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Neurology in Practice

THE BARE ESSENTIALS

Epilepsy
P E Smith

c An appendix containing a The diagnosis and management of epilepsy c No ‘‘trial of treatment’’. Epilepsy diagnosis is
seizure recurrence formula is involves many disciplines, especially neurology, often difficult, but tablets are not an easy
published online only at http:// psychiatry, learning disability, general practice, option; being prescribed AEDs imprints a
pn.bmj.com/content/vol8/issue3
paediatrics, geriatrics, emergency medicine and diagnostic label and is seldom diagnostically
cardiology. A major challenge is to coordinate all helpful.
the currently provided services. c Overdiagnosis. Epilepsy is often over-diag-
Correspondence to:
Professor P E Smith, The Welsh nosed and AEDs given unnecessarily. Blackout
Epilepsy Unit, University Hospital diagnosis relies on careful history taking and is,
of Wales, Heath Park, Cardiff EPIDEMIOLOGY therefore, labour intensive; no costly machin-
CF14 4XW, UK; SmithPE@ Epilepsy incidence is 5 per 10 000 per year. Among ery replaces quality time with an experienced
cardiff.ac.uk patients with suspected ‘‘first seizures’’, most have clinician.
syncope, many others have provoked seizures,
especially by alcohol.
Epilepsy prevalence is 7.5 per 1000. Among those
prescribed antiepileptic drugs (AEDs) for recurrent DIFFERENTIAL DIAGNOSIS
episodes, 20% do not have epilepsy, most often The core business of epilepsy clinicians is distin-
psychogenic non-epileptic attacks. guishing seizure, syncope, and psychogenic
attacks; other causes are far less common.
Epilepsy is suggested by stereotyped, unprovoked
DIFFERENCES FROM OTHER CHRONIC events, either without warning or with a char-
CONDITIONS acteristically ‘‘indescribable’’ aura, events with
c Public misconceptions. Seizures seen by lay automatisms, posturing, convulsions, lateral ton-
people, in life or on screen, are often the gue biting and post-ictal confusion—for example,
frequent seizures of the severely learning waking up in an ambulance.
disabled (reinforcing a stereotype), or psycho-
genic (reinforcing ideas of seizures provoked by
Syncope
emotion), or provoked by flashing lights (not
common), or with associated aggression (rare). c Vasovagal syncope is suggested by the situa-
c Low profile. People with epilepsy often under- tion (bathroom, restaurant, aeroplane, etc),
achieve having missed education and career prodrome (hot, prickly, nauseated, visual dar-
opportunities, making them poorly placed to kening, pallor), brief unconsciousness (with or
advocate for better services. Those who could without uncoordinated jerks) and subsequent
make a difference—for example, celebrities in rapid orientation but prolonged fatigue. Cough
the public eye—almost invariably conceal their and micturition syncope are variants. Several
condition. features may mimic seizures (myoclonic jerks,
head turning, automatisms, incontinence).
c Intermittent disorder. Epilepsy is a back-
ground threat rather than an obvious disability c Cardiac syncope is suggested by cardiac
with any stigma deriving more from concern symptoms, abnormal ECG, abrupt unprovoked
about having seizures (felt stigma) than actu- collapse, brief unconsciousness, and rapid
ally having them (enacted stigma). recovery.
c All ages. Epilepsy affects neonates to the c Others include orthostatic syncope (auto-
elderly, and generally is long-term; its cumula- nomic failure, elderly, anti-parkinsonian medi-
tive lifetime prevalence and morbidity is far cations), and carotid sinus syncope (elderly).
greater than comparably prevalent adult-onset
chronic neurological disorders such as stroke or
multiple sclerosis. Psychogenic episodes
c Many conditions. There are many causes and c Panic attacks are suggested by the circum-
types of epilepsy and many more conditions stances (for example, shops, crowds, in bed but
that resemble epilepsy, so the diagnosis of not asleep), slow build up with increasing
‘‘blackouts’’ requires a broad clinical perspec- anxiety, breathlessness, tingling, blurred vision,
tive. long duration and tearfulness.
c No test. There is no one test for epilepsy, c Dissociative convulsions (pseudoseizures)
despite the public’s and many clinicians’ often may begin as panic, before a prolonged (many
misplaced faith in the EEG, and no test for minutes) convulsion, with much movement
seizure control (unlike diabetes and HbA1c). (pushing, flailing), closed eyes and mouth,

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Neurology in Practice

resisting eye opening or eye contact, rapid c Skin - tuberous sclerosis, café au lait patches,
breathing or breath holding in inspiration, and haemangioma, craniotomy scar, and wrists
tearfulness. Features previously considered (previous self-harm).
exclusively non-organic—for example, pelvic c Cardiovascular examination can be more
thrusting and bicycling—can occur in frontal important than neurological examination—for
lobe seizures. example, irregular pulse.
c Neurological examination should include
visual fields (for example, upper homonymous
Other causes quadrantanopia in temporal lobe tumours),
c Parasomnias resemble frontal lobe seizures, fundi, and search for lateralising signs. In new
but usually with single rather than multiple onset focal epilepsy it is worth identifying
events, and occurring earlier in the night rather hemi-smallness (by comparing thumbnail sizes
than later. for subclinical hemiparetic cerebral palsy) and
c Migraine can cause loss of consciousness, but cranial bruit (for intracranial vascular malfor-
usually gradual onset with typical migraine mation).
symptoms. c Seeing seizures greatly facilitates their correct
c Hypoglycaemia, though rare, should always diagnosis. Patients or carers might make video
be considered, especially sleep-related episodes, (or mobile phone) recordings of the events.
before meals or after exercise, those associated
with abnormal behaviour and AED-unrespon-
siveness, and in diabetics on blood glucose CLASSIFICATION
lowering drugs. Seizures and epilepsy are classified according to the
1989 Commission on Classification and Termino-
logy of the International League Against Epilepsy
CLINICAL FEATURES (6).
History taking
c Adequate time is crucial; there is no short cut. Seizure classification
c Witness account is ideal, despite clinician Seizures are categorised as generalised, focal or
inconvenience—for example, telephoning from unclassified on clinical and EEG grounds. Complex
clinic. partial (loss of awareness) and simple partial
c Previous notes and investigations (contem- (retained awareness) are terms still used despite
poraneous history, EEG before medication) are the overlap in ictal retention of consciousness.
essential, even if troublesome to obtain.
c Direct questions for other events may Secondarily generalised tonic-clonic seizures
identify myoclonus or minor seizures, or hint Most generalised convulsions starting in adulthood
at sleep-related events (blood on pillow, bitten are secondarily generalised. Convulsions in sleep
tongue). are usually secondarily generalised, whereas con-
c Medications - those that are epileptogenic vulsions on awakening are typically primary
(tramadol, neuroleptics) or syncope-inducing generalised.
(vasodilators causing postural hypotension;
drugs provoking long QT, see http://www.
Temporal lobe seizures
torsade.org).
c Slow head turn at onset suggests an ipsilateral
c Previous history - early life events (gestation,
focus (head turns towards seizure focus);
birth history and weight, incubator, febrile
subsequent forced head turning is contralateral
seizures, cerebral infection or significant head
(adversive, away from seizure focus).
injury) and psychiatric problems (depression,
panic disorder, overdose, self-harm). c Automatisms (fidgeting, picking) characteris-
tically are ipsilateral to the seizure focus;
c Family history of fits, faints or blackouts, but
also (in view of cardiac mimics) of sudden or dystonic limb posturing is contralateral.
young deaths. c Nose wiping towards seizure end is character-
c Lifestyle issues - driving, alcohol, relation- istically mesial temporal, but non-lateralising.
ships, education, occupation, leisure, preg- c Ictal spitting, vomiting, coughing, and
nancy, contraception, etc. peri-ictal water drinking all suggest non-
dominant temporal involvement.
c Unilateral eye blinking is rare, but suggests
Examination an ipsilateral medial temporal focus.
Notwithstanding neurological tradition, the phy- c The final limb jerk in a secondary generalised
sical examination adds little in patients with seizure is characteristically ipsilateral.
blackouts; its greatest value is in offering opportu-
nity for additional history away from parents/
carers (if in a separate cubicle) and for reassuring Frontal lobe seizures
patients of the clinician’s thoroughness. However, The frontal lobe’s large size is reflected in the
productive areas are: breadth of its seizure types:

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Neurology in Practice

c Jacksonian seizures show a ‘‘march’’ of limb Symptomatic focal epilepsies


jerking, often spreading from the thumb, c Hippocampal (mesial temporal) sclerosis is
occasionally with post-ictal transient focal the commonest cause of adult epilepsy. The
weakness (Todd’s phenomenon). typical history is of an early life cerebral
c Adversive seizures—forced head and eye insult—for example, prolonged focal febrile
turning away from the seizure focus, with seizure, a latent interval of sometimes many
arm jerking or elevation (‘‘fencing’’) contral- years, then onset of complex partial seizures
ateral to the focus. characteristically with epigastric aura.
c Supplementary motor area seizures are c Other symptomatic focal epilepsy causes
characteristically brief (,30 seconds), fre- include head injury (typically frontal and
quently from sleep, often with retained con- temporal lobe involvement), tumours (espe-
sciousness, and with ‘‘hypermotor’’ cially low-grade tumours involving cortex,
phenomena—for example, running, punching, causing treatment-resistant, frequent simple
shouting, cycling. The surface ictal EEG may partial seizures), cortical dysplasias (ranging
even be unchanged, reflecting the deep midline from minor focal areas with normal intellect to
seizure onset. The combination of bizarre generalised cortical abnormality with severe
behaviour and normal ictal EEG risk their intellectual disability), arteriovenous malfor-
mislabelling as psychogenic. mations and cavernous malformations.
c Speech arrest or dysphasia suggests domi-
nant hemisphere involvement; clear ictal
speech is more likely non-dominant. Idiopathic focal epilepsies
c Benign epilepsies of childhood are easily
treated and often self-remitting—for example,
Occipital lobe seizures
benign childhood epilepsy with centrotemporal
Occipital seizures present with contralateral visual
spikes, benign occipital epilepsy.
hallucinations—for example, lights or colours, but
with ipsilateral eye deviation to the side of the c Monogenic focal epilepsies are increasingly
recognised—for example, autosomal dominant
focus. There is clinical overlap with migraine.
nocturnal frontal lobe epilepsy, and familial
temporal lobe epilepsy with variable phenotype
Parietal lobe seizures severity.
Parietal seizures are rare and characterised by
lateralised positive sensory disturbance—for exam-
ple, tingling or pain contralateral to the focus. Symptomatic and cryptogenic generalised epilepsies
These include the severe childhood onset epilepsies
Epilepsy classification and syndromes typically associated with intellectual disability—
Epilepsy classification is commonly overlooked but for example, Lennox-Gastaut syndrome, myoclonic
important for management and prognosis, and astatic epilepsy.
depends on two characteristics.

c Site of seizure onset determines an epilepsy INVESTIGATIONS


as being either generalised, focal (a simpler term All new onset unprovoked seizures must be
than localisation-related) or unclassified. investigated: the adage that everyone is allowed
c Presumed aetiology is symptomatic (a known one seizure is nonsense and potentially dangerous.
structural cause), probable symptomatic (or
cryptogenic, where a structural cause is pre- Brain imaging
sumed but cannot be identified), or idiopathic This is indicated for all new-onset unprovoked
(implying more than ‘‘unknown cause’’, but
seizures in adults.
rather a presumed genetic cause with age-
specific seizure onset and offset, normal brain c Computed tomography is more available
imaging, and an expected good AED response). than MR, making it sometimes the appropriate
initial investigation.
c Magnetic resonance imaging is the modality
Idiopathic generalised epilepsies of choice, being more sensitive than CT to
c Juvenile myoclonic epilepsy. Morning myo- structural causes of epilepsy—for example,
clonus, generalised tonic-clonic seizures on hippocampal sclerosis, cortical malformations,
awakening, sometimes absences and photosen- and benign cortical tumours (ganglioglioma
sitivity—all more likely following sleep depri- and dysembryoplastic neuroepithelial tumour,
vation. Typically begins in adolescence but, etc). Hippocampal volume loss is more impor-
despite its name, the epilepsy tendency tends tant than signal change; there may be asso-
to persist lifelong. The EEG usually contains ciated volume loss in the ipsilateral temporal
inter-ictal generalised polyspike-and-wave. lobe and fornix. Not all MR scans are equal:
c Other syndromes include juvenile absence adequate epilepsy imaging requires a standard
epilepsy, generalised tonic-clonic seizures on detailed protocol, with reporting by a neuror-
awakening, and eyelid myoclonia with adiologist. Current best practice is for MR
absences. imaging in all adult-onset epilepsy, apart from

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Neurology in Practice

those with clinically definite idiopathic general- c Choosing AEDs. All available AEDs are
ised epilepsy. potentially effective for focal epilepsies;
c Functional imaging (functional MR, MR although most AEDs can control generalised
spectroscopy, magnetoencephalography) adds tonic-clonic seizures, some (for example, carba-
additional information, potentially identifying mazepine) may actually worsen myoclonus
resectable focal abnormalities in MR-negative and absences: the choice for idiopathic general-
patients. MR tractography can map the visual ised epilepsy is therefore more limited. The
pathway facilitating safer surgical resection. SANAD study suggested lamotrigine as the
first choice for focal epilepsy and valproic acid
the first choice for generalised epilepsy.
Electroencephalography c Sex differences in AED adverse effects mean
c Standard inter-ictal EEG may indirectly different choices for men and women—for
indicate an epilepsy tendency; however, it is example, oral contraceptives and pregnancy
an adjunct to diagnosis, not to be relied upon (see below).
alone. It is more useful in children and c Monotherapy is preferred, starting with
adolescents than adults. The first EEG before established medications (for example, carba-
starting treatment is usually the most valuable mazepine, lamotrigine or valproate) then
and worth tracking down. Videotaping during sequential monotherapy should the first choice
all EEG recordings enhances their value should fail. The first monotherapy gives seizure free-
any events occur. EEG sensitivity is enhanced dom in 47%, the second in a further 13% and
by longer recordings (time consuming and the third in a further 4%; thus the first
expensive), arranging it within 72 h of events monotherapy response predicts the overall
(requiring rapid access), and following sleep outcome.
deprivation (increased seizure risk). c Randomised controlled trials evidence does
c Prolonged video EEG capturing actual sei- not easily translate into clinical practice. Their
zures is the gold standard, but even then some main aim is licensing, so they are short-term,
epilepsies with deep-seated foci have an mostly using polytherapy in resistant epilepsy,
unchanged surface EEG during attacks. often with doses higher than those used
subsequently in clinical practice. The relevance
to individuals of 50% seizure reduction as
Electrocardiography the principal outcome measure is also ques-
This is indicated for all undiagnosed blackouts, for tionable.
all syncope presenting to neurologists, and resis- c Adverse effects. Short-term problems are well
tant epilepsy, especially where imaging and/or EEG documented from clinical trials: almost all
are normal. Neurologists should learn to assess AEDs potentially cause sedation. Longer-term
ECGs systematically, measure the QTc interval, adverse effects may emerge only after years; the
and recognise the ECG patterns of rare but nine years to recognise that over half taking
potentially fatal and often familial, cardiac dis- vigabatrin developed permanent visual field
orders, such as long QT syndromes and hyper- defects justifies caution in judging the long-
trophic cardiomyopathy. term safety of all new drugs.
c Drug interactions. Although interactions
MANAGEMENT with other AEDs, warfarin or digoxin present
Epilepsy management aims at seizure freedom difficulties, the most important interaction in
without adverse drug effects which is realistic adult practice is with the contraceptive pill,
and achievable in most cases. People with epilepsy especially as failure exposes potential terato-
need long-term follow-up, maybe in primary care, genicity. Enzyme inducers (for example, carba-
but even those seizure free and coping with mazepine, phenytoin and phenobarbital)
clearly interact and require additional contra-
medication deserve regular specialist contact. In
ceptive precautions. Others interact only at
practice, few adults are suitable for permanent
higher doses—for example, topiramate, lamo-
discharge from secondary care; some arrangements
trigine and possibly zonisamide. Nonetheless,
for contact with specialist services—for example,
caution is required as initial pharmaceutical
telephone, email—would be ideal.
company reassurance is sometimes later super-
seded.
Antiepileptic drugs (AEDs) (see table) c Rational prescribing uses known AED
c Diagnostic certainty. It is almost always mechanisms to facilitate choice and minimise
better to await a definite diagnosis rather than additive adverse effects. Rational polytherapy
to start perhaps a lifetime of medication avoids combinations with similar mechanisms
without diagnostic certainty. (for example, carbamazepine with lamotri-
c Is any AED necessary? AEDs are usually not gine); rational monotherapy uses sequential
recommended following a first seizure. AEDs with differing mechanisms.
c Long-term treatment. The decision to pre- c Once or twice daily prescription is possible
scribe AEDs is major and long-term, and taken for all AEDs (except gabapentin) and clearly
jointly by patient and epilepsy specialist preferable; a midday dose taken to school or
following informed discussion. work is often forgotten and generates stigma.

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Neurology in Practice

c Brand names are more acceptable when min) and/or intubate and ventilate under
prescribing for epilepsy than elsewhere in general anaesthetic (thiopentone, midazolam
medicine, especially for slow release formula- or propofol), aiming for EEG (continuous
tions—for example, of carbamazepine. Minor monitoring) of ‘‘burst suppression’’ or deeper,
changes in formulations may alter drug avail- woken 2–4 hourly initially to check for seizure
ability with potential breakthrough seizures, remission.
and patients are understandably nervous about
changes to their drug brand and consequent
threat to livelihood. Lifestyle aspects
c Blood levels are generally unnecessary except c Partnership of care. Effective epilepsy man-
when using phenytoin. agement requires the sharing with patients of
c Free AED prescriptions apply to many verbal and written information about lifestyle
countries including the UK. and balance of risks, encouraging joint decision-
c Medication concordance with prescribed making, and facilitating patient responsibility
medication may be poor for several reasons: for epilepsy self-management. Useful patient
fear or experience of adverse effects, inadequate information sources are available at Epilepsy
understanding of the indications, complacency Action (http://www.epilepsy.org) and
after seizure freedom, rebellion against author- National Society of Epilepsy (http://www.
ity, decisions to conceive, etc. epilepsynse.org).
c Withdrawing AEDs in children is relatively c Challenge assumptions. Both patients and
straightforward, usually when two years sei- clinicians may accept inadequate control or
zure free; several age-specific syndromes of AED adverse effects, yet the range of available
childhood allow a reasonable chance of success. treatments suggests that often more can be
It is more difficult for adults with considerable done.
pressure to remain seizure-free (retaining driv- c Lifestyle restrictions. ‘‘You can do every-
ing privileges, employment, freedom from thing you did before, except drive’’ overstates
stigma, social status, etc). Thus adults com- the position, but emphasises that everything
monly remain on AEDs, even when many years except driving is negotiable, given an apprecia-
seizure-free. The recurrence risk following AED tion and understanding of the balance of risks.
withdrawal, derived from randomised con-
trolled trials, can help patients in decision- c Driving. Eligibility rules vary throughout the
making. See seizure recurrence formula online. world, placing differing responsibilities on clin-
icians. The UK ordinary (Group 1) driving licence
currently requires one-year freedom from all
seizures, no matter how minor, or an established
Tonic-clonic status epilepticus pattern of sleep-related seizures only for three
Status epilepticus—seizures for .30 min without years or more. Group 2 drivers (heavy goods and
consciousness recovering in between—is an passenger vehicles) must be seizure-free and off
uncommon medical emergency. However, tonic- all AEDs for 10 years before eligible to drive.
clonic seizures lasting .5 min (status in evolution) Group 1 entitlement is based on a less than 20%
are common (5% of patients), justifying urgent annual seizure recurrence risk; Group 2 on a less
intervention to prevent secondary neurological than 2% annual risk.
damage. c Pregnancy, now or later, dominates the AED
prescribing decision in women. The UK epi-
Management lepsy and pregnancy register (fig) provides
Check blood glucose immediately (also biochem- useful guidance on major malformation rates
istry, toxicology, AED levels) but generally do not with common AEDs but the data are observa-
delay treatment for the results. At each stage, tional rather than randomised, acquired only
consider ‘‘status pseudoepilepticus’’ (almost 50% through pregnancy despite advice or by mis-
of apparent status admitted to adult intensive take; there is very limited information on the
care). newer AEDs; valproate may have been selected
for certain epilepsies, the genetic basis of
c Immediate. ABC (airway, breathing, circula- idiopathic epilepsies giving possible greater fetal
tion), intravenous thiamine 100 mg (alcohol- abnormality risk; taking valproate in pregnancy
ism suspected) or intravenous 50% glucose sometimes reflects poor access to or interest in
(hypoglycaemia identified). optimal antenatal care; and pregnancy registers
c Early (1–10 min). mostly do not address concerns about valproate
– Community: buccal midazolam 0.2–0.4 mg/kg. or other AEDs causing neuro-developmental
delay.
– Hospital: intravenous lorazepam 0.1 mg/kg
repeated if necessary at two min. c Regular sleep pattern is an important part of
self-management, especially in idiopathic gen-
c Established (5–30 min). Intravenous pheny- eralised epilepsies.
toin infusion (15–20 mg/kg over 20–30 min) c Alcohol in moderation is fine—for example, 2–
with cardiac monitoring. 4 units in 24 h. Some alcohol consumption is
c Refractory (30–90 min) in intensive care unit. important for social participation in teenagers.
Intravenous phenobarbital (20 mg/kg, 100 mg/ Although alcohol is in theory anti-epileptic,

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Table 1 The major antiepileptic drugs


Drug Mechanisms and kinetics Prescribing Adverse effects Interactions

Carbamazepine c Stabilises voltage-gated c Partial-onset and generalised tonic clonic c Dose-related. Tiredness, c Effect on others: lowers warfarin, steroids
sodium channels seizures (not absence or myoclonus) dizziness, unsteadiness, (including the contraceptive pill),
c Strongly protein bound, c Start 100 mg daily, maintenance 400– diplopia lamotrigine, phenytoin, phenobarbital.
highly lipid soluble, liver 1600 mg c Idiosyncratic. Rash (5%), Increases carbamazepine epoxide, giving
metabolised (active c Frequency: 26 daily; 36 daily at .800 mg neutropenia, inappropriate toxic symptoms
metabolite 10,11-epoxide) (half-life 5–26 h) antidiuretic hormone c Effect of others: reduced by phenytoin,
c Slow release preparations preferred to secretion phenobarbital; increased by erythromycin,
minimise adverse effects and allow twice- c Teratogenicity. Spina bifida dextropropoxyphene. Alcohol disrupts
daily prescription rate increased but carbamazepine metabolism
c In elderly on diuretics check electrolytes reasonably safe (fig)
before prescribing. If seizures persist despite
carbamazepine, check serum sodium
Gabapentin c Unknown mechanism: c Partial-onset and secondarily generalised c Dose-related. Drowsiness, c Nil
despite the name, not seizures dizziness, headache, tremor
GABAergic c Start 300 mg daily, maintenance 900– c Idiosyncratic. Weight gain
c Not protein bound; 80% 3600 mg (36 daily: half-life 5–7 h) c Teratogenicity. Insufficient
renally excreted unchanged human data
Lamotrigine c Stabilises voltage- c Partial-onset seizures and generalised c Dose-related. Drowsiness, c Effect on others. Increases carbamazepine
dependent sodium channels tonic-clonic seizures, some benefit to headache, diplopia. epoxide (dizziness, diplopia). Lowers
c 50% protein bound; liver generalised absences c Idiosyncratic. Rash (10%) contraceptive pill level (uncertain
metabolised – Monotherapy. Start 25 mg daily sometimes severe in mechanism)
(introduce slowly avoiding rash), children (Stevens-Johnson c Effect of others. Valproate inhibits
maintenance 200–600 mg. syndrome), especially with lamotrigine’s metabolism, halving its
– Adding lamotrigine to valproate, valproate necessary dose. Contraceptive pill lowers
start 25 mg alternate days, c Teratogenicity. Major lamotrigine levels
maintenance 100–150 mg. malformations low risk (fig),
– Adding lamotrigine to enzyme but dose-related. May
inducers, start 50 mg daily, include oral clefts
maintenance 300–600 mg.
c Frequency: 1–26 daily (half-life 12–60 h)

Levetiracetam c Binds to SV2A synaptic c Partial-onset and generalised tonic-clonic c Dose related. Tiredness, c Nil known
vesicle protein seizures, myoclonus and possibly absences mood change
c Not protein bound; not c Start 250 mg daily; maintenance 750– c Idiosyncratic. Weight loss
liver metabolised; renally 4000 mg c Teratogenicity. Insufficient
excreted largely c Frequency: 1–26 daily (half life 6–8 h) data; preliminary data
unchanged encouraging
Oxcarbazepine c Stabilises voltage- c Partial-onset and generalised tonic-clonic c Dose-related. Tiredness. c Effect on others. Lowers contraceptive pill
dependent sodium seizures c Idiosyncratic. Rash, level
channels (keto-analogue c Maintenance 900–2400 mg daily hyponatraemia, especially c Effect of others. Nil major
of carbamazepine) c Frequency: 26 daily (half-life 8–10 h). elderly or on diuretics
c 40% protein bound, liver c Elderly on diuretics, check electrolytes c Teratogenicity. Insufficient
metabolised to 10- beforehand. Seizures persisting despite human data
monohydroxy- oxcarbazepine, check serum sodium
oxcarbazepine
(pharmacologically active)
Phenobarbital c Enhances GABA c Partial-onset and generalised seizures, c Dose related. Drowsiness, c Effect on others. Reduces other liver-
transmission and probably including absences cognition, behaviour metabolised drugs, including contraceptive
stabilises voltage- c Start 60 mg daily, maintenance 60–180 mg changes in up to 50% pill.
dependent sodium daily (1–26 daily: half-life 60 h) c Idiosyncratic. Reduced c Effect of others. Valproate induces excess
channels c Withdraw only slowly: no faster than 25% bone mineral density sedation.
c 50% protein bound and every 6 weeks c Teratogenicity. Insufficient
liver metabolised human data despite
extensive use
Phenytoin c Stabilises voltage- c Partial-onset and generalised tonic-clonic c Dose-related: unsteadiness, c Effect on others. Enzyme induction lowers
dependent sodium channels seizures. Also, with rapid effect, cerebellar ataxia, many medications—for example,
c 90% protein bound; liver intravenously for acute symptomatic nystagmus, involuntary carbamazepine, lamotrigine, oral
metabolised with seizures and status epilepticus movements contraceptive pill
‘‘saturation’’ kinetics c Start 200 mg daily; maintenance 200– c Idiosyncratic. Rashes, c Effect of others
500 mg lymphadenopathy, cosmetic – Liver metabolised drugs (for
c Frequency: 1–26 daily (half-life 7–42 h). (coarsened features, gum example, isoniazid, rifampicin,
Emergency loading, eg, status, 20 mg/kg by hypertrophy, hirsutism, carbamazepine) impairing phenytoin
slow infusion (filtered and under ECG acne), folate and vitamin D metabolism increasing its levels
control) deficiency (osteomalacia: – Protein-bound drugs (for example,
c Blood levels needed because of difficult check bone density in aspirin, valproate) displace
kinetics (therapeutic range 40–80 mmol/l elderly on long-term phenytoin from protein binding sites,
(10–20 mg/ml)). Adjust in 25–50 mg steps phenytoin), cerebellar lowering its total levels
according to response, adverse effects or ataxia, peripheral – Enzyme inhibitors (for example,
blood levels neuropathy valproate) increase phenytoin blood
c Teratogenicity. Despite levels (note valproate’s opposite
teratogenic potential, effects: no net therapeutic effect)
relatively low risk in
monotherapy (fig)
Continued

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Table 1 Continued
Drug Mechanisms and kinetics Prescribing Adverse effects Interactions

Pregabalin c Binds to voltage-gated c Partial-onset and generalised tonic-clonic c Dose related. Somnolence, c Nil
calcium channels; reduces seizures dizziness, ataxia
glutamate release c Dose. Start 150 mg daily; maintenance c Idiosyncratic. Weight gain.
c Not protein bound; no liver 150–600 mg c Teratogenicity. Insufficient
metabolism c Frequency: 1–26 daily (half-life 6 h) human data
Tiagabine c Inhibits neuronal GABA c Partial-onset seizures, generalised tonic- c Dose-related. Dizziness, c Effect on others. Nil significant
uptake clonic seizures sedation, headache c Effect of others. Enzyme-inducers (for
c 95% protein bound; liver c Monotherapy: start 15 mg daily; c Teratogenicity. Insufficient example, carbamazepine) accelerate its
metabolised maintenance 30–45 mg (with enzyme human data metabolism, reducing half-life to 2–3 h
inducers, up to 60 mg)
c Frequency: 26 daily (half-life 5–9 h); 36
daily with enzyme-inducers (half-life 3 h)
Topiramate c Blocks voltage-gated c Partial-onset and generalised tonic-clonic c Dose-related. Sleepiness, c Effect on others. Increases contraceptive
sodium channels, AMPA seizures, absences and myoclonus slowed thought and speed pill clearance
and kainate receptors, c Start 15 mg daily, maintenance of articulation, c Effect of others. Nil significant
carbonic anhydrase; 100–600 mg paraesthesiae
enhances GABA c Frequency: 1–26 daily (half-life 19–25 h) c Idiosyncratic. Weight loss,
c 15% protein bound; liver renal calculi
metabolised c Teratogenicity. Insufficient
human data
Valproic acid c Raises GABA levels c Partial onset seizures, primary and c Dose-related: nausea, c Effect on others
(uncertain mechanism) secondarily generalised seizures (including vomiting, diarrhoea, tremor, – Enzyme inhibition elevates
c 90% protein bound, liver myoclonus and absence) irritability, poor sleep, lamotrigine (care in combination),
metabolised c Start 200–500 mg daily; maintenance confusion carbamazepine 10,11-epoxide
500–3000 mg c Idiosyncratic. Hair loss, (adverse effects at ‘‘therapeutic’’
c Frequency. 1–26 daily (half-life 12–17 h, weight gain, polycystic level), phenobarbital, and alcohol
therapeutic effect longer) ovaries, hyperammonaemia (increased sedation)
(occult urea cycle – Protein binding displacement raises
disorders), hepatotoxicity other medications’ free level (for
(especially young children example, warfarin)
with Alpers’ disease (1 in c Effect of others
50 000)) – Enzyme inducing drugs lower total
c Teratogenicity. Spina bifida valproate levels (for example,
aperta in 2% (fig); concern carbamazepine, phenytoin)
over ‘‘fetal valproate – Protein bound drugs displace and
syndrome’’ and possible increase free valproate levels (for
neuro-developmental delay example, aspirin)
Zonisamide c Blocks voltage-gated c Partial-onset, generalised tonic-clonic c Dose related. Somnolence, c Effect on others. Probably increases
sodium channels, T-type seizures, some effect in generalised seizures ataxia, dizziness contraceptive clearance
calcium currents, glutamate including progressive myoclonic epilepsy c Idiosyncratic. Rash, renal c Effect of others. Nil significant
transmission, carbonic c Dose. Start 50 mg daily; maintenance calculi, heat stroke
anhydrase 200–600 mg c Teratogenicity. Insufficient
c 50% protein bound; liver c Frequency: Once daily (half-life 49–69 h) human data
metabolised

excess alcohol lowers seizure threshold through c Folate. Despite the lack of evidence of benefit
poor sleep quality; alcohol withdrawal is a in humans, we still advise women on AEDs
common cause of provoked seizures. Valproate who may become pregnant (for example, not
inhibits alcohol metabolism, promoting intox- on the contraceptive pill) to take folate 5 mg
ication. daily.
c Flashing lights are worth mentioning to all c Disability benefit presents eligibility difficul-
epilepsy patients, because so many erroneously ties because the seizures are intermittent and
believe they must avoid them. variable. The payments are not inconsiderable

Figure 1 Major
malformation risk (mean ¡
95% confidence interval)
from the UK Epilepsy and
Pregnancy Register
(***p,0.001; *p,0.05).

2008;8:195–202. doi:10.1136/pn.2007.134031 201


Neurology in Practice

surgery itself is relatively straightforward, it


Further reading requires prolonged pre-surgical workup to establish
firstly if the lesion is definitely the epileptogenic
c National Institute for Clinical Excellence. Diagnosis and care of children and focus and, secondly, if it is safe to remove (memory
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trial. Lancet 2005;365:2007–13. c Hemispherectomy can be surprisingly bene-
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randomised controlled trial. Lancet 2007;369:1000–15. hemiplegia and refractory seizures.
c Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs c Multiple subpial transections interfere with
in pregnancy: a prospective study from the UK Epilepsy and Pregnancy horizontal transmission within the cortex
Register. J Neurol Neurosurg Psychiatry 2006;77:193–8. through multiple cortex-deep cuts to isolate
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cardiac death that every doctor should recognise. Acta Cardiologica effective as adding a new AED: 30–50% obtain
1997;6:473–84. .50% seizure reduction. Although invasive it gives
c Commission on Classification and Terminology of the International League 100% compliance without drug interactions or
Against Epilepsy, 1989. Proposal for revised classification of epilepsies and sedative effects. Adverse effects include implanta-
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from seizures. J Am Coll Cardiol 2002;40:142–8.

CONCLUSIONS
c Epilepsy is a common, complex and often
and may present a conflict of interest for many chronic condition affecting all ages.
people with epilepsy. c Diagnosis can be surprisingly challenging, and
c Sudden unexplained death in epilepsy relies not on tests but on a full and accurate
(SUDEP). Although discussing such a sensitive history.
issue is difficult, saying nothing risks patients c Management encompasses lifestyle choices,
later resenting the apparent concealment. AEDs and surgery, with special considerations
SUDEP can be discussed positively, emphasis- for certain client groups.
ing its rarity, and the possible steps in
avoidance including taking AEDs regularly, c Many people with epilepsy can now realisti-
and avoiding excess alcohol. cally expect seizure freedom without medica-
tion adverse effects.
c Genetics. Several monogenic epilepsies have
been identified but for practical purposes there c Greater clinical openness together with widely
are as yet no specific epilepsy genetic tests available information has facilitated improving
available. knowledge and awareness about epilepsy
among patients, their families and carers.
c People with epilepsy can now expect to be
Surgery better integrated into home, working and
Lesional epilepsy surgery community life, and ultimately lead fuller,
This is the removal of a clearly demonstrated more independent, and more active lives than
lesion—for example, hippocampal sclerosis, gang- previously thought possible.
lioglioma. Following hippocampal sclerosis sur- Acknowledgements: This article was reviewed by Margaret
gery, up to 80% may become seizure-free, half of Jackson, Newcastle upon Tyne, UK.
these withdrawing AEDs. The results are less good Competing interests: The author has received (since 2005) funding
for cortical dysplasia and less good again for for research, teaching and travel from Janssen-Cilag, Pfizer and UCB
patients with normal imaging. Although the Pharma.

202 2008;8:195–202. doi:10.1136/pn.2007.134031