consensus epilepsy

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CONSENSUS GUIDELINES ON THEMANAGEMENT OF EPILEPSY

2005

Epilepsy Council, Malaysian Society of Neurosciences



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Statement of Intent

This guideline is not intended to be construed or to serve as a standard ofmedical care. Standards of medical care are determined on the basis of all clinicaldata available for an individual case and are subject to change as scientific

knowledge and technology advance and patterns evolve. These parameters ofpractice should be considered guidelines only. Adherence to them will notensure a successful outcome in every case, nor should they be construed asincluding all proper methods of care aimed at the same results. The ultimate judgement regarding a particular clinical procedure or treatment plan must bemade by the health care provider in the light of the clinical data presented by thepatient and the diagnostic and treatment options available.



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Panel of experts:

Professor Dr Raymond Azman Ali(Chairman)Senior Consultant NeurologistDepartment of MedicineUniversiti Kebangsaan Malaysia

Professor Dr Tan Chong TinSenior Consultant NeurologistDepartment of MedicineUniversiti Malaya

Datuk Dr. Raihanah Abdul Khalid

Consultant Neurologist and HeadDepartment of NeurologyKuala Lumpur Hospital

Professor Dr Benedict SelladuraiSenior Consultant NeurosurgeonDepartment of SurgeryUniversiti Kebangsaan Malaysia

Professor Dr Ong Lai ChooSenior Consultant Paediatric NeurologistDepartment of PaediatricsUniversiti Kebangsaan Malaysia

Dr Azmi Abdul RashidConsultant NeurologistDamansara Specialist Centre

Dr Vimalan RamaNeurologistDepartment of MedicineUniversiti Malaya

Dr Kathleen YeapNeurologist

Department of NeurologyIpoh Hospital

Dr Tan Hui JanNeurologistDepartment of MedicineUniversiti Kebangsaan Malaysia

Panel of reviewers:

Dr Hussain Imam bin Hj Muhammad IsmailSenior Consultant Paediatric Neurologistand HeadInstitute of PaediatricsHospital Kuala Lumpur

Dr Khoo Teik BengConsultant Paediatric NeurologistInstitute of PaediatricsHospital Kuala Lumpur

Dr Wong Sau WeiPaediatric Neurologist

Department of PaediatricsUniversiti Kebangsaan Malaysia

Dr Haniffah Abdul GafoorConsultant NeurologistIsland Medical CentrePenang



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Table of Contents

1. INTRODUCTION 6

2. DEFINITION AND CLASSIFICATION OF EPILEPSY 7 - 10

Introduction 7Idiopathic epilepsies 9Non-idiopathic epilepsies 10

3. DIFFERENTIAL DIAGNOSIS OF EPILEPSY 11 - 13

4. INVESTIGATIONS IN EPILEPSY 14 - 20Purpose of investigations 14

Electroencephalography 14Video-EEG monitoring 16Invasive EEG recording/sphenoidal electrodes 17Neuroimaging 17Other investigations 19

5. GENERAL PRINCIPLES OF THE TREATMENT OF EPILEPSY 21 - 27Prophylactic treatment 21Single seizures 21Recurrent seizures 22Decision to withdraw AEDs 25Driving and epilepsy 26Education and epilepsy 27

6. LONG-TERM PHARMACOLOGICAL TREATMENT 28 – 35Introduction 28Initiation and continuation of treatment of AEDs 28Drug monitoring 32Choice of first line therapy 33AED toxicity 34Stopping treatment 34

7. SURGICAL TREATMENT OF EPILEPSY 35 - 39Introduction 35Early diagnosis of seizure intractability and timing of surgery 35Surgically remediable epilepsy syndromes 36Presurgical investigations and patient selection 36Establishment of a resection strategy 37



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Results of Surgical Treatment 39

8. EMERGENCY TREATMENT OF EPILEPSY 40 - 47Introduction 40Initial supportive management 40

Postictal care in uncomplicated seizures 40Treatment of prolonged seizures 40Treatment of convulsive status epilepticus 43Emergency treatment of other prolonged seizure types 49

9. SPECIAL ISSUES 50-57

Epilepsy in women 50Epilepsy in children 55Epilepsy in the elderly 57

10. CONCLUSION 58

11. REFERENCES 59 - 66

Appendix 1: Counselling checklist 67



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1.0 INTRODUCTION

The Epilepsy Council of Malaysia was established in February 2002 tocomplement the activities organised by the already well established lay person-based Malaysian Epilepsy Society. Its members agreed that one of the most

important early tasks of the council was to come up with a set of guidelines forthe management of epilepsy in the country. It had sufficient expertise to makestrong recommendations to general practitioners, physicians, paediatricians,psychiatrists, neurologists, and all relevant healthcare providers pertaining to themanagement of epilepsy. The chapters in this consensus guidelines have beenwritten by local specialists who have national, regional and/or internationalrecognition in the field of epilepsy. In the last decade or so, there have been moreantiepileptic drugs introduced and more epilepsy surgery candidates operatedthan in the last 100 years. This exponential growth in new drugs, together withadvances in epilepsy surgery and neuroimaging, calls for a reappraisal of how

we manage our patients with epilepsy. This guidelines is the first of its kind inMalaysia, and as its name suggests, is only a set of guidelines. Nevertheless therecommendations made are based on recent publications as well as consensus ofa panel of experts. There is a large chapter on epilepsy surgery, and a chapter hasalso been dedicated to special issues pertaining to women, children and theelderly.



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2.0 DEFINITION AND CLASSIFICATION OF EPILEPSY

2.1 Introduction

An epileptic seizure is defined as a paroxysmal stereotyped disturbance ofconsciousness, motor function, sensation, emotion, behaviour or perception thaton clinical grounds results from cortical neuronal discharge. Epilepsy can bedefined as recurrent, usually unprovoked epileptic seizures that result fromexcessive synchronous and abnormal firing patterns of the cerebral corticalneurons. Therefore, epileptic seizures may be viewed as the symptoms of thedisease, epilepsy.

Epileptic seizures are classified on the basis of their clinical features alone (table 1)whereas the classification of the epilepsies and epileptic syndromes is based onelectroclinical criteria (International Classification of Epilepsies and Epileptic

syndromes) (table 2). The latter also provides information about the possibleaetiology, anatomical basis, precipitating factors, age of onset, severity,chronicity, diurnal and circadian cycling, and sometimes prognosis of theepilepsies.

TABLE 1: The International Classification of Epileptic Seizures

1. Partial seizures1.1 Simple partial seizure

1.1.1 Motor signs1.1.2 Sensory symptoms1.1.3 Autonomic symptoms or signs

1.1.4 Psychic symptoms1.2 Complex partial seizure

1.2.1 Simple partial at onset (with or without automatism)1.2.2 With impairment of consciousness (with or with automatism)

1.3 Partial seizures evolving into generalized seizures

2. Generalized seizures2.1 Absence seizure

2.1.1 Typical2.1.2 Atypical

2.2 Myoclonic seizure2.3 Clonic seizure2.4 Tonic seizure

2.5 Tonic-clonic seizure2.6 Atonic seizure

3. Unclassified epileptic seizuresConsciousness is maintained in simple partial seizures but impaired in complex partial seizures. The symptomatology ofpartial seizures (seizure semiology) reflects the anatomical origin of the seizures. Hence, partial seizures may becharacterised by motor, special sensory, autonomic or psychic symptoms. In addition, complex partial seizures aretypically accompanied by automatisms; consisting of involuntary movements, e.g. lip smacking, chewing, fidgeting andwandering.



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TABLE 2: International Classification of Epilepsies and Epileptic Syndromes1. Localisation-related (focal, local, partial) epilepsies and syndromes

1.1 Idiopathic (with age-related onset)• Benign childhood epilepsy with centrotemporal spikes

• Childhood epilepsy with occipital paroxysms

• Primary reading epilepsy

1.2 Symptomatic1.2.1 Characterised by simple partial seizures*1.2.2 Characterised by complex partial seizures*1.2.3 Characterised by secondarily generalised seizures*

1.3 Unknown as to whether the syndrome is idiopathic or symptomatic

2. Generalised epilepsies and syndromes2.1 Idiopathic

• Benign neonatal familial convulsions

• Benign neonatal convulsions

• Benign myoclonic epilepsy in infancy

• Childhood absence epilepsy (pyknolepsy)

• Juvenile absence epilepsy

• Juvenile myoclonic epilepsy

• Epilepsy with generalised tonic-clonic seizures on awakening

2.2 Cryptogenic or symptomatic• West syndrome

• Lennox-Gastaut syndrome

• Epilepsy with myoclonic-astatic seizures

• Epilepsy with myoclonic absences

2.3 Symptomatic2.3.1 Non-specific aetiology

• Early myoclonic encephalopathy

2.3.2 Specific syndromes• Epileptic seizures complicating disease states

3. Epilepsies and syndromes undetermined, whether focal or generalised3.1 With both generalised and focal seizures

• Neonatal seizures

• Severe myoclonic epilepsy in infancy

• Epilepsy with continuous spike and wave EEG during slow-wave sleep

• Acquired epileptic aphasia (Landau-Kleffner syndrome) 3.2 Without unequivocal generalised or focal features

4. Special syndromes4.1 Situation-related seizures

• Febrile convulsions

• Isolated seizures or isolated status epilepticus

• Seizures occurring only when there is an acute metabolic or toxic event

*With the characteristics of seizures arising from frontal, parietal, temporal, occipital, or multiplelobes; or the locus of onset is unknown.



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In addition to their distinct seizure semiologies, generalised seizures are alsodistinguished by their characteristic EEG features (table 3).

TABLE 3: EEG features of generalised epileptic seizures

• Absence seizures - generalised 3Hz spike-wave activity• Myoclonic seizures - generalised polyspikes or polyspike and wave

activity

• Clonic seizures - generalised spike-wave activity

• Tonic seizures - paroxysmal fast activity

• Tonic-clonic seizures - combination of the two seizure types

• Atonic - spikes or spike-wave activity or abrupt flattening of EEG

In the classification of the epilepsies and epileptic syndromes, the terms

“idiopathic”, “symptomatic” and “cryptogenic” are often misunderstood. Theidiopathic epilepsies are genetically determined and have no structural cause, noassociated clinical signs, normal brain imaging and normal EEG background.The symptomatic epilepsies have known causes and cryptogenic epilepsies havean underlying cause that cannot be documented objectively. Thus, thecryptogenic epilepsies are more likely to be symptomatic than idiopathic.

2.2 Idiopathic epilepsies:

2.2.1 Idiopathic localisation-related epilepsy:

The two common types of benign focal epilepsy of childhood are those withcentrotemporal spikes (BCECTS) and those with occipital paroxysms (table 2).Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a newlydescribed epilepsy syndrome.

2.2.2 Idiopathic generalised epilepsies:

These syndromes are genetically determined, and patients have a normalneurological examination and normal intelligence. The EEG shows generalised

epileptiform discharges and may show photosensitivity (table 3).

Childhood absence epilepsy, previously known as petit-mal epilepsy, ischaracterised by an age of onset between 4 and 10 years, typical absences,generalised tonic-clonic seizures (GTCS) in about 50% of patients, myoclonicseizures in a minority of patients, and generalised 3Hz spike-wave activity onEEG. A variant of this epilepsy is juvenile absence epilepsy characterised by alater age of onset.



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Patients with juvenile myoclonic epilepsy (JME) tend to be older (onset inadolescence), and have myoclonic jerks usually in the morning on awakeningwith or without GTCS, generalised bilateral symmetrical polyspikes andgeneralised spike-wave complexes on their EEG, and rarely, go into remission.

2.3 Non-idiopathic epilepsies:

2.3.1 Symptomatic and cryptogenic localisation-related epilepsies

Seizures arise from a localised region of the brain. If the cause is found, theseepilepsies are symptomatic and if the cause is not found, they are cryptogenic.The common causes are low-grade tumours, hippocampal sclerosis and corticaldysgenesis.

Mesial temporal lobe epilepsy, most commonly caused by hippocampal sclerosisin adults and cortical dysgenesis and low-grade tumours in children, ischaracterised by epigastric (abdominal), psychic auras and complex partialseizures with orofacial and manual automatisms with or without secondarygeneralisation.

The causes of temporal, occipital, frontal and parietal neocortical epilepsy aremore diverse, and include traumatic scars, neoplasms, vascular malformations,infarcts, haemorrhages and cortical malformations. Seizure semiology, consisting

of simple partial or complex partial seizures, depends upon the area of neocortexaffected.

2.3.2 Symptomatic and cryptogenic generalised epilepsies

These epilepsies (table 3) are associated with diffuse brain dysfunction. Commoncauses include anoxic birth injury, a metabolic derangement or chromosomaldefect. There is usually clinical evidence of intellectual deficiency and/ordevelopmental delay. The clinical and EEG findings are usually abnormal andage-dependent.



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3.0 DIFFERENTIAL DIAGNOSIS OF EPILEPSY

Often, clinicians are faced with the dilemma of making a diagnosis of epilepsy ina patient who presents with unexplained loss of consciousness. Seizure andsyncope usually rank high on the list of diagnostic possibilities. In the evaluation

of a patient with a lapse of consciousness, a few factors need to be determined,namely, the setting in which the event occurred, the history from a reliableeyewitness and the associated symptoms and signs. The differential diagnosis ofseizures may be subdivided according to different age groups (table 4).

TABLE 4: Differential diagnosis of seizures

Neonates and infants

• Jitteriness and benign myoclonus

• Apnoea

• Shuddering attacks• Gastro-oesophageal reflux

• HyperekplexiaYoung children

• Breath holding spells

• Reflex syncope

• Parasomnias

• Benign paroxysmal vertigo

• Tics and ritualistic movements

• Rage attacks

Adults• Syncope

• Migraine

• Transient global amnesia

• Transient ischaemic attacks

• Narcolepsy

• Paroxysmal movement disorders andataxias

Any age

• Endocrine, metabolic and toxic causes

• Drug induced dystonia• Cardiac dysrhythmias

• Delirium



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In adults, syncope is the most common cause of altered consciousness. Syncoperefers to the transient alteration of consciousness accompanied by loss ofmuscular tone that results from an acute, reversible global reduction in cerebralblood flow. The causes of syncope are diverse (table 5).

TABLE 5: Causes of syncope (Adapted from Rowland, 2000)

Neurocardiogenic syncope

• Vasovagal

• Carotid sinus syndrome

• Micturition syncope

• Cough and other Valsalva-induced syncope

• Emotional states

Vasomotor syncope• Medications*

• Postural changes

• Autonomic neuropathies

• Peripheral vascular disease

• Neurodegenerative disease with orthostatic hypotension

• Blood loss/hypovolaemia

Cardiac syncope

• Tachyarrhythmias• Asystole and heart block

• Outflow obstruction

• Failing myocardium

Psychogenic syncope

• Panic attacks

• Anxiety

• Hyperventilation

Note: *Medication frequently implicated include phenothiazines, antihypertensives, diuretics,

arterial vasodilators, levodopa, calcium channel blockers, tricyclic antidepressants, beta-blockersand lithium.



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Important features in the history that favour vasovagal syncope rather thanepileptic seizures include a clear precipitating stimulus or situation, the fall thatoften occurs in stages, presence of prodromal symptoms, brief period ofunconsciousness, rapid recovery and absence of any true postictal phase.Identifiable precipitants are getting up quickly, prolonged standing, frightening,

emotional or unpleasant scenes, painful stimuli, and Valsalva manoeuvres.Syncopal attacks typically begin with the premonitory phase where the personfeels light-headed. Peripheral vasoconstriction imparts a pale appearance, andthe pulse is rapid. Profuse sweating is accompanied by nausea. Vision blurs andcharacteristically fades out before consciousness is lost. The patient loses muscletone of the legs and may fall. Rapid recovery occurs if the patient is allowed to lieflat.

In cardiac syncope, there are often prodromal features of palpitations, chest pain,shortness of breath or other features of cardiovascular insufficiency. Other clues

to cardiac syncope include attacks with little relation to posture, position orspecific triggers. Both tachyarrhythmias and bradyarrhythmias can producesyncope. In both vasovagal and cardiac syncope, the fall may be accompanied bybrief myoclonic twitches of the extremities, urinary incontinence and tonguebiting, and mislead bystanders into thinking that the attack is epileptic.

Psychogenic or pseudoseizures (non-epileptic attack disorder) can usually bedistinguished both clinically and by video-EEG recording. Features useful indistinguishing pseudoseizures from epileptic convulsions are the triggers(frustration, suggestion, in company), duration (often very prolonged), erratic

movements (flailing, pelvic thrusting), remaining pink and breathing, resistingeye opening and eye contact, and often prompt recovery.

In transient global amnesia, consciousness is preserved and patients mayperform complex activities but have no recollection of the events. In transientischaemic attacks (TIAs) paraesthesiae do not show the same kind of segmentalspread typically seen in epilepsy with focal sensory symptoms that spread fromone part of the body to another. The absence of clonic motor activity andconfusion favours focal ischaemia rather than epilepsy. In the absence of otherfocal clinical features (dysarthria, ataxia, diplopia, etc.), episodes of loss ofconsciousness alone are not usually due to TIAs.



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4.0 INVESTIGATIONS IN EPILEPSY

4.1 Purpose of investigations

Although the diagnosis of epileptic seizures is still based on a good historyderived from the patient and witness, the diagnosis of epilepsy (epilepsysyndrome), on the other hand, is incomplete without knowing its aetiology andprognosis. A complete diagnosis is necessary for proper treatment. Thesefeatures of the epilepsy require careful selection of certain key investigations.

Several factors have changed the way we investigate patients with epilepsy. Thegeneral acceptance of epilepsy surgery, the introduction of more sophisticatedand clearer neuroimaging techniques and better understanding of epilepsysyndromes and their response to pharmacological and surgical treatment haveeither obviated or augmented the need for certain investigations. To avoid

requesting unnecessary, or to omit essential investigations, a rational approach torequesting investigations in epilepsy is needed.

The main objectives of investigating patients with epilepsy are to:

a) Clarify the diagnosis of epilepsy and non-epileptic attacksb) Determine the nature of the seizure types and epilepsy syndromec) Identify the laterality and localization of seizure onset (partial seizures)d) Identify the aetiology of epilepsye) Identify concomitant problems, both neurological and general

f) Monitor the progression of the condition, and the consequences of theepilepsy and its treatment

These objectives are achieved through the electroencephalogram (EEG),neuroimaging, neuropsychological assessment and other investigations(including blood tests and muscle biopsy).

4.2 Electroencephalography

Except for adult patients with a clear metabolic or structural abnormality onbrain imaging, all patients with epilepsy will require an EEG. The aim of the EEGis to clarify, rather than confirm, the diagnosis of epilepsy. Several types of EEGmay be requested:



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4.2.1 Routine interictal scalp EEG

Technique:In general, a routine interictal scalp EEG must be requested for ALL patients. Theroutine EEG requires placement of at least 21 electrodes on the scalp, based on

the international 10-20-electrode placement system. The recording should beperformed during wakefulness and incorporate hyperventilation, intermittentphotic stimulation and a period of natural sleep (particularly in temporal lobeepilepsy) to maximize the detection of interictal epileptic activity. Natural sleepcan be obtained in children, and chloral hydrate is only used in the occasionalchild who is anxious or combative. A period of relative sleep deprivation theprevious night by a few hours may enhance the chance of natural sleep.

Findings in certain epilepsy syndromes:

Epileptiform abnormalities are seen in less than 1% of healthy individuals. In thepresence of a structural lesion, epileptiform abnormalities not related to clinicalepilepsy occur more commonly. The detection of epileptic spikes from a singleawake record is only about 30-40%. A sleep record reveals epileptic discharges inabout 70-80% of patients with epilepsy, and in 50% of patients with unhelpfulawake records. Both the EEG background and the characteristics (distributionand activation method) of the epileptic spikes (when present) help to clarify theepilepsy syndrome.

The key EEG features in idiopathic generalised epilepsy (IGE) are:

• Bilaterally synchronous, anteriorly predominant 3-5 Hz spike-wave activity

• Normal background

• Photosensitivity in many cases

Overnight sleep deprivation may help activate the epileptic discharges in IGE.However, sleep deprivation may rapidly put patients in deep sleep or precipitatepotentially harmful GTCS. Additional focal spikes may be present in IGE.

The key EEG features in partial epilepsy are:

• Focal or multifocal epileptic discharges

• Abnormal background in many cases

• Rarely, photosensitivity

Focal spikes may propagate to produce bilaterally synchronous dischargesmimicking IGE.



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Characteristic EEG features of some other common epilepsy syndromes areshown in table 6.

TABLE 6: EEG features of common epilepsy syndromes

EPILEPSY SYNDROME EEGBACKGROUND

EPILEPTIC DISCHARGES

West syndrome Abnormal Hypsarrhythmia –disorganised high voltagepattern (spikes, slow waves,periods of attenuation)

Benign childhood epilepsywith centrotemporal spikes

Normal Unilateral or bilateral,triphasic large amplitudespikes maximal in the centralor centrotemporal region

Benign occipital epilepsy Normal Posterior 1.5-3 Hz spike andslow wave discharges thatattenuate with eye opening

Lennox-Gastaut syndrome Abnormal 1-2.5 Hz generalised,anteriorly predominant spikeand slow wave discharges

4.3 Video-EEG monitoring

The purpose of recording the EEG and video of the patient simultaneously is torecord the ictal EEG and to correlate it with the clinical behaviour of the patientduring the attack(s). This may be done on a short term (outpatient) or long term(inpatient) basis. The former is similar to the routine scalp EEG, with the additionof simultaneous video recording, the principal aim of which, is to establish thediagnosis; absence seizures and non-epileptic disorders are best recorded thisway. In a non-epileptic seizure, the EEG is often obscured by movement andmuscle artefact, but “normal” alpha rhythm is often seen “through” or inbetween, and always abruptly following the attack. Asymmetric thrashing,flailing movements, pelvic thrusting and partial responsiveness are common

clinical features that can be recorded on video. The patient is usuallyimmediately responsive after the attack. During an absence seizure, which canusually be induced by hyperventilation, the EEG will show the characteristic 3-5Hz bilaterally synchronous spike and slow wave activity.

Long-term monitoring is usually a presurgical investigation, the main purpose ofwhich is to localise the epileptic focus. Often, however, the recording may revealadditional or only non-epileptic attacks. The recording is performed over several



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days, and occasionally, up to a fortnight. This will enable the recording of severalattacks so that the localisation of the ictal onset can be determined with greaterconfidence. The ictal onset is usually electrographic (preceding the change inclinical behaviour), and takes several forms, namely, rhythmic theta activity thatevolves in amplitude and frequency, attenuation of the background, or spike-

wave activity. Localisation of this activity correlates with the epileptic focus, andthis to be correlated with the change in clinical behaviour.

4.4 Invasive EEG recording/sphenoidal electrodes

Sphenoidal, subdural and depth electrodes are inserted for long-term recordingin selected patients to enhance the localisation of the ictal onset. These electrodeshave the advantage of detecting the first electrographic change before any spreadof electrographic activity can be detected on the scalp. The risk of infection and

their invasiveness limit their use, and are no longer used in most centres.

4.5 Neuroimaging

4.5.1 Structural neuroimaging

The skull radiograph is now obsolete and X-ray computed tomography of thebrain is now the initial investigation of choice if structural imaging is deemednecessary. However, in centres where it is available, MRI would be the initial

investigation of choice, being superior to the CT with regards to the detectionand delineation of epileptogenic lesions and lack of ionising radiation. The usualcontraindications to MR imaging must be observed. Structural neuroimaging ofthe brain is mandatory in the following circumstances:

• Partial seizures based on the history and/or EEG

• Fixed or progressive neurological or psychological deficit

• Onset of generalised seizures before the age of 1 year and after 20 years

• Difficulty obtaining seizure control with AED

• Loss of seizure control or status epilepticus, if this does not have a clear

explanation such as omission of medication• Acutely, after significant head trauma



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Imaging may be deferred in the following circumstances:

• There is a clear provoking factor, such as alcohol withdrawal

• Children with benign epilepsy with centrotemporal spikes

• Pregnant women with no acute problems, such as a possible intracerebral

haemorrhage or infection

The following MRI protocol is recommended for patients being evaluated forepilepsy surgery:

• 1.5 Tesla magnet

• A volume acquisition (contiguous) T1-weighted coronal data set of the wholebrain in 1.5 mm-thick slices using IRPF SPGR (GE) or MPRAGE (Siemens)sequences, allowing reformatting in any orientation or plane, 3Dreconstruction and surface-rendering

• An oblique (heavily) T1-weighted coronal inversion recovery sequenceorientated perpendicular to the long axis of the hippocampus (parallel to aline joining the base of the splenium of the corpus callosum to the inferiorposterior border of the frontal lobe)

• An oblique (heavily) T2-weighted coronal spin echo (VEMP) (GE) or double-echo STIR (Siemens) or a FLAIR sequence orientated perpendicular to thelong axis of the hippocampus

Hippocampal sclerosis, the most common cause of temporal lobe epilepsy, notvisible on CT, is characterised by loss of volume (compared with the normal

side), decreased signal intensity on T1-weighted images, increased signalintensity on T2-weighed images, and often, a small ipsilateral posterior fornix.This MRI protocol, apart from detecting gross lesions (such as large vascularmalformations, tumours, etc) is capable of detecting other subtle lesions,including focal cortical malformations (e.g. polymicrogyria), cavernoushaemangiomas, post-traumatic scars and dysembryoplastic neuroepithelialtumours. The decision to subject a patient to epilepsy surgery is greatlyinfluenced by what is seen on the MRI. Many subtle or additional lesions may bemissed on a brain CT.

In cases where the hippocampal sclerosis is not clear or the possibility of bilateraldisease cannot be excluded, quantitative MRI, such as measurement ofhippocampal volumes and T2 relaxation times, requiring special post-processingtechniques or software, may be employed. Surface coils provide better definitionof the cortical ribbon, and may be required for better delineation of subtleneocortical lesions prior to surgery.

4.5.2 Functional neuroimaging



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Functional imaging includes single photon emission computerised tomography(SPECT), positron emission tomography (PET) and functional MRI. Only theformer is available in a few centres in the country. These techniques areexpensive and are used to further localise the epileptogenic lesion prior to

surgery in cases where structural imaging is equivocal. In addition, functionalMRI may also help localise specific functional areas (e.g. sensory or motor cortex)prior to the surgical excision of lesions in eloquent areas of the brain.

4.6 Other investigations

At the initial evaluation of the patient, the following investigations should beconsidered:

4.6.1 Blood biochemistry

A serum biochemical profile is performed to identify possible metabolic causesor factors in certain seizure types as well as prior to starting certain AEDs.Hypoglycaemia, for instance, may cause attacks that mimic complex partialseizures. In patients with typical absences and a characteristic EEG, a fullbiochemical profile is probably not necessary at initial patient evaluation otherthan a liver profile and full blood count prior to starting sodium valproate. Inother patients, the recommended biochemical profile includes:

• Random blood glucose• Renal profile

• Liver profile

• Serum calcium and magnesium (especially in children)

If hypoglycaemic attacks are strongly suspected, the patient should beinvestigated for an underlying endocrinopathy, such as an insulinoma.

4.6.2 Cardiac assessment

As cardiac arrhythmias and obstruction to cardiac output may cause generalised(tonic) seizures, a chest radiograph, ECG and often an echocardiogram aremandatory in all elderly patients and in those suspected of having cardiacdisease. The presence of heart block is also a relative contraindication to usingcarbamazepine.

4.6.3 Investigations for inborn errors of metabolism



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These investigations are usually only requested for infants and children, whooften have other neurological manifestations, and hence, must be individualisedand ordered judiciously.

4.6.4 Other specific investigations

Investigations such as serum or CSF VDRL, CSF studies, HIV serology andconnective tissue screening must be individualised and ordered judiciously. Ifnon-epileptic seizures are suspected, demonstration of a normal serum prolactinlevel performed within 20 minutes of an apparent GTCS may be diagnostic; it isless helpful for complex partial seizures and unhelpful for simple partial seizures.

During subsequent follow up, the decision to repeat these investigations orperform other investigations must be individualised:

• Repeat EEG and neuroimaging if there is a need to reassess the cause of theepilepsy or suspicion that there is progression of the underlying disease; inchildren it is important to periodically assess cognitive function as its declinemay be subtle but often greatly influences prognosis; appropriateinvestigations must then be done to exclude rare neurodegenerative disorderssuch as progressive myoclonic epilepsy, metabolic disorders and progressivestructural disorders

• Repeat biochemical and haematological profiles to detect adverse effects ofAED treatment or to further evaluate adverse events that have already

developed• In patients taking enzyme-inducing AEDs, repeat the full blood count, liver

profile and serum calcium every 1-2 years

• In patients on valproate, repeat full blood count annually or before surgicalprocedures

• Monitoring of serum AED concentrations is discussed in Section 6.3.



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5.0 GENERAL PRINCIPLES IN THE TREATMENT OFEPILEPSY

Once the diagnosis of epilepsy has been established, its treatment must beindividualised. This includes the need for treatment and choice of AEDs. Carefulconsideration must be given to several factors, including the certainty of thediagnosis of epilepsy, severity of seizures, level of function, occupation andfamily support. Few decisions are more critical in the management of epilepsythan the decision to initiate drug therapy. As far as the patient is concerned,starting an AED confirms the state of ‘epilepsy’, which can affect self-esteem,social relationships, education and employment. The benefits of therapy on theother hand, include lower risk of seizure recurrence and of death or injuries.Drawbacks of therapy include potential drug side effects, cost, stigmatisationand inconvenience. The decision to treat essentially depends on the balancebetween benefits and drawbacks of therapy. Effective treatment also includes

proper education and counselling. Important issues like driving, schooling,employment, pregnancy and compliance must be discussed, and advice must beindividualised.

5.1 Prophylactic treatment

Prophylactic treatment has sometimes been advocated, notably in patients withhead injuries or large haemorrhagic strokes. While immediate treatment mayreduce the risk of early post-traumatic seizures (within one week of injury), it

does not influence the risk of late post-traumatic epilepsy. Studies done inneurological conditions with high prospective risk of epilepsy have failed toshow any evidence of benefit.

5.2 Single seizures

Patients presenting with a first single unprovoked seizure present a commonclinical dilemma. A meta-analysis of prospective studies indicates an overalltwo-year risk of further seizures of 30-40%. The lowest risk (24%) is in patients

with no identified cause who have a normal EEG, and the highest risk (65%) is inthose with a remote neurological insult and epileptiform abnormalities in theEEG.

Treatment after a first GTCS halves the two-year risk of seizures from about 40%to 20%. However, this is not associated with any improvement in longer-termoutcomes such as proportion of patients achieving a one-year remission.



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Given the potentially significant social and physical implications, patients with ahigh risk of recurrence should be given the option to start treatment.

Recommendations:

• Patients with a certain diagnosis of unprovoked GTCS should be treated afterthe first seizure if:

1. The seizures are associated with a previous absence and/or myoclonicseizures, and/or

2. The patient or physician considers the risk of recurrence unacceptable (e.g.if there is an underlying structural brain abnormality)

• The decision to treat simple and complex partial seizures will depend on the

seizure frequency and severity and patient preference. Generally, mostpatients would seek treatment after at least two seizures have occurred.

• Seizures due to alcohol withdrawal or other metabolic or drug-related causesor sleep deprivation should not be treated with AEDs. Treatment should beconsidered only if there are recurrences suggestive of epilepsy.

• All patients developing seizures within a week of head injury should betreated, but AED withdrawal should subsequently be considered.

• Patients should not be treated if there is uncertainty about the diagnosis.

5.3 Recurrent seizures

The decision is more straightforward in patients with recurrent seizures and aclear-cut diagnosis of epilepsy.

5.3.1 Newly diagnosed epilepsy

Factors influencing the decision to treat include:

1. A firm diagnosis of epilepsy based on a good first-hand witnessed account ofthe attacks. There is no place at all for a ‘trial of treatment’ to clarify thediagnosis.

2. About 50-80% of all patients who have a non-febrile seizure will have furtherseizures, the greatest risk being in the first 6 months. There is a further 9%



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risk in the next 6 months and 8% in the following 12 months. The risk isinfluenced by the following factors:

• Aetiology: the risk is greatest with structural cerebral lesions and least inacute symptomatic epilepsy. The risk in idiopathic epilepsy is about 50%.

In those with pre-existing learning disability or cerebral damage, the riskapproaches 100%.

• Age: the risk is greater in those under the age of 16 and over 60 years.

• Seizure type: partial seizures are more likely to recur than generalizedseizures.

3. Seizures must be sufficiently troublesome. Some seizure types have aminimal impact on quality of life e.g. simple partial, absence or nocturnalseizures. The benefits of AEDs in such seizures may be outweighed by theirdisadvantages. If the baseline seizure frequency is very low e.g. less than once

every 2 years, the disadvantages of chronic drug therapy may be high, andshould probably not be prescribed.

4. Epilepsy syndrome - some benign epilepsy syndromes have an excellentprognosis without treatment e.g. benign childhood epilepsy withcentrotemporal spikes, and do not require long term therapy.

5. Compliance –AEDs need to be taken reliably and regularly to be effective. Incircumstances where compliance is doubtful, the decision to treat will need tobe re-considered.

6. Reflex seizures and acute symptomatic seizures- seizures precipitated onlyunder specific circumstances e.g. alcohol or photosensitivity, may be treatedby avoiding these precipitants, obviating the need for drug therapy.

7. Patients’ wishes-the final decision is left to the patient; the physician’s role isto explain the relative advantages and disadvantages of therapy.

Once the diagnosis is clear, and decision to treat is established, the goal oftherapy is to achieve complete seizure control, with a drug taken once or twice aday with minimal or no side-effects.

Formulation of a treatment plan at the time of the patient’s initial evaluationwould include:

1. Identifying precipitating factors such as drug abuse, alcohol, excessive fatigueand photosensitivity. Patients and their care-giver should be counselled abouttheir avoidance.



24

2. Counselling the patient and/or caregiver with respect to the reasons for

starting therapy, expectations, limitations and likely duration of therapy,need for good compliance and potential risks of therapy.

3. Syndromically classifying each patient's epilepsy. A detailed documentationof seizure type/types should be made, particularly when the syndrome isunclear. This will avoid aggravation/worsening of certain syndrome/seizures with incorrect medication.

4. Commencing the patient on a low dose of one (monotherapy) of the 1st lineAEDs recommended for their type of seizures/epilepsy syndrome (table 8).Single drug therapy provides optimal seizure control in about 70% of patients,and has the advantages of better tolerability and compliance, fewer sideeffects, simpler regime, and lower teratogenic risk.

5. If seizures continue, titrating the dose upwards to a higher maintenance dose.The ideal dose for a patient is that dose that gives good seizure controlwithout significant adverse side effects.

5.3.2 Treatment of chronic active epilepsy

If seizures continue beyond 2-3 years, the patient is considered to have chronicepilepsy (accounting for about 10-20% of all epileptic patients), and the following

management steps must be taken:

1. Review the diagnosis and aetiology- history, EEG, neuroimaging, etc. Thepossibility of pseudoseizures must be considered.

2. Re-classify the epilepsy (seizure type(s) and syndrome).

3. Review compliance.

4. Review drug history - which AEDs have or have not been useful in the past,which have not been tried, drug and blood levels of previous therapy.

5. Set a treatment plan - sequence of drug changes, serum level monitoring.

6. Consider surgical therapy.

7. Recognise limitations of therapy; patients with intractable epilepsy must beable to accept their disability and continue with life. There are limits to the



25

effectiveness of AEDs available and it is important to create a balancebetween seizure frequency, side effects from AEDs, and quality of life.

For both newly diagnosed and chronic epilepsy, a staged approach is advised:

• Tolerability and long-term safety are the most important factors in choosingthe first drug.

• If the first AED is poorly tolerated at low dosage or fails to improve seizurecontrol, an alternative should be substituted.

• If the first well-tolerated AED greatly improves but does not completelyabolish seizures, combination therapy may be tried. Although themechanisms of action of many AEDs are not fully understood, this remains alogical basis for choosing combination therapy. Evidence is emerging thatcertain combinations offer better efficacy than others.

• Work up for epilepsy surgery should be considered after failure of 2 well-tolerated treatment regimes.

• If needed, subsequent combinations of 2 or at most 3 AEDs may be effective.

5.4 Decision to withdraw AEDs

When freedom from seizures has been achieved for a period of at least 2 years,drug withdrawal may be considered. Exceptions occur in certain epilepsysyndromes e.g. JME, which has a high relapse rate. No guarantee of seizurefreedom can ever be given when a drug is withdrawn. There is a 40- 50% risk of

relapse within the 1st year of cessation. The risk of relapse is higher in patients:• > 16 years of age

• whose age at seizure onset was < 3 , or > 30 years

• with tonic-clonic (primary or secondary) or myoclonic seizures

• with partial onset seizures

• with seizures needing > 1 AED for good control at the time ofdiscontinuation

• with an abnormal EEG. (The EEG is not helpful in predicting seizurerecurrence, although a normal EEG is reassuring.)

• with a past history of status epilepticus

• with a history of afebrile or atypical febrile seizures in childhood• experiencing one or more seizures after the start of treatment

• with a short duration of seizure-freedom

• whose duration of treatment exceeds 10 years

• with a known aetiology of seizures (symptomatic epilepsy) and associatedneurological handicap

• with a fast rate of drug withdrawal



26

Patients in whom seizure recurrence is less likely include:

• those who have been seizure- free for five or more years, or between threeand five years at least

• those with benign Rolandic and familial neonatal convulsions

Discussion of whether to withdraw AEDs should take into account:

• the patient’s need to work and drive a motor vehicle

• the patient’s fear of seizures and attitude to prolonged AED therapy

5.5 Driving and epilepsy.

The possession of a driver’s licence is an important contributor to health-relatedquality of life in epilepsy, especially denoting independence, and may be a

necessity for continued employment. However, epileptic seizures can result inroad traffic accidents by causing sudden incapacity at the wheel. Although theydo not contribute greatly to the totality of road safety, most countries and stateshave some laws or guidelines governing fitness to hold both ordinary andvocational licences. There is, however, a worldwide variability, from somenations imposing a blanket lifelong prohibition, through to systems of individualdriver’s risk assessment. There is a lack of adequately researched data on relativeaccident risk in epilepsy compared to a non-epileptic population, which allowsfor this inequitable variability in regulations.

In Malaysia, the Akta Pengangkutan Jalan (APJ) 1987 and Kaedah-Kaedah Kenderaan Motor (Lesen Memandu) 1992 applies, and states:

• Under Section 30 (2) and (3) APJ 1987 , the Pengarah of JPJ may refuse anapplication for a licence if the licensee is found to have a condition (disease ordisability) that may endanger other road users. In this context, Kaedah 18 danKaedah-Kaedah Kenderaan Motor (lesen memandu) 1992 clearly states ‘epilepsy’as one such condition; this applies to all and any forms of licences.

• If a licensee has obtained a licence before developing this condition, thePengarah can revoke this licence under Seksyen 30 APJ 1987 based on a

medical report from any medical officer stating the level of disease/disability.

Legally, the doctor is not duty bound to notify JPJ . Generally, the decision todrive or not to drive is a choice best made after discussions between the treatingphysician and patient. Some conditions that may allow for safe driving include:

• Well-controlled epilepsy, and is on treatment



27

• Seizure freedom for at least 1 year, off or on treatment.

• Preceding aura –however, auras may not occur with every seizure, or thedriver may not have enough space on the road to pull over despite an aurasignalling an impending seizure.

• Purely nocturnal seizures.

Someone who is a newly diagnosed epileptic and is being started on medicationis advised to stop driving for 6 – 12 months, until the seizures have stabilized,and any drug-related side effects have settled. Certain occupations are prohibitedfor people with epilepsy –these include driving heavy machinery e.g. tractorsand public buses, as well as flying commercial or military airplanes. As such,obtaining driving licences in these situations is clearly not possible. Driving isconsidered a privilege, not a right. If a patient’s epilepsy is against him/herobtaining a driver’s licence, use of public transport or carpooling is encouraged.

5.6 Education and epilepsy

The Kementerian Pendidikan Malaysia has confirmed that there are nodiscriminatory policies or action against any person with epilepsy who wishes topursue higher education. There are no specific disciplines which are barred forpeople with epilepsy. Any person who wishes to enrol in an Institute of HigherLearning (Institut Pendidikan Tinggi Awam or IPTA) is required to undergo amedical check up, including people with epilepsy. People with epilepsy and anyother chronic medical conditions are advised to inform the authorities of their

condition, so as to facilitate any modification to their surroundings or courses asnecessary.



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6.0 LONG TERM PHARMACOLOGICAL TREATMENT

6.1 Introduction

Epilepsy is a chronic disease associated with physical, psychological, and socio-economic consequences that may compromise the quality of life. Therefore,measures to prevent seizure recurrence are of paramount importance. Thedecision to treat with AEDs should be made after extensive discussion with thepatients or parents about the risks and benefits of treatment. The goal should bethe restoration of a normal life through complete control of seizures with the useof a single drug that has little or no side effects.

6.2 Initiation and continuation of AEDs

A systematic approach to the long-term pharmacological treatment of epilepsy isrecommended:

1. Establish the diagnosis of epilepsy and the need for long term AEDs (chapter5).

2. Start with a single first line AED after deciding on the type of seizure(s) andthe epilepsy syndrome (table 7).

3. Begin with a low dose and increase gradually over 2 to 3 weeks (table 8).4. Counsel and educate the patient and caregivers about his/her epilepsy and

treatment. The information can be given by doctors treating the patient or anurse trained in epilepsy care (appendix 1)

5. Review the patient within a month to assess compliance, side effects andseizure control (table 9).

6. Review every 6 to 8 weeks. If the seizures are not controlled and there are noside effects, increase the dose appropriately. In about 60-70% of patients,these steps are sufficient to achieve good seizure control.

7. If the AED fails to control seizures:

• Review the diagnosis and seizure pattern.

• Review compliance (see also “drug monitoring”).

• Ensure that the maximum tolerated dosage has been used.8. If the first AED continues to be ineffective at the maximum tolerated dose,

introduce an alternative AED slowly (table 7) without tapering the first.



29

TABLE 7: List of commonly used AEDs and their indications:

SEIZURE TYPE FIRST CHOICE SECOND CHOICE

Partial seizures

Simple partialComplex partialSecondarily generalised

Carbamazepine (M/A)Valproate (M/A)Oxcarbazepine (M/A)

Phenytoin (M/A)Lamotrigine (A)Topiramate (A)Levetiracetam (A)Gabapentin (A)Phenobarbitone (A)Acetazolamide (A)Clonazepam (A)

Generalised seizures

Tonic-clonic,clonic

Valproate (M/A)Carbamazepine (M/A)

Phenytoin (M/A)Lamotrigine (A)Topiramate (A)Phenobarbitone (A)Acetazolamide (A)

Absence Valproate (M/A)Ethosuximide (M/A)

Lamotrigine (M/A)Clonazepam (A)Acetazolamide (A)

Atypical absences,atonic,tonic

Valproate (M/A) Lamotrigine (A)Topiramate (A)Clonazepam (A)Phenytoin (M/A)

Acetazolamide (A)Myoclonic Valproate (M/A) Clonazepam (M/A)

Phenobarbitone (M/A)Piracetam (A)Acetazolamide (A)?Lamotrigine (A)

Infantile spasms ACTH (M)Corticosteroids (M)Vigabatrin (M)*

Clonazepam (A)Valproate (A)

M = monotherapyA = adjunctive therapy*Currently not registered in Malaysia



30

TABLE 8: Dosages of commonly used AEDs

AED Usual daily dose No. ofdoses/day

Carbamazepine

Clonazepam

Ethosuximide

Gabapentin

Lamotrigine

Levetiracetam

Oxcarbazepine

Phenobarbitone

Phenytoin

Topiramate

Valproate

Initial: 100 mg at night (adults); 5 mg/kg (children).

Maintenance: 400 – 1600 mg (adults); 10 – 20mg/kg (children).

Initial: 0.25 mg (adults); 0.02 mg/kg (children).Maintenance: 0.5-4 mg (adults); 0.1-0.2 mg/kg(children).

Initial: 250 mg (adults); 10 mg/kg (children).Maintenance: 750-2000 mg (adults); 20-40 mg/kg(children).

Initial: 300 mg (adults); 10 mg/kg (children).

Maintenance: 900-3600 (adults); 30-60 mg/kg(children).

Initial: 25 mg (adults); 0.15 mg/kg (with valproate),0.6 mg/kg (without valproate) (children).Maintenance: 100-200 mg (adults); 1-5 mg/kg (withvalproate), 5-15 mg/kg (without valproate)(children). Adjunctive therapy with valproate:gradual increment in the dose over one month(adults).

Initial: 500 mg. Maintenance: 1000-3000 mg; 20-50mg/kg (children).

Initial: 600 mg (adults); 10mg /kg (children)Maintenance: 1200-2400 mg (adults); 20-40 mg/kg(children)

Initial: 30 mg. Maintenance: 30-180 mg (adults); 3-5mg/kg (children).

Initial: 200-300 mg. Maintenance: 300-400 mg(adults); 5 mg/kg (children)

Initial: 25-50 mg (adults), 0.5-1 mg/kg (children).Maintenance: 200-400 mg (adults); 3-9 mg/kg(children).

Initial: 400-600 mg (adults); 10-20 mg/kg (children).Maintenance: 400-2500 mg (adults); 20-40 mg/kg(children under 20 kg); 20-30 mg/kg (children over20 kg).

2-3

2-3

2-3

2-3

1-2

2

2

1-2

1

2

2



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TABLE 9: Common and important side effects of AEDs

AED Side effects (acute and chronic)

Carbamazepine

Clonazepam

Gabapentin

Lamotrigine

Levetiracetam

Phenobarbitone

Phenytoin

Topiramate

Valproate

Drowsiness, fatigue, dizziness, ataxia, diplopia, blurring ofvision, rash and other skin reactions, leucopaenia, andhyponatraemia.

Sedation, drowsiness, ataxia, and blurring of vision.

Drowsiness, dizziness, ataxia, headache, and myoclonus.

Rash (sometimes severe), dizziness, and somnolence.

Somnolence, asthenia, dizziness, and headache.

Sedation, ataxia, dizziness, and hyperactivity in children.

Ataxia, dizziness, lethargy, sedation, gingivalhypertrophy, and hirsutism.

Dizziness, ataxia, paraesthesiae, tremor, somnolence,cognitive dysfunction, emotional lability, word- findingdifficulties, nephrolithiasis, open angle glaucoma,hypohidrosis (children), and weight loss.

Drowsiness, tremor, hair thinning and hair loss, menstrualirregularities, weight gain, and thrombocytopaenia.



32

9. If the patient has a good response to the second AED, consider withdrawing

the original AED gradually.10. Consider long-term two-drug therapy if monotherapy has not achieved

remission or good seizure control.

11. If the first add-on AED is ineffective, or produces undesirable side effects,withdraw it slowly, and simultaneously replace it with a second add-on AEDfrom the remaining choices. This process can be repeated for other possibleadd-on AEDs.

12. If the seizures are still not adequately controlled on two AEDs, some patientsmay benefit from an additional third AED.

13. Review the diagnosis if seizures continue despite the above logical approach,and a period of 2-3 years has elapsed. The possibility of pseudoseizures orpoor compliance should be considered. When these possibilities have beenexcluded the patient should be evaluated for a possible progressive structural

lesion, especially if the patient has partial seizures, and surgery may beconsidered.

14. Patients and care-givers must be fully involved in decisions about theirtreatment. Their views on treatment such as achieving the right balancebetween side effects and seizure control should be taken into account whenconsidering changes in medication.

15. The importance of compliance should be stressed to patients and care-givers.

6.3 Drug monitoring

AED concentrations are over-requested and often misinterpreted, leading toinjudicious alteration of treatment. When employed as a guide to dosing, serumconcentrations of phenytoin are the most useful, given its narrow therapeuticrange and zero order kinetics. Assays of carbamazepine, phenobarbitone, andbenzodiazepines are moderately helpful. Serum assays for valproate areunhelpful due to large fluctuations in levels and lack of correlation with efficacy.Serum assays for the newer drugs such as lamotrigine, topiramate andgabapentin are not available and generally unnecessary.

The major indications for assaying serum AED levels are:

• To check compliance

• To determine if signs or symptoms are the result of AED toxicity

• As a guide to dosing of certain AEDs (in particular, phenytoin)

• To monitor pharmacokinetic interactions

• As a guide in certain situations e.g. pre-pregnancy planning, duringpregnancy, and status epilepticus



33

As a general rule, serum AED levels should be measured at steady state, i.e.when at least 5 elimination half-lives have elapsed since the last dose change.Blood should be drawn in the morning before the first daily dose, when theconcentration is usually at its trough. The time of sampling is unimportant forAEDs with long half-lives like phenobarbitone. For drugs with significant

variation in serum concentrations during the dosing interval (e.g. sodiumvalproate and carbamazepine), a second sample should be taken a few hourslater. If drug toxicity is suspected, peak levels should be taken.

6.4 Choice of first line therapy

6.4.1 Treatment of partial seizures (simple, complex, with or without secondarygeneralisation)

• The choice of first-line treatment for partial seizures is either carbamazepineor valproate.

• If first-line treatment is ineffective or unacceptable, the following drugs maybe tried: phenytoin, lamotrigine, topiramate, gabapentin or levetiracetam.

• The appropriate choice of AED in an individual patient is a balance ofefficacy, tolerability and cost.

6.4.2 Treatment of generalised seizures (absence, primary generalised tonic-clonic, and myoclonic seizures)

• The recommended first-line treatment is sodium valproate. Carbamazepineand phenytoin are not only ineffective for, but may exacerbate absence andmyoclonic seizures.

• If first-line treatment is ineffective or unacceptable, the next choice of AEDdepends on the seizure type and syndrome:

• Absence and myoclonic seizures: clonazepam, ethosuximide orlamotrigine.

• Primary GTCS: carbamazepine, phenytoin, lamotrigine, gabapentin,phenobarbitone, clonazepam or topiramate.

6.4.3 Treatment of chronic epilepsy

The principles of treatment in chronic active epilepsy are covered in chapter 5. Ininstituting long-term pharmacological treatment in such patients, the followingsteps should be observed:



34

• Review previous treatment history i.e. the various AEDs tried including drugdosages, effectiveness, drug withdrawal and side effects.

• Review compliance to AEDs.

• Consider using the newer AEDs, including lamotrigine, topiramate,gabapentin, and levetiracetam after the standard AEDs have been used.

• Intermittent usage of rectal diazepam (after the first seizure) can beconsidered in patients with predictable clustering, especially perimenstrually.

6.5 AED toxicity

Important points pertaining to AED toxicity include:

• Acute dose-related toxicity is common and predictable although the doserequired to produce symptoms varies between individuals.

• Inappropriate rapid introduction of AEDs is a common reason for toxicityand apparent drug failure.

• Carbamazepine, lamotrigine and topiramate produce non-specific centralnervous system manifestations, in particular drowsiness.

• Allergic reactions, manifested initially by rash occur in 2-4% of patientsexposed to carbamazepine, phenytoin, phenobarbitone, and lamotrigine. Thismay occur even after a few weeks of starting treatment, with the peakincidence at 10-21 days (table 9).

• Chronic toxicity may affect any system. The side effects are quite specific foreach AED (table 9).

6.6 Stopping treatment

Important points pertaining to the withdrawal of AEDs include:

• In more than 60% of patient who remain free of seizures, the medication caneventually be withdrawn successfully.

• AEDs should be withdrawn slowly, with a gradual reduction over a 6 month- 1 year period. With polytherapy, one drug at a time should be withdrawn,

starting with the least useful one.• Withdrawal of AEDs can be discussed with patients after 2 years of seizure

freedom.

• The decision to stop medication involves a balance of the risks ofcontinuation (chronic toxicity, teratogenicity, etc.) with the implication ofrelapse (injury, death, loss of driving license, unemployment, etc.).



35

7.0 SURGICAL TREATMENT OF EPILEPSY

7.1 Introduction

In well developed health care systems with dedicated epilepsy managementprogrammes and easy access to AEDs, about 30% of patients continue to haveseizures despite appropriate drug therapy. Patients with medically intractableseizures are candidates for surgical treatment with the aim of achieving betterseizure control. Another group of patients who might benefit from surgery arethose whose seizures may be relatively well controlled but who have lesions thatstrongly suggest that surgical intervention might be curative (e.g. some lowgrade tumours, vascular malformations).

Several developments have contributed to the increasingly prominent role of

surgery in control of refractory seizures. These include the recognition of“surgically remediable epileptic syndromes” which have a clearly definedclinical presentation and natural history, recent advances in diagnosticprocedures, particularly electrophysiological studies (long-term video-EEGmonitoring) and high resolution MRI that allow reliable, non-invasiveidentification of these syndromes, and improvement in surgical techniques thathave greatly increased the efficacy and safety of surgical procedures for thecontrol of seizures. In less developed health care systems, it is likely that asubstantial number of patients with a potential for surgical cure of seizures donot have the benefit of surgical treatment.

7.2 Early diagnosis of seizure intractability and timing of surgery

Traditionally, therapeutic failure of 3 AEDs has defined medical intractability.However, refractory epilepsy may be suspected at the outset, when:

• Patients present with more than 20 seizures before treatment is initiated,

• There is inadequate response to the first AED prescribed, and

• There is an underlying well defined structural cerebral abnormality onimaging studies

Patients who have persistent seizures despite adequate therapy with anappropriate initial AED have only a 12% to 14% chance of complete seizurecontrol with alternate AED monotherapy and a 3% to 11% chance with AEDpolytherapy. The diagnosis of intractability should be individualized withconsideration given to the following:



36

• Seizure type – major seizure type, presence of unpleasant auras, significantpostictal disability, unpredictable occurrence, seizures with risk of injury

• Seizure burden – number of refractory seizures, degree of interference withquality of life, education and employment

• Adverse effects of AED polytherapy (extreme fatigue, clouded thinking,

dizziness, etc)

How long epilepsy should be present before surgery is considered depends onthe natural history of the epilepsy syndrome, e.g. in infants, several months offrequent seizures might be sufficient, given the deleterious effects of refractoryseizures on the developing brain. In adolescents and adults, at least 1 year ofnon-remitting seizures should elapse before surgery is considered.

7.3 Surgically remediable epilepsy syndromes

The preferred surgical technique for each syndrome may vary from centre tocentre and from case to case. Detailed information regarding each syndrome andthe technical details of each surgical option are beyond the scope of thisguidelines. Table 10 summarizes the surgical options currently used.

TABLE 10: Surgical options for various epilepsy syndromes

Epilepsy syndrome Surgical options

Mesial temporal lobe epilepsy Anterior temporal lobectomy; selective

amygdalohippocampectomyDiscrete focal lesions Lesionectomy; tailored resection

Tuberous sclerosis Lesionectomy (single tuber)

Infantile spasms secondary to discretecortical lesion

Lesionectomy

Intractable seizures associated withdiffuse, unilateral hemisphericpathology in children

Functional hemispherectomy

7.4 Presurgical investigations and patient selection

The single most important determinant of a successful surgical outcome ispatient selection. The presurgical evaluation of potential candidates shouldpreferably be carried out at a multi-disciplinary centre experienced in theinvestigation and treatment of epilepsy.



37

7.4.1 Selection of patients for presurgical evaluation

Prior to embarking on presurgical evaluation it is important to ascertain that:

• The epilepsy syndrome is accurately identified (i.e. identification of asurgically remediable syndrome)

• The seizures are indeed intractable to appropriate medical therapy

• The seizure burden is such that surgical treatment is a reasonableconsideration (seizure frequency , degree of interference with psychosocialfunctioning and development)

7.4.2 Presurgical Evaluation

The aims of the presurgical evaluation of patients in whom resection of an

epileptogenic zone is planned are to:

• accurately localise the epileptogenic zone

• establish a resection strategy

• establish definite goals once seizure control is achieved by surgery

Accurate localisation of the epileptogenic zone is achieved by examining andcorrelating data acquired from the seizure semiology and a series ofinvestigations:

• Routine scalp EEG and continuous video-EEG monitoring• High-resolution (preferably volumetric) brain MRI

• Full psychometric analysis by a trained clinical neuropsychologist

7.5 Establishment of a resection strategy

Several adjunct investigations may be performed prior to surgery to maximisethe benefit and minimise the risk from the operative procedure:

• Functional MRI

• Intracarotid amylobarbital test• Intraoperative EEG mapping with electrocorticography (ECoG)

• Awake craniotomy and cortical stimulation

• Image guided surgery

• Ultrasonic aspirator



38

The objectives of these investigations are to:

• Identify the proximity of eloquent brain tissue to the epileptogenic zone

• Minimise the risk of injuring adjacent eloquent brain tissue (speech, handmotor, visual, and memory centres)

• To identify dual pathology

Division of the corpus callosum (corpus callosotomy) and multiple subpialresection are some of the disconnection procedures in current use for palliation(in intractable patients without a surgically remediable lesion). Patients in whomthere is a risk of injury from intractable sudden akinetic seizures (drop attacks),consideration should be given to corpus callosotomy.

Complications related to large cortical resections, and intra- and postoperativemorbidity may be higher in infants and younger children than in older children

and adults. However, there is a greater potential for functional recoveryfollowing resection of eloquent cortex due to greater plasticity of the developingbrain in this age group. The goals of resection in children are often to stop severe,disabling seizures and reverse an epileptic encephalopathy. Control of severe,disabling seizures and a decrease in the consumption of AEDs have been shownto result in an improvement in the rate of neurodevelopment, and an enhancedquality of life for both the patients and their families. In some instances, thepersistence of minor seizures postoperatively is acceptable.

7.6 Results of Surgical Treatment

Surgical outcome in terms of seizure control and operative risks for differentepilepsy surgery procedures are shown in table 11.



39

Table 11: Results of surgical treatment for control of seizures

Epilepsy surgeryprocedure

Postoperative seizureoutcome Risks of complications

Surgery forhippocampal sclerosis(ATL, SAH)

Seizure free rate ofabout 70%

- Mortality risk < 1%- Major permanent neurologicmorbidity <2% ( coma,

hemiplegia)

- Some degree of decline of verbalmemory with dominanthemisphere resections (only insome patients)- Minor hemianopic deficit in 50%(non-disabling)

Lesionectomy Seizure free rates of40-60%

- Mortality risk < 1%- Major permanent neurologicmorbidity variable (determined bylocation, thoroughness ofpresurgical selection)

Functionalhemispherectomy

Seizure free ratesof 56-82%

- Mortality- Complications (haemorrhage,cerebral oedema, increased ICP,hydrocephalus, meningitis)

Corpus callosotomy

for akinetic seizures

Significant seizure

reduction in 50-80%

- Mortality Risk < 1%- Significant neurological deficit

<5%- Disconnection syndrome is

usually transient (hemineglect,mutism, and motor coordinationdeficits)



40

8.0 EMERGENCY TREATMENT OF EPILEPSY

8.1 Introduction

Most seizures are self-limiting. Studies show that the mean time for a GTCS is 62seconds and a complex partial seizure is about 120 seconds. In most cases ofGTCS, treatment is usually supportive and patients will recover fully after aperiod of rest of about 30-60 minutes.

8.2 Initial supportive management

During an acute epileptic seizure, the following measures should be taken:

• Place the patient on a smooth surface, if possible.

• Remove any harmful objects.

• Loosen tight clothing.

• Turn the patient to the left lateral position, and place the head on a softsupport (bundle of cloth or pillow).

• Avoid placing any objects in the patient’s mouth.

• Stay with the patient until he or she recovers fully, and gather informationabout the patient’s background and epilepsy history.

• Get the patient to the nearest hospital if the seizure persists beyond 10minutes, or there is no recovery of consciousness after 30 minutes, significant

fever, serious injury, or a recent increase in seizure frequency.

8.3 Postictal care in uncomplicated seizures

Once the patient is in a hospital, oxygen is given via nasal prongs during thepostictal phase. Rapid blood glucose estimation via a glucometer is done andblood is drawn for urea and serum electrolytes, including calcium andmagnesium assessment. An arterial blood gas analysis must be performed if theseizures are persistent.

8.4 Treatment of prolonged seizures

In the event that the seizure does not stop, vital parameters, including the bloodpressure, heart rate, oxygen saturation and ECG must be monitored. The patientis maintained in a left lateral position and intravenous access is established. Theairway must be patent and the possibility of rapid sequence endotracheal



41

intubation considered. The respiratory rate and pattern is observed. Oxygen isdelivered through a high flow mask. If there is any suspicion of hypoglycaemiaas the cause of the seizures, 50 ml of 50% glucose should be given intravenously.In addition, if Wernicke’s encephalopathy is suspected, an intravenous bolus ofthiamine 100 mg should be given prior to the glucose administration. Prolonged

seizures may be aborted with the following AEDs:

8.4.1 Benzodiazepines (BDZ)

Intravenous lorazepam and diazepam are the principal first line AEDs used forprolonged seizures. The former is not available in Malaysia but there is goodevidence in favour of lorazepam as the drug of first choice. Compared withdiazepam, lorazepam results in lower seizure recurrence (due to its longerredistribution and elimination half-life), lower rate of respiratory depression(inactive metabolites), and better response rates (see table 12). The response rate

is estimated at 76-100% for lorazepam and 50% for diazepam.

8.4.2 Alternative parenteral benzodiazepines

When intravenous access is difficult, alternative routes for BDZ administrationmay be used, namely, rectal, buccal or intranasal. Rectal diazepam is therecommended alternative route (table 14). The onset of action is marginallyslower (2-5 minutes) compared to the intravenous route (< 2 minutes).Intravenous midazolam (5 mg/ml) solutions may be given intranasally or ontothe buccal mucosa. In the former, midazolam at a dose of 0.2mg/kg is dropped

into the nasal cavity, which is rapidly absorbed into the circulation in the absenceof an upper respiratory tract infection. Similar doses are used for buccalmidazolam. The efficacy of intranasal midazolam is equivalent to that of rectaldiazepam.

8.4.3 Pre-hospital treatment

The duration and recurrence rate of seizures may be reduced by proper pre-hospital treatment. Paramedical personnel can be trained to use parenterallorazepam or diazepam at a reduced dose to control seizures in up to 56% ofpatients. Caregivers of patients with recurrent clusters of seizures or prolongedseizures may be trained to administer rectal diazepam at doses predetermined bytheir medical practitioner.



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TABLE 12: Comparison of the pharmacokinetics of lorazepam and diazepam

TABLE 13: Rectal diazepam dosing

Rectal diazepam dosing according to age

2- 5 years 0.5mg/kg

6-11 years 0.3mg/kg

> 11 years andadults

0.2mg/kg

Maximal

Loadingdosing

Administration

Time

Distribution

half life

Elimination

half life

Metabolites

Diazepam 0.15mg/kg

< 5 minutes 15-90minutes

36 hours Active

Lorazepam 0.1-0.15mg/kg

1-2 minutes 4-6 hours 16 hours Inactive



43

8.5 Treatment of convulsive status epilepticus

Convulsive status epilepticus (SE) is defined conventionally as a seizure or aseries of seizures lasting more than 30 minutes, without recovery of fullconsciousness. However, most seizures abate within 2 minutes. The capacity for

spontaneous resolution falls, and the risk of mortality and morbidity rises withtime. Seizures that last longer have a higher mortality and recurrence rate, andare more resistant to conventional treatment (table 7). Even seizures lasting from10-29 minutes have a better prognosis than those lasting more than 30 minutes.

Time appears to be of the essence and an increasing number of authors areredefining the time frame for SE to any convulsion lasting more than 5 minutesor a series of seizures without recovery of consciousness.

In the management of established SE, intravenous diazepam, lorazepam,phenytoin, phenobarbitone, sodium valproate, or paraldehyde may be used. The

dosages of, and efficacy of these AEDs in acute overt and chronic subtle SE aresummarized in tables 14 and 15. Phenytoin is the preferred AED because it iswidely available and is less sedating than the other AEDs. An additional dose ofphenytoin at 5-10 mg/kg can be given if the first loading dose is unproductive.Sodium valproate has been shown to be useful in acute repetitive seizures andearly SE in children. The intravenous formulation administered at a bolus of 15-25mg/kg (slow i.v. push in 30 minutes) followed by an infusion at 1mg/kg/hour has proven to be haemodynamically safe and not arrhythmogenic.Its role in the treatment cascade is, however, debatable. Fosphenytoin is arelatively new and expensive AED that is safer to use than phenytoin, but is

currently not available in Malaysia (table 16). Intravenous lignocaine andketamine may be used but their effectiveness is not proven. Their role is probablyin the acute phase while awaiting definite therapy.

TABLE 14: Dosages of AEDs used in the initial phase of acute seizures

• i.v. diazepam 10 mg repeated once after 15’

• i.v. lorazepam 0.07 mg/kg (usu. 4 mg) bolus

• i.v. phenytoin 15-18 mg/kg at ≤50 mg/min, or

• i.v. phenobarbitone 20 mg/kg at ≤100 mg/min, or

• i.v. sodium valproate 15-25 mg/kg slow bolus (over ½ hour), followed byinfusion at 1 mg/kg/hr for 6 hours

• Paraldehyde 0.2 ml/kg i.m. (adults) or 0.4 ml/kg diluted with equal volumeof olive oil rectally (children)



44

About 60-90 minutes into the seizure, the patient should be subjected to generalanaesthesia. At this point, respiratory depression and hypotension from theseizure or effects of the phenytoin or BDZ are of prime concern. The

administration of barbiturates or other anaesthetic agents may compound theproblem and intubation will be necessary. Inotropes and fluid resuscitation willbe needed. General anaesthesia should be induced and maintained in anintensive care unit and the patient should be connected to an EEG monitor. Thedrugs that can be used include one of the barbiturates (table 17), midazolam orpropofol. The underlying aetiology will usually need to be treated. Refractory SEis defined as seizures unresponsive to BDZ, phenytoin and barbiturates.Midazolam (0.2-0.5 mg/kg bolus at < 4 mg/min; 0.1-2.0 mg/kg/hr infusion) andpropofol (1-2 mg/kg bolus at < 25 mg/min; 2-15 mg/kg/hr infusion) infusionsare usually used at this stage, and the principal goal will be to achieve EEG

background suppression. There is no difference in terms of achieving this goalbetween the agents.

TABLE 15: Response rates of acute overt and chronic subtle SE to variousAEDs

TABLE 16: Comparison of phenytoin and fosphenytoin

Overt SE (%) Subtle SE (%)

Lorazepam 64.9 17.9

Phenobarbitone 58.2 24.2

Diazepam/Phenytoin 55.8 8.3

Phenytoin 43.6 7.7

Loadingdose

Infusionrate

Ingredient Eliminationhalf -Life

Phenytoin 15-18mg/kg 50mg/min Activemoiety

20-40 hours

Fosphenytoin 20mg/kg 150mg/min

Prodrug Converted tophenytoin



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TABLE 17: Barbiturate dosing

Other than monitoring the adequacy of general anaesthesia, continuous EEGrecording will also help detect electrographic seizures, which if present, requireaugmentation of AED therapy.

The flow chart below is a useful step-by-step guide to the management ofconvulsive status epilepticus in adults. However, it is recommended that eachhospital develops its own protocol.

Loadingdose

Administration rate Maintenancedose

Eliminationhalf life

(hours)Phenobarbitone 20 mg/kg

max 600 mg 60mg/min (adult) 30mg/min (paediatric)

3-6 mg /kg /hr

200-320mg/day

53-180

Pentobarbitone 5 mg/kg Titrate to EEG/vitalsigns

1-5 mg/kg/hr

21-42

Thiopentone 2-4 mg/kg Titrate to EEG/vitalsigns

2-8 mg /kg /hr

3-8



46

MANAGEMENT OF CONVULSIVE STATUS EPILEPTICUS IN ADULTS

TIME FROMSTART OFTREATMENT

PROCEDURE.

0 - 8 minutes.( EmergencyDept)

1. Diagnose status epilepticus by observing continuedseizure activity or one additional seizure.

2. Assess cardiorespiratory status and vital signs at onsetand periodically thereafter. ( ABC’s of resuscitation ).

3. Give oxygen by nasal cannula or face - mask 15L/min.

4. Ensure airway patency and oxygenation at all times.

5. Establish i.v. access, through large veins, preferably2 lines (branula size 18 G). Fluids: 0.9% NaCl.

6. Blood investigations: Glucose level / dextrostix.: Blood urea & electrolytes

: Full blood count: Serum calcium / magnesium.: Serum drug levels (AEDs &

toxicology.

7. Draw arterial blood for arterial blood gas and applyPulse oximeter (if available ).

8 - 10 minutes. If hypoglycaemia is established, or a blood glucosedetermination is unavailable, administer i.v. thiamine

100mg followed by 50 ml of 50% glucose (direct pushinto the i.v. line).

10 - 20 minutes. 1. Administer i.v. diazepam 0.2 mg/kg at 5 mg/min.



47

2. Repeat after 15 minutes if seizures persist.(Total dose = 20 mg )

ED WARD20 - 60 minutes. 1. If seizures persist:-

[LOADING DOSE] : i.v. phenytoin 15 - 18 mg/kg infusion (diluted in 100 mlof normal saline), at a rate not exceeding 50 mg/min.

Monitor ECG and BP throughout.

Followed by :-

[MAINTENANCE DOSE] :i.v. phenytoin 100 mg 8 hourly after 12 hours of loadingdose, and start ORAL ANTIEPILEPTICS via Ryles tube(patient’s regular drugs) if known epileptic onmedication.

> 60 minutes. 1. If seizures persist :-

Additional dose of phenytoin at 5 mg/kg at rate 50mg/min, whilst arranging to TRANSFER patient toICU, and EEG monitoring.

OR

Phenobarbitone 10 mg/kg I/V at 100 mg/min.

if seizures persist

3. Assisted ventilation :

i.v. thiopentone 100 - 200 mg bolus over 20 seconds,followed by 50 mg every 2 - 3 minutes until seizurecontrolled or EEG shows burst suppression

Thiopentone maintenance: 3 - 5 mg/kg/hr Monitor thiopentone blood level ~ 40 ug/L

After 24 hours: infusion based on blood levels After 2 - 3 days : infusion based on blood levels or

decrease dose if systolic BP < 90 mmHg Slowly discontinue once seizure controlled (reduce

by 25 mg/hr every 6 hours after, at least, a 24-hourseizure-free period)



48

OR

i.v. phenobarbitone at 1 - 4 mg/kg maintenancedose.

If anaesthetist / ICU bed not immediately available :

In ward:

i.v. lignocaine 100 mg bolus (1.5 - 2 mg/kg) at < 50 mg/min with ECGmonitoring

followed by

i.v. infusion at 50 - 100 mg in 250 ml Dextrose 5% at rate of 3-4 mg/kg/hr

OR

i.v. sodium valproate : loading dose 15 mg/kg,followed, 30 minutes later, by maintenance dose of 1 mg/kg/min for 6 hours



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8.6 Emergency treatment of other prolonged seizure types

8.6.1 Myoclonic status

In hospital practice, anoxic brain damage and acute renal deterioration are the

commonest causes of myoclonic seizures. Treatment should be aimed at, and theeventual prognosis will depend on the underlying cause. More rapid resolutioncan be obtained with intravenous BDZ like midazolam or sodium valproate.Levetiracetam is also useful for anoxia-induced myoclonus.

8.6.2 Tonic status

Treatment should proceed as for GTCS.

8.6.3 Non-convulsive SE (NCSE)

This condition may present de novo, or as a sequel to convulsive SE, after whichthe patient is slow to recover consciousness. The incidence of NCSE in SE isestimated at 14%. The condition carries a risk of convulsive SE recurrence and itmust be treated aggressively as for convulsive SE.

The de novo form of NCSE may occur as a complex partial SE or absence SE.Patients present with a change in behaviour or detachment from theenvironment. These must also be treated expeditiously but not as aggressively asabove. The first line of treatment is an infusion of a BDZ, i.e. midazolam or

diazepam, and the simultaneous introduction of oral treatment likecarbamazepine, phenytoin, or sodium valproate. In the event that BDZ infusiondoes not work, infusion of phenytoin or sodium valproate may be tried.Resistant patients may need a barbiturate for control. The risk of brain damage isminimal in comparison to convulsive SE.



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9.0 SPECIAL ISSUES

9.1 Epilepsy in women

9.1.1 Introduction

There are special issues when managing women with epilepsy. These include:

• Menstruation

• Fertility

• Contraception

• Pregnancy

• Pre-conception management and counselling

• Labour

• Foetal malformations

• Breast feeding and the puerperium

• Bone health

These issues arise because of the hormonal changes that take place duringdifferent phases of a woman’s life. Women of child-bearing age must be madeaware of these issues, and the attending physician needs to take these intoaccount when planning management strategies.

9.1.2 Menstruation

Juvenile myoclonic epilepsy and photosensitive epilepsy tend to develop atpuberty whereas childhood absence epilepsy and BCECTS tend to remit atpuberty. Between 5% and 12% of women experience catamenial exacerbation oftheir seizures. Either intermittent clobazam or acetazolamide given over themenstrual period may alleviate catamenial exacerbation of seizures.

9.1.3 Fertility

The fertility of men and women with epilepsy has been estimated to be 85% and80% of the expected levels, respectively. Phenytoin, in particular, has beenreported to be associated with reduced sperm production and motility.



51

9.1.4 Contraception

There is an increased risk of oral contraceptive pill (OCP) failure with AEDs thatinduce hepatic microsomal enzymes (barbiturates, phenytoin, carbamazepine,and oxcarbazepine). Patients on the OCP need to be advised about additional

contraceptive measures. If a woman wishes to rely on the OCP alone, she shouldbe prescribed a preparation containing 50 µg of oestradiol. Intramuscular Depo-Provera at a dose of 150 mg every 12 weeks is an acceptable alternative as it isnot affected by enzyme-inducing AED. There is no evidence that hormonalcontraception adversely affects seizure control.

9.1.5 Pregnancy

Sixty percent of women will experience no change in seizure frequency during

pregnancy, 30% increased frequency and 10% decreased frequency. Although theincreased seizure frequency in some women may be due to pregnancy-relatedfall in plasma drug concentrations, sleep deprivation, poor compliance,inappropriate reduction in AED therapy and vomiting may also be contributory.

There is little evidence that seizures adversely affect pregnancy other thanincreasing the risk of trauma on the developing foetus. There are only anecdotalreports of miscarriage following GTCS. Whether epilepsy is associated with anincreased risk of obstetric complications remains controversial.

Pregnancy does not increase the risk of developing new epileptic seizures for thefirst time. However, if seizures do develop de novo in pregnancy, certain specialcauses must be considered and appropriately ruled out because they are morecommon in pregnancy (table 18). A brain MRI or CT with lead shielding willoften be required. The principles of treatment of new epileptic patients inpregnancy are the same as for the non-gravid state. Certain underlying causesneed specific treatment. Of special note is the treatment of eclamptic seizures;along with specific treatment of the eclampsia, magnesium sulphate is oftenadvocated by obstetricians but this is a poor anticonvulsant, and phenytoin orbenzodiazepines are probably better alternatives.

Serum AED concentrations often fall during pregnancy, particularly in the firstand third trimesters. Penytoin, carbamazepine and phenobarbitone serum levelsshould be measured every 2-3 months through gestation so that dose incrementscan be made without delay to return the concentrations to the levels that gaveoptimum seizure control pre-conception should there be an increase in seizures.Dose adjustments should not, however, be based on AED concentrations alone.



52

TABLE 18: Special causes of epilepsy developing in pregnancy

• Enlarging meningioma

• Enlarging arteriovenous malformation

• Ischaemic stroke

• Cerebral venous or venous sinus thrombosis• Vasculitides

• Subarachnoid haemorrhage

• Eclampsia

Women on AEDs should be monitored throughout pregnancy to detect foetalmalformations so that their view on a possible termination of pregnancy can besought early. Recommended investigations are listed in table 19.

TABLE 19: Prenatal diagnosis of malformations

Malformation Investigation Sensitivity/timing

Neural tube defects(NTDs)

Serum alpha-fetoproteinin maternal blood

80% at 16 weeks

NTDs Serum alpha-fetoproteinin amniotic fluid

>80%, but reserved whenultrasound cannotreliably exclude a NTD

NTDs Ultrasound 94% at 16-18 weeks

Major cardiac, facial and

limb anomalies

Ultrasound 20-24 weeks

9.1.6 Pre-conception management and counselling

Ideally, women should be advised against getting pregnant until they becomeseizure free and are off AEDs. However, for various personal, cultural orreligious reasons, this is seldom possible or practical. Hence, in all women withchildbearing potential, the risk of teratogenicity while on AEDs and the risk of

recurrent seizures if AEDs were to be withdrawn must be discussed long beforethey wish to conceive. The latter risk is low if the patient has been seizure-free formore than 2 years and tapering is done gradually. If the epilepsy is still activebut seizure control has been deemed optimal, the AED should not be changed.However, if seizure control is poor, therapy should be adjusted until a singledrug at the lowest effective dose delivers the best seizure control.

9.1.7 Labour



53

The risk of seizures is greatest during the delivery period; 1-2% of epilepticwomen suffer a GTCS during labour. This must be made known to the patientand her obstetrician so that necessary precautions can be taken. The patient’sregular AEDs must be continued through labour, via a nasogastric tube or

intravenously, if necessary. As pain, emotional stress and hyperventilation mayincrease the risk of seizures, epidural anaesthesia should be considered earlyduring labour. If frequent GTCS or complex partial seizures do occur duringlabour, a caesarean section is indicated. An elective caesarean section is alsorecommended if frequent GTCS or complex partial seizures occur during the lastweeks of pregnancy; the treatment of the seizure itself should proceed in theusual manner.

Owing to the risk of potentially fatal bleeding in infants born to mothers onAEDs (particularly hepatic enzyme-inducing drugs), patients should be given 20

mg/day of oral vitamin K1 in the last month of pregnancy, and/or theirnewborns given 1 mg of vitamin K1 intramuscularly at birth. If there is evidenceof bleeding in the newborn, intravenous fresh frozen plasma should be given.

9.1.8 Foetal malformations

The risk of foetal malformations is 4-8% if one AED is taken (compared with 1-3% in the general population) and 15% if more than one AED is taken. Thecombination of valproate, carbamazepine and phenytoin, however, has been

associated with up to a 50% risk of foetal malformation.

There is insufficientevidence that one AED has a higher teratogenic risk than another AED. In a largeretrospective cohort study, phenytoin monotherapy has not been shown to beassociated with an increased risk of major congenital abnormalities. However, ofgreatest fear is the association of valproate with NTDs (1-2% risk compared with0.2-0.5% in the general population). Valproate doses exceeding 1000 mg dailycarry the greatest risk. The reported teratogenic effects of commonly used AEDsare summarised in table 20. Data for most of the newer AEDs is still limited, butthere is growing evidence that they are safe in pregnancy, in particular,lamotrigine. Folic acid supplementation has been shown to have a protective rolein the prevention of NTDs, and is recommended for all women of child-bearingage taking AEDs, starting before conception, at a dose of at least 4 mg daily.



54

TABLE 20: Teratogenic effects of AEDs

AED Reported teratogenic effects

Phenytoin Cleft lip and palate, cardiac defects; craniofacial

defects, digital hypoplasia? Recent evidence suggestsno increased risk

Valproate NTDs, cardiac defects, urogenital malformations

Carbamazepine NTDs

Ethosuximide Cleft palate

Barbiturates Cleft palate

Vigabatrin Cleft palate

Lamotrigine NTDs? Recent evidence suggests no increased risk

9.1.9 Breast feeding and the puerperium

The dose of the AEDs should be reduced to pre-conception levels over the fewweeks following delivery if the dose has been increased during pregnancy toavoid drug toxicity. As most AEDs are secreted in breast milk, the infant maybecome sedated or hypotonic if breast-fed (occurring in 5-10% of babies). If thishappens, the breastfeeds can be reduced and supplemented with bottle feeds.Mothers should breastfeed their babies whilst seated on floor cushions andshould not be allowed to bathe their babies in a bathtub unless assisted to avoiddropping their babies in case a seizure occurs.

IMPORTANT STEPS IN THE MANAGEMENT OF PREGNANT WOMEN WITH EPILEPSY

• Preconception counselling of patient about risks of teratogenesis andpossible adverse effects of uncontrolled seizures to maternal healthand pregnancy

• Preconception review of AEDs; aim for minimal effectivemonotherapy if active epilepsy; consider drug withdrawal if seizure-free

• Commence folic acid supplements preconception• Screen for malformations

• Monitor condition and AED concentrations through pregnancy (referto section 9.1.5)

• Vitamin K1 in last month of pregnancy, or for neonate

• Reassure patient that >90% pregnancies proceed with no problem inwomen with epilepsy



55

9.1.10 Bone health

Women are more likely than men to develop bone health abnormalities,including osteopenia, osteoporosis and osteomalacia, from the hepatic enzyme

inducing AEDs (namely phenytoin, carbamazepine, and phenobarbitone) as wellas sodium valproate. All patients who have been taking these drugs for morethan 5 years should be subjected to a bone densitometry, and treated withcalcium and vitamin D supplementation as necessary. Weight-bearing exercises,adequate sunlight exposure, cessation of smoking, and avoidance of caffeineshould be encouraged. Early treatment of metabolic bone disease will reducemorbidity and mortality from long bone fractures.

9.2 Epilepsy in children

Most epilepsies begin in childhood, usually before 15 years of age. It is importantto make the correct diagnosis and syndromic classification, for appropriatecounselling and treatment. There are many paroxysmal events, with and withoutaltered consciousness, that mimic seizures (chapter 3). Care should be taken toavoid misdiagnosis, resulting in the child being mislabelled as "epileptic" andsubjected to unnecessary treatment.

Neonatal seizures are often either under- or over-diagnosed. Generalised tonicclonic seizures do not occur in neonates, and most seizures are fragmented and

subtle. Conversely, not all movements are seizures. Simultaneous video-EEGrecording of these events might resolve some of this difficulty, but there is stillthe issue of "electroclinical dissociation". The aetiologies are varied and may bedetermined by a careful history of the age of onset, preceding antenatal andintrapartum events, family history and physical examination. If the history is notsuggestive of perinatal asphyxia, an initial screen (blood glucose, electrolytes,calcium, magnesium and acid-base balance, cranial ultrasound and basic work-up for sepsis and cerebrospinal fluid analysis) should be done, followed by morespecific investigations for metabolic disorders and underlying brainmalformations. Treatment is targeted at correcting the underlying electrolyte

disturbance, metabolic disorder or infection, but AEDs should be used if theseizures are recurrent. Phenobarbitone and phenytoin are the first line AEDs,mainly because the pharmacokinetics of other drugs has not been worked out inthe neonate. Large doses of BDZ should be used with caution in very prematureinfants or those with severe unconjugated jaundice as bilirubin can be displacedfrom its binding site. A trial of pyridoxine (and perhaps folinic acid) is warrantedif seizures are resistant to standard AEDs. The long term prognosis depends



56

more on the underlying aetiology than the severity of the seizures during theneonatal period itself.

Rapid growth in the preschool age has important effects on the doserequirements and drug metabolism, and recommended doses based on weight

are often 2-4 times higher than adults. Some AEDs have specific adverse effectsin children that are not common in adults. Phenobarbitone is known to causehyperactive behaviour. Acute fatal liver failure has been reported with the use ofsodium valproate in infants who have developmental delay and are on multipleAEDs; this appears to be related more to an undiagnosed inborn error ofmetabolism than to the direct effect of the drug itself. The incidence of rasheswith the use of lamotrigine is higher in children than adults, and appears relatedto the rate at which the drug is escalated, especially with concomitant sodiumvalproate therapy.

Generally, children tend to outgrow their seizures. However, there are someintractable epilepsy syndromes that begin in childhood and carry a poorprognosis. Hence, in most epilepsies, the arbitrary period for AED therapy isuntil the patient has been seizure free for two years. The EEG tends to be moreuseful in predicting recurrence of seizures than in adults.

Parent and patient education is a vital but often neglected aspect of management.Once the diagnosis of epilepsy is made, an explanation of what epilepsy andseizures are, the inheritance (if any), and prognosis is necessary. Treatmentconsiderations (purpose and objectives, compliance and dosing schedule,

possible adverse effects, concurrent use with other medication like antipyreticsand antibiotics) are discussed, and the care-giver given specific guidance on thetreatment of prolonged seizures (rectal diazepam) and intercurrent illnesses insituations where the seizures are exacerbated during febrile illnesses.

Uncontrolled seizures with onset in early childhood are associated with a higherincidence of mental retardation, learning difficulties and behavioural problems.While it is likely that uncontrolled seizures contribute to intellectual impairment,very often it is the underlying brain pathology that leads to both mentalretardation and epilepsy. The additional problems of polypharmacy (producingincreased side effects), pseudoseizures, and non-epileptic episodic movements(e.g. Sandifer's syndrome) often complicate the picture.

Schooling and leisure activities also need to be discussed. The need for goodcommunication between the school teacher, family and doctor cannot beoveremphasised. Teachers need specific instructions on the measures that needto be taken when the child has a seizure at school. Teacher and peer groupacceptance are crucial for the child's self esteem. There is a tendency to



57

"overprotect" the child with epilepsy, and appropriate advice on the type ofphysical activities that the child can participate is needed. Epilepsy mayadversely affect family relationships and lead to further psychosocialdisturbances. Proper counselling and advice for both child and family goes along way towards improving the quality of life in these children.

9.3 Epilepsy in the elderly The prevalence of active epilepsy in those >70 years is 1.5% as compared to 0.5%for the general population. The principal causes of epilepsy among the elderlyinclude cerebrovascular disease (30-40%), degenerative diseases of the CNS(10%), and tumours (10%); a large proportion of cases remain cryptogenic (30-40%). Generalised convulsions and complex partial seizures are the main clinical

manifestations of the seizures in the elderly. Unlike the complex partial seizuresseen in younger patients, the epileptic focus in the elderly more often involvesthe parietal and frontal lobes rather than the temporal lobe. Thus, orofacial andlimb automatisms, olfactory hallucinations, and déjà vu are less common amongthe elderly. On the other hand, altered cognition, periods of staring andunresponsiveness, blackouts, and “dizziness” are common presentations. Post-ictal confusion may be quite prolonged. Tonic posturing may be interpreted asparalysis, and thus mistaken for a TIA. The EEG changes are often non-specific.Thus, differentiation from cardiac syncope may be difficult. As far as treatment isconcerned, one should note the many differences in pharmacodynamics, which

are common in the elderly. Most AEDs are metabolised by the liver and excretedby the kidney. As hepatic and renal functions diminish with age, the requiredtotal dose of AED may be lower. Drug interactions are also more importantamong the elderly, as the elderly often take many other medications. Forexample, aspirin may compete with phenytoin and valproic acid for protein-binding and cause toxicity. It is thus not surprising that the elderly haveincreased side effects to AEDs. Nevertheless, elderly patients with epilepsy oftenhave a good response to AED treatment.



58

10. CONCLUSION

The management of epilepsy is a rapidly evolving area of neurology. Whereaspreviously, initial AED therapy was based on personal preference andavailability, treatment must now be tailored to the individual patient. The choice

of AED will depend on several factors; most importantly, the epilepsy syndromeand psychosocial factors. The attending physician must be able to differentiateepileptic seizures from other paroxysmal events that may mimic an epilepticattack, and understand that the patient’s seizure is only one of several possiblemanifestations or symptoms of the entire epilepsy syndrome. An individualpatient may have several seizure types, but only one epilepsy syndrome. Correctdiagnosis of the epilepsy syndrome will guide the physician to selectinvestigations judiciously. Not all patients, for instance, require a brain scan, andnot all patients are amenable to epilepsy surgery.

The mode of action of most of the newer AEDs is poorly understood, but thesedrugs have proven efficacy in large randomised trials, albeit as add-on therapyin refractory cases. As this guidelines is being prepared and published, the newerAEDs are being tested in large monotherapy trials, which may change the orderin which we choose AEDs for a particular epilepsy syndrome in the future.Greater efficacy in comparison with the older AEDs is unlikely to be the reasonfor the change in clinical practice, but rather the better safety and tolerabilityprofile of the newer AEDs. Long-term, non-pharmacological issues, includingdriving, employment, pregnancy, and education must feature prominently in thephysician’s management plan. He or she must also be sensitive to the special

needs of children and the elderly. In cases where AEDs fail to control theseizures, or when the side effects are intolerable despite good seizure control,epilepsy surgery may be an option. Epilepsy surgery should be considered earlyin patients where the MRI-identified lesion per se may be lethal (e.g. a vascularmalformation, or a brain tumour with malignant potential). The presurgicalevaluation of a patient is the single most important pre-requisite of epilepsysurgery. In this regard, the neurologist may be viewed as the architect, and theneurosurgeon the contractor. The onus is on the neurologist to ensure that theepileptogenic zone is correctly identified, and that the operation produces a goodseizure as well as neurological outcome.

The number of cryptogenic cases of epilepsy will continue to decline as thequality of neuroimaging improves and our knowledge about the genetics ofseizure generation expands. Pharmacogenomics in the future may allow us toidentify the AED that has the greatest efficacy and least side effects for anindividual patient.



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Appendix 1: Counselling checklist

The diagnosis

Does the patient/care-giver know/understand:

• that the diagnosis is epilepsy?

• what epilepsy is?• what the seizures are like ?

The medication

Does the patient/care-giver know:

• the purpose of the medication?

• the importance of compliance?

• about possible side effects?

• about drug interactions e.g. with oral contraceptive pills?

• the dose of the AED?

Life-style

Has guidance been given on:

• leading an active and independence life?

• regular and sufficient sleep?

• safety at home (e.g. fires, bathing, stairs, cooking)?

• safety/risk for sport and recreation (e.g. swimming, cycling, riding)?

• informing schools, employers, insurance companies, etc?

Parenthood

Has advice been given on:

• fertility, pregnancy and parenthood?

• the importance of pregnancy planning (e.g. reviewing medication and seizurecontrol)?

Ongoing dialogue

Has the parent/care-giver been encouraged to:• ask questions during clinic follow-up?

consensus epilepsy

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