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HongKongMedJVol15No5# Supplement5# October2009 1
EDITOR-IN-CHIEF
Richard Kay 祁理治
SENIOR EDITORS
PT Cheung 張璧濤
Albert KK Chui 徐家強
Michael G IrwinIgnatius TS Yu 余德新
EDITORS
KL Chan 陳廣亮
KS Chan 陳健生
Henry LY Chan 陳力元
Annie OO Chan 陳安安
CB Chow 周鎮邦
William B Goggins WK Hung 熊維嘉
Alvin KH Kwok 郭坤豪
Paul BS Lai 賴寶山
Eddy KF Lam 林國輝
Stephen TS Lam 林德深
WY Lam 林永賢
Nelson LS Lee 李禮舜
Danny WH Lee 李偉雄
Danny TN Leung 梁子昂
WK Leung 梁惠強
Janice YC Lo 羅懿之
Herbert HF Loong 龍浩鋒
James KH Luk 陸嘉熙
Jacobus KF Ng 吳國夫
Hextan YS Ngan 顏婉嫦
Martin W Pak 白威
PC Tam 談寶雛
SW Tang 鄧兆華
William YM Tang 鄧旭明
Clement CY Tham 譚智勇
Peter CY Tong 唐俊業
TW Wong 黃大偉
Patrick CY Woo 胡釗逸
TK Yau 游子覺
SH Yeung 楊世雄
Volume 15 # Number 5 # October 2009
S U P P L E M E N T 5
The hong Kong epilepsy guideline 2009
The Hong Kong Epilepsy Society (HKES) 3
Editorial 4
The Guideline
1. Preamble 6
2. Diagnosis,review,andreferral 6
3. Patienteducation 6
4. Followingafirstseizure 6
5. Investigations 8
6. Classification 9
7. Principlesofmanagement 9
8. PharmacologicalorAEDmanagement 9
9. Managementofdrug-resistantepilepsy 10
10.Side-effectsofAEDs 11
11.Presurgicalevaluationofdrug-resistantepilepsy 11
12.Otherformsoftreatment 12
13.Prolongedseizuresinthecommunity 13
14.Treatmentofstatusepilepticus 13
15.Perioperativemanagementofseizure 14
16.Womenwithepilepsy 14
17.Olderpeoplewithepilepsy 15
18.Childrenandyoungpeoplewithepilepsy 15
19.Lifestyleandsocialissues 17
References 18
Appendices
AppendixA:Gradingschemeofevidence 21
AppendixB:Differentialdiagnosisofepilepticseizuresandepileptiformdischarges
AppendixB1:Differentialdiagnosisofepilepsyinadults 22AppendixB2:Differentialdiagnosisofepileptiformdischarges 22AppendixB3:Differentialdiagnosisofepilepsyinchildren 23
AppendixC:Classificationofseizuretypeandepilepsysyndrome
AppendixC1:TheILAEclassificationofepilepticseizures 24
2 HongKongMedJVol15No5# Supplement5# October2009
INTERNATIONAL EDITORIAL ADVISORY BOARD
Sabaratnam Arulkumaran United Kingdom
Robert AtkinsAustralia
Peter CameronAustralia
James DickinsonCanada
Adrian DixonUnited Kingdom
Willard Fee, JrUnited States
Robert HoffmanUnited States
Serena HuUnited States
Sean HughesUnited Kingdom
Arthur KleinmanUnited States
Xiaoping LuoChina
Jonathan SametUnited States
Rainer SchmelzeisenGermany
David WeatherallUnited Kingdom
Homer YangCanada
EXECUTIVE EDITORS
Margaret H ChengCyrus R Kumana
MANAGING EDITOR
Yvonne Kwok 郭佩賢
ASSISTANT MANAGING EDITORS
Warren Chan 陳俊華
Betty Lau 劉薇薇
AppendixC2:TheILAEclassificationofepilepsiesandepilepsysyndromes 25
AppendixD:Pharmacologicaltreatment
AppendixD1:SuggestedchoiceofAEDsbyseizuretypesinadolescentsand 26adults(modifiedfromNICE)
AppendixD2:SuggestedchoiceofAEDsbyepilepsysyndromes 26AppendixD3:PositionstatementofHKESongenericAEDsubstitution 27AppendixD4:Side-effectsofAEDs 27
AppendixE:ExamplesoffactorstoconsiderinselectinganAED 28innewlydiagnosedepilepsy
DeclarationThe authors received an educational grant from the Hong Kong Epilepsy Society in supportof theirresearchforandpreparationof thisguideline.Theydidnotreceivepaymentsorotherbenefits,oracommitmentoragreementtoprovidesuchbenefitsfromacommercialentity.
List of abbreviations
AED antiepilepticdrugCNS centralnervoussystemCT computedtomographyECG electrocardiogramEEG electroencephalogram/electroencephalographyHKES HongKongEpilepsySocietyICU IntensiveCareUnitILAE InternationalLeagueAgainstEpilepsyIM intramuscularIV intravenousMEG magnetencephalogramMRI magneticresonanceimagingPET positronemissiontomographySPECT singlephotonemissioncomputedtomography
# Percentage body fat in Chinese children #
Hong Kong Med J Vol 15 No 5 # Supplement 5 # October 2009 �
The Hong Kong Epilepsy SocietyThe Guideline Development Group
Chairman FONG Ka Yeung, Jason, MBBS, FRCP (Lond, Edin), FHKAM (Medicine), Specialist in Neurology
Vice Chairman KWAN Kwok Leung, Patrick, MBBChir (Camb), PhD, FRCP (Lond), FHKAM (Medicine), Specialist in Neurology
Members CHAK Wai Kwong, MBBS, FHKAM (Paediatrics), Specialist in Paediatrics
FONG Chung Yan, Gardian, MBBS, MD, PhD, FRCP (Glasg), FHKAM (Medicine), Specialist in Neurology
FONG Dawson, MBBS, FRCS (Edin), FHKAM (Surgery), Specialist in Neurosurgery
FUNG Cheuk Wing, MBBS, FHKAM (Paediatrics), Specialist in Paediatrics
HUI Che Fai, Andrew, MBBS, FRCP (Edin), FHKAM (Medicine), Specialist in Neurology
LEUNG Howan, MBBS, FHKAM (Medicine), Specialist in Neurology
LUI Hui Tung, MBBS, FHKAM (Medicine), Specialist in Neurology
WONG Virginia, MBBS, FRCP (Lond, Edin), FRCPCH, DCH, FHKAM (Paediatrics), Specialist in Paediatrics
YAM Kwong Yui, MBBS, FRCS (Edin), FHKAM (Surgery), Specialist in Neurosurgery
YEUNG Hon Ming, Jonas, MBBS, FRCP (Lond, Edin, Glasg), FHKAM (Medicine), Specialist in Neurology
YUNG Wing Yan, Ada, MBBS, FHKAM (Paediatrics), Specialist in Paediatrics
ZHU Xia Lun, LMCHK, FRCS (Edin), FHKAM (Surgery), Specialist in Neurosurgery
External Reviewer Prof Josemir W SANDER, MD, PhD, FRCP
UCL Institute of Neurology, University Department of Clinical and Experimental Epilepsy, Queen Square, London, United Kingdom
� HongKongMedJVol15No5# Supplement5# October2009
The Hong Kong Epilepsy Guideline 2009E D I T O R I A L
Introduction to Hong Kong Epilepsy Society (HKES)The HKES is a non–profit-making organisation established in November 2002. It aims at maintaining effective cooperation of all persons active in the field of medical sciences, public health, and social care, who are concerned with problems related to epilepsy. Every year various congresses, symposia, workshops or meetings are held to promote dissemination of scientific knowledge on epilepsy. The executive council mainly consists of medical professionals with adult and child neurologists, neurosurgeons, neuroradiologists, and neuopsychologists. The Society has published a booklet “Your Guide of Epilepsy” which covers essential information regarding epilepsy and enjoys popularity among people with epilepsy.
Modern management of epilepsyIn the past two decades we have witnessed a huge explosion in literature on epilepsy, followed by introduction of many more AEDs and innovative surgical techniques in controlling intractable seizures. Modern management of epilepsy requires sound knowledge on seizure differential diagnosis and neuropharmacology, proper classification of epilepsy, prompt referral for epilepsy surgery in drug-resistant epilepsy, as well as providing counselling and information at appropriate times.1 Special population groups comprising children, elderly, and women require careful considerations on certain issues, eg learning and behaviour in children, pregnancy and AED teratogenicity in reproductive women, drug interactions with polypharmacy and co-morbidities in the elderly. An appraisal of the medical literature and translating evidence into practice guideline appears timely.
Epilepsy care in Hong KongThe standard of epilepsy care in Hong Kong is heterogeneous and people with epilepsy are often managed by general practitioners, physicians, paediatricians, geriatricians, psychiatrists, neurosurgeons, neurologists, developmental paediatricians, child neurologists, or child psychiatrists. While quality care is often deficient in the primary sector, the specialist clinics are overloaded with people with stable epilepsy. People with drug-resistant epilepsy also lack referral channels. These problems may be attributed to the absence of a tertiary epilepsy centre, which accounts for underdevelopment of epilepsy surgery and paucity in structured
teaching programmes. It is envisaged that the future establishment of the Neurosicence Institute in Hong Kong would resolve these issues. During this interim period, an evidence-based and up-to-date epilepsy guideline would be useful in setting the standard of medical care.
Epilepsy guidelinesGuidelines can be defined as systematically developed statements to assist practitioner decisions about appropriate health care for specific clinical circumstances. Professional societies and scientific bodies have published various guidelines and topical reviews on epilepsy, such as the NICE (www.nice.org.uk) and SIGN (www.sign.ac.uk) guidelines from the UK and Scotland respectively, practice parameters by American Academy of Neurology (www.aan.com), and topical reviews by ILAE (www.ilea-epilepsy.org). Other regional guidelines are available from Malaysia, China, and Italy. As always, people are skeptical about guidelines. Criticisms include non–evidence-based, potential for misuse during legal litigations, bias towards health economics with restriction of physician’s autonomy, and irrelevant to clinical practice. On the other hand, formulation of a guideline does provide an essential link between clinical practice and advances in basic and clinical sciences. It helps us to identify gaps in evidence and areas of uncertainty, which in turn would generate further research. Modification of clinical practice would ensue following clinical auditing and medical education and after all the benefit will be translated into patient’s interest.
Methodology Both the NICE (CG 20, 2004) and SIGN (no. 70, 2003, revised 2005) guidelines were well-written, comprehensive, and evidence-based. They were employed as templates in preparing the Hong Kong Epilepsy Guideline. Literature search was conducted via Medline retrieving original and review articles using key words—eg epilepsy, epileptic seizures, convulsions, neuroimaging, EEG, meta-analysis—from 2003 to mid-2007. The new evidence is classified and translated into recommendations as shown in Appendix A. The first draft was prepared in 2007 and revised after a number of consensus meetings. The second version was scrutinised by our external reviewer in 2008. Review of the latest medical literature from mid-2008 to mid-2009 was finally conducted and new recommendations were added.
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Appraisal of evidenceThe choice of AED in newly diagnosed epilepsy has been a controversial topic for many years, and this is taken as an example to illustrate the gap between existing evidence and translated recommendation. Many studies have shown that the newer AEDs are similar to standard AEDs in terms of efficacy. The SANAD trial (UK)2,3 was a pragmatic study designed to answer the question of the best monotherapy for new-onset epilepsy. It comprised two populations with partial (arm A, n=1721) and generalised/unclassified epilepsy (arm B, n=716) respectively. Arm A was randomised to carbamazepine (standard), or gabapentin, lamotrigine, topiramate or oxcarbazepine and arm B was randomised to valproate, lamotrigine or topiramate. The endpoints were time to treatment failure and time to 12 months’ remission.
In conclusion, valproate was more effective than lamotrigine and better tolerated than topiramate in arm A. Hence valproate is the drug of choice except in reproductive women because of concern of teratogenicity. This recommendation was consistent with our daily clinical practice. In arm B, lamotrigine was comparable to carbamazepine or oxcarbazepine in terms of efficacy but tolerability is better. Gabapentin and topiramate were relatively less potent. Shall we recom-mend lamotrigine as the standard AED in partial epilepsy based on SANAD study? The simple answer is “no”.
The recommendation based on a composite measure of efficacy and general side-effects is not far from the truth. However, a number of points have to be borne in mind. First, the impact of rare but serious side-effects of lamotrigine has not been considered (eg toxic epidermal necrolysis and Stevens-Johnson syndrome). Second, different titration schedule of lamotrigine vs carbamazepine may account for the observed difference in tolerability. Third, other new AEDs such as levetiracetam and pregabalin are not included in this randomised drug trial. Our consensus is that such a simple approach may limit physician’s choice of AED in matching AED profile with patient’s characteristics. Instead of making specific recommendations about AED therapy, we feel that the best treatment strategy should be individualised according to the seizure type and severity, epilepsy syndrome, co-medication and co-morbidity, the individual’s lifestyle and preference (see Guideline Section 8).
Dissemination of the guidelineIt is a common conception that passive methods of dissemination (eg professional journals) rarely lead to changes in practice. This impression is reinforced by the UK TIGER trial, which aimed at determining the effectiveness of dissemination strategies regarding the use of the 1997 SIGN guideline.4 Altogether 68 practices were randomised as follows:
(1) Control group were sent copies of guideline in post;
(2) Intermediate group received guideline plus invitation to workshops and two protocol documents; and
(3) Intensive group was also offered services of Epilepsy Specialist Nurse.
It turned out that the number of planned reviews per patient did not change after the intervention and the number of sessions at which counselling given only increased marginally. Essentially there was no change in practice among the three groups.
ConclusionPhysicians are busy but they may find a guideline useful if this is brief, simple, evidence-based, and comes from reputable source and quality. Alternatively, the guideline is also invaluable if the problem is complex or it adapts to particular patient needs. The Hong Kong Epilepsy Guideline is prepared to fulfil these criteria and we are looking forward to a change in clinical practice in the next decade.
AcknowledgementWe are indebted to Prof JW Sander, Professor of Neurology, UCL Institute of Neurology, UK, for his critical comments and proofreading of our drafts.
Jason KY Fong, MBBS, FRCP (Lond, Edin), FHKAM
(Medicine)
E-mail: [email protected] Specialist in NeurologyOn behalf of the Guideline Development GroupHong Kong Epilepsy Society
References1. Elger CE, Schmidt D. Modern management of epilepsy: a practical approach. Epilepsy Behav 2008;12:501-39. Erratum in:
EpilepsyBehav2008;13:575.2. MarsonAG,Al-KharusiAM,Alwaidh M, et al, SANAD Study group.The SANAD study of effectiveness of carbamazepine,
gabapentin, lamotrigine,oxcarbazepine,or topiramatefor treatmentofpartialepilepsy:anunblindedrandomisedcontrolledtrial.Lancet2007;369:1000-15.
3. MarsonAG,Al-KharusiAM,AlwaidhM,etal,SANADStudygroup.TheSANADstudyofeffectivenessofvalproate,lamotrigine,ortopiramateforgeneralisedandunclassifiableepilepsy:anunblindedrandomisedcontrolledtrial.Lancet2007;369:1016-26.
4. DavisJ,RobertsR,DavidsonDL,etal.ImplementationstrategiesforaScottishnationalepilepsyguidelineinprimarycare:resultsoftheTaysideimplementationofGuidelinesinEpilepsyRandomized(TIGER)trial.Epilepsia2004;45:28-34.
� HongKongMedJVol15No5# Supplement5# October2009
The Hong Kong Epilepsy Guideline 2009T H E G U I D E L I N E
1 Preamble1.1 This guideline addresses the diagnosis and
medical management of epilepsy in children,adults, and older people. It does not coverneonatalseizuresorthemanagementoffebrileconvulsions.Theguidelinemayalsoberelevantto professionals working in the occupationalhealth services, social services, educationalservices,orthevoluntarysectors.
1.2 Thisguidelineisevidence-basedandthegradingschemeusedfortherecommendations(A,B,C,D, good practice point [GPP]) is described inAppendixA.
1.3 Thisguidelinerepresentsconsensusviewsofthe Guideline Development Group and hasbeen approved by the council of HKES. It isbased on an appraisal of current scientificevidence and clinical information. It is notintended to cover all treatment modalitiesrelevant to epilepsy, or to replace clinicaljudgement.Thefinaltreatmentdecisionpathshould be reached by a formal discussionbetween individual patient and the treatingphysician.
2 Diagnosis, review, and referral 2.1 Diagnosis
• All individuals with a recent-onset seizureshould be seen urgently (ie being seenwithin2weeks)byaspecialist(aspecialistis defined as a medical practitioner withtraining and expertise in epilepsy) toensure correct diagnosis and initiation ofappropriatetherapy.
• Theseizuretype(s)andepilepsysyndrome,aetiology, and co-morbidity should bedetermined.
2.2 Reviewandreferral• A comprehensive care plan should be
agreedamonghealthcareprofessional,theindividual with epilepsy, and their familyor carers. All parties should participate indecisionsabouttheirhealthcare,andtakeintoaccountanyspecificneeds.
• All individuals with epilepsy should havea regular structured review. This reviewshould be carried out at least yearlydepending on how well the epilepsy iscontrolled and the presence of specificlifestyleissues.
3 Patient education3.1 Individuals with epilepsy and their families or
carersshouldbegiveninformationabout:C• epilepsyingeneral• diagnosisandtreatmentoptions• medicationandside-effects• seizure type(s), triggers and seizure
control• riskmanagementandself-care• first aid, safety and injury prevention at
home/school/work• psychologicalissues• socialservices• educationandhealthcareatschool• employment and independent living for
adults• importanceofdisclosingepilepsyatwork• homesafetyanddriving• prognosis• suddendeathinepilepsy• statusepilepticus• lifestyle,leisure,andsocialissues(including
recreational drugs, alcohol, sexual activity,andsleepdeprivation)
• familyplanningandpregnancy• voluntary organisations, eg support
groupsMost of the above information is included inthebooklet,Your Guide to Epilepsy,publishedbytheHKES(4thedition,2008).
3.2 Thetimeatwhichthisinformationisgivenwilldependon thecertaintyof thediagnosis, andtheneedforconfirmatoryinvestigations.GPP
3.3 Adequate time should be given to provideinformation.Checklistsmaybeusedtoremindboth individualsandhealthcareprofessionalsabout information that should be discussedduringconsultations.GPP
4 Following a first seizure4.1 Urgencyofevaluation
Hospital admission is recommended after theoccurrenceofafirstconvulsiveseizureorinthepresenceofthefollowingconditions:D• Feverorsignssuggestiveofinfection• Prolonged seizure lasting more than 5
minutes• Clusterofseizuresegtwoormoreseizures
within24hours• Incomplete recovery after a seizure, eg
drowsinessformorethan2hours
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• Persistent post-ictal focal neurologicaldeficit
Advantagesofhospitaladmissioninclude:• Prompt diagnostic evaluation looking for
animportantortreatablecause• Close monitoring for possible emergence
intostatusepilepticus• Gatheringimportantprognosticinformation
forcounsellingIfhospitaladmissionisconsideredunnecessary,aspecialistappointmentshouldbemadewithin2weeks.GPP
4.2 Theinitialevaluation• A detailed history including a witness
accountandthecircumstancesatthetimeofseizureisnecessary.B
• The differential diagnosis is wide (AppendixB1)andmisdiagnosisiscommon.
• Preceding auras (eg epigastric risingsensation,auditoryorvisualhallucination,déjà vu) or Todd’s paralysis are suggestiveofpartialseizure.C
• Limb stiffening, myoclonic jerks, jawclenching, cyanosis, hypersalivation, headandneckversion,andpost-ictalconfusionarefeaturessuggestiveofgeneralisedtonic-clonicseizure.C
• Physical examination during the post-ictalperiodisusuallynon-rewardingbutcertainclinicalsigns(eglateraltonguebiting,scaldinjury, posterior shoulder dislocation)would lend support to the diagnosis ofepilepticseizure. C
4.3 ClassificationofsingleseizuresSingleseizurescanbeclassifiedintotwogroups(AandB):GroupA:reactiveorsystemiccauses• Reactive seizures due to sleep
deprivation, fever, drug withdrawal ortoxicity
• Systemic diseases, eg infection,hypoglycaemia, hypoxia, hypocal-caemia
Group B: central nervous system insult orepilepsy• Direct central nervous system insult, eg
head injury, stroke, encephalitis, brainneoplasm
• First-seizure manifestation ofsymptomaticoridiopathicepilepsy
4.4 Theclinicalimportanceofclassification• In Group A, seizures are usually self-
limiting and recurrence may be reducedby correction of the provoking factor. Incontrast,seizuresinGroupBareassociatedwithsubsequentrecurrenceandlong-termAEDsmaybenecessary.
• AlthoughAEDmayreducetheriskofseizuresinreactiontohead injury,craniotomyandcerebral malaria, such treatment does notaffect the future development of epilepsyand hence routine prophylaxis is notindicated.C
4.5 BiochemicalandhaematologicaltestsThefollowingtestsshouldbeperformed:B• Completebloodcellcount• Urea, creatinine, electrolytes, calcium,
glucose• Liverfunctiontest,creatinekinase• Urinalysis and toxicology screening (if
indicated)
4.6 Otherinvestigations• EEGperformedwithin24hoursof seizure
has a higher probability of detectingepileptiformdischarges thananEEGdoneonsubsequentdays. B
• CT/MRI of the brain is indicated to lookfor a structural brain lesion—CT brainis more appropriate in the emergencysettinginassociationwithbonefractureorhaematoma, otherwise MRI brain is moresensitive.C
• Cerebrospinalfluidexaminationisindicatedin the presence of fever and meningealsignstoestablishthediagnosisofcerebralinfection. D
4.7 Emergencymanagementafterthefirstseizure• In general, a single seizure usually self-
terminateswithin2 to3minutesanddrugtreatmentmaynotbenecessary.D
• Short-acting benzodiazepine (eg IVdiazepam, diazemuls or midazolam)is indicated under the followingcircumstancestoaborttheonsetofstatusepilepticus: C(a) aconvulsiveattacklastingmorethan
2minutes(b) remaining drowsy in between
attacks(c) in the presence of a serious
underlying cause, eg encephalitis,stroke
• See also the management of statusepilepticus(Section14)
• Theunderlyingcauseshouldbedeterminedand specific treatment should commenceas soon as possible (eg correction ofbiochemical abnormality, acyclovir forherpesencephalitis).GPP
4.8 AEDtreatmentafterfirstseizure• The initiation of AED treatment is
determined by the risk of recurrence.GPP
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� HongKongMedJVol15No5# Supplement5# October2009
• AED is not recommended in those with anormal workup as the cumulative risk ofrelapsein2yearsislessthan20%.GPP
• The highest risk of recurrence occurs inthose with both epileptiform EEG and astructural brain lesion (80-100%). An EEGwith epileptiform discharges will increasethechanceofrecurrencefrom20%to80%(AppendixB2).
• AED may be commenced if the benefitsof reducing the risk of a second seizureoutweightheriskofpharmacologicalside-effects.GPP
• The initial choice of AED should beindividualised(seeSection8).A
• Early AED treatment does not affect thelong-termremissionofepilepsy.B
• Multiple seizures within 24 hours areregardedasasingleevent.B
4.9 Generaladvicetopatientsafterafirstseizure• The overall probability of developing a
secondseizureisabout42%.• The tendency of recurrence can be
determined after a period of observation,eg6monthsto2years
• To minimise the risk and impact ofrecurrence,advisethefollowing: GPP(a) Stopdrivingandinformthetransport
department(b) Avoidoperatingdangerousmachinery
orworkatheight(c) Restriction for at-risk hobbies, eg
hiking,diving,androckclimbing(d) Avoid sleep deprivation, recreational
drugs,andalcohol(e) Learn about the first-aid measures
duringaseizure
5 Investigations5.1 EEG
• EEGisausefultesttoconfirmthediagnosisof epilepsy but it must be appropriatelyinterpretedtoavoidmisdiagnosis.Itshouldbe performed within 4 weeks after it hasbeenrequested.GPP
• An EEG may be used to help determineseizuretypeandepilepsysyndromewhichcarry prognostic information. C Followinga first unprovoked seizure, epileptiformdischarges shown on EEG can be used toassess the risk of seizure recurrence (seeSection4.8).B
• A normal EEG should not be used toexcludeepilepsyeventhoughtheclinicalpresentation supports the diagnosis ofnon-epileptic event. On the other hand,an abnormal EEG should not be used
alonetomakeadiagnosisofepilepsyasfalse-positiveresultmayoccur(AppendixB2).C
• Repeated standard EEGs may be helpfulwhen the diagnosis of the epilepsy orthe syndrome is unclear. However, if thediagnosis has been established, repeatEEGs are unlikely to be helpful in guidingresponsetotreatment.C
• When a standard EEG is non-rewarding,a sleep or sleep-deprived EEG should beperformed.C
• Long-term video/ambulatory EEG mayestablish diagnosis in difficult cases.Provocationbysuggestionmaybeusedinthe evaluation of non-epileptic seizures.However, false-positive results may occurinsomeindividuals.C
• Photic stimulation and hyperventilationshould remain part of standard EEGassessment unless contra-indicated (egcarotidstenosis).Theindividualandfamilyand/or carer should be made aware thatsuch activation procedures may induceaseizureandtheyhavearight torefuse.GPP
5.2 Neuroimaging• Neuroimaging should be used to identify
structural abnormalities that cause certainepilepsies and MRI is the preferred modeofimaging.C
• MRIbrainisparticularlyindicatedinthose:C(a) with partial seizure onset based on
history,examination,orEEG(b) with seizures continuing in spite of
first-linemedication• Neuroimaging should not be routinely
requested when a diagnosis of idiopathicgeneralised epilepsy is firmly established.C
• CT brain should be used to identifyunderlying gross pathology if MRI is notavailableor iscontra-indicatedor inacutesetting.C
5.3 Othertests• Serumprolactinlevelisnotrecommended
fordiagnosisofepilepsy.C• Other investigations, includingbloodand
urinebiochemistry,shouldbeundertakenat the discretion of the specialist toexcludeotherdiagnoses,todeterminetheunderlying cause of the epilepsy and co-morbidity.GPP
• A 12-lead ECG should be performedwith suspected epilepsy or diagnosticuncertainty.Referraltoacardiologistshouldbeconsidered.GPP
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• Genetic or metabolic causes of epilepsyshould be considered and investigatedin selected cases, eg muscle biopsyfor mitochondrial disease, urine foruroporphyrinogeninsuspectedporphyria.GPP
5.4 Neuropsychologicalassessment• Neuropsychological assessment should
beconsideredin individuals inwhomit isimportant to evaluate learning disabilitiesand cognitive dysfunction, particularly inregardtolanguageandmemory.D
• Referral for a neuropsychologicalassessmentshouldbeconsidered: D(a) ifthereareeducationaloroccupational
difficulties(b) when MRI shows abnormalities in
certain brain regions (eg temporallobe)
(c) when an individual complains ofmemoryorothercognitivedeficits
(d) aspartofpresurgicalevaluation
6 Classification6.1 Epileptic seizures and epilepsy syndromes in
individuals should be classified using a multi-axial diagnostic scheme. The axes that shouldbeconsideredare:descriptionofseizure(ictalphenomenology); seizure type; syndromeand aetiology. Failure to classify the epilepsysyndrome correctly can lead to inappropriatetreatmentandpersistenceofseizures.C
6.2 Individuals with epilepsy should be giveninformation about their seizure type(s) andepilepsy syndrome, and the likely prognosis.GPP
6.3 The ILAE diagnostic scheme (1981) dividedthe various seizures into partial-onset andgeneralised-onset. The former seizure type isfurther subdivided into simple and complexpartial seizures and seizures evolving tosecondarilygeneralisedseizures.ClassificationofseizuretypeprovidesaguidetoAEDtherapy(AppendixC1).
6.4 TheILAErevisedclassificationoftheepilepsiesand epileptic syndrome in 1989 has gainedwidespread acceptance among worldwideepileptologists (Appendix C2). It takes intoaccountaetiologicfactors,ageofonset,regionof onset, and carries prognostic information.ThechoiceofAEDcanbefurtherrefinedbasedonthesyndromicdiagnosis(AppendixD2).
7 Principles of management7.1 A comprehensive care plan and counselling
on important issues (eg driving, schooling,employment, and pregnancy) should bediscussed.GPP
7.2 In newly diagnosed epilepsy, the aim of AEDtreatment is to achieve seizure freedom withminimal or no side-effect. In drug-resistantepilepsy, the treatment target would beachieving the best quality of life by strikinga balance between AED efficacy and theirassociatedside-effects.GPP
8 Pharmacological or AED management8.1 The AED treatment strategy should be
individualised according to the seizure typeandseverity,epilepsysyndrome,co-medicationand co-morbidity, the individual’s lifestyle,characteristics,andpreference(Table1).A
8.2 TheinitialchoiceofAEDisguidedbytheseizuretypeorepilepsysyndrome(AppendicesDandE).Becauseoflackofhigh-qualitycomparativestudiesamongAED,onlysuggestionsaremadeforeachcategory.Otherpublishedguidelines(eg ILAE, American Academy of Neurology)maybeconsulted.D
8.3 In general, patient factors should be matchedwith AED characteristics in terms of efficacyagainst seizure type/epilepsy syndrome,potential side-effects, teratogenicity, meta-bolism, and possible AED interactions. Forinstance,theside-effectsofAEDmaybemoreapparent in certain patient groups and thesemayaffectthechoiceofAED(Table2).GPP
8.4 Switching AED between different manufacturersis not recommended because of differentbioavailability and pharmacokinetic profiles.Substitution may increase the potential forbreakthroughseizuresorexcessiveside-effects(AppendixD3).GPP
TABLE 1. Factors affecting the choice of AEDs
AED-specific variable Patient-specific variable Nation-specific variable
Seizure or epilepsy syndrome
Genetic background AED availability
Specific efficacy/effectiveness
Gender AED cost
Dose-dependent adverse effects
Age
Idiosyncratic reactions Co-medications
Chronic toxicities Co-morbidities
Teratogenicity Insurance coverage
Carcinogenicity Relative wealth
Pharmacokinetics Ability to swallow pills/tablets
Interaction potential
Formulations
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8.5 Single AED (monotherapy) treatment ispreferred to polytherapy wherever possible.A If the first AED is unsuccessful, anothermonotherapymaybestartedandbuiltuptoanadequate dose before the first AED is taperedoffslowly.GPP
8.6 Iftheseconddrugisunhelpful,eitherthefirstorseconddrugmaybetapered,dependingontheirrelativeefficacyandside-effects.GPP
8.7 Combination (adjunctive or ‘add-on’) therapyshouldbeconsideredifmonotherapytrialsfailtocontroltheepilepsy.A
8.8 Bewareofdrug-druginteractionsamongAEDsandbetweenAEDsandnon-AEDs,egwarfarin,oral contraceptive pills via effects of AED onhepatic cytochrome P450 enzyme system.Carbamazepine, phenobarbital, phenytoinare broad enzyme inducers with manyinteractions including oral contraceptive pills.Oxcarbazepine and topiramate (>200 mg perday) induce metabolism of oral contraceptivepills.Gabapentinandpregabalin(bothexcretedrenally unchanged), and levetiracetam (non-hepatic hydrolysis) have lowest potential ofdrug-druginteractions. A
8.9 Valproatesignificantly inhibits themetabolismof lamotrigine. When lamotrigine is addedto a drug regimen containing valproate, itshouldbetitratedmoreslowlytoreachalowermaintenancedose.A Thispracticemayreducethe incidence of dose-dependent adverseeffectsoflamotrigine,particularlyskinrash.B
8.10 Regularbloodtestsfor‘routine’haematologicalandrenalandliverfunctionsarenotnecessaryandshouldbedoneonlyifclinicallyindicated.Asymptomatic minor laboratory abnormalitiesdo not necessarily require changes inmedication.C
8.11 Routine monitoring of serum AED level is not
indicated. Specific indications for monitoringofserumAEDlevelsinclude: D• suspectedAEDtoxicity• detection of non-compliance to the
prescribedAED• adjustmentofphenytoindose• management of pharmacokinetic inter-
actions• specific conditions, eg status epilepticus,
organfailure,andpregnancy
Withdrawal of pharmacological treatment
8.12 Foradultswhohavebeenseizure-freefor2yearsormore,thedecisiontocontinueorwithdrawAEDshouldbetakenbytheindividualandthespecialistafterafulldiscussionoftherisksandbenefitsofwithdrawal.A (seeSections18.1 to18.13).
8.13 AED treatment should be discontinued slowlywithonedrugbeingwithdrawnata time.DAmoreprolongedtimecourse(upto6months)isrequiredforwithdrawingbenzodiazepinesandbarbituratetoavoidwithdrawalsymptomsandseizure recurrence. If seizure recurs, the lastdosereductionisreversedandmedicaladviceissought.GPP
9 Management of drug-resistant epilepsy
9.1 About 70% of people with newly diagnosedepilepsy respond well to AED. Drug-resistantepilepsy may be operationally defined aspersistence of seizures despite optimal andadequatetreatmenttrialswithtwoAEDs(eithermonotherapy or polytherapy) appropriatelychosenfortheseizuretype/epilepsysyndrome.D
9.2 In people with drug-resistant epilepsy,
TABLE 2. Special considerations in different patient groups
Patient group Considerations
Elderly Impaired drug clearance and increased susceptibility to side-effect, eg hyponatremia due to carbamazepine; risk of polypharmacy and potential drug interactions
Children Avoid phenobarbitone (behavioural disturbance) and phenytoin (cosmetic side-effect and erratic absorption)
Reproductive women Avoid high-dose valproate (teratogenicity [see Section 16.5]), and avoid enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital) if oral contraceptives are required
Cognitive dysfunction Avoid phenobarbitone, benzodiazepines and topiramate if risk of cognitive slowing is unacceptable
Mitochondrial diseases Avoid valproate
Advanced renal failure Reduce dose of AEDs that are primarily excreted by renal route, eg gabapentin, pregabalin
Active liver disease Avoid valproate (risk of hepatic encephalopathy)
Eating disorders Avoid topiramate
Morbid obesity Avoid valproate, pregabalin
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considerationshouldbegiventothepossibilityof ‘pseudo-resistance’, referring to treatmentfailuredueto:C• incorrectdiagnosisofepilepsy• inappropriatechoiceofAEDfortheseizure
type/epilepsysyndrome• inadequatedosageofAED• poorcompliancetotreatment• unsatisfactory lifestyle such as drug or
alcoholabuse
9.3 People fulfilling a diagnosis of drug-resistantepilepsy should undergo, preferably at aspecialist centre, comprehensive evaluationof the diagnosis and management, which mayincludeworkupforepilepsysurgery.C
10 Side-effects of AEDs (Appendix D4)Dose-related adverse reactions
10.1 Neurotoxic side-effects (eg dizziness,somnolence, diplopia, ataxia) are mostlydose-related and predictable. These can bereducedbygradualescalationofdoseanddosereductionifsymptomspersist.A
Idiosyncratic drug reactions
10.2 Idiosyncraticdrugreactionsusuallyoccurinthefirstfewweeksoftreatmentandarepotentiallyserious.Skinrashisthemostcommon,occurringin up to 10% of patients on carbamazepine,lamotrigine, oxcarbazepine, phenobarbital,and phenytoin. Cross hypersensitivity iscommon. Most rashes are mild and resolvepromptly on discontinuation of the AED, butsevere cutaneous reactions (Stevens-Johnsonsyndrome and toxic epidermal necrolysis) areseeninupto1:1000patients.
10.3 HLA-B*1502 allele (present in 10-20% ChineseinHongKong)isassociatedwithadramaticallyincreasedriskofcarbamazepine-inducedseverecutaneousreactionsinpeoplewithsusceptibleethnic backgrounds, eg Han Chinese. Priorto starting carbamazepine, people who areethnically Chinese should be tested for HLA-B*1502. Carbamazepine should be avoidedif the test is positive unless the benefits fromtreatment outweigh the risk of developingsevere cutaneous reactions (see FDA Alert:Information for healthcare professionals:carbamazepine <www.ifap.de/pdf/FDA_carba-mazepin-warning_2007-12-12.pdf>).
10.4 AED hypersensitivity syndrome of fever, rash,lympadenopathy, and multi-organ failureoccurs in up to 4:10 000 patients, mostly witharomatic AEDs (carbamazepine, phenytoin,phenobarbital)orlamotrigine.Cross-sensitivity
mayoccurbetweenaromaticAEDsinupto50%ofpatients.B
10.5 Minor blood dyscrasias are associated withmanyAEDs,egleukopeniawithcarbamazepine,thrombocytopeniawithvalproate. GPP
10.6 Hyponatremia(sodium125-135mmol/L)isseeninabout20%ofpatientstakingcarbamazepineoroxcarbazepine,whichisusuallyasymptomatic.Mild elevation of liver enzymes (gamma GTPor alkaline phosphatase) is commonly seen inpeopletakingenzyme-inducingAEDs.GPP
Chronic side-effects
10.7 Vigabatrin should be used as drug of lastchoice (except infantile spasm) because of itsassociation with high incidence of visual fielddefects.B
10.8 Weight gain is seen with many AEDs (egvalproate, gabapentin, pregabalin) and maybesignificant(>10%bodyweight).Incontrast,topiramatecancauseweightloss.B
10.9 Peoplewithepilepsytakinglong-termAEDarepronetohaveosteoporosis,osteomalacia,andfractures. Cytochrome P450 enzyme-inducingAEDs are most commonly associated with anegative impact on bone, but studies alsosuggestaneffectofvalproate.TherearelimiteddataregardingthenewerAED.Theyareadvisedtohaveadequateintakeofdietarycalciumandvitamin D together with regular bone densitymonitoring.D
10.10TeratogenicityofAEDisdiscussedinSection16.
10.11CertainAEDmayexacerbatesomeseizuretypesandepilepsysyndromesandshouldbeavoidedaccordingly(AppendixD1andD2).
11 Presurgical evaluation of drug-resistant epilepsy
11.1 A comprehensive presurgical evaluationentails a multidisciplinary team of experts(neurologists, paediatricians specialising inneurology/epilepsy, neurosurgeons, neuro-radiologists, psychiatrists, and clinicalpsychologists).Multi-modalinvestigationsmaybeundertaken includingvideo-EEGrecording,CT, MRI, functional MRI, PET, SPECT, MEG,angiogram and intracarotid amobarbital test,intracranial EEG monitoring, and functionalmappingtoevaluatebrainfunction.
Referrals for presurgical evaluation
11.2 If there is diagnostic uncertainty or treatmentfailure,individualsshouldbereferredtotertiary
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servicesforfurtherassessment.Indicationsforreferralincludethefollowing:D• drug-resistantepilepsy• theindividualisagedunder2years• unacceptable side-effects from
medication• thereisaunilateralstructurallesion• there is psychological and/or psychiatric
co-morbidity• thereisdiagnosticdoubtastothenatureof
theseizures• thereisatestablehypothesisforlocalising
theepileptogeniczone
11.3 Different scenarios determine complexity ofinvestigations:
Scenario 1: a focal lesion on MRI withconcordantscalpEEGandcongruentresultsoffunctional evaluation. The classical prototypeis a right-handed individual with right mesialtemporal sclerosis, ictal right temporal EEGonset,interictalrighttemporalEEGdischarges,clinicalpsychologicaltestingshowingimpairedfigurativememoryandnormalverbalmemory.A
Scenario 2: focal or multiple lesions on MRIwith our without discordant scalp EEG orincongruent results of functional evaluation.This entails a heterogeneous group ofpatients with discordant results. Multi-modalinvestigationsandmultidisciplinarydiscussionsareusuallyundertakenandtheremaybeaneedfor intracranial implantation to localise theepileptogenic zones. Individualised approachisusuallyadopted.C
Scenario 3: resection close to eloquent areas.Consideration should be given to functionalmapping, which may be undertaken intra-operatively or extra-operatively with gridimplantation. Extra-operative functionalmapping may provide more sophisticatedtestingofbrainfunctions.C
Scenario 4: non-lesional or ‘cryptogenic’cases. Investigations are necessary to rule outidiopathic generalised epilepsy. Multi-modalinvestigationsandintracranialimplantationwillberequiredinthemajorityofcases.C
Scenario 5: resective surgery not applicable.Palliativeneurosurgery,egcorpuscallosotomyorvagusnervestimulation,maybeconsidered.C
Special considerations in paediatric epilepsy surgery
11.4 The spectrum of localisation-related epilepsyis often heterogeneous in childhood andmay present with generalised seizures or EEG
patterns, as well as progressive neurologicaldysfunction.C
11.5 Unclassifiable childhood epilepsy should bereferred for presurgical evaluation, eg non-idiopathicpartialseizuresor lesionalepilepsy.D
11.6. Age-appropriate neuropsychological anddevelopmental assessments are mandatoryin those with developmental delay but suchimpairment should not exclude them fromepilepsysurgery.D
11.7 Epilepsysurgeryconsistsofcorticalresectionordisconnectionprocedures.Surgicalremediablesyndromes were more diverse in children,including mesial temporal sclerosis, corticaldysplasia, developmental brain anomaliesand tumour, tuberous sclerosis, Rasmussen’sencephalitis, hypothalamic hamartoma, andvascularmalformations.D
11.8 Functional plasticity in the child’s brain couldenhancetherecoveryoflinguisticcompetenceand facilitate neurological re-organisationafter surgical treatment. Early intervention istherefore critical in infants with catastrophicepilepsy to prevent developmental arrest orregression. C
11.9 Corpus callosotomy is a palliative epilepsysurgery to block interhemispheric spreadof secondarily generalised seizures. Corpuscallosotomyisespeciallyeffectivefortonicandatonic seizures causing falls and consequentinjuries,egLennox-Gastautsyndrome.C
12 Other forms of treatmentPsychological interventions
12.1 Psychological interventions (relaxation, cogni-tive behaviour therapy, biofeedback) may beused in conjunction with AED in adults. Thisapproachmaybeassociatedwithanimprovedqualityoflifeinsomeindividuals.A
12.2 Psychological therapy has not been proven toaffectseizurefrequencyandisnotanalternativetoAEDtreatment.A
Ketogenic diet
12.3 The ketogenic may be considered anadjunctive treatment in children with drug-resistant epilepsy. The responder rate (morethan 50% seizure reduction) is close to 40%.A Side-effects include constipation, vomiting,lethargy, hunger, acidosis, easy bruising, andnephrolithiasis. Contra-indications includethose with fat metabolic disorders andporphyria.
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12.4 The modified Atkins diet (restrictingcarbohydrateintaketo10ginchildrenand15ginadults)hasa45%responderrate.C
Vagus nerve stimulation
12.5 Vagus nerve stimulation is indicated as anadjunctive therapy in reducing the frequencyof seizures in drug-resistant epilepsy notamenabletosurgery.TheefficacyofvagusnervestimulationissimilartothatobtainedwithnewAEDs.A Side-effectsareusuallymild,egcoughandtransienthoarsenessofvoice.
Gamma knife radiosurgery
12.6 Gamma knife radio surgery may be effectivein patients with mesial temporal sclerosis butadelayedresponseby10months isobserved.The long-term side-effects are unknown. Itis also effective in treating focal epilepsy dueto cavernous angiomas in central region andgelasticseizures inhypothalamichamartomas.C
13 Prolonged seizures in the community13.1 An individual who has prolonged convulsive
seizures (lasting 5 minutes or more) or serialseizures(threeormoreseizuresinanhour)inthecommunityshouldreceiveurgentcareandtreatment. A
13.2 Rectal diazepam is a safe and effective first-linetreatmentofprolongedseizures.A Buccalmidazolamisanalternativewhichiseasiertobeadministeredandconsideredmoreacceptableforpatientsandadministers.C
14 Treatment of status epilepticus 14.1 Convulsive status epilepticus is a medical
emergency.• General measures include airway
management,settingupIVaccess,oxygensupplement, cardiorespiratory functionmonitoring. GPP
• IV lorazepam is a first-line treatment instatus epilepticus and alternatives includeIVdiazemuls,diazepam,andmidazolam.DThese can be repeated if necessary. Closemonitoringofcardiorespiratoryfunctionismandatory.
• Full blood count, urea, and electrolytes,liver function tests, blood gases, calcium,glucose, clotting profile andAED level(s)
General measures Pharmacological treatment
Premonitory status (prehospital)• Out-of-hospital management for acute seizure• Common sense to prevent injuries, eg cushion the person’s head,
loosen any tight neckwear, turn the person on his or her side• Do not hold the person down or restrain the person• Do not place anything in the mouth • Do not try to pry the teeth apart• Observe seizure characteristics—length, type of movements, direction
of head or eye turning
1. Rectal diazepam 10-20 mg, repeated once 15 minutes later if seizure continues, OR
2. Buccal midazolam 10 mg
If seizures continue, call emergency ambulance service and continue anticonvulsant as below.
Early status I (0-10 minutes) • Resuscitation, secure airway (consider intubation), administer
oxygen, assess cardiorespiratory function and establish IV access, haemoglucostix
1. Lorazepam IV 0.1 mg/kg (usually 2-4 mg bolus, repeated once after 10-20 minutes) OR
2. Diazepam IV 0.1 mg/kg (usually IV 5-10 mg bolus, repeated once after 5-10 minutes) OR
3. If already on AED, resume usual medication
For sustained control or if seizures continue, treat as below.
Early status II (0-30 minutes) • Institute regular monitoring, emergency investigations• Administer glucose (50 mL of 50% solution) and/or IV thiamine (250
mg) • Treat acidosis if severe • Consider the possibility of non-epileptic status
Established status (0-60 minutes) • To establish aetiology • Arrange ICU bed• Identify and treat complications, including use of vasopressor, if
appropriate
1. Phenytoin infusion at a dose of 15-18 mg/kg at a rate of 50 mg/minute OR
2. Fosphenytoin infusion at a dose of 15-20 mg phenytoin equivalents (PE) per kg at a rate of 50-150 mg PE/minute AND/OR
3. phenobarbitone bolus of 10-15 mg/kg at a rate of 100 mg/minute
Refractory status (30-90 minutes) • Transfer to ICU, and EEG monitoring• Consider the possibility of non-epileptic status• Intracranial pressure monitoring, if appropriate • Initiate long-term, maintenance AED therapy
General anaesthesia, with one of the following:a. propofol (1-2 mg/kg bolus, then 2-10 mg/kg/hour) b. midazolam (0.1-0.2 mg/kg bolus, then 0.05-0.5 mg/kg/hour) c. thiopentone (3-5 mg/kg bolus, then 3-5 mg/kg/hour) [after 2-3
days infusion rate needs reduction as fat stores are saturated]
Anaesthetic continued for 12-24 hours after the last clinical or electrographic seizure, then dose tapered.
TABLE 3. Guideline for treating convulsive status epilepticus
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areindicated. C• Give 50 mL of 50% glucose IV for
hypoglycaemia and IV thiamine if alcoholabuseorpoornutritionalstatusissuspected.C
• For patients with epilepsy, the usual AEDshall be resumed with dosage adjustmentif necessary. Otherwise a loading dose ofAED should be given (Table 3). B The rateof AED infusion may need to be adjustedif hypotension or arrhythmia occurs. Inselectedcases,IVvalproateorlevetiracetammaybeused. D
• If seizure continues, ICU admission isindicatedforadministrationofanaestheticagent (Table 3), EEG monitoring andcritical life support.The cause of statusepilepticus shall be investigated andtreated.C
14.2 Non-convulsive status epilepticus is lesscommon. Continuation of usual AED and IVbenzodiazepines with EEG monitoring areuseful.GPP
15 Perioperative management of seizure15.1 LossofseizurecontrolduetomissedoralAED
can occur during surgery, labour and whenthere is difficulty in swallowing. Table 4 listssomealternativeroutesofAEDadministration.Sometimes changes in drug doses will benecessary due to pharmacokinetic differencesbetweenformulations.C
15.2 AEDs should be administered by alternativeroutes or by giving additional doses asappropriate. When patients have beendesignatednilbymouthpriortosurgery, theyshouldstillbegiventheirusualoralAEDunlessabsorptionisimpaired.GPP
15.3 Whenaprolongedproblemwithadministered
drugs not available parenterally is anticipated,and oral or enteral administration is notpossible, consideration should be given toseizureprophylaxiswithparenterally availableagents.GPP
16 Women with epilepsy16.1 Women with epilepsy and their spouses
shouldreceiveinformationandcounsellingoncontraception, conception, pregnancy, child-care,breastfeeding,andmenopause.C
16.2 Preconceptioncounsellingshouldbegiven towomenofchildbearingagewithepilepsy.Theyshould be reassured that most can have anuneventfulpregnancyanddelivery.GPP
16.3 In women of childbearing potential, the riskof AEDs causing harm to foetus should beadequately discussed. The treatment strategyshouldbetargetedatthelowesteffectivedoseof the most appropriate AED. Monotherapy ispreferredtopolytherapy.C
Teratogenicity of AEDs
16.4 Common associated major congenitalanomaliesconsistofhypospadias,heartdefects,clubfoot,cleftliporpalate.Theseoccurinthegeneralpopulationatarateof2to5%.Theriskofsuchmajorcongenitalanomaliesisincreasedto4to10%ininfantsexposedtotheoldAEDsespecially for those who are receiving AEDpolytherapy.C
16.5 Neural tube defects occur in 1 to 2.2% withcarbamazepine but a dose-escalating riskhas been observed with both valproate andlamotrigine: 4.1% with valproate at <600 mg/day;1.3% with lamotrigine <100 mg/day, 6% withvalproate600-1000mg/day,1.9%withlamotrigineat100-200mg/day,9.1%withvalproateat>1000mg/day, 5.4% with lamotrigine >200 mg/day. CScreeningofneuraltubedefectsbyultrasoundandalpha-fetoproteinshouldbecarriedoutat18to22weeks’gestation.GPP
16.6 In-utero exposure to high-dose valproate isassociated with an increased risk of impairedcognitive function at 3 years of age. Thisfindingsupportsarecommendationthatotheralternativesshouldbeconsideredasfirst-choicetherapyinwomenofchildbearingpotential.C
16.7 There are insufficient data to evaluate theteratogenicity potential among other newerAEDs, eg topiramate, levetiracetam, andgabapentin.
16.8 Dailyfolate(5mg)supplementshouldbegivenbeforepregnancy.D
AED Alternative administration
Carbamazepine Liquid or suppositories (dose amendment required)
Phenytoin IV or liquid phenytoin; IV or IM fosphenytoin
Gabapentin Capsule contents via feeding tube (unlicensed)
Levetiracetam Liquid or IV
Lamotrigine Dispersible tablets can be given via feeding tube
Valproate IV, liquid, or suppositories (unlicensed)
Topiramate Sprinkle capsules
Vigabatrin Powder
Phenobarbital Liquid; IV or IM injection
TABLE 4. Alternative methods of AED administration
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Contraception
16.9 AED interaction with oral contraceptive pillsshouldbediscussed.GPP
16.10If a woman taking enzyme-inducing AEDs(carbamazepine,oxcarbazepine,phenobarbital,phenytoin, primidone, topiramate) requireshormonal contraception, the followingregimensarerecommended:• For combined oral contraceptive pills, a
minimuminitialdoseof50µgofoestrogenshouldbecommenced.D
• Ifbreakthroughbleedingoccurs,thedoseof oestrogen should be increased to 75or 100µg per day, and ‘tricycling’ (takingthree packs without a break) should beconsidered.D
• A shorter repeat injection interval isrecommended (10 weeks rather than12 weeks) for depot injections ofprogesterone (eg Depo-Provera 150 mg)D
• Foremergencycontraception, thedoseoflevonorgestrel should be increased to 1.5mgand750µgwith12hoursapart.D
Pregnancy
16.11Women should be reassured that there is noevidence that simple partial, complex partial,absence and myoclonic seizures affect thepregnancy or developing foetus adverselyunlesstheyfallandsustainaninjury.D
16.12Sixtypercentofwomenexperiencenochangeinfrequencyduringpregnancy,30%increasedfrequency and 10% decreased frequency. Theincrease in seizure frequency may be due topregnancy-related fall in AED concentration,sleepdeprivation,orpoorcompliance.B
16.13Routine monitoring of most AED levels inpregnancyisnotnecessary.However,thismaybe used to guide dosage adjustment shouldseizurefrequencyincrease.D
16.14Both total and free clearance of lamotriginemay increase substantially during pregnancywith peak at the third trimester (up to 90-230%). A drop of lamotrigine level to 65% ofthepreconceptionallevelisassociatedwithanincreaseinseizurefrequency.A Monitoringoflamotriginelevel,ifavailable,isusefultoadjustdosageoflamotrigineduringpregnancy.
Labour
16.15About1to2%ofwomenwithepilepsydevelopa generalised tonic-clonic seizure duringlabour.AEDsshouldbecontinuedorallyorviaIV route if necessary. Epidural anaesthesia is
recommended to reduce pain and emotionaldistress. Elective caesarean section may benecessaryifseizuresarefrequent.D
16.16To prevent haemorrhagic disease of newborn,mothers taking enzyme-inducing AEDs maybe given 20 mg/day of oral vitamin K1 in thelast month of pregnancy. Alternatively, theirnewborns should be given 1mg of vitamin K1parenterallyatdelivery.C
Breastfeeding and the puerperium
16.17Allwomenwithepilepsyshouldbeencouragedto breastfeed, which is safe in the majorityof cases. GPP As most AEDs are secreted inbreast milk in small quantities, the infant maybecomesedated(inabout5-10%).Underthesecircumstances, bottle-feeding can be used tosupplementbreastfeeding.
16.18Mothers should breastfeed their babies whilesittingonfloorcushionstoavoiddroppingtheirbabyshouldaseizureoccur.Bathingthebabiesinthebathtubisnotrecommended.GPP
Menopause
16.19Clinician must remind patients that hormonalreplacementtherapyissignificantlyassociatedwith increase in seizure frequency duringmenopause,particularlyinwomenwithhistoryofcatamenialepilepsy.C
17 Older people with epilepsy17.1 Generalised convulsions and complex partial
seizures (mainly extra-temporal) are the mainclinicalmanifestationsofepilepsyintheelderly.The lattermaypresentwithstaring,blackouts,ordizzinesswhichmaybemistakenastransientischaemicattackorsyncope.
17.2 In view of the altered pharmacokinetics andpharmacodynamics in the elderly, side-effects ofmost AEDs are more apparent and a lower start-ing dosage is recommended. Drug interactionsmay constitute a significant problem because ofpolytherapy associated with co-morbidities. ThenewerAED,eggabapentin,lamotrigineareshownto be better tolerated in the elderly with similarefficacycomparedwiththeoldAEDs.B
18 Children and young people with epilepsy
After first seizure
18.1 ‘Airway, breathing and circulation’ should bepreserved according to established paediatriclife support guideline. If the child shows full
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recoveryafterthefirstseizure,itisnotnecessarytocheckfullbloodcountorelectrolytesunlessthere are specific features on history andexaminationtosuggestthismightbehelpful.
Differential diagnosis
18.2 Misdiagnosis of epilepsy appears to be asignificantproblemandmayhavemajorlonger-termimplications(AppendixB3).Thediagnosisof epilepsy should be made by a paediatricneurologist or paediatrician with expertise inchildhood epilepsy. D Home video camerarecordingsshouldbeusedinordertocapturerecurrent events where the diagnosis is indoubt. GPP
Investigations
18.3 Investigations• All children presenting with convulsive
seizures should have an ECG with acalculation of the QTc interval, in orderto rule out epileptic or epileptic eventsassociatedwithcardiogenicsyncope.GPP
• All children with recurrent epilepticseizures other than recurrent or complexfebrileseizuresshouldhaveanEEG.C AEDsshouldnotusuallybestartedbeforeanEEGrecording since it may mask a syndromicdiagnosis.GPP
• Most children with epilepsy should havean elective MRI brain scan. Children withthe following epilepsy syndromes (whichfollow a typical course) do not needbrain imaging—eg idiopathic generalisedepilepsies (childhood absence epilepsy,juvenile myoclonic epilepsy, juvenileabsence epilepsy etc); benign childhoodepilepsywithcentrotemporalspikes.D
Genetic testing
18.4 Where one person in a family has idiopathicepilepsy, the recurrence risk for siblings is2.5to6.7%andforchildrenis1.6to6.3%.Therecurrence risk for symptomatic epilepsiesrelates to the underlying aetiology. In allpatients with newly diagnosed epilepsy, athree-generation family history should betaken (ie siblings, parents and grandparents,uncles,aunts,cousins).Familieswithahistoryof epilepsy should be referred to the ClinicalGenetic Service particularly if three or moremembersofthefamilyareaffected.GPP
Pyridoxine dependency
18.5 Pyridoxine-dependent seizures form a rare,
but easily treatable epilepsy syndrome whereseizuresarelargelyresistanttoAED.Whilethereare typical neonatal presentations, childrenmaypresentupuntilthethirdyearoflife.Atrialof pyridoxine and its withdrawal is needed todiagnosepyridoxinedependencyandshouldbeconsideredinchildrenwithintractableepilepsywithonsetundertheageof3years.GPP
Febrile seizures
18.6 Childrenwithfebrileseizures,evenifrecurrent,should not be treated prophylactically withAED. B Fordetails,pleaserefertothefollowingwebsite: <http://www.fmshk.org/hkcpaed/member/guideline/fc.pdf>
Choice of AEDs (Appendices D and E)
18.7 WhenWest’ssyndrome iscausedby tuberoussclerosis, vigabatrin is superior. For otheraetiologies and cryptogenic forms of West’ssyndrome, corticotrophin or corticosteroidsshouldbeusedasfirst-linetreatment.B
18.8 In drug-resistant idiopathic generalised epilepsy,topiramate, lamotrigine, levetiracetam andclobazam are effective as add-on treatments.Lamotrigine, topiramate and nitrazepam areeffective add-on treatments in Lennox-Gastautsyndrome. Stiripentol has antiepileptic activityinDravet’ssyndromewhenusedwithclobazamand sodium valproate. High-dose valproate,nitrazepam and topiramate are efficacious inresistantWest’ssyndrome.B
18.9 Prolongedorserialseizuresshouldbetreatedwith either nasal or buccal midazolam orrectaldiazepam.B Allunitsadmittingchildrenshouldhaveaprotocolforthemanagementofconvulsivestatusepilepticus.GPP
18.10Clearadviceonthemanagementofthepotentialadverse effects of AED should be discussedwithchildrenandparentsorcarers.Adolescentgirls taking AED and their parents should beadvisedoftherisksoffoetalmalformationsanddevelopmentaldelay(seeSection16).GPP
Withdrawal of AED treatment
18.11AED withdrawal should be considered inchildren who have been seizure-free for 2 ormoreyears.Reasonsforwithdrawalinclude:• concernaboutside-effectsofAED• avoid teratogenic side-effects on the
foetus• psychological gratification, eg feeling
cured,removalofstigmata
18.12Risk factors for seizure relapse include
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symptomatic epilepsy, more than 12 years ofageatseizureonset,shortdurationofseizurefreedom (less than 6 months), an abnormalEEG at discontinuation and certain syndromaldiagnosis,suchasjuvenilemyoclonicepilepsy.A
18.13Ifseizurerecurs,itusuallyoccursshortlyafterAED withdrawal. The risk of relapse is about30% in children and 40% in adults. Seizurecontrolmaynotberegainedinupto20%afterrelapse. These risks have to be balanced withthepotentialgainandthefinaldecisionshouldbeindividualised.GPP
Behaviour and learning
18.14Learningandbehaviouralproblemsaremoreprevalentinchildrenwithepilepsythaninthegeneral childhood population. All childrenwith epilepsy should have their behaviouraland academic progress reviewed on aregular basis by the epilepsy team. Childrenwith academic or behavioural difficultiesshould have appropriate educational and/orpsychological assessment and intervention. GPP
Use of other medications
18.15Neurostimulantsshouldnotbewithheld,whenindicated, from children with epilepsy andattention deficit and hyperactivity disorders. D
18.16Selective serotonin reuptake inhibitors andatypicalneurolepticssuchasrisperidoneshouldnot be withheld, when indicated, in childrenwith epilepsy and associated behavioural andpsychiatricdisorders.GPP
Transitional care
18.17Duringadolescence,smoothtransitionofcareto adult services and the possible need forcontinuing multi-agency support should beconsidered.GPP
18.18Adolescents may be stressed by restriction ofrecreationalactivities.Theyareconcernedaboutside-effectsofAEDs (egweightgain) andmayfeel inferiortotheirpeergroup.Psychologicalcounsellingisessential.GPP
19 Lifestyle and social issues Advice on minimising hazards at home
19.1 Clinicians should give advice on minimisingpossible hazards at home in case seizureshappen(eguseshowerratherthanbathtub).D
Hazards at work
19.2 Advice should be given on suitability ofparticular job to people with epilepsy takingintoaccountthejobrequirementsandseizurecharacteristics.D
Sports and leisure activities
19.3 People with epilepsy are recommended tohaveappropriatesports forhealthandsocialwell-being.Epilepsyisnotareasontoprohibitthem from sports (even competitive types),providedadequatesafetymeasureshavebeentaken.D
19.4 Seizurerisk ishigherduringrelaxationperiodaftersportascomparedtoduringsport-playing.D
19.5 Eitherswimmingaloneordiving ishazardous.Accompanying person with lifesaving skills isessential.D
Driving and epilepsy
19.6 Since seizures may result in losing control ofthe vehicle leading to road traffic accidents,people with epilepsy are legally prohibited todriveinHongKong.
19.7 People with epilepsy are obliged to notify theTransportDepartment regarding theirmedicaldiagnosis.
19.8 Anindividualwithinactiveepilepsymayapplyforadrivinglicenceunderspecialcircumstancesbut theoutcome issubject toapprovalby theTransportDepartment.
19.9 Driving is considered a privilege, not a right.Use of public transport is recommended forpeoplewithepilepsy.
19.10Certain occupations are restricted for peoplewith epilepsy, eg drivers for public transport,pilots,operatorsofheavymachinery,egcranes,tractors.
# Sung et al #
18 Hong Kong Med J Vol 15 No 5 # Supplement 5 # October 2009
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Original articles42.Annegers JF,HauserWA,Lee JR,RoccaWA. Incidenceofacute symptomatic seizures inRochester,Minnesota,1935-1984.
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EpiscreenStudy.Seizure2003;12:203-10.45.HosainSA,GreenNS,SolomonGE,ChutorianA.NitrazepamforthetreatmentofLennox-Gastautsyndrome.PediatrNeurol
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Recommendation grade Evidence
A Directly based on category I evidence
B Directly based on:• category II evidence, or• extrapolated recommendation from category I evidence
C Directly based on:• category III evidence, or• extrapolated recommendation from category I or II evidence
D Directly based on:• category IV evidence, or• extrapolated recommendation from category I,II or III evidence
GPP Good practice point based on the clinical experience of the Guideline Development Group
Evidence category Source
I Evidence from:• meta-analysis of randomised controlled trials, or at least one randomised controlled trial
II Evidence from:• at least one controlled study without randomisation, or• at least one other type of quasi-experimental study
III Evidence from non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies
IV Evidence from expert committee reports or opinions and/or clinical experience of respected authorities
AppendicesAppendix A. Grading scheme of evidence
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Appendix B. Differential diagnosis of epileptic seizures and epileptiform dischargesAppendix B1. Differential diagnosis of epilepsy in adults
PsychologicalAdjustment, stress Affective orders, OCDPanic attacksConversion, PTSDPersonality disorderBehavioural disorderMalingeringSomatoform disorderTrauma, abuse
PhysiologicalCardiac/syncopeDrugsMetabolic/toxic infectionMigraine, TGATIASleep disorderMovement disorderDystonia, drop attack
Provoked (group A)AlcoholLack of sleepDrugsMetabolicFeverInfection
Unprovoked (group B)
Epilepsy
Recurrent
Generalised Focal
Non-epileptic seizures Epileptic seizures
Seizures (paroxysmal events)
TGA denotes transient global amnesia, TIA transient ischaemic attack, OCD obsessive compulsive disorder, and PTSD post-traumatic stress disorder
Interictal epileptiform discharges Benign EEG variants and sleep transients Common EEG artifacts
Spikes Small sharp spikes Eye movement
Spikes and slow waves Occipital spikes of the blind Electrocardiogram
Sharp waves 14 and 6 Hz positive spike Head movement
Sharp and slow waves Rhythmic temporal theta bursts Muscle
Polyspikes±slow waves Wicket spikes Swallowing
(Pseudo) Periodic complexes Occipital 6 Hz spike and wave Tongue movement
Paroxysmal lateralised epileptiform discharges Vertex sharp waves Electrode
Positive sharp transients of sleep Pulse
K-complexes Electrical mains
Appendix B2. Differential diagnosis of epileptiform discharges
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Group Age Diagnosis
Infants 2 months-2 years Stiff baby/hyperekplexiaCyanotic and pallid breath-holding spells, reflex anoxic seizure, reflex asystolic syncopeShuddering attacksParoxysmal torticollis, extrapyramidal drug reactions, dystoniaSandifer syndromeStereotypies, constipation, infantile gratification disorderFabricated and induced illnessSpasmus nutans Benign paroxysmal vertigoBenign myoclonus of early infancyAlternating hemiplegia of childhoodSleep disorders: rhythmic movement sleep onset disorder, benign neonatal sleep myoclonus
Childhood 2-12 years Cyanotic and pallid breath-holding spells, reflex anoxic seizure, reflex asystolic syncopeSyncopeMigraine and migraine equivalentsRecurrent abdominal painCyclic vomitingBenign paroxysmal vertigoTicsParoxysmal torticollisParoxysmal kinesigenic choreoathetosisSandifer syndromeDystonic drug reactionConstipationStereotypies, daydreamingGratification disorderFabricated and induced illnessPsychogenic seizuresSleep disorders: rhythmic movement sleep onset disorder, night terrors, sleep walking, talking in sleep, narcolepsy
Adolescent 12 years to adult SyncopeMigraine and migraine equivalentsPsychogenic seizuresMovement disordersParoxysmal kinesigenic choreoathetosisParoxysmal dystonic choreoathetosisParoxysmal hereditary ataxiasTremorTicsTransient global amnesiaSleep disorders: nocturnal myoclonus, hypnic jerks, night terrors, sleep walking, talking in sleep, narcolepsyAdditional non-epiletpic events in children with learning difficultiesSelf stimulationHyperventilationSterotypiesSandifer syndromeSpasticityConusHeadache/painDystonic posturingChoreoathetosis
Appendix B3. Differential diagnosis of epilepsy in children
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Appendix C. Classification of seizure type and epilepsy syndromeAppendix C1. The ILAE classification of epileptic seizures
(I) Partial (focal, local) seizures(A) Simple partial seizures (consciousness not impaired)
(1) With motor signs(2) With sensory symptoms(3) With autonomic symptoms or signs(4) With psychic symptoms
(B) Complex partial seizures (consciousness impaired)(1) Simple partial onset, followed by impairment of consciousness
(a) With simple partial features (A1-A4), followed by impaired consciousness(b) With automatisms
(2) With impairment of consciousness at onset(a) With impairment of consciousness only(b) With automatisms
(C) Partial seizures evolving to secondarily generalised seizures (tonic-clonic, tonic or clonic)(1) Simple partial seizures (A) evolving to generalised seizures(2) Complex partial seizures (B) evolving to generalised seizures(3) Simple partial seizures evolving to complex partial seizures, evolving to generalised seizures
(II) Generalised seizures (convulsive or nonconvulsive)(A) Absence (petit mal) seizures(B) Myoclonic seizures(C) Tonic seizures(D) Atonic seizures(E) Clonic seizures(F) Tonic-clonic (grand mal) seizures
(III) Unclassified epileptic seizures (caused by incomplete data)
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Appendix C2. The ILAE classification of epilepsies and epilepsy syndromes
(1) GeneralisedIdiopathic generalised epilepsies with age-related onset (in order of age)
Benign neonatal familial convulsionsBenign neonatal convulsionsBenign myoclonic epilepsy in infancyChildhood absence epilepsyJuvenile absence epilepsyJuvenile myoclonic epilepsyEpilepsy with generalised tonic-clonic seizures on awakeningOther generalised idiopathic epilepsies not defined aboveEpilepsies with seizures precipitated by specific modes of activation
Cryptogenic or symptomatic generalised epilepsies (in order of age)West syndromeLennox-Gastaut syndromeEpilepsy with myoclonic-astatic seizuresEpilepsy with myoclonic absences
Symptomatic generalised epilepsiesNon-specific aetiologyEarly myoclonic encephalopathiesEarly infantile encephalopathy with burst suppressionOther symptomatic epilepsies not defined aboveSpecific syndromesEpilepsies in other disease states
(2) Localisation-relatedLocalisation-related epilepsies—idiopathic with age-related onset
Benign epilepsy with centrotemporal spikesChildhood epilepsy with occipital paroxysmsPrimary reading epilepsy
Localisation-related epilepsies—symptomaticEpilepsia partialis continuaSyndromes characterised by specific modes of precipitationTemporal lobe epilepsies
Central region epilepsiesFrontal lobe epilepsiesParietal lobe epilepsiesOccipital lobe epilepsies
Localisation-related epilepsies—cryptogenic
(3) Epilepsies undetermined as to whether focal or generalisedWith both generalised and focal seizures
Neonatal seizuresSevere myoclonic epilepsy in infancyElectrical status epilepticus in slow wave sleepAcquired epileptic aphasia
Other undetermined epilepsies (not defined above) with unequivocal generalised or focal features(4) Special syndromes
Febrile convulsionsIsolated seizures or isolated status epilepticusSeizures occurring only when there is an acute metabolic or toxic event caused by factors such as alcohol, drugs, eclampsia, non-ketotic hyperglycaemia
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Seizure type First-line drugs Second-line drugs Other options Drugs to be avoided
Primary Generalised Tonic-clonic
Sodium valproateCarbamazepinePhenytoinLamotrigineTopiramate
Clobazam LevetiracetamOxcarbazepine
PrimidoneClonazepam Phenobarbital
Absence EthosuximideSodium valproate Lamotrigine
ClobazamClonazepamTopiramate
CarbamazepineGabapentinPregabalinOxcarbazepine
Myoclonic Sodium valproateLevetiracetam
ClobazamClonazepam PiracetamTopiramate
Lamotrigine CarbamazepineGabapentinPregabalinOxcarbazepine
Tonic Sodium valproate Lamotrigine
ClobazamClonazepam TopiramateLevetiracetam
PrimidonePhenobarbitalPhenytoin
CarbamazepineOxcarbazepine
Atonic Sodium valproate Lamotrigine
ClobazamClonazepamLevetiracetamTopiramate
PhenobarbitalPrimidone
CarbamazepineOxcarbazepinePhenytoin
Focal with/without secondary generalisation
CarbamazepinePhenytoinSodium valproateLamotrigineOxcarbazepineTopiramateLevetiracetam
ClobazamGabapentinPregabalin
ClonazepamPhenobarbitalPrimidone
Appendix D. Pharmacological treatmentAppendix D1. Suggested choice of AEDs by seizure types in adolescents and adults (modified from NICE)
Epilepsy syndrome First-line drugs Second-line drugs Other drugs Drugs to be avoided
Childhood or juvenile absence epilepsy
EthosuximideSodium valproateLamotrigine
LevetiracetamTopiramate
CarbamazepineGabapentinPregabalinOxcarbazepinePhenytoin
Juvenile myoclonic epilepsy
Sodium valproate Levetiracetam LamotrigineClobazamClonazepam Topiramate
CarbamazepineGabapentinPregabalinOxcarbazepinePhenytoin
Infantile spasms (IS) ACTH/SteroidsVigabatrin** (first line for IS with tuberous sclerosis)
ClobazamClonazepam Sodium valproateTopiramate
Nitrazepam CarbamazepineOxcarbazepine
Benign epilepsy with centrotemporal spikes or occipital paroxysms
CarbamazepineLamotrigineOxcarbazepineSodium valproate
LevetiracetamTopiramate
Severe myoclonic epilepsy of infancy
ClobazamClonazepamSodium valproateTopiramate
Levetiracetam Phenobarbital CarbamazepineLamotrigineOxcarbazepine
Lennox-Gastaut syndrome LamotrigineSodium valproateTopiramate
ClobazamClonazepamEthosuximideLevetiracetam
CarbamazepineOxcarbazepine
Landau-Kleffner syndrome LamotrigineSodium valproateSteroids
LevetiracetamTopiramate
CarbamazepineOxcarbazepine
Myoclonic astatic epilepsy ClobazamClonazepamSodium valproateTopiramate
LamotrigineLevetiracetam
CarbamazepineOxcarbazepine
Appendix D2. Suggested choice of AEDs by epilepsy syndromes
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Appendix D3. Position statement of HKES on generic AED substitution
• A narrow therapeutic range is well known for many AEDs, eg phenytoin, carbamazepine, valproate. Although a wider therapeutic range probably exists for new AEDs, serum drug concentration monitoring is not routinely available to measure the difference in AED absorption and guide the proper dosage.
• There are many case reports of adverse events or breakthrough seizures following generic substitution but systematic studies are lacking to determine the impact of generic substitution.
• According to the US Food and Drug Administration (FDA) requirement, bioequivalent generic AEDs have serum drug concentrations between 80 and 125% of the brand AED. Mathematical deduction implies that the variation in rate and extent of absorption among multiple generic AEDs (with different manufacturers) may result in up to 50% difference in serum drug concentrations.
• Switching of AEDs (brand to generic or generic to generic) may result in breakthrough seizures with serious physical and psychosocial consequences, including unemployment, injury and even death.
The HKES recommends the following regarding generic AED substitution
• The treating physician is allowed to choose between brand and generic AEDs at initiation of treatment and subsequent switching should be avoided whenever possible.
• Switching from brand to generic or between generics should be avoided if possible.• We oppose automatic substitution of generic AEDs at pharmacy level.• Before switching from brand to generic AEDs, or between different generic AEDs, verbal consent should be obtained
from patient by the treating physician.• When generic AEDs are prescribed, counselling should be given to patient to improve compliance and reduce anxiety.
Adequate follow-up and monitoring logistics should be implemented wherever possible.• Switching from brand to generic AEDs or between generic AEDs is not recommended in patients whose epilepsy is in
remission.
AED Side-effects
Carbamazepine Allergic skin reactions may be severe. Blurred vision, diplopia, ataxia and nausea common
Clobazam Drowsiness but tolerance may develop after prolonged use
Clonazepam Somnolence and fatigue are usually transitory
Ethosuximide Headache, nausea, and drowsiness are usually mild and transient
Gabapentin Somnolence, dizziness, and fatigue; emotional lability in children
Lamotrigine Skin rash or fever usually within 8 weeks of starting treatment. Adverse effects include drowsiness, diplopia, dizziness, headache, insomnia, confusion, and hallucinations
Levetiracetam Common undesirable effects include dizziness and somnolence. Irritability, insomnia, ataxia, tremor, headache, nausea, and affective symptoms are rare
Oxcarbazepine Diplopia, headache, nausea, skin rash, ataxia, and confusion
Phenobarbital Drowsiness, lethargy, mental depression, and allergic skin reactions
Phenytoin Hypersensitivity reactions including skin rash. Dose-related side-effects include drowsiness, ataxia, and slurred speech. Coarsening of facial features, gingival hyperplasia, and hirsutism may occur rarely. Anaemias are usually responsive to folic acid. Dyskinesias, tremor, and mental confusion are rare
Piracetam Weight gain, somnolence, nervousness, depression, and rash
Primidone Drowsiness and listlessness are common
Sodium valproate Sedation, tremor, weight gain, and transient hair loss has often been reported. Severe liver damage, encephalopathy, pancreatitis, transient hyperammonaemia and blood dyscrasias are rare. Amenorrhoea, irregular periods and foetal neural tube defect may occur
Topiramate Headache, somnolence, dizziness, paraesthesia, weight loss, difficulty with memory and concentration has been reported. Increased risk of nephrolithiasis and glaucoma; rarely reduced sweating in children
Vigabatrin Somnolence, nausea, agitation, aggression, irritability, and depression are common. Psychosis is rare. Visual field defects common and may occur after months to years of vigabatrin treatment. Visual field should be tested every 6 months
Appendix D4. Side-effects of AEDs
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28 Hong Kong Med J Vol 15 No 5 # Supplement 5 # October 2009
Example 1
F/17, College student
Seizure types: Generalised tonic-clonic seizure and early morning myoclonus
Syndromic diagnosis:Juvenile myoclonic epilepsy
• Valproate is the standard AED to be used but in view of its teratogenicity, other broad-spectrum AEDs may be selected.
• Topiramate has more cognitive side-effect but it may be preferred if there is co-existing migraine or morbid obesity. • Lamotrigine is a reasonable alternative but it may worsen myoclonus; its serious allegic reaction should be made
known to the patient. • Clonazepam or clobazam may cause daytime sleepiness with issues of tolerance in the long term. • Levetiracetam is a suitable alternative as it has a good side-effect profile.
Example 2
M/70, retired businessman
Seizure type:Secondary generalised tonic-clonic seizure
Aetiological diagnosis:Post-stroke epilepsy, atrial fibrillation on warfarin
• Carbamazepine and oxcarbazepine are more likely to give rise to hyponatremia with its consequent side-effects; testing for HLA B1502 should be done before commencement of carbamazepine; oxcarbazepine is better than carbamazepine as it does not interact with warfarin.
• Phenytoin is favoured by some physicians as response to treatment is usually satisfactory, but dosage adjustment should be cautious in view of its non-linear pharmacokinetics. It may increase or decrease efficacy of warfarin.
• For sodium valproate, some side-effects (eg hand tremor) may be more common in the elderly and valproate may enhance effect of warfarin.
• Lamotrigine and levetiracetam are better tolerated in the elderly without problem of drug interaction but their use is limited by their cost. Gabapentin and pregabalin are useful if there is co-existing neuropathic pain (eg thalamic stroke) and polypharmacy (virtual absence of drug interactions).
• Topiramate may have a negative impact on cognition which may already be compromised after stroke; side-effects, eg paresthesia, may generate worries about recurrent stroke.
• Clonazepam and clobazam are sometimes useful if there is co-existing tremor, myoclonus, anxiety, sleep-related behavioural disorder, insomnia, or restless leg syndrome.
• Phenobarbitone may adversely affect cognition but advantages include low cost and availability of parenteral formulation. It is an enzyme inducer, which may reduce efficacy of warfarin.
Example 3
F/9, schoolgirl Seizure type:Partial motor seizure of left face with secondary generalised tonic-clonic seizure
Epilepsy syndrome:Benign epilepsy with centraltemporal spikes (BECT)
Co-morbidityMigraine
• Carbamazepine and oxcarbazepine are the standard drugs of treatment but HLA B1502 status should be checked before commencement of carbamazepine.
• Sodium valproate is useful for preventing co-existing migraine; side-effects including weight gain, transient hair loss and menstrual disturbances are undesirable.
• Lamotrigine may induce serious drug rash particularly in children and very slow escalation of dose is necessary; it has not been licensed for monotherapy in children younger than 12 years old.
• Topiramate is non–enzyme inducing and also effective against migraine but it may cause anhydrosis in children. • Levetiracetam may rarely induce behavioural disturbance especially for those with a history of psychiatric disorder; it
has not been licensed for monotherapy in children younger than 16 years old.• Gabapentin is less efficacious compared with other standard AEDs.• Pregabalin is only licensed for treatment of adult epilepsy.• Phenytoin is not favoured in view of its cosmetic side-effects, erratic absorption and non-linear pharmacokinetics.• Phenobarbitone is not preferred as it may cause irritability, behavioural disturbance and cognitive impairment in
children.• Clobazam and clonazepam may cause excess daytime drowsiness; they are mainly used as adjunctive therapy instead
of monotherapy.
Appendix E. Examples of factors to consider in selecting an AED in newly diagnosed epilepsy