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Beghi Et Al 2011 Epilepsia
Beghi Et Al 2011 Epilepsia
3):40–44, 2011
doi: 10.1111/j.1528-1167.2011.03035.x
*Department of Neuroscience, Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milano, Italy; and yDepartment
of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom
Several clinical reports have documented the effects of characteristics of the available compounds, which may
antiepileptic drugs (AEDs) on the immune system. How- affect the individual’s susceptibility to develop immune-
ever, the published findings refer mostly to the first-gen- mediated adverse reactions. These explanations can be
eration compounds, are frequently inconsistent, and are also offered for the interpretation of the clinical relevance
sometimes conflicting. Several explanations can be of these adverse drug effects, which may present as seri-
given: (1) The effects of drugs on the immune system ous, life-threatening conditions such as in the antiepilep-
cannot be easily separated from the effects of seizures tic hypersensitivity syndrome (AHS).
(see also Aronica & Crino, 2011; and Friedman & With this background information in mind, we discuss
Dingledine, 2011); (2) First-generation drugs have been three topics in this subject area: (1) The immunologic
more intensively used than the new compounds, which effects of AEDs; (2) The interactions between antiepilep-
may explain their predominant involvement in immune- tic drugs and immunotherapies; and (3) The antiepileptic
mediated reactions; (3) The individual’s genetic back- hypersensitivity syndrome.
ground and/or the concurrent use of immunotherapies
may interact with AEDs, with differences across patients
in the risk of adverse events, in terms of incidence and
Immunologic Effects of
severity; (4) Differences are also present in the underly- Antiepileptic Drugs
ing mechanisms of action and the pharmacokinetic (F. Vigevano, Genova, Italy)
The role of inflammation in the development and persis-
Address correspondence to Ettore Beghi, Department of Neurosci-
ence, Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milano, Italy.
tence of epileptic seizures has been recently emphasized
E-mail: beghi@marionegri.it (Aarli, 2000). AEDs can directly affect both humoral and
Wiley Periodicals, Inc. cellular immunity, modifying the expression and the syn-
ª 2011 International League Against Epilepsy thesis of some molecules, mainly cytokines. This regula-
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Antiepileptic Drugs and the Immune System
tory effect could be due to a direct effect of AEDs in modu- tory cells and thereby provides the background for the
lating the activity of some transcription factors, particu- establishment of an interaction between cytokines and
larly nuclear factor-kappaB (NF-jB). However, the periodontal connective tissue cells (Sasaki & Maita, 1998;
underlying data are few and conflicting, and the mecha- Moder et al., 2000; Sume et al., 2010).
nisms of the effects are often not understood. It is often dif-
ficult to discriminate between the effects of AEDs and Vigabatrin
those of seizures or other, potentially confounding factors There are some data in the literature demonstrating that
(e.g., intercurrent illness). Some data suggest that AEDs vigabatrin can interfere with the cellular immune response.
can modulate the immune system activity, and may, there- Pacifici et al. (1995) studying 29 pediatric patients after 1
fore, either increase or reduce the epileptic threshold. and 3 months of treatment with vigabatrin, found that the
Notably, AEDs can lead to an increase in serum levels of percentage and absolute number of T and B lymphocytes,
proinflammatory cytokines. T-helper–inducer lymphocytes, and T-rosetting lympho-
cytes were not significantly different in controls and in
Valproate children with epilepsy before and after treatment; that the
No consistent data are available about valproate effects percentage and absolute number of T cytotoxic-suppressor
on the immune system. Ichiyama et al. (2000) revealed that lymphocytes and NK cells were significantly increased
the production of cytokines [e.g., tumor necrosis factor after l and 3 months of treatment with vigabatrin; and that
(TNF)-a and interleukin (IL)-6] by monocytes and glia was the serum levels of IgA, IgG, and IgM did not differ signif-
decreased; this effect is probably due to an inhibitory action icantly from those of the control group.
of valproate on NF-kB translocation to the nucleus. Shiah
et al. (2005) conducted research on 10 healthy volunteers Levetiracetam
who were treated with valproate, and on the seventh day of Data on the effect of levetiracetam on the immune sys-
therapy, all of them had significantly higher serum levels tem are sparse. Recently, Kim et al. (2010), studying the
of IL-6. Verrotti et al. (2001) reported in a case series of effects of levetiracetam on IL-1b system in the hippocam-
pediatric patients an increase in serum levels of IL-1a, pus and pyriform cortex of chronic epileptic rats, found
IL-1b, and IL-6, whereas IL-2 production was unchanged. that levetiracetam reduced reactive gliosis and expression
levels of IL-1bsystem in the hippocampus and the pyri-
Carbamazepine form cortex, whereas valproate did not. These findings
Verrotti et al. (2001) showed in their study an increase suggest that levetiracetam may have, at least in part, anti-
in IL-1a, IL-1b, IL-2, and IL-6 serum levels in pediatric inflammatory effects, particularly against IL-1b system in
patients after 1 year of AED therapy. Comparing cytokine neuroglia within epileptic brain (see Friedman & Dingle-
levels before and after carbamazepine, the authors dine, 2011).
excluded seizure influence on cytokines. More equivocal
are the results concerning carbamazepine and immuno- Diazepam
globulin (Ig) serum level modification, as both increased This is the only benzodiazepine in which the effects on
and decreased IgA, IgM, and IgG levels are reported. Paci- the immune system have been studied. Wei et al. (2010)
fici et al. (1991) studied 39 adult patients treated with car- reported that diazepam inhibits human T-cell function
bamazepine for 2 years, comparing them with a control through peripheral benzodiazepine receptors, decreasing
group of 40 healthy nonsmokers: The serum levels of IgA, interferon (IFN)-c production. It is apparent that IFN-c pos-
IgG, and IgM in control subjects did not differ signifi- sesses antiviral and immunomodulatory activities. IFN-c
cantly from those obtained from carbamazepine-treated knockout mice showed deficiencies in natural resistance to
patients; there was, in addition, a significant increase in bacterial, parasitic, and viral infections. In addition to
cytotoxic activity of NK cells in the carbamazepine group recurrent infection, infants with deficient production of
as compared with controls. Isolated cases with drug- IFN-c exhibited decreased neutrophil mobility and NK cell
induced immunoglobulin deficiency are recorded (Gilhus activity (Wei et al., 2010).
& Lea, 1988).
Future directions
Phenytoin A systematic study of the effects of AEDs on the
This drug can provoke a decrease of suppressor T cells immune systems is required, as knowledge is sparse and
and a reversible IgA deficiency in patients with epilepsy. inconsistent. The clinical frequency and relevance of such
The gingival overgrowth is probably due to the increased effects need to be established. The mechanisms of these
production of both IL-6 and IL-8, combined with eleva- effects need to be elucidated. The possibility that differ-
tions of basic fibroblast growth factor as observed in vitro ences in AED effects on the immune system in individual
using human gingival fibroblasts; this increase contributes cases are related to individual genetic predisposition
to an enhanced recruitment and activation of inflamma- should be explored.
Epilepsia, 52(Suppl. 3):40–44, 2011
doi: 10.1111/j.1528-1167.2011.03035.x
42
E. Beghi and S. Shorvon
focal seizures every 1–2 min. The woman became seizure 50–90% of cases); this involvement can be dangerous, and
free, and although she was taking concomitant AEDs (lev- fulminant hepatic necrosis can occur. Other potentially
etiracetam, oxcarbazepine, zonisamide, and phenobarbi- fatal internal organ involvement includes kidney (with a
tal) the authors did not report on any pharmacokinetic spectrum of presentation from nephritis to acute renal fail-
interaction (Thilo et al., 2009). ure), heart (with myocarditis, pericarditis or congestive
heart failure), lung (from pneumonia to respiratory dis-
Future directions tress syndrome), and vasculitis.
Further studies are required to establish the clinical The most important therapeutic action is to immediately
importance of these drug interactions, for instance in discontinue the offending drug. Different approaches to
transplantation or cancer therapy. therapy include high-dose steroids, other immunotherapy,
and sometimes desensitization.