Epilepsy is a common disorder and most adult patients will be managed primarily by general practitioners. Despite new developments in the classification and treatment of epilepsy, basic principles of diagnosis and treatment remain valid, such as the importance of an accurate, detailed history and adjusting antiepileptic drug (AED) doses on the basis of seizure control and adverse effects rather than blood test results.
This article addresses current issues in the diagnosis and management of epilepsy, including initial evaluation and use of AEDs.
Older AEDs are still prescribed commonly; newer AEDs have similar efficacy and improved tolerability. Human leuko-cyte-associated antigen (HLA) testing is recommended before commencing Asian patients on carbamazepine to minimise the risk of Stevens-Johnson syndrome (SJS). Referral to an epilepsy specialist is recommended if seizures are not controlled after trialling two AEDs. Important issues pertaining to reproductive and bone health are complex and poorly understood.
Classification of epileptic seizures and epilepsy syndromes
Older epilepsy nomenclature imbued terms such as ‘symptomatic’ and ‘complex’ with non-intuitive meanings not seen elsewhere in medical parlance.1 A revised classification replaced those terms with more meaningful and accurate terms, although the older terminology remains in common clinical usage.2
Patients most commonly seek medical attention for generalised tonic-clonic seizures (GTCS; grand mal seizures). In the initial phase of stiffening, consciousness is lost for a few seconds, causing falls, often with a forced scream (ictal cry). All-limb jerking then occurs, lasting for up to 2 minutes. Cyanosis, tongue-biting and urinary incontinence are common during these seizures. Post-ictal stertor, confusion and amnesia typically persist for several minutes.
Generalised absence seizures (petit mal seizures) are frequent (>daily), brief (<30 seconds) episodes of behavioural arrest without prominent motor features and with immediate recovery of alertness when the seizure ends. They occur in some forms of genetic generalised epilepsies (primary/idiopathic generalised epilepsies) with onset in childhood or adolescence.
Myoclonic seizures are single jerks of muscles, usually generalised, occurring during wakefulness, but otherwise similar to hypnic jerks. Specific inquiry is necessary as most patients do not recognise these as seizures.
Focal seizures are confined to one cerebral hemisphere, but may evolve to become bilateral convulsive seizures (secondary generalisation). Clinical features are myriad, spanning motor, somatosensory, autonomic, visual, auditory and experiential/psychic disturbances. In the individual patient, seizures show a high degree of stereotypy. Focal seizures without and with impairment of consciousness (simple or complex partial seizures, respectively), are often (mis)labelled by patients and doctors as petit mal seizures as distinct from grand mal seizures. Typically, focal seizures with impairment of consciousness are less frequent and more prolonged than absence seizures, and post-ictal recovery of full alertness is delayed.
Confusion between different seizure types, or between seizures and other episodes such as syncope,3 (Table 1) is minimised with careful history-taking and documentation, preferably assisted by eyewitness account and/or video recording (eg. using a smartphone). Additional history identifies provoking factors4 (Table 2) and previous, possibly unrecognised, seizures.
Table 1. Differential diagnosis of epileptic seizures
Psychogenic non-epileptic seizures
Transient ischaemic attack
After a first unprovoked epileptic seizure, the risk of another seizure is approximately 40%.5 A diagnosis of epilepsy implies demonstrated tendency for recurrent unprovoked seizures,6 thus justifying long-term use of antiepileptic drugs (AEDs). The diagnosis is often made after two unprovoked seizures (>24 hours apart) or after one seizure if EEG or neuroimaging findings indicate a genetic or structural basis for a seizure tendency.
Epilepsy remains a clinical diagnosis. Normal EEG and neuroimaging do not exclude the diagnosis; rather, abnormal findings assist in classifying the epilepsy syndrome. In structural/metabolic epilepsies, seizures are due to a structural brain lesion or metabolic disturbance; the remaining epilepsies are proven or presumed to have a genetic basis and are hence termed genetic epilepsies.2
Juvenile myoclonic epilepsy is a common, under-recognised genetic generalised epilepsy syndrome in which myoclonic seizures, GTCS and sometimes absence seizures commence around adolescence.7 Typically, excellent seizure control is achieved with low doses of some medications (eg. valproate, levetiracetam). Some other AEDs may control GTCS in this condition but can potentiate absence or myoclonic seizures. Most patients require lifelong treatment.8
Table 2. Causes of provoked epileptic seizures
|Acute neurological insult
Alcohol (and other drugs) intoxication or withdrawal
Older medications, especially carbamazepine, phenytoin and valproate, remain in common use in Australia as first-line therapy, largely because of Pharmaceutical Benefits Scheme (PBS) restrictions on newer agents. Newer medications have similar efficacy but lower incidence of adverse effects and less potential for pharmacokinetic interactions with other medications, compared with the older AEDs. All antiepileptic medications have dose-dependent, neurotoxic adverse effects, such as somnolence, cognitive impairment and ataxia, although the dose at which these emerge varies markedly between individuals. These adverse effects resolve rapidly on discontinuation.
Table 3 lists, in chronological order of development, AEDs approved for use in Australia prior to 2010 and still prescribed commonly in adults. Four AEDs have been registered more recently.
Table 3. Characteristics of AEDs approved for use in Australia prior to 2010
|Medication||Typical dose||Adverse effects of note||Other notes|
||200–400 mg od
||Hirsutism, acne, coarse facies
|Non-linear pharmacokinetics (steady-state serum concentration not proportional to dose)
||0.5–2 mg bd
|Tolerance (reduced efficacy) may develop with long-term use
||200–600 mg bd
|Available in standard-release and controlled-release formulations
Autoinduction of metabolism
||400–1000 mg bd
|Use with caution in women of childbearing age
Also used as mood stabiliser
||50–200 mg bd
||Rash/SJS (risk reduced with slow titration to target dose over ~8 weeks; refer to Product Information, Dosage and Administration)
||Lower dose requirement (approximately half) if also taking valproate
Also used as mood stabiliser
||300–800 mg tds
||100% renal excretion
||50–200 mg bd
||Anorexia, weight loss
|Also PBS approved for migraine
||300–900 mg bd
||Hyponatraemia (more frequently than with carbamazepine)
||Oxcarbazepine:carbamazepine dose equivalence approximately 1.5:1
||500–1500 mg bd
|Largely renally excreted
||75–300 mg bd
||Not PBS approved for epilepsy
100% renal excretion
|Phenobarbitone, primidone, acetazolamide, sulthiame, vigabatrin, tiagabine and ethosuximide are not often prescribed in adults. Typical doses are an approximate guide only. PBS = Pharmaceutical Benefits Scheme; SJS = Stevens-Johnson syndrome. *enzyme-inducing AEDs (although topiramate and oxcarbazepine are weaker enzyme inducers).
- Lacosamide enhances inactivation of voltage-gated sodium channels. Common adverse effects, including dizziness and ataxia, are enhanced by concomitant use of other sodium channel blockers, such as carbamazepine and phenytoin. PBS prescription requires treatment initiation by a neurologist.
- Zonisamide has effects on voltage-gated sodium and calcium channels and inhibits carbonic anhydrase. It has a long half-life (>60 hours) and is thus suitable for once daily administration. Anorexia and reduced serum bicarbonate are common; nephrolithiasis is a less common adverse effect.
- Retigabine activates voltage-gated potassium channels. A particular adverse effect is blue-grey skin discolouration and retinal pigmentation. Although registration was approved by the Therapeutic Goods Administration, it is not yet marketed in Australia.
- Clobazam has less sedative and cognitive adverse effects than other benzodiazepines.9 Registered as an anxiolytic in 1984, it has long been used off-label for epilepsy and is now registered for adjunctive treatment of paediatric epilepsy. It can be a useful ‘circuit-breaker’ for patients with seizure clusters, catamenial seizures, or for long-haul flights.
Stevens-Johnson syndrome (SJS)
This is a severe cutaneous adverse reaction seen with carbamazepine, phenytoin, phenobarbitone, primidone, zonisamide, lamotrigine and oxcarbazepine, occurring within the first 8 weeks of drug exposure.10 Initiation of lamotrigine treatment should comprise gradual dose escalation over several weeks in accordance with the product information. The safest approach is to discontinue antiepileptic medication if any rash develops within 8 weeks of commencement, and thence to avoid other causative AEDs.
In patients of Han Chinese and South-East Asian ethnicity, the presence of HLA-B*1502 allele predicts a higher risk of SJS, whereas the absence of HLA-B*1502 is protective. HLA testing is recommended before such patients commence carbamazepine, and could be considered in patients commencing other causative agents.11 In patients of Japanese and European background, there is an association between carbamazepine SJS and HLA-A*3101, but routine screening is not recommended.12
Therapeutic drug monitoring (TDM)
An appropriate dose of AED is that which controls seizures without causing significant adverse effects. Hence, from a purist perspective, optimal dosing does not require TDM. Standard assays report total drug levels rather than the more clinically relevant free fraction, and this is subject to variable plasma-protein-binding, especially for valproate.13 TDM may be useful in selected cases when patient adherence is questioned or when altered pharmacokinetics is expected, (eg. due to pregnancy, drug–drug interactions (including polytherapy) or hepatic or renal impairment). In Australia, TDM is readily available for carbamazepine, phenytoin, phenobarbitone, valproate and lamotrigine.
While AEDs are the mainstay of epilepsy treatment, up to 40% of patients will continue to have seizures.14 Pharmacoresistance is defined as failure to achieve seizure control with adequate doses of two appropriate AEDs.15 Referral to a comprehensive epilepsy service is useful for:
- diagnostic clarification to distinguish between epilepsy and non-epileptic seizures
- further pharmacotherapy, including rational polytherapy and access to AEDs through clinical trials
- non-pharmacological treatment, including vagal nerve stimulation16 and resective epilepsy surgery.17
National standards governing medical fitness to drive were revised in March 2012. In most cases, patients with epilepsy on AEDs and patients after first epileptic seizure will be judged fit to return to driving after being seizure-free for 6 months.18
Expectations of patients and driver licensing authorities (DLAs) that treating doctors should adjudicate on fitness to drive undermine the doctor–patient relationship, discourage reporting of seizures, encourage doctor-shopping and expose the practitioner to legal risk.19 The author’s preference is to provide a concise medical report allowing the DLA to make the decision (Figure 1).
Figure 1. A sample letter to the DLA regarding fitness to drive
Reproductive health issues
Enzyme-inducing AEDs (Table 3) reduce the efficacy of the combined oral contraceptive pill by increasing clearance of oestrogen and progestogen components. A common, albeit illogical, strategy is to prescribe a high-dose (50 µg) oestrogen formulation; ovulation is likely to occur if the progestogen dose is unchanged. More plausible strategies include doubling the dose; using active pills continuously rather than 21 days on, 7 days off; alternative contraceptive methods; or changing AEDs. Efficacy of etonogestrel subcutaneous implant is also compromised by enzyme-inducing AEDs, but depot medroxyprogesterone acetate and levonorgestrel-releasing intrauterine system remain effective.20
The risk of congenital malformations in AED-exposed pregnancies is about 6%, compared with about 3% in non-exposed pregnancies. No specific agent has been shown to be higher risk, with the exception of valproate if the daily dose exceeds 1100 mg.21 The time frame for organogenesis suggests that the first trimester is most important for exposure. Although not proven to mitigate risk, preconceptional folate supplementation is recommended. There is an association between lower intelligence and valproate exposure in utero; this is likely to be dose-dependent and related to exposure in all trimesters.22 It has been posited that autism and behavioural disorders are more common in children with in utero exposure to AEDs, but evidence for this is lacking.
AED dose requirements are increased during pregnancy after the first trimester, particularly for lamotrigine and levetiracetam;23,24 TDM can be extremely useful. Failure to anticipate these changes can lead to gestational deterioration in seizure control. Generally, AED penetration into breast milk is not clinically significant.25
Increasing evidence is emerging suggesting that long-term use of AEDs is associated with low bone mineral density (BMD).26 Increased fracture risk in patients with epilepsy is not entirely attributable to reduced BMD and both seizure- and non-seizure-related falls are likely contributors.27 General preventive measures include optimising physical exercise and dietary calcium intake, correcting vitamin D deficiency and smoking cessation. Unfortunately, there are no evidence-based guidelines for how early and often to perform bone mineral densitometry (which for many patients would be unsubsidised), nor whether AEDs should be altered or anti-resorptive therapy commenced.
- Diagnosis of seizures and epilepsy is based on accurate history.
- AED treatment is usually reserved until after two seizures have occurred.
- HLA testing should be performed in Asian patients before commencing carbamazepine treatment.
- AED dosing should be adjusted on clinical grounds; TDM is useful in selected patients.
- Specialist referral is recommended after failure of two AEDs.
Competing interest: Meng Tan has received payment from Eisai and Upsher-Smith Laboratories for travel to and accommodation at national conferences, and is a sub-investigator on clinical trials for Bial, UCB, Eisai, Upsher-Smith and GlaxoSmithKline.
Provenance and peer review: Commissioned; externally peer reviewed.
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- Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 2010; 51:676–85.
- Sheldon R, Rose S, Ritchie D, et al. Historical criteria that distinguish syncope from seizures. J Am Coll Cardiol 2002;40:142–48.
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- Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46:470–72.
- Delgado-Escueta AV, Enrile-Bacsal F. Juvenile myoclonic epilepsy of Janz. Neurology; 1984 34:285–94.
- Senf P, Schmitz B, Holtkamp M, Janz D. Prognosis of juvenile myoclonic epilepsy 45 years after onset: Seizure outcome and predictors. Neurology 2013; 81:2128–33.
- Hindmarch I, Gudgeon AC. The effects of clobazam and lorazepam on aspects of psychomotor performance and car handling ability. Br J Clin Pharmacol 1980;10:145–50.
- Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology 2005;64:1134–38.
- Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, Lohitnavy M, Tassaneeyakul W. Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol Chic Ill 2013;149:1025–32.
- McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 2011;364:1134–43.
- Gugler R, Mueller G. Plasma protein binding of valproic acid in healthy subjects and in patients with renal disease. Br J Clin Pharmacol 1978;5:441–46.
- Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–19.
- Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:1069–77.
- Morris GL 3rd, Gloss D, Buchhalter J, Mack KJ, Nickels K, Harden C. Evidence-based guideline update: Vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2013;81:1453–59.
- Wiebe S, Blume WT, Girvin JP, Eliasziw M, Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001;345:311–18.
- Assessing fitness to drive for commercial and private vehicle drivers: medical standards for licensing and clinical management guidelines [Internet]. Austroads; 2012. Available at www.austroads.com.au/ images/stories/assessing_ fitness_to_drive_2013.pdf [Accessed 10 February 2014].
- Somerville ER, Black AB, Dunne JW. Driving to distraction – certification of fitness to drive with epilepsy. Med J Aust 2010;192:342–44.
- Schwenkhagen AM, Stodieck SRG. Which contraception for women with epilepsy? Seizure J Br Epilepsy Assoc 2008;17:145–50.
- Vajda FJE, Hitchcock A, Graham J, et al. Fetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry. Eur J Neurol Off J Eur Fed Neurol Soc 2006;13:645–54.
- Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597–605.
- De Haan G-J, Edelbroek P, Segers J, et al. Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study. Neurology 2004; 63:571–73.
- Reisinger TL, Newman M, Loring DW, Pennell PB, Meador KJ. Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy. Epilepsy Behav EB 2013;29:13–18.
- Harden CL, Pennell PB, Koppel BS, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73:142–49.
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- Vestergaard P. Epilepsy, osteoporosis and fracture risk – a meta-analysis. Acta Neurol Scand 2005;112:277–86.