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Epilepsia, 47(8):1285–1287, 2006

Blackwell Publishing, Inc.



C 2006 International League Against Epilepsy

Critical Commentary

Is Tolerance to Antiepileptic Drugs Clinically Relevant?

The success of the pharmacological treatment of to a drug may be due to the coexistence of factors related
epilepsy is not infrequently hampered by the fact that to the pathogenesis of the epilepsy. These factors can be
an initial early period of temporary efficacy (the “hon- important in a number of the epileptic disorders that are
eymoon” effect) is followed by a loss of effectiveness that typically refractory to AEDs, such as infantile epileptic
may became complete within a period of 3-4 months; al- encephalopathies and temporal lobe epilepsy with hip-
ternatively, or additionally, a reduction in the response to pocampal sclerosis (TLE HS). These disorders are thought
antiepileptic drugs (AEDs) may develop more gradually to be the result of processes set in motion by “early”
during prolonged treatment and lead to a condition of in- seizures that occur during an initial acute phase of epilep-
tractability epilepsy. One of the various factors that can togenesis. In such cases, early seizures are thought to in-
account for such an unfavourable course is tolerance (i.e. duce a cascade of events (2), and these seizure-dependent
a reduced response to a drug after repeated administra- processes then lead to a secondary self-sustained epilepto-
tions), which may play a significant but still insufficiently genic mechanism that can be responsible for progression
acknowledged role. The review by Wolfang Löscher and towards a condition of medical intractability. The concept
Dieter Schmidt published in this issue of Epilepsia is of an epileptogenic process leading to increasingly severe
therefore particularly welcome. The authors not only have epilepsies that eventually become refractory to AEDs is
great experience in the field, but their work has also signifi- supported by the natural history of TLE HS and epileptic
cantly advanced our understanding of the “tolerance” phe- encephalopathies, and by experimental animal data drawn
nomenon. In particular, this article provides readers with from the kindling, pilocarpine and kainic acid models.
a comprehensive review that starts with definitions, an- However, responsiveness to AEDs during the course of
alyzes experimental and clinical evidence, and discusses epilepsy may decrease not only because of the progression
possible mechanisms and strategies aimed at preventing of the underlying epileptogenesis, but also because of the
the development of tolerance to AEDs. development of tolerance due to prolonged AED exposure.
What immediately catches the reader’s attention is the The limited information obtainable from the analysis of
imbalance between the wealth of experimental results and surgical specimens resected from drug-resistant patients
the rather limited amount of information that can be drawn undergoing epilepsy surgery does not allow us to choose
from clinical studies. Since Millichap’s work on acetazo- decisively between these two possible interpretations. For
lamide (1), a number of studies have analyzed the biolog- example, the alterations in molecular structure and Na+
ical basis of tolerance to AEDs in various animal models. channels (3), or the altered effect of CBZ on Na+ cur-
Most of these studies (including those by Löscher him- rents observed in temporal lobe tissue taken from drug-
self) have involved the kindling model, and have used resistant patients with TLE HS (4), could be induced by the
experimental protocols capable of analyzing both acute epileptogenic process itself or by exposure to the drug (i.e.,
tolerance (i.e., the tolerance that develops after a single by the development of “tolerance”). More recently, Remy
drug exposure) and the chronic tolerance that develops et al. (5) have used patch clamp recordings to re-investigate
gradually during repeated or continuous drug administra- the drug sensitivity of voltage-dependent Na+ channels
tions. In principle, a decrease in the effect of a drug could in hippocampal neurons from 13 patients with drug-
be due to changes in its distribution or metabolism (phar- resistant TLE HS, and shown that the use-dependent
macokinetic tolerance) or adaptive changes in the AED CBZ-induced blockade of these channels was completely
target systems (pharmacodynamic tolerance). The occur- lost in the CBZ-resistant patients, but completely pre-
rence of pharmacokinetic tolerance in patients treated with served in three patients who had never been treated with
enzyme-inducing AEDs is usually easy to detect by means CBZ or had responded well to CBZ received for only
of plasma level monitoring, which provides a sound ba- a short time before surgery. They also showed that the
sis for preventing or resolving the problem. It is much loss of use-dependent Na+ channel inhibition in the CBZ-
more difficult to demonstrate the occurrence of pharma- resistant patients was due to the complete loss of CBZ
codynamic tolerance in a patient who fails to respond to effect on fast recovery from inactivation. These data
rational pharmacological therapy, because refractoriness demonstrated for the first time the usefulness of in vitro

1285
1286 G. AVANZINI

preparations of human tissue when investigating the mech- of this variable in a clinical setting in which the therapy
anisms of drug resistance, as well as the existence of a re- is administered at fixed intervals and the seizures occur
lationship between long-term treatment with a given drug randomly. Contingent tolerance, therefore, may have no
and the development of refractoriness to it. It is still too practical clinical relevance, with the notable exception of
early to say if this is a cause-effect relationship (i.e., the status epilepticus (SE).
loss of CBZ effect on Na+ channel recovery from inac- During SE, the acutely administered drugs (usually dif-
tivation develops through a tolerance mechanism during ferent from those taken chronically by the patient) are de-
long-term exposure to the drug), but this reasonable hy- livered while the seizure activity is ongoing. It is therefore
pothesis deserves further investigation. Indeed, if the con- reasonable to wonder whether the acute development of
tribution of tolerance to drug refractoriness is confirmed, contingent tolerance contributes to the loss of efficacy of
appropriate preventive strategies can be developed. the drug administered during SE, and whether there is any
Interestingly, the tolerance induced by a specific drug strategy that is capable of reducing such negative interfer-
also affects responsiveness to other drugs of the same cat- ence. Common clinical experience shows that the longer
egory (cross-tolerance). The experimental evidence for SE lasts, the more difficult it is to stop; i.e., SE becomes
cross-tolerance, extensively discussed by Löscher and refractory to pharmacological treatment over time. Experi-
Schmidt, supports the conclusion that the between-drug mental results support the idea that this gradual loss of drug
transfer of tolerance indicates common mechanisms of responsiveness is due to SE-dependent changes in phar-
action (6). For example, CBZ and lamotrigine (LTG), macological targets, such as receptors and voltage-gated
both of which act by modulating voltage-dependent Na+ channels, which become less sensitive to AEDs (11). The
channels, exhibit bidirectional tolerance; in contrast, there potential role of tolerance to AEDs acutely administered
is no cross-tolerance between the benzodiazepines (BZs) in a condition corresponding to the definition of contin-
(which act through a different mechanism) and CBZ or gent tolerance (i.e., due to the concomitant occurrence of
LTG. However, this conclusion is not supported by ex- seizures) is difficult to demonstrate. For example, it can
amples of cross-tolerance between drugs with different be argued that, when SE persists for more than 60 min-
mechanisms of action, such as levetiracetam (LEV) and utes, it is because seizure activity failed to respond to early
CBZ, or the absence of cross-tolerance between drugs with pharmacological treatments and was thus refractory from
a similar mechanism of action, as in the case of the two the start, and that the development of tolerance has noth-
Na+ channel modulators phenytoin (PHT) and CBZ (7). ing to do with its pathogenesis. However, it is not unusual
Given the potential relevance of cross-tolerance to the clin- to see patients with ongoing SE that has been repeatedly
ical problem of multidrug resistance, it is clear that further treated elsewhere with insufficient doses of first-line drugs
studies are needed. (namely BZs), and where subsequent administration of an
In general, despite the experimental evidence, the real “adequate” i.v. bolus dose does not stop the SE; in such
contribution of tolerance to the development of drug re- cases, the contribution of tolerance can be reasonably sus-
fractoriness in TLE HS and epileptic encephalopathies is pected. To the best of my knowledge, this hypothesis has
still largely unknown. Specifically designed, controlled never been systematically tested, but there is circumstan-
studies are warranted with the aim of disentangling the tial evidence of the presence of acute drug tolerance during
roles of epileptogenesis and long-term drug exposure. SE. For example, Osorio and Reed (12) observed some de-
One intriguing tolerance–related phenomenon, first re- gree of pharmacodynamic tolerance (manifested as a loss
ported by Pinel et al. (8), is the influence of the temporal of anesthetic effect and ability to induce an EEG pattern
relationship between drug administration and seizures on of burst suppression) in four out of 12 cases of refractory
the development of tolerance: i.e., tolerance contingent SE treated with pentobarbital infusion; after 4-5 days of
upon seizure occurrence. Contingent tolerance can there- infusion, these patients regained consciousness at pento-
fore be defined as a decline in the therapeutic efficacy barbital concentrations that had earlier caused unrespon-
of a given drug that emerges only if the drug is present siveness and the loss of all brainstem reflexes. Although
while the treated episode occurs (9). Candidate mecha- tolerance to anesthetic effects does not necessarily paral-
nisms that may contribute to this phenomenon include the lel tolerance to antiepileptic activity, this observation does
adaptation of GABAA receptors, changes in the release demonstrate the occurrence of some tolerance to pento-
of peptides (e.g., thyrotropin-releasing-hormone (TRH) barbital during SE. Controlled studies of the role (if any)
and neuropeptide Y (NPY)), and alterations in adenosine of contingent tolerance in the development of SE refrac-
receptors and voltage-gated ion channels (9, 10). The con- toriness could help in developing sorely needed evidence-
cept of contingency adds another dimension to interpreting based guidelines for SE treatment (13,14).
the role of tolerance in the development of drug refrac- Another interesting and clinically-relevant point, appro-
toriness, since we must evaluate the temporal relationship priately discussed by Löscher and Schmidt, is the fact that
between seizure occurrence and drug exposure. In most in- pharmacodynamic tolerance to side-effects usually devel-
stances, it is practically impossible to assess the influence ops more rapidly than tolerance to efficacy; moreover,

Epilepsia, Vol. 47, No. 8, 2006


CRITICAL COMMENTARY 1287

tolerance to adverse effects seems to develop more easily and the use of receptor antagonists) are impracticable or
with low than with high drug doses, whereas the opposite is of unproved efficacy.
true in the case of tolerance to therapeutic effects. These Overall, the Löscher and Schmidt review should be
observations have major implications for clinical prac- highly prized for providing us with a comprehensive and
tice as they suggest that antiepileptic treatment should be thoughtful account of a subject that has not received ad-
started using slow titration schedules rather than loading equate attention from epileptologists. I am sure that the
doses (unless the clinical situation requires rapid seizure readers of Epilepsia will enjoy it as much as I did.
control as is often the case when dealing with infant and Giuliano Avanzini
childhood epilepsies), because slow titration reduces the Istituto Nazionale Neurologico C.
risk of loss of pharmacological effect and simultaneously Besta, Milan, Italy
minimizes adverse effects.
Other questions of particular interest to clinicians are:
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Epilepsia, Vol. 47, No. 8, 2006

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