDEP in children with epilepsy because of under-reportingand inappropriate coding of both epilepsy and the precise There are clearer data about the risks of submersion injury and cause of death.’ He advocates a large community-based drowning in children with epilepsy20,21. The risk of submersion injury is about four times that of children without epilepsy. Ina population based cohort study the relative risk of drowning One wonders whether sudden deaths that occur in people with for children with epilepsy was 96 in the bath and 23 4 in epilepsy are sometimes attributed to SUDEP without sufficient swimming pools. The number of these drowning deaths due to investigation; that the known association leads to death seizures is unknown as by their nature these events are usually certificates being completed where for other sudden deaths this would not be possible. More rigorous contemporaneousscrutiny of the circumstances of epilepsy related deaths in b) Deaths due to status epilepticus children would help to clarify these important issues. This could In the Dutch and Canadian population-based follow up studies be done by a prospective Confidential Enquiry or perhaps by no child died in status epilepticus (or as a result of the ‘orange card’ system run by the Paediatric Surveillance Unit injury/accidents)15,16. In a prospective community based cohort at the Royal College of Paediatrics and Child Health. This is a study22 9.5% of children had one or more episodes of status monthly card reporting scheme relying on responses from epilepticus after being given a diagnosis of epilepsy. A history British paediatricians which allows the gathering of of previous status epilepticus, young age and symptomatic epidemiological data on rare childhood diseases.
epilepsy were strong risk factors, and mortality was higher inchildren with status before diagnosis largely secondary to the 3. How common is SUDEP in children? In adults the incidence
underlying cause. Several other studies have shown that the ranges from 1–2 per 1000 person years in population based morbidity and mortality of status epilepticus is low in the studies26 to 1 per 100 person years in a cohort of candidates for absence of acute neurological insult or progressive epilepsy surgery27. There are a number of studies in children but most suffer from the problems of definition and caseascertainment already mentioned.
c) Deaths due to SUDEPThis is a confusing and fraught subject! There are so many • Harvey et al 199313. A community based study of children less than 14 years. 12% of 93 deaths over a 5 year period considered to be SUDEP.
1. What is the definition of SUDEP? These differ. One
• Nashef et al 199528. Children age 11–15 years with severe suggests that SUDEP is, ‘the sudden, unexpected, witnessed or epilepsy at a specialist residential school with 4135 person unwitnessed, non-traumatic or non-drowning death in years follow-up. 20 of 28 deaths were epilepsy related of patients with epilepsy, with or without evidence for a seizure which 14 were considered SUDEP. An incidence of 1:295/ and excluding convulsive status epilepticus in which post- year for sudden deaths was found. Coroner’s reports and mortem examination does not reveal a toxicological or post mortem findings were available for 11/14.
anatomical cause for death’23. Another suggests, ‘SUDEP is a • Camfield and Camfield 199929. This was a population death occurring in an individual with epilepsy, who dies based follow-up study of 693 children with epilepsy. There unexpectedly while in a reasonable state of health, and with were 25 deaths from a variety of causes. The only child to death happening suddenly (in minutes), and during normal die of SUDEP was 21 years old and had tuberous sclerosis, activities and benign circumstances, without obvious medical frequent seizures and poor medication compliance.
cause, and not as a result of a seizure or status epilepticus’24.
• Donner et al 200130. Documented an incidence of 1 per Different studies and reviews use different definitions. ‘With or 10000 person years for SUDEP in childhood.
without evidence of a seizure’ and ‘not the direct result of the • Weber et al 200531. Cases of SUDEP in children attending a seizure’ are difficult to reconcile.
paediatric hospital in Switzerland over an 18 year period. 4cases were identified. The incidence was 4.3 per 10000 2. What are the problems with case ascertainment?
Appleton summarised the difficulties of retrospective caseascertainment in his 1997 paper25 ‘Sudden unexpected death in 4. What are the risk factors for SUDEP in children? A recent
epilepsy in children’. Death certificates from all children (< 15 systematic review32 of the current literature has suggested that years) dying with or due to epilepsy in 1993 were examined.
young age (< 45 years), early onset of seizures (< 45 years), Ninety seven such death certificates were found, 60 from generalised tonic-clonic seizures, male sex and being in bed children with epilepsy and another condition, and 37 with were strong risk factors for SUDEP. Weak risk factors were epilepsy as the only diagnosis. Of these 37, 24 died due to a prone position, sub-therapeutic blood levels, being in complication of epilepsy (e.g. drowning, status epilepticus, bedroom, a structural brain lesion and sleeping. Some aspiration) and 13 due to epilepsy alone. In the latter group interesting factors not considered to be risks for SUDEP were only the word ‘epilepsy’, ‘epileptic seizure/convulsion’, or symptomatic epilepsy, high frequency of seizures, learning ‘grand mal convulsion’ appeared in the ‘Cause of death’ difficulties, increasing numbers of prescribed antiepileptic section. He comments that, ‘retrospective mortality data drugs (AEDs) and poor compliance with AEDs. This study relies Dr Daniel Hindley,
Consultant Paediatrician,
Bolton PCT
on studies in adults. The risk factors differ dramatically from a of diagnosis and 50% when seizures proved difficult to control.
similar study which gives risk factors as a seizure before death,sub-therapeutic AED levels, youth (15-30 years), high seizure 6. Personal note.
frequency, high number of AEDs and long duration of epilepsy looked after in a District General Hospital clinic five epilepsy33. These differences are said to be explained by different definitions of risk factors and differing methodology.
• Age 11 months died of multi-organ failure following a It is difficult to be clear about risk factors when pooled prolonged bout of status epilepticus. He had poorly literature reviews give contradictory findings.
controlled seizures, microcephaly, spastic quadraparesis andglobal developmental impairment following severe There are similar contradictions in the children’s literature with postpartum hypoxic ischaemic encephalopathy.
all children in one study having early onset, polytherapy and • Age 9 months. Died in her sleep unwitnessed. She had refractory epilepsy with developmental delay31, whereas in an global developmental impairment and occasional seizures alternative study polytherapy was not significant and 30% of following cystic encephalomalacia caused by herpes cases occurred in children with idiopathic epilepsy30.
• Age 2 years. Died of pneumonia. Severe global In 2002 the National Sentinel Clinical Audit of Epilepsy-Related developmental impairment with incompletely controlled Deaths34 was published. This focussed on the investigation of epilepsy due to neuronal migration disorder.
epilepsy related deaths, the care of patients before death and • Age 4 years. Died in bed with his Mum. Severe probably the care of bereaved families. Disclosure of information to this symptomatic epilepsy with severe learning difficulties but study was voluntary so that there was limited information little motor impairment. SUDEP following post mortem.
available. Of 81 childhood deaths in the 12 months of the • Age 14 years. Drowned in the bath. Frequent severe audit period information was only available for 22 cases. Most secondarily generalised tonic-clonic seizures probably of of these children had early onset, poorly controlled epilepsy frontal lobe origin resistant to all treatments tried.
and other neurodisabilities. The authors suggest that SUDEPwas considered to have been a possible cause of death in at I do not routinely talk about SUDEP to all families at diagnosis.
least 6 of the 22 audited children but acknowledge that clear I do work with a Children’s Epilepsy Specialist Nurse who gets ascertainment of this was hampered by the lack of medical and to know the families very well. If this is raised as an issue by families we talk about it. We explain that the risk is small andthat the research in children is patchy and confusing. Very 5. Giving families information about SUDEP in children?
occasionally we have raised the issue ourselves; sometimes it There is NICE guidance about this vexed question11. It states has been constructive, at other times less so. I feel it is hard to that, ‘information on SUDEP should be included in literature be dogmatic about this given our current state of knowledge provided about epilepsy to show why preventing seizures is and the amazingly varied scenarios and attitudes we come important. Tailored information on the individual’s relative risk across in our daily work. We could learn a lot more to inform of SUDEP should be part of the counselling checklist for people ourselves and the families of children and young people with with epilepsy and their families (recommendation level 3).’ It epilepsy better with a National Confidential Enquiry into also states that, ‘the risk of SUDEP can be minimised by Epilepsy Related Deaths in Children as has been conducted for optimising seizure control and being aware of the potential consequences of nocturnal seizures (good practice point)’ andthat, ‘tailored information and discussion between the Conclusion
individual with epilepsy, family and/or carers (as appropriate) To coin a generalisation, with epilepsies generalisations are and healthcare professionals should take account of the small unwise. There is evidence that there is an increased risk of but definite risk of SUDEP (recommendation level 3).’ There is accidents, injury and death but this varies from a minimal to a no guidance on when and how this information should be serious concern depending on the individual’s predicament.
This evidence with regard to children with epilepsy is notrobust. There is difficulty distinguishing risk due to epilepsy The SIGN guidelines35 state, ‘that there is no general consensus from risk due to associated co-morbid conditions.
on when the risks of SUDEP or other causes of premature deathshould be discussed with families but that it may be In an attempt to avoid overprotection and exclusion in appropriate to discuss this issue with parents of children with everyday life it is useful to inform children and families about symptomatic epilepsy or drug resistant epilepsies with tonic- very simple risk assessment, as per the process described by Chappell & Brown10. This does bring some sort of logic intowhat children can and should do, irrespective of their epilepsy.
In a recent survey of UK and Irish paediatric neurologists36 20%of respondents stated that they discussed SUDEP with all The discussion of SUDEP does continually present a challenge families with a child with epilepsy, 7% never did and 74% and Internet access means more families will be aware of it and provided information to a group that included those with therefore take the lead in discussion as opposed to the intractable seizures, nocturnal seizures, symptomatic epilepsy professional choosing ‘when’ (NICE11 & SIGN35 do not really and surgical candidates. 30% provided information at the time References
1. Appleton RE. Seizure-related injuries in 26. Ficker DM, So EL, Shen WK et al.
Population based study of the incidence of sudden unexplained death in epilepsy.
2. Ziegler AL, Reinberg O, Deonna T.
14. Sillenpaa M, Jalava M, Kaleva O et al.
Epilepsy and accidents: what is the risk in Long term prognosis of seizures with onset children? Arch Pediatr 1994; 1(9):801-801.
relationship to sudden cardiac death. J Clin 3. Kirsch R, Wirrell E. Do cognitively normal children with epilepsy have a higher rate of injury than their nonepileptic peers? J Child Geerts AT et al. Mortality risk in children 28. Nashef L, Fish DR, Garner S et al.
with epilepsy: the Dutch study of epilepsy incidence in a young cohort with epilepsy 4. Deekollu D, Besag FMC, Aylett SE.
Seizure-related injuries in a group of young 16. Camfield CS, Camfield PR, Veugelers PJ.
29. Camfield CS, Camfield PR. Good news – circumstances. Seizure 2005; 14:347-353.
5. Sherrard J, Tonge BJ, Ozanne-Smith.
epilepsy. Epilepsia 1999; 40(s7):159.
Injury risk in young people with intellectual 17. Hauser WA, Annegers JK, Elveback LR.
disability. J Intellect Dis Res 2002; 46(1):6- Mortality in patients with epilepsy.
30. Donner EJ, Smith CR, Carter Snead O.
Sudden unexplained death in children withepilepsy. Neurology 2001; 57:430-434.
Dooley JM, Gordon KE. Accidental injury is et al. Mortality from epilepsy: results from 31. Webber P, Bubl R, Blaunstein U et al.
a prospective population based study.
Sudden unexplained death in children with epilepsy: a cohort study with an eighteen accidents in patients with epilepsy: results epilepsy. Epilepsia 1998; 39(8):904-907.
32. Monte CPJA, Arends JBAM, Tan IY et al.
20. Diekema DS, Quan L, Holt VL. Epilepsy patients: a systematic review. Seizure 2007; as a risk factor for submersion injury in 8. van den Broek M, Beghi E. Accidents in children. Pediatrics 1993; 91(3):612-616.
33. Telez-Zenteno JF, Hernandez Ronquillo children and the risk of drowning. Arch Dis incidence and risk factors. Epilepsy Res2005; 65(1-2):101-115.
9. ILAE Commission Report. Restrictions for 22. Berg AT. Shinnar S. Testa FM. Levy SR.
34. Hanna NJ, Black M, Sander JWS et al.
epilepticus after the initial diagnosis of 10. Chappell B, Brown S. Assessing risk in Shadows. 2002. The Stationary Office.
epilepsy. Epilepsy Care 2001; 2:6-8.
epilepsy: terminology and definitions.
epilepsies in children and young people.
24. Annegers JF, Coan SP. SUDEP: overview of definitions and review of incidence data.
36. Pysden K, Ferrie C, Gayatri N. A survey into the practice of paediatric neurologists 12. Safety leaflet. Epilepsy Action. 2006 Mary E O’Regan, Consultant Paediatric
Neurologist, Fraser of Allander
Neuroscience Unit, Royal Hospital for
Sick Children, Glasgow
Epilepsy and Genetics
Mary E O’Regan, Consultant Paediatric Neurologist, Fraser of Allander Neuroscience Unit, Royal Hospital for Sick
Children, Glasgow
Introduction
The aim of this review is to discuss the role genetics play inepilepsy, to update some of the recent discoveries in epilepsy Classification
genes and to consider briefly pharmacogenomics and It is useful to categorise genetic epilepsies according to the pharmacoresistance. Hopefully this review will introduce some mechanism of inheritance. For the purpose of this review the basic ideas about epilepsy and genetics, to help clinicians genetic epilepsies will be subdivided into three categories.
recognise and diagnose children and their families who may 1. Chromosomal disorders, where a gross cytogenetic benefit from genetic testing. It will also review the 2. Mendelian disorders, in which a single major locus canaccount for segregation of the disease trait. These can be Epilepsies, once regarded as demoniacal possession can have both genetic and acquired causes. The concept of genetic a. Idiopathic Mendelian epilepsies in which recurrent seizures predisposition to epilepsy was proposed over 400 years BC, the occur in otherwise neurological and cognitively intact children approximate date of the first recognition of the sacred disease, and who have no detectable anatomical or metabolic attributed to Hippocrates 1. In the many centuries following, clinicians and scientists have articulated varying notions of its b. Symptomatic Mendelian epilepsies in which the recurrent heritability. Twin studies have shown that the genetic factors seizures are one component of a multifaceted neurological are particularly important in the generalised epilepsies but also play a role in the partial epilepsies. Evidence from a large study 3. Non-Mendelian or complex diseases in which the pattern of involving about 2000 families with epilepsy suggest a genetic familial clustering can be accounted by the interaction of basis for both idiopathic and cryptogenic epilepsies and that several loci with environmental factors.
these two categories could be considered together 2. Geneticinfluences do appear to be considerably stronger in generalised 1. Chromosomal disorders
compared to focal epilepsies. Finally the strong genetic Chromosomal disorders usually occur spontaneously. Epilepsy contribution to epilepsy appears limited to seizures in people is a complication of many chromosomal abnormalities particularly those involving autosommal chromosomalimbalances 6, 7. However, there are only a small number of Epilepsy is a broad term that refers to a group of conditions in chromosome disorders that have epilepsy as a consistent which an individual is susceptible to repeated, unprovoked feature. These include Miller-Dieker syndrome, Angelman seizures. The epilepsies are a heterogeneous group of syndrome, Ring chromosome 20, Ring chromosome 14 and conditions with great variation in aetiology, clinical and electroencephalographic (EEG) features. The InternationalLeague Against Epilepsy (ILAE) provides classification for Leshima et al 8 found that 6% of patients with learning seizure types and epilepsy syndromes. According to the difficulties and epilepsy had a chromosome disorder. This International Classification of Epilepsy Syndromes, epilepsy figure rises to 50% in children with major congenital syndromes are divided into three major classes according to malformations. The commonest clues to the underlying presumed aetiology. Symptomatic epilepsies describe those diagnosis are the presence of dysmorphic features and conditions resulting from injury to the central nervous system particularly congenital malformations. However through stroke, head trauma, infection or metabolic insult.
dysmorphisms may be absent. McLeod et al 9 described a series Idiopathic epilepsies describe those syndromes with no clear of children with largely drug-resistant epilepsy who were non- cause. Cryptogenic syndromes are those which lack sufficient dysmorphic and had a chromosomal disorder. The group of children least likely to have cytogenetic studies are those thathave a period of normal development prior to the onset of A major goal in clinical and basic research is to ultimately seizures. In the series by McLeod et al 9 four children had a classify the epilepsies on a molecular basis. This could delayed diagnosis of their underlying disorder. Delayed circumvent the currently largely subjective approach when diagnosis can result in inappropriate investigations and identifying the epilepsy syndromes. Research into the basic mechanisms of epileptogenesis may also lead to thedevelopment of specific drug therapies to target molecular The following examples represent some of the more commonly defects. This knowledge will improve diagnosis, prognosis and encountered chromosomal abnormalities associated with management and thereby improve the quality of life of group ‘UNIQUE’ (http://www.rarechromo.org)10.
Seizures occur in 5-6% of children with Down syndrome andmay initially manifest as infantile spasms. Epilepsy occurs in Modern cytogenetic studies should be routine in the other trisomies, and is prevalent in 20-25% of cases of assessment of all children with learning difficulties and trisomies 18 (Edwards syndrome), trisomy 13 (Patau syndrome) epilepsy, even in the absence of dysmorphic features.
2. Single gene or Mendelian disorders
These result when a mutation causes a single gene to be The 1p36 deletion syndrome; seizures often present in infancy, altered. The mutations in single genes that cause epilepsy fall children have characteristic facial features, a large fontanelle into several categories including those that code for ion and horizontal eye brows. Cardiac abnormalities and deafness channels (voltage gated or ligand gated), genes that are responsible for progressive neurodegeneration,neurocutaeneous syndromes, mutations that produce abnormal brain development or disturbed energy production.
Ring chromosome abnormalities are rare disorders that occurwhen both ends of a chromosome are damaged and the 2a) Idiopathic Mendelian epilepsies
chromosome reforms in a ring shape. The amount of genetic These syndromes are individually rare and account for no more material lost in the formation of the ring determines the than 1% of epilepsies. They may be either generalised or focal.
phenotype. Two ring chromosomes are particularly associatedwith epilepsy: Benign Familial Neonatal SeizuresThis epilepsy syndrome was first described in the English literature in 1968 11. Since 1989, benign familial neonatal Clinically this syndrome is characterised by frequent nocturnal seizures have appeared in the classification of epilepsy and seizures, focal seizures with vivid hallucinations and periods of epilepsy syndromes; classified as idiopathic generalised non-convulsive status. The EEG shows prolonged runs of epilepsy. Clinically, the seizures occur between 2-8 days of age.
bifrontal slow activity of high voltage intermixed with spike If there has been premature delivery neonates will not develop and sharp waves. Seizures can present at a variety of ages from seizures until they are 2-8 days post term rather than 2-8 days 1 day of age to 17 years. Epilepsy appears to be the first and chronological age. The seizures occur in full term neonates major clinical symptom of this syndrome. The seizures are after a normal delivery and pregnancy. The neonate is normal often refractory to treatment. Behavioural problems are prior to, between and after seizures. The seizures may either be relatively common as are learning difficulties, these can be of focal clonic or generalised tonic-clonic and are often varying severity. Development prior to the onset of seizures accompanied by an episode of apnoea. The seizures are brief may be unremarkable. Unlike other chromosomal disorders but the frequency of seizures may be high. The seizures dysmorphisms and other congenital abnormalities are rarely respond well to carbamazepine, usually in relatively low part of this disorder. Ring chromosome 20 should be considered in every child with refractory epilepsy.
Development is normal in most infants but the risk of epilepsy is increased later in life with 5% of individuals developing Epilepsy begins most frequently in infancy often with tonic febrile seizures and approximately 10% developing epilepsy.
seizures; infants have distinct facial features, short stature anddevelopmental delay.
Benign familial neonatal seizures are a rare dominantlyinherited epileptic syndrome. The disease was first mapped to chromosome 20q 12. Current evidence indicates that the Angelman syndrome is the best characterised of the imprinted syndrome exhibits genetic heterogeneity and is caused by disorders. Seizures occur in 80-90% of cases. A deletion of mutations in the voltage gated potassium channel sub unit 15q1-13 on the maternally derived chromosome is responsible KCNQ2 located at 20q13.3 13,14 and KCNQ3 mutations on for 70% of cases. Among the remainder, paternal uniparental chromosome 8q24 15. Currently there are more than 10 disomy (2-3%), imprinting centre mutations within the 15q11- mutations identified in KCNQ2 but only 2 in KCNQ3. Mutations 13 and mutations within the maternally derived UBE 3A gene in either KCNQ2 or KCNQ3 can produce the same phenotype.
result in critical lack of product from maternally expressed KCNQ2 and KCNQ3 are expressed in the brain. They contribute genes within this region of chromosome 15. The EEG often to the M current, which regulates the sub-threshold electrical shows characteristic generalised high amplitude slowing, excitability and determines their firing properties and which is seen mainly posteriorly with spikes and sharp waves responsiveness to synaptic inputs. Retiagabine, a new antiepileptic drug in phase III trials is reported to act on the Mcurrent. While a chromosome-based diagnosis is unlikely to lead to aspecific therapy, additional support for families is often necessary and greatly appreciated, including the provision of This is also an autosommal dominant idiopathic epilepsy.
details of the international chromosome abnormality support Seizure onset is usually between 3 and 7 months, but can occur Mary E O’Regan, Consultant Paediatric
Neurologist, Fraser of Allander
Neuroscience Unit, Royal Hospital for
Sick Children, Glasgow
upto 20 months of age. All infants have a normal characteristic presentation is when the febrile seizures psychomotor development. An almost constant characteristic continue beyond the defined age range of 6 months to 6 years.
is the occurrence of brief seizures in clusters. Vigevano 16 In this situation the child may have febrile seizures that documented the presence during the seizure of slow deviation continue into late childhood or adolescence. A second type of of head and eyes to one side, diffuse hypertonia, cyanosis, and presentation of FS+ is where afebrile GTCS occur in addition to unilateral limb jerks. The side of the head and eye deviation febrile seizures or alternatively they may occur after the febrile sometimes changes from seizure to seizure in the same infant.
seizures remit. Other phenotypes that may occur include Linkage analysis studies have hypothesised loci on absences, focal seizures, myoclonic seizures, atonic seizures chromosome 19q, chromosome 2q24 and chromososome 16p 17, 18, 19 again demonstrating genetic heterogeneity. In familieswith the latter linkage, affected individuals may have attacks of Focal epilepsies in individuals with GEFS+ include temporal paroxysmal choreoathetosis by about 10 years of age. This is lobe epilepsy and frontal lobe epilepsy. The seizures in GEFS+ called the “infantile convulsions and choreathetosis usually remit by the teenage years. The GEFS+ spectrum syndrome”. The exact gene is not yet recognised but ion includes more severe phenotypes including the epileptic encephalopathies, myoclonic-astatic epilepsy (MAE) and severemyoclonic epilepsy of infancy. Although the two syndromes just mentioned are rare theirrecognition is important so a correct diagnosis may be Genes encoding both voltage-gated and ligand-gated ion established and appropriate prognosis given to the affected channel subunits have been implicated in GEFS+ and specifically, sodium channels and GABA receptors. Mutations in the genes encoding three sodium channel subunits, SCN1A, Autosomal dominant nocturnal frontal lobe epilepsies SCN1B and SCN1B and SCN2A have been found in different families with GEFS+. Neuronal voltage-gated sodium channels ADNFLE is characterised by clusters of nocturnal motor seizures are essential for the generation and propagation of the action that are often brief and stereotyped, varying from simple potential. Sodium channels are also modulated by antiepileptic arousals from sleep to dramatic often bizarre, hyperkinetic drugs such as phenytoin and carbamazepine.
events with tonic or dystonic features. A minority of individualsexperience daytime seizures. Onset ranges from infancy to The GABA receptor is a ligand-gated chloride channel that has adulthood, with a mean age of 10 years. The differential a major role in inhibition in the brain. Several mutations have diagnosis is wide including night terrors, hysteria, sleep been found in genes encoding for the various subunits of this paralysis, restless leg syndrome, REM sleep disorders and paroxysmal nocturnal dystonia. The seizures occur in clustersof between 4 and 11 episodes at night. Affected individuals are The wide variation in phenotypes caused by different types of neurologically and intellectually normal. There is a marked mutations in the one gene and within the families and variation in severity of seizures among family members and mutations in different genes producing a similar phenotype this makes it easy for the family tendency to be overlooked.
highlights the complexity of genotype-phenotype correlation The diagnosis of ADNFLE is a clinical one supplemented by video-EEG monitoring. In large families with this syndromemutations have been identified in the genes (CHRNA2, Severe Myoclonic Epilepsy of Infancy (SMEI) CHRNA4, CHRNB2) that code for the neuronal nicotinic Severe Myoclonic Epilepsy of Infancy was first described by acetylcholine receptor. Muations are found in 20-30% of Charlotte Dravet 21 in 1978. SMEI does appear to be a individuals with a positive family history and in fewer than 5% distinctive epilepsy syndrome: a previously well and of individuals with a negative family history. developmentally normal infant develops febrile seizures ataround 6-9 months of age often presenting with hemiclonic or Carbamazepine is the drug of choice for this epilepsy syndrome generalised febrile status epilepticus. One to four months later with upto 70% of individuals responding.
they then present with hemiclonic seizures on the alternateside or with further generalised seizures and they may have Generalised Epilepsy with Febrile Seizures plus (GEFS+) and frequent episodes of febrile status. Between one and four Severe Myoclonic Epilepsy of Infancy (SMEI) years, but usually by two years of age, other types of seizures GEFS+ is a familial epilepsy syndrome first described in 1997 in develop including myoclonic seizures in most, but not in all.
a large Australian family 20. GEFS+ has an autosomal dominant Focal seizures are frequent and atonic and atypical absence pattern of inheritance and is characterised by heterogeneous seizures may also occur. In addition frequent episodes of non epilepsy phenotypes or subsyndromes within families. convulsive status epilepticus are common. These children areoften prone to seizures with fever or in warm water such as the The phenotypes within GEFS+ usually have a seizure onset in bath. Development is normal in the first year of life with the first decade of life and the vast majority begin with febrile psychomotor slowing thereafter. Ataxia and pyramidal signs seizures. The most common phenotypes within GEFS+ are may evolve. Intellectual outcome is usually poor and seizures febrile seizures (FS) and febrile seizures plus (FS+). FS+ may remain refractory. The EEG may be normal on first have a number of different presentations. The most obvious or presentation but the second year of life will usually reveal generalised abnormalities. Up to 40% of cases demonstrate infantile spasms and in families with X-linked learning disabilities have mapped the disease gene to chromosomeXp21.3-Xp22.1. The aristaless-related, homeobox gene, ARX SMEI is a difficult epilepsy syndrome to manage, the seizures was considered to be a candidate gene because of its are often drug resistant, the myoclonic seizures can be expression pattern in foetal, infant and adult brain. Screening exacerbated by lamotrogine. This syndrome is best managed in of this gene identified mutations in four of five of the families conjunction with a paediatric neurologist.
with infantile spasms. Mutations were also identified infamilies with learning disabilities with myoclonic seizures or SMEI is considered to be the most severe phenotype within the dystonia, but no infantile spasms. XMESID, a rare x-linked spectrum of GEFS +. SMEI is a malignant epileptic syndrome, recessive myoclonic epilepsy with spasticity and intellectual whilst GEFS + is usually benign 22. SMEI is often associated with difficulties in boys has also been associated with a mutation in de novo mutations of SCN1A, the gene encoding the alpha -1 subunit of the sodium channel 23. Many groups have describedSCN1A mutations in SMEI with the reported frequency varying 2b) Mendelian Disorders in which epilepsy forms part of
from 33-100% 23, 24. Over 100 mutations have been described the phenotype
and most commonly describe truncation, although splice site The most commonly encountered Mendelian epilepsies are deletions and missense mutations have also been reported.
‘symptomatic’. The recurrent seizures result from one or moreidentifiable structural lesions. Some of the more common ones Despite the fact that 95% of SCN1A mutations arise de novo in SMEI many probands have a family history of seizures. Familystudies have identified that family members have seizure disorders consistent with the GEFS+ spectrum 25, 26. The high Neurofibromatosis is an autosommal dominant disorder proportion of SMEI individuals with de novo SCN1A mutations affecting about 1 in 3000 individuals. It is characterised by does not explain the relatively high rate of a family history of multiple hyperpigmented areas and peripheral seizures, which suggests the potential involvement of other neurofibromata. The gene for NF1 has been mapped to chromosome 17. Seizures are 10 times more frequent in NF1than in the general population, but are rarely the presenting Severe myoclonic epilepsy of infancy borderlands/borderline symptom. Infantile spasms with onset between 4 and 6 (SMEB) is another epilepsy phenotype within this group. Many months have been observed in children with NF1. individuals have many but not all the key features of SMEI; forexample they may not have myoclonus or generalised spike wave on the EEG. SMEB cases have SCN1A mutational rates of Tuberous sclerosis complex is a multisystem disorder involving around 30%, usually arising de novo.
primarily the central nervous system, the skin and kidney. Thecharacteristic neuropathological features are cortical tubers, Highlighting the increasing complexity of phenotype-genotype subependymal nodules and giant cell tumours. TSC is correlations in the epilepsy-channelopathies, a recently transmitted as an autosommal dominant trait with variable discovered mutation in the alpha-2 subunit of the sodium expression. About 2/3 of mutations arise spontaneously.
channel has been reported with seizure onset in the first fewmonths of life. Currently termed ‘benign familial neonatal- Linkage studies have allowed the identification of two loci, infantile seizures’, it is an intermediate phenotype between mapping to chromosome 9q34 (TSC1) and 16p13.3 (TSC2).
benign familial neonatal seizures and benign infantile seizures Epileptic seizures are frequent in TSC, but it is not clear whether the epilepsy phenotype and long term seizureoutcome of patients with TSC1 and TSC2 are different. The X-Linked Infantile Spasms (ISSX) and X-linked myoclonic seizures usually begin before 15 years of age and 70% present epilepsy with generalised spasticity and intellectual disability before the 2nd year of life. Infantile spasms are the most common manifestation of epilepsy in the first year of life. Infantile spasms are divided into those that are symptomaticand those that are cryptogenic or idiopathic. Most (70-80%) are symptomatic and may be attributed to a prenatal, perinatal Typical Rett syndrome in girls is characterised by an initial 6-18 or postnatal cause of which prenatal aetiologies are the most month period of apparently normal development followed by a loss of learned language and motor skills. In the moreadvanced stages, epilepsy is usual but occasionally seizures or Many causes of infantile spasms are genetically determined even status epilepticus are the initial events. The identification including disorders of brain development, neurocutaneous of the causative gene, x-linked methyl–CpG binding protein syndromes, metabolic disorders and chromosomal (MECP2), provides a diagnostic test.
abnormalities. Most cases of idiopathic infantile spasms aresporadic and the recurrence risk is less than 1%. However several familial cases have been identified consistent with The PMEs are a clinically and aetiologically heterogeneous X-linked inheritance. Linkage analysis in families both with group of rare inherited disorders characterised by the Mary E O’Regan, Consultant Paediatric
Neurologist, Fraser of Allander
Neuroscience Unit, Royal Hospital for
Sick Children, Glasgow
association of epilepsy, myoclonus and progressive neurological deterioration and specifically ataxia anddementia. The most common examples are Unverricicht- The recurrence risk of IGE for first degree relatives is 10 -15 fold Lundborg disease, Lafora body disease, and the Neuronal greater than the life time risk for IGE in the general population.
Twin and family studies indicate an overlapping geneticcomponent that is shared across the IGE syndromes, but these The Neuronal Ceroid Lipofuscinoses are a group of at least 10 studies also provide evidence that genetic configurations disorders that are characterised by the accumulation of determine the phenotypic expression of certain seizures such autofluorescent lipopigment in neurons and other cell types.
as absence and myoclonic seizures 33. Many linkage studies All the childhood onset types exhibit autosommal recessive have implicated many regions on different chromosomes but inheritance. They are the most common cause in childhood of replication studies have failed to establish unequivocal linkage neurodegeneration and all are characterised by seizures and relations probably because of the confounding effects of progressive visual, motor and cognitive decline. Six genes have phenotypic variability, complex inheritance and genetic been mapped and four clones, with at least two more to be Unverricht-Lundborg disease is an autosomal recessive CAE is a syndrome in which absence seizures have an onset progressive myoclonus epilepsy with a high prevalence in between 2 and 12 (usually, 5-8) years of age and a typical EEG Finland that has been mapped to chromosome 21q22.3. The showing generalised synchronous, symmetrical discharges of gene has been identified (EPM2) and encodes cystatin B, a 2.5-4Hz spike wave or polyspike complexes on a normal cysteine protease inhibitor. In mice with myoclonic epilepsy background occur. CAE does not appear to follow a Mendelian and ataxia, in which the cystatin gene has been knocked, there pattern of inheritance, although autosomal dominant appears to be a link between reduced cystatin B and apoptotic inheritance has been shown for the trait of bilateral cerebellar cell death. Cognitive decline (dementia) occurs less symmetrical 3Hz spike and slow wave complexes 34.
Pharmacogenetics
Lafora disease is characterised by an onset in adolescence with Currently eight million AED prescriptions are dispensed in the a rapid neurological and cognitive decline towards death. It is UK annually, a 70% increase in prescriptions per year since diagnosed by the presence of Lafora bodies on an axillary skin 2000. Despite this enormous increase adequate drug treatment remains a major problem in epilepsy managementwith as many as 30-35% of children and adults having seizures that are refractory to current medical treatment. The malformations of cortical development (MCD) mostrelevant in childhood epilepsy are usually characterised by It is now clear that genetic mechanisms contribute to malposition and faulty differentiation of grey matter 29. The refractoriness via pharmacodynamic and pharmacokinetic epilepsy is usually severe, has onset during childhood and is mechanisms. The difference in the pharmacodynamic response associated with developmental delay. The incidence of epilepsy to AEDs might be influenced by genetic differences in receptor is variable in different malformations. MRI has played a major subunits. This is evident in studies showing that the response role in the diagnosis of MCD. Genetic linkage studies have led to benzodiazepines can be genetically modified. Multidrug to the identification of several genes regulating brain resistance (MDR) essentially means resistance to some development 30. Mutations in these genes have been structurally and functionally unrelated agents. The human associated with specific malformations. Brain development MDR-1 gene encodes an integral membrane protein, P- and the genetics of brain development is a review topic in glycoprotein, the function of which is energy transport of itself. Children with a MCD should be reviewed by a paediatric molecules across neuronal membranes. Increased expression of neurologist and a genetist with an interest in neurogenetics. this protein has been demonstrated in the brain of somepatients with medically intractable epilepsy 35. The diversity in 3. Non-Mendelian epilepsies
response to AEDs is likely to be a direct or indirect reflection of Idiopathic generalised epilepsy (IGE) accounts for 20% of all underlying diversity in molecular and cellular physiology that is epilepsies and affects 0.2% of the general population. The IGE syndromes are characterised by the age related occurrence ofrecurrent unprovoked seizures in the absence of detectable Adverse effects are not an uncommon problem in AED brain lesions or metabolic abnormalities. The most common treatment and some AEDs increase seizure frequency 36. Certain subtypes are childhood absence epilepsies (CAE), juvenile adverse drug reactions may also have a genetic basis; there is absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) and family aggregation of phenytoin hypersensitivity and epilepsy with generalised tonic-clonic seizures (EGTCS). The concordance of carbamazepine hypersensitivity in MZ twins 37.
EEG signature of IGE is marked by generalised spike-wave Also a functional epoxide hydrolase defect has been noted to discharges that reflect a synchronized hyperexcitable state of be responsible for fatal anticonvulsant hypersensitivity 38. thalamocortical circuits 31. The IGEs are genetically determinedbut the underlying genetic architecture of these common IGE There is also evidence that the teratogenic effects of AEDs may also be genetically determined with some individuals more Understanding that the seizures have a genetic cause can allow susceptible than others; this in the future may allow risk to be parents to release this burden of guilt. Finality in stratified 39. An experimental mouse model to this effect has understanding the diagnosis and the cause will often enable been studied and offers evidence that the offspring liability to families to deal constructively with the problem rather than valproate toxicity is genetically determined.
Genetic counselling
Genetic testing is currently available for several progressive Prior to any genetic counselling about the mode of inheritance myoclonic epilepsies (myoclonic epilepsy with ragged red and recurrence risk of a particular syndrome there needs to be fibres, several neuronal ceroid lipofuscinoses, Lafora disease an accurate diagnosis of the seizure and syndrome type. This and Unverricht-Lundborg disease) as well as for X-linked requires a familiarity, knowledge and understanding of myoclonic epilepsy and learning disabilities, and SMEI. For the epileptic seizures and syndromes. A complete family history latter in the UK testing for the SCN1A gene mutations is will also need to be documented. Taking a family history can available from RHSC Glasgow; this service is free of charge. The often be very difficult and it can never be said to be complete request form for this test is available from the British Paediatric until the oldest living female relative has been interviewed. Neurology Association website (http://www.bpna.org) 40.
The history of epilepsy has not been a very happy one. A Conclusion
genetic component to epilepsy has long contributed to the There is now a wealth of knowledge known about some of the prejudice against people with epilepsy often causing them to rarer epileptic syndrome such as the Benign Familail Neonatal conceal the disorder and rendering the collection of family and Infantile seizures. These epilepsy syndromes are associated pedigrees a challenge for the clinicians. The concealment of with mutations in the genes that encode for subunits of epilepsy is more likely in the older generations. The voltage and ligand gated ion channels. The recognition of the identification of genetic aetiologies of epilepsy also could GEFS+ syndrome has been a major advancement in the affect the mechanisms of stigma, discrimination and social classification of epilepsy as the GEFS+ is a common epilepsy isolation already associated with epilepsy. Genetic information syndrome in childhood. The identification of the many might make it seem as if having epilepsy is an enduring and mutations in the SCN1A gene in SMEI allows accurate essential part of the person with epilepsy.
diagnosis of this syndrome for which there is specificpharmacological treatment. One of the most striking features The ascendance of genetic information about epilepsy and its is the variable epilepsy phenotypes that are associated with possible clinical applications raise a variety of ethical, legal and known gene mutations and the genetic heterogeneity that social issues. Many of these issues are not unique to epilepsy, underlies all known monogenic syndromes. The heterogeneity for example ethical and legal concerns that are raised by of mutations described to date has precluded the development genetic testing generally include appropriate informed of simple diagnostic tests and does not make for easy genetic consent, autonomy, confidentiality and privacy of genetic information and the imperative of balancing individualparental and social interests when considering genetic testing Significant progress has been made in unravelling the genetics for a minor. Similarly, the potential of genetic information of symptomatic epilepsies, including the progressive myoclonic being able to contribute to psychological distress, adverse epilepsies (PME) and the neuronal ceroid lipofuscinoses.
labelling and discrimination in life insurance and employment Progress has been very slow in dissecting the genetic basis of is an important consideration for genetic testing for any the more common idiopathic generalised and focal epilepsy syndromes such as JME or Benign Epilepsy withCentrotemporal Spikes encountered in everyday practice.
Genetic information may also transform the experience ofbeing the family member of a person with epilepsy. Insofar as Future Directions
epilepsy becomes popularly conceived as something that “runs The major challenge in the future is the identification of in the family” relatives of persons may be affected by “courtesy susceptibility for the common idiopathic epilepsies. It will also stigma”. This occurs when stigma becomes attached to a be important to translate success in the field of molecular person who is related through the social structure to a genetics into practical therapeutic application. Hopefully this stigmatized individual - a relationship that leads the wider will aid improvement in the management of seizures and society to treat both individuals in some respects as one. avoidance of some adverse reactions associated with AEDtreatment. The clinician involved in the diagnosis of epilepsy Conversely genetic testing may bring substantial benefits to has a major role to play, as to unravel the genetic mysteries, the individual child and his or her family. Confirmation of a very accurate diagnosis of epileptic seizures and syndrome is diagnosis through genetic testing may render other invasive or crucial. It is also important for clinicians to identify and recruit expensive tests unnecessary. A positive test result even without families containing many affected individuals for collaborative specific treatment implications often gives greater peace of studies. Gene discovery in the genetically complex epilepsies is mind. Similarly many parents blame themselves for their child’s a formidable task. Future studies should employ very large seizures, attributing them to an action or event that took place sample sizes to ensure adequate statistical power; only large during pregnancy or infancy such as injury or vaccination.
collaborative studies will be able to achieve these goals. Mary E O’Regan, Consultant Paediatric
Neurologist, Fraser of Allander
Neuroscience Unit, Royal Hospital for
Sick Children, Glasgow
References
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and still counting Neurobiol Dis 1998; 5: Hopkins University Press, Baltimore. 1971 29. Barkovich AJ, Kuzniecky RI, Jackson GD, 17. Guipponi M, Rivier F, Vigevano F, et al .
infantile convulsions (BFIC) to chromosome 3. Ottman, R Annegers JF, Risch N, HauserWA, Susser M. Relations of genetic and 18. Szepetowski P, Rochette J, Berquin P, paroxysmal choreoathetosis: a newneurological syndrome linked to the 4. Ottman R, Lee JH, Hauser WA, Risch N.
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epilepsies genetically distinct? Archives ofNeurology.1998; 55:339-44 5. Berkovic SF, Howell RA, Hay DA, Hopper suggest allelism to infantile convulsions Grinton BE, Phillips FL et al. Geneticarchitecture of idiopathic generalized: 20. Scheffer IE, Berkovic SF. Generalised clinical genetic analysis of 55 multiplex families. Epilepsia 2004; 45:467-478.
genetic disorder with heterogenous clinical clinician’s and gene hunters. Epilepsia centrencephalic epilepsy. Neurology 1961; 22. Ohmori I, Ouchida M, Ohtsuka Y, OKAE, Shimizu K. Significant correlation of the abnormalities and epileptic seizures. Jpn J gene expression in brain of patients with medically intractable epilepsy. Epilepsia 9. Macleod S, Mallik A, Tolmie JL,Stephenson JBP, O’Regan ME, Zuberi SM.
36. Guerrini R, Belmonte A, Genton P.
11. Bjerre I, Corelius E. Benign neonatal 37. Gennis MA, Vemuri R, Burns EA, Hill JV, familial neonatal convulsions. Acta Pediatr Miller MA, Spielberg SP. Familial occurrence of hypersensitivity to phenytoin. American Bernardina B, Dulac O, Madia F, Bertini E, Capovilla G, Chiron C, Cristofori G, Elia M, 39. Lindhout D, Meinardi H, Meijer JW, Nau H. Antiepileptic drugs and teratogenesis in 14. Singh NA, Charlier C, Stauffer D et al A prescription policy paralleled by changes in 26. Veggiotti P, Cardinali S, Montalenti E et seizures plus and severe myoclonic epilepsyin infancy: a case report of two Italian 15. Hirose S, Zenri F, Akiyoshi H, Fukuma G et al. A novel mutation of KCNQ3 in aJapanese family with benign neonatal et al Sodium-channel defects in benignfamilial neonatal–infantile seizures. Lancet2002; 14:851-2 MSc Epilepsy Practice (by distance learning)
For the first time ever it is now possible to study for epilepsy Year 3 - MSc Epilepsy Practice
qualifications at Masters level by distance learning.
Dissertation – Contributing to Practice Development Following on from its other very successful epilepsy coursesthe Centre for Community Neurological Studies at Leeds Criteria for Admission
Metropolitan University has recently launched this initiative.
The MSc Epilepsy Practice course is open to applicants whoalready hold (or will hold on entry) a degree or equivalent in Development of the Masters courses has been supported by a biological, behavioural science, or health or social care Epilepsy Action and very importantly funding has kindly professional subject, or a related health or social care professional qualification, such as Professional Diplomaawards completed at Leeds Metropolitan University. Course Structure
Non-Certificated Entry Requirements to Year 1 of the The courses offer three awards at Masters level as follows: Postgraduate Certificate / Postgraduate Diploma /
Applicants may demonstrate prior non-certificated learning MSc Epilepsy Practice.
equivalent to that identified above – please apply to theUniversity for further details. People can either specify any of these awards at the point ofregistration or receive the Certificate or Diploma as a Admission with Advanced Standing on the Basis of Prior contained award, subject to satisfactory completion of the Certificated or Non-Certificated Learning Applicants may claim advanced standing for appropriatestudies previously completed at Masters level - please apply The full MSc in Epilepsy Practice comprises nine twenty • Four specific epilepsy modules: “Diagnosis and Assessment”, “Management”, “Psychosocial Further Admissions Criteria
Implications” and one work-based independent learning In addition to the requirements set out above, all applicants • Two core modules in evidence-based practice • A high level of interest and insight into the profession. (“Understanding and Evaluating Evidence” and This can be gained through work experience and/or by • A three-module dissertation Contributing to Practice • Evidence of excellent communication skills • Evidence of self directed study skills • Evidence of recent personal/academic development, Typical part-time attendance patterns are illustrated
• Evidence of an understanding of the research process People may negotiate their pattern of attendance andselection of modules to meet their specified needs Applicants must be prepared to bring or develop knowledge • Knowledge of human anatomy, physiology and Year 1 - Postgraduate Certificate in Epilepsy Practice
psychosocial issues relating to health care Understanding and evaluating the evidence (core) 20 credits Further Information
Year 2 - Postgraduate Diploma in Epilepsy Practice
For further information telephone the Centre for Community Neurological Studies on 0113 283 5918.
Applying the evidence (to epilepsy practice; core) 20 credits Recently Published Papers
This section highlights recently
Seizure. 2007 Jan 5; [Epub ahead of print] published papers. Hopefully this will
be very useful to all, helping to keep
Surgical outcome and prognostic factors of resistant and 50 seizure-free patients.
everyone up to date with the latest
Piazzini A, Ramaglia G, Turner K, Chifari R, developments. It will certainly save
you research and reading time, not
having to search so many journals.
There are many (often over 100)
epilepsy papers published every three
months, so what follows has been
edited. All animal papers have been
excluded and as many review papers
Allain H, Schuck S, Nachit-Ouinekh F, Plouin as possible have been included. We
hope you find the papers of interest
in your pursuit to keep abreast of the
neurology group on neonatal seizures.
very latest knowledge. You can
instantly access the abstracts for all
Prospective study of first-choice topiramate the papers by using the on-line pdf
version of PECAS. This is available at
http://www.i3sixty.co.uk/ne02/web/.
Prolonged focal negative motor seizures: a Zou LP, Ding CH, Fang F, Sin NC, Mix E.
From this home page click on
“Professional Downloads”. You will
Villani F, D'Amico D, Pincherle A, Tullo V, need a username and password. The
username is – pecas – and the
password is – 2006 – (without the
Cherian PJ, Blok JH, Swarte RM, Govaert P, dashes). You will be asked for these
twice; once before entering the home
page and once before entering the
“Professional Downloads” section.
Childs Nerv Syst. 2006 Aug;22(8):936-44.
MH, Fujimoto S, Ishikawa T, Togari H.
Childs Nerv Syst. 2006 Aug;22(8):931-5.
Bourgeois M, Di Rocco F, Sainte-Rose C.
Seizure. 2007 Jan 11; [Epub ahead of print] A study of idiopathic generalised epilepsy Childs Nerv Syst. 2006 Aug;22(8):852-66.
Hemimegalencephaly: clinical implications valproate using isobolographic analysis.
Di Rocco C, Battaglia D, Pietrini D, Piastra Ann Neurol. 2007 Jan 25; [Epub ahead ofprint] Childs Nerv Syst. 2006 Aug;22(8):982-91.
Tamburrini G, Pietrini D, Di Rocco C.
Mikati MA, Dib L, Yamout B, Sawaya R,Rahi AC, Fuleihan Gel-H.
Childs Nerv Syst. 2006 Aug;22(8):960-6.
Frequency and predictors of nonconvulsive Transsylvian functional hemispherectomy.
Psychotropic effects of antiepileptic drugs.
critically ill children.
Jette N, Claassen J, Emerson RG, Hirsch LJ.
The development of intellectual abilities in A prospective study of postictal psychoses with emphasis on the periictal type.
Cormack F, Cross JH, Isaacs E, Harkness W, Wright I, Vargha-Khadem F, Baldeweg T.
Use of a modified Atkins diet in intractable Kang HC, Lee HS, You SJ, Kang du C, Ko TS, Characteristics in Patients with and without Epilepsy.
Mari F, Di Bonaventura C, Vanacore N, Fattouch J, Vaudano AE, Egeo G, Berardelli A, Manfredi M, Prencipe M, Giallonardo AT.
for intractable epilepsy in children with Koenig SA, Buesing D, Longin E, Oehring R, Brinciotti M, Matricardi M, Cantonetti L, Jungck A, Bruckner R, Seitz R, Boxtermann complications, and adaptive function.
Darra F, Fiorini E, Zoccante L, Mastella L, Marsh ED, Brooks-Kayal AR, Porter BE.
memory deficits in children with temporal Fontana E, Negrini F, Francione S, Mai R, Zadikoff C, Munhoz RP, Asante AN, Politzer Ictal emotional expressions of children with Against Epilepsy working group on generic Perucca E, Albani F, Capovilla G, Bernardina Cook WB, Avellino AM, Ellenbogen RG.
Joannidis M, Zimmerhackl LB, Stein J, Luef Retention rate of Levetiracetam in children Beghi E, De Maria G, Gobbi G, Veneselli E.
with intractable epilepsy at 1 year.
Rittey C, Donnelly J, Whitehouse WP, Philip Montagnini A, Avantaggiato P, Seri S.
weeks of hypsarrhythmia duration.
Primec ZR, Stare J, Neubauer D.
Safe and effective use of the ketogenic diet Kang HC, Lee YM, Kim HD, Lee JS, Slama A.
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“Paediatric Epilepsy” is funded by an
unrestricted educational grant from
UCB Pharma.
Forthcoming Courses & Conferences
Below are details of forthcoming conferences and courses in context; (4) Understand the principles and limitations of drug epilepsy and general paediatric neurology. Relevant web management in childhood (5) Be aware of when to consider addresses for further details and an application form are alternative forms of management (6) Recognise the listed. The downloadable form of PECAS provides hyperlinks comorbidities and likely expectations.
as opposed to typing web addresses manually. The downloadis available at http://www.i3sixty.co.uk/ne02/web/. You will 8th European Congress on Epileptology
need to use the username and password as listed on page 16.
21 - 25 September 2007, Berlin, Germany
http://www.comtecmed.com/cony/
British Paediatric Neurology Association
This controversies congress stems from the fact that current (epilepsy training – levels 1 & 3)
congresses fail to promote true clinical discussion between practising physicians and researchers on unresolved pressing See http://www.bpna.org.uk/meetings/default.htm
for information on the Level 1 course.
The purpose of the congress is to disseminate information on Level 3 courses take place annually. The next course will be controversial issues in our field. The congress will include held on 29-30th October 2007 in Edinburgh.
special interest sections such as: degenerative diseases,vascular disorders, headache and other pain syndromes, British Institute for Learning Disabilities
autoimmune neurological diseases, and others.
(BILD) (Various aspects of autism)
7th Congress of the European Paediatric
Neurology Society (EPNS)
http://www.bildservices.org.uk/acatalog/Autistic_spectrum
_disorder.html for information on all the courses.
26 - 29 September 2007, Kusadasi, Izmir, Turkey Courses are offered in a few cities including Sheffield, London http://www.epns2007.org/invitation.php
Over 800 participants from child neurology and related fieldsare expected to attend the congress to exchange their ideas 27th International Epilepsy Congress
and findings in research, diagnosis and treatment, finding anexcellent opportunity to assess the state of knowledge in the http://www.epilepsysingapore2007.org/
The scientific and educational programme will cover cutting
61st American Epilepsy Society Conference
edge topics and provide clinical updates essential forcontinuing professional development of clinicians. The 30 November - 4 December 2007, Philadelphia, USA programme will also be broad enough for clinicians who are http://www.aesnet.org/Visitors/AnnualMeeting/index.cfm
non-epileptologists and allied health professionals involved in The American Epilepsy Society's annual meeting is the premiere conference for epilepsy and other seizure disorders.
The annual meeting is an international forum for the 6th International Course on Epilepsy: Clinical
exchange of current findings in epilepsy research. Informationis communicated and disseminated through symposia, and Therapeutic Approaches to Childhood
lectures, scientific exhibitions, poster and platform Epilepsy
The annual meeting attracts attendees from all over the http://www.epilepsy-academy.org
world and provides educational and networking opportunities Aims of this advanced course are to teach attendees to: (1) for the academic and practicing neurologist, epileptologist, Utilize knowledge of the underlying basis to epilepsy; (2) neurophysiologist, neuroscientist, neurosurgeon, internist, Describe the nature and evolution of childhood epilepsies; (3) paediatrician, pharmacist, nurse, social worker and other Plan neurophysiological, video EEG and imaging investigations and interpret their results in the clinical “Paediatric Epilepsy” is published by:NEUROEDUCATION, The authors, editors, owners and publishers do not accept any PO Box 17, Golcar, Huddersfield, HD7 4YX. responsibility for any loss or damage arising from actions ordecisions based on information contained in this publication;ultimate responsibility for the treatment of patients and interpretations of published material lies with the health “Paediatric Epilepsy”, NEUROEDUCATION, PO Box 17, practitioner. The opinions expressed are those of the authors and the inclusion in this publication of material relating to aparticular product, method or technique does not amount toan endorsement of its value or quality, or of the claims made NEUROEDUCATION is an independent non-profit makingproject which is part of the York Hospitals and Hammersmith

Source: http://www.neuroeducation.org.uk/vncc/professional/bs2/PECAS%20Issue%202-2.pdf