Ruling Out Pseudoresistance

'Pseudoresistance', in which seizures persist because the disorder has not been adequately or appropriately treated, must be excluded or corrected before AED treatment can be declared as having failed [3]. It may arise in a number of situations (Table 8.1), of which misdiagnosis of epilepsy is probably one of the most common. Conditions that frequently mimic epileptic seizures include vasovagal syncope, cardiac arrhythmias and metabolic disturbances [4]. Pseudoseizures or non-epileptic psychogenic seizures are estimated to account for 10% to 45% of patients with apparently refractory epilepsy [5]. Mistaking other conditions for epilepsy can lead to unnecessary and potentially harmful treatments and delays in initiating appropriate therapy.

Incorrect classification of syndrome or seizure type is another common cause of drug failure. This is because various AEDs have different profiles of activity. AEDs may be inappropriately chosen for a particular seizure type, resulting in increase in seizure frequency and/or severity, presumably due to adverse pharmacodynamic interactions between the mode of action of the specific drug and the pathogenetic mechanisms underlying the specific seizure type. The idiopathic generalized epilepsies seem to be more vulnerable to aggravation by

Patrick Kwan, MD, PhD, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, People's Republic of China

Howan Leung, MD, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, People's Republic of China

Table 8.1 Some reasons for 'pseudoresistance' to anti-epileptic drug therapy wrong lifestyle wrong diagnosis wrong drug(s)

wrong dose

Syncope, cardiac arrhythmia, etc.

Malingering, pseudoseizures

Underlying brain neoplasm

Inappropriate for seizure type

Kinetic/dynamic interactions

Too low (ignore target range)

Side-effects preventing dose increase

Poor compliance with medication

Inappropriate lifestyle (e.g. alcohol or drug abuse)

inappropriately chosen AEDs compared with focal epilepsies [6]. For instance, carbamazepine and oxcarbazepine are well documented to aggravate generalized seizures, including typical and atypical absence seizures, myoclonic and atonic seizures in a substantial proportion of patients [7, 8]. In a retrospective series, lamotrigine was reported to worsen seizure control in 80% of patients with severe myoclonic epilepsy in infancy, although the drug appears to be generally effective in other idiopathic generalized epilepsies [9].

In some circumstances, an AED fails to control seizures satisfactorily because it is not prescribed at optimal dosage. This may arise due to injudicious reliance on monitoring serum drug concentration, including a 'therapeutic range' that can be interpreted as dictating dosage adjustment without adequate clinical correlation. Instead, an individualized approach must be adopted when titrating an AED because wide interindividual variability exists in the dosages at which beneficial and toxic effects are observed as a result of genetic and environmental factors [10].

Other possible causes of 'pseudoresistance' are related to the patient's lifestyle or behaviour. As with other chronic medical conditions, imperfect adherence to the therapeutic regimen is one of the most common factors resulting in epilepsy treatment failure. Abuse of alcohol and recreational drugs can cause seizures as well as non-compliance to AED treatment. Sleep deprivation and stress are common precipitating factors for seizures. Therefore, social and lifestyle factors should be considered when evaluating the efficacy of pharmacological treatment.

Before the specific treatment strategies for drug-resistant epilepsy are discussed, it is important to first consider who should receive such treatment; that is, when is drug resistance recognized? Such consideration has practical implications, particularly given that some of the treatments for drug-resistant epilepsy may be associated with permanent complications, as in the case of surgery.

elements of definition

A unifying definition of drug resistance in epilepsy remains hotly debated [11]. The term is often used interchangeably with 'medical intractability', pharmacoresistance or refractory epilepsy. It should be emphasized that, by default, intractability is a relative concept rather than an absolute designation, which is influenced by the context in which it is intended to apply. Thus, the definition may vary in different settings, such as selection of patients for

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