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
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
‘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
‘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
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
Dr Daniel Hindley, Consultant Paediatrician, Bolton PCT
I have direct experience of the sometimes peculiar restrictions
5. Sherrard et al 2002
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 1996
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 2004
7,8 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 2002
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 1994
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 2001
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 2005
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,
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
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 SUDEP
This is a confusing and fraught subject! There are so many
• Harvey et al 1993
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 1995
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 1999
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 2001
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 2005
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?
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,
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
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
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
The aim of this review is to discuss the role genetics play inepilepsy, to update some of the recent discoveries in epilepsy
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
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.
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 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
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
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
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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.
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
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
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
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.
Gerstner T, Woelfing C, Witsch M, LonginE, Bell N, Konig S.
Bergqvist AG, Schall JI, Stallings VA.
palmitate) therapy for intractableepileptic seizures in infancy.
Yamamoto H, Fukuda M, Miyamoto Y,Murakami H, Kamiyama N.
Epileptic Disord. 2007 Feb;9(1):43-50. Epub
Pediatric Language Mapping: Sensitivity of
Velis D, Plouin P, Gotman J, da Silva FL;
Kuzniecky R, Pacia S, Vazquez B, Luciano D,
Epileptic Disord. 2007 Feb;9(1):1-10. Epub
Cantello R, Rossi S, Varrasi C, Ulivelli M,
Testa SM, Schefft BK, Szaflarski JP, Yeh HS,
Quartarone A, Crupi D, Lagana A, Inghilleri
M, Giallonardo AT, Berardelli A, Pacifici L,
Postsurgical Health-related Quality of Life
Hemispherectomy for Intractable Epilepsy.
Seizure. 2007 Feb 8; [Epub ahead of print]
Griffiths SY, Sherman EM, Slick DJ, Eyrl K,
Aetiology, course and outcome of children
de Vries L, Karasik A, Landau Z, Phillip M,
controlled-release carbamazepine in newly
Mormann F, Andrzejak RG, Elger CE,
Donner EJ, Shroff M, Chuang S, Hawkins C,
Further evidence of genetic heterogeneity
Refractory epilepsy: clinical overview.
J Child Neurol. 2006 Dec;21(12):1036-40.
Civitelli D, Candiano IC, Tarantino P, Annesi
Seizure. 2007 Feb 1; [Epub ahead of print]
long-term prospective controlled study.
Pavlidou E, Tzitiridou M, Panteliadis C.
J Child Neurol. 2006 Oct;21(10):898-900.
Kohelet D, Shochat R, Lusky A, Reichman B;
Childs Nerv Syst. 2006 Sep;22(9):1167-9.
Infantile spasm-associated microencephaly
Blount JP, Tubbs RS, Kankirawatana P, Kiel
JW, Huynh MN, Cepeda C, Leite JP, NederL, Koh S, Vinters HV, Mathern GW.
Epilepsia. 2007 Feb;48(2):385-9. EEG-fMRI in Children with
De Tiege X, Laufs H, Boyd SG, Harkness W,
Curr Opin Neurol. 2007 Apr;20(2):208-12.
epilepsy: revisiting temporal aspects.
Krishnamoorthy KS, Wang NC, Rekate HL.
Curr Opin Neurol. 2007 Apr;20(2):188-93.
Curr Opin Neurol. 2007 Apr;20(2):169-74.
Holmes GL, Stafstrom CE; doubledaggerThe Tuberous Sclerosis Study Group.
intractable epilepsy ineligible for surgery.
Clinical aspects of the ketogenic diet.
Madia F, Gennaro E, Paravidino R, BeccariaF, Capovilla G, Bernardina BD, Darra F, Elia
Lancet. 2007 Mar 24;369(9566):970-1.
N, Vigevano F, Striano S, Tortora F, Rossi A,
valproate, lamotrigine, or topiramate for
generalised and unclassifiable epilepsy: an
Benign epilepsy of childhood with rolandic
spikes: typical and atypical variants.
ADHD, Neurological Correlates and Health-
related Quality of Life in Severe Pediatric
PJ, Howell SJ, Hughes A, Jackson M, Jacoby
Rolandic EEG trait-impact on cognition.
Nicolaides P, Roberts R, Shackley P, Shen J,
Characteristic Distribution of Interictal
Lancet. 2007 Mar 24;369(9566):970-1.
oxcarbazepine, or topiramate for treatment
Hulsman J, Lambrechts D, Leenen L, Majoie
PJ, Howell SJ, Hughes A, Jackson M, Jacoby
Nicolaides P, Roberts R, Shackley P, Shen J,
Discontinuing the ketogenic diet in seizure-
Optimizing therapy of seizures in children
Grosso S, Cordelli DM, Franzoni E, Coppola
encephalopathies: study of 29 cases.
“Paediatric Epilepsy” is funded by an
unrestricted educational grant from
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, Germanyhttp://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
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)
for information on all the courses.
26 - 29 September 2007, Kusadasi, Izmir, Turkey
Courses are offered in a few cities including Sheffield, London
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
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
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
The annual meeting attracts attendees from all over the
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
Minutes of the City Council The regular meeting of the City Council was held Tuesday, September 14, 2010. President Edward R Podmanik called the meeting to order at 7:03 PM. THE INVOCATION WAS GIVEN BY: Council Chaplin, Kay Fantauzzi, who, then led in the Pledge of Allegiance. ********************** ROLL CALL OF MEMBERS ******************* Present: Podmanik, Rosso, Smith, Kovach, Bri
SAFETY DATA SHEET Engemycin® Page 1 of 5 Section 1: Identification of the Substance and Supplier Product name Engemycin Liquid containing 8-23% oxytetracycline hydrochloride Recommended use Veterinary broad-spectrum antibiotic injection for use in horses, cattle, sheep, pigs, dogs and cats. Company details MSD Animal Health, 33 Whakatiki Street, Upper Hu