Epilepsia, 52(Suppl.
3):40–44, 2011
IMMUNITY AND INFLAMMATION IN EPILEPSY
Antiepileptic drugs and the immune system
*Ettore Beghi and ySimon Shorvon
*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
SUMMARY
Data on the effects of antiepileptic drugs on the
immune system are frequently inconsistent and
sometimes conflicting because the effects of drugs
cannot be separated from those of seizures, first-
generation drugs have been most intensively
investigated, the patient’s genetic background,
the mechanism of action and the pharmacokinetic
profile of AEDs and the concurrent use of immu-
nosuppressant drugs may act as confounders.
Valproate, carbamazepine, phenytoin, vigabatrin,
levetiracetam, and diazepam have been found to
modulate the immune system activity by affecting
humoral and cellular immunity. AEDs are associ-
ated with pharmacokinetic interactions (most fre-
quently occurring with carbamazepine, phenytoin,
phenobarbital and valproate). Hepatic metabo-
Several clinical reports have documented the effects of
antiepileptic drugs (AEDs) on the immune system. How-
ever, the published findings refer mostly to the first-gen-
eration compounds, are frequently inconsistent, and are
sometimes conflicting. Several explanations can be
given: (1) The effects of drugs on the immune system
cannot be easily separated from the effects of seizures
(see also Aronica & Crino, 2011; and Friedman &
Dingledine, 2011); (2) First-generation drugs have been
more intensively used than the new compounds, which
may explain their predominant involvement in immune-
mediated reactions; (3) The individual’s genetic back-
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
severity; (4) Differences are also present in the underly-
ing mechanisms of action and the pharmacokinetic
Address correspondence to Ettore Beghi, Department of Neurosci-
ence, Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milano, Italy.
E-mail: beghi@marionegri.it
Wiley Periodicals, Inc.
ª 2011 International League Against Epilepsy
40
doi: 10.1111/j.1528-1167.2011.03035.x
lism is the primary site of interaction for both
AEDs and immunotherapies (ACTH, dexametha-
sone, hydrocortisone, methylprednisolone, cyclo-
phosphamide, methotrexate, rituximab), which
entail induction or inhibition of drug effects. How-
ever, the clinical importance of these drug interac-
tions is still far from defined. An important
adverse effect of the action of AEDs on the
immune system is antiepileptic hypersensitivity
syndrome (AHS), a life-threatening, idiosyncratic
cutaneous reaction to aromatic AEDs resulting in
end organ damage. Phenytoin, carbamazepine,
phenobarbital, lamotrigine, oxcarbazepine, felba-
mate, and zonisamide have been implicated. The
pathogenic mechanisms of AHS are incompletely
understood.
KEY WORDS: Antiepileptic drugs, Immune system.
characteristics of the available compounds, which may
affect the individual’s susceptibility to develop immune-
mediated adverse reactions. These explanations can be
also offered for the interpretation of the clinical relevance
of these adverse drug effects, which may present as seri-
ous, life-threatening conditions such as in the antiepilep-
tic hypersensitivity syndrome (AHS).
With this background information in mind, we discuss
three topics in this subject area: (1) The immunologic
effects of AEDs; (2) The interactions between antiepilep-
tic drugs and immunotherapies; and (3) The antiepileptic
hypersensitivity syndrome.
Immunologic Effects of
Antiepileptic Drugs
(F. Vigevano, Genova, Italy)
The role of inflammation in the development and persis-
tence of epileptic seizures has been recently emphasized
(Aarli, 2000). AEDs can directly affect both humoral and
cellular immunity, modifying the expression and the syn-
thesis of some molecules, mainly cytokines. This regula-

tory effect could be due to a direct effect of AEDs in modu-
lating the activity of some transcription factors, particu-
larly nuclear factor-kappaB (NF-jB). However, the
underlying data are few and conflicting, and the mecha-
nisms of the effects are often not understood. It is often dif-
ficult to discriminate between the effects of AEDs and
those of seizures or other, potentially confounding factors
(e.g., intercurrent illness). Some data suggest that AEDs
can modulate the immune system activity, and may, there-
fore, either increase or reduce the epileptic threshold.
Notably, AEDs can lead to an increase in serum levels of
proinflammatory cytokines.
Valproate
No consistent data are available about valproate effects
on the immune system. Ichiyama et al. (2000) revealed that
the production of cytokines [e.g., tumor necrosis factor
(TNF)-a and interleukin (IL)-6] by monocytes and glia was
decreased; this effect is probably due to an inhibitory action
of valproate on NF-kB translocation to the nucleus. Shiah
et al. (2005) conducted research on 10 healthy volunteers
who were treated with valproate, and on the seventh day of
therapy, all of them had significantly higher serum levels
of IL-6. Verrotti et al. (2001) reported in a case series of
pediatric patients an increase in serum levels of IL-1a,
IL-1b, and IL-6, whereas IL-2 production was unchanged.
Carbamazepine
Verrotti et al. (2001) showed in their study an increase
in IL-1a, IL-1b, IL-2, and IL-6 serum levels in pediatric
patients after 1 year of AED therapy. Comparing cytokine
levels before and after carbamazepine, the authors
excluded seizure influence on cytokines. More equivocal
are the results concerning carbamazepine and immuno-
globulin (Ig) serum level modification, as both increased
and decreased IgA, IgM, and IgG levels are reported. Paci-
fici et al. (1991) studied 39 adult patients treated with car-
bamazepine for 2 years, comparing them with a control
group of 40 healthy nonsmokers: The serum levels of IgA,
IgG, and IgM in control subjects did not differ signifi-
cantly from those obtained from carbamazepine-treated
patients; there was, in addition, a significant increase in
cytotoxic activity of NK cells in the carbamazepine group
as compared with controls. Isolated cases with drug-
induced immunoglobulin deficiency are recorded (Gilhus
& Lea, 1988).
Phenytoin
This drug can provoke a decrease of suppressor T cells
and a reversible IgA deficiency in patients with epilepsy.
The gingival overgrowth is probably due to the increased
production of both IL-6 and IL-8, combined with eleva-
tions of basic fibroblast growth factor as observed in vitro
using human gingival fibroblasts; this increase contributes
to an enhanced recruitment and activation of inflamma-
41
Antiepileptic Drugs and the Immune System
tory cells and thereby provides the background for the
establishment of an interaction between cytokines and
periodontal connective tissue cells (Sasaki & Maita, 1998;
Moder et al., 2000; Sume et al., 2010).
Vigabatrin
There are some data in the literature demonstrating that
vigabatrin can interfere with the cellular immune response.
Pacifici et al. (1995) studying 29 pediatric patients after 1
and 3 months of treatment with vigabatrin, found that the
percentage and absolute number of T and B lymphocytes,
T-helper–inducer lymphocytes, and T-rosetting lympho-
cytes were not significantly different in controls and in
children with epilepsy before and after treatment; that the
percentage and absolute number of T cytotoxic-suppressor
lymphocytes and NK cells were significantly increased
after l and 3 months of treatment with vigabatrin; and that
the serum levels of IgA, IgG, and IgM did not differ signif-
icantly from those of the control group.
Levetiracetam
Data on the effect of levetiracetam on the immune sys-
tem are sparse. Recently, Kim et al. (2010), studying the
effects of levetiracetam on IL-1b system in the hippocam-
pus and pyriform cortex of chronic epileptic rats, found
that levetiracetam reduced reactive gliosis and expression
levels of IL-1bsystem in the hippocampus and the pyri-
form cortex, whereas valproate did not. These findings
suggest that levetiracetam may have, at least in part, anti-
inflammatory effects, particularly against IL-1b system in
neuroglia within epileptic brain (see Friedman & Dingle-
dine, 2011).
Diazepam
This is the only benzodiazepine in which the effects on
the immune system have been studied. Wei et al. (2010)
reported that diazepam inhibits human T-cell function
through peripheral benzodiazepine receptors, decreasing
interferon (IFN)-c production. It is apparent that IFN-c pos-
sesses antiviral and immunomodulatory activities. IFN-c
knockout mice showed deficiencies in natural resistance to
bacterial, parasitic, and viral infections. In addition to
recurrent infection, infants with deficient production of
IFN-c exhibited decreased neutrophil mobility and NK cell
activity (Wei et al., 2010).
Future directions
A systematic study of the effects of AEDs on the
immune systems is required, as knowledge is sparse and
inconsistent. The clinical frequency and relevance of such
effects need to be established. The mechanisms of these
effects need to be elucidated. The possibility that differ-
ences in AED effects on the immune system in individual
cases are related to individual genetic predisposition
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
Interactions between
Antiepileptic Drugs and
Immunotherapy (P. Patsalos,
London, United Kingdom)
Combination AED therapy (the use of two or more
drugs) is taken by approximately 30% of patients with epi-
lepsy, and a significant minority of such patients may
require treatment with immunotherapies including adre-
nocorticotropic hormone (ACTH), corticosteroids (dexa-
methasone, hydrocortisone, prednisone/prednisolone, and
methylprednisolone), cyclophosphamide, methotrexate,
and rituximab. These immunotherapies, however, are not
licensed for the treatment of epilepsy.
AEDs are associated with more pharmacokinetic inter-
actions than any other therapeutic drug class. Interactions
particularly occur with carbamazepine, phenytoin, pheno-
barbital, and valproate. Many of the newer AEDs (e.g.,
eslicarbazepine acetate, gabapentin, lacosamide, lamotri-
gine, levetiracetam, pregabalin, topiramate, tiagabine,
vigabatrin, and zonisamide) have less ability to cause
enzyme induction or inhibition and have a low propensity
to interact. The AEDs with the lowest interaction poten-
tial are those that are renally eliminated (gabapentin,
levetiracetam, pregabalin, and vigabatrin) (Johannessen
Landmark & Patsalos, 2010).
Although pharmacokinetic interactions can be the con-
sequence of interactions at the level of drug absorption,
plasma/serum protein binding, metabolism, and elimina-
tion/excretion, by far the most important site is that of
hepatic metabolism and can entail induction or inhibition
(Patsalos et al., 2002). This also appears to be the primary
site of interaction involving the immunotherapies; how-
ever, the data are limited.
ACTH is rapidly metabolized via the plasma plasmino-
gen system (half-life approximately 15 min). Conven-
tional pharmacokinetics does not apply to ACTH because
it is inactivated in the gastrointestinal tract and thus is
administered intramuscularly. To date there have been no
pharmacokinetic interactions reported between AEDs and
ACTH (Patsalos & Bourgeois, 2010).
Dexamethasone is metabolized via hepatic cytochrome
P450 3A4 (CYP3A4) isoenzyme with a half-life of 36–
54 h. The AEDs carbamazepine, phenobarbital, and phe-
nytoin, which are known to induce the activity of
CYP3A4, enhance the metabolism of dexamethasone so
that its clearance increases 2–4-fold (Patsalos, 2005).
Interestingly, the interaction with phenytoin may be bidi-
rectional, but the data are conflicting in that dexametha-
sone has been reported to both induce (Lackner, 1991) and
inhibit (Lawson et al., 1981) phenytoin metabolism.
Hydrocortisone metabolism is via hepatic 11-b-hydrox-
ysteroid dehydrogenase system, and the enzyme-inducing
AEDs (i.e., carbamazepine, phenobarbital, and phenytoin)
Epilepsia, 52(Suppl. 3):40–44, 2011
doi: 10.1111/j.1528-1167.2011.03035.x
enhance the metabolism of hydrocortisone so that lower
blood levels are achieved (Patsalos, 2005). Prednisone is
biologically inactive and acts as a prodrug for predniso-
lone, but prednisolone is also available as a specific for-
mulation. Prednisolone undergoes metabolism via hepatic
6-b –hydroxylation with a half-life of 1.3 h. Carbamaze-
pine, phenobarbital, and phenytoin induce the metabolism
of prednisolone so that its clearance increases by 79%,
41%, and 77%, respectively (Bartoszek et al., 1987).
Methylprednisolone similarly undergoes metabolism in
the liver by 6-b–hydroxylation, but the contribution of this
pathway appears to be greater than that for prednisolone in
that induction of methylprednisolone is substantially
greater. Therefore, carbamazepine and phenobarbital
increase methylprednisolone clearance 3.4-fold and
2-fold, respectively. In contrast, phenytoin increases
methylprednisolone clearance by 77%, an effect that is
similar to that seen with prednisolone (Bartoszek et al.,
1987).
Cyclophosphamide acts as a prodrug in that it is metab-
olized to 4-hydroxycyclophosphamide, which is pharma-
cologically active. Metabolism is primarily via CYP2C9,
CYP3A4, and CYP2B6; however, there is a minor contri-
bution by CYP2A6, CYP2C8, and CYP2C19. A single
case of a 42-year-old man with germ-cell cancer treated
with cyclophosphamide and who developed generalized
epilepsy treated with phenytoin was reported by de Jonge
et al. (2005). Phenytoin enhanced the metabolism of
cyclophosphamide in that the cyclophosphamide area
under the curve (AUC) value decreased by 67%, whereas
the AUC value for 4-hydroxycyclophosphamide increased
by 51%. The authors suggested that this interaction could
result in an increase in toxicity, although such toxicity was
not observed in their particular patient (de Jonge et al.,
2005). Valproic acid, an AED considered to be an inhibi-
tor of hepatic metabolism, has been observed in a series of
five healthy volunteers to inhibit the metabolism of cyclo-
phosphamide (Goto et al., 1987). In these healthy volun-
teers, 4-hydroxycyclophosphamide blood levels were
significantly lower.
Methotrexate is metabolized via hepatic and intracellu-
lar enzymes to various methotrexate polyglutamates.
Metabolism is dose-dependent with a half-life of 3–
15 hours. Carbamazepine, phenobarbital, and phenytoin
induce the metabolism of methotrexate so that its clear-
ance increases 1.5-fold (Patsalos, 2005). Recently, Riva
et al. (2000) reported on a series of 12 breast cancer
patients prescribed methotrexate and various AEDs. They
confirmed the profound induction of methotrexate metab-
olism by enzyme-inducing AEDs and additionally that
topiramate probably does not interact with methotrexate
(Riva et al., 2000).
Rituximab, a monoclonal antibody, was recently
reported to be particularly effective in a 20-year-old
woman with biopsy-proven Rasmussen encephalitis with

focal seizures every 1–2 min. The woman became seizure
free, and although she was taking concomitant AEDs (lev-
etiracetam, oxcarbazepine, zonisamide, and phenobarbi-
tal) the authors did not report on any pharmacokinetic
interaction (Thilo et al., 2009).
Future directions
Further studies are required to establish the clinical
importance of these drug interactions, for instance in
transplantation or cancer therapy.
Antiepileptic Hypersensitivity
Syndrome (A. Verrotti,
Rome, Italy)
Antiepileptic hypersensitivity syndrome (AHS) is a
severe, dose-independent, idiosyncratic cutaneous reac-
tion to aromatic AEDs that may result in end organ dam-
age and death (Schlienger & Shear, 1998). Aromatic
AEDs such as phenytoin, carbamazepine, and phenobarbi-
tal, as well as some newer agents, including lamotrigine,
oxcarbazepine, felbamate, and zonisamide, have been
implicated in eliciting a whole repertoire of hypersensitiv-
ity reactions ranging from simple maculopapular skin
eruptions to a severe life-threatening disorder (Hirsch
et al., 2008).
This syndrome also known as drug hypersensitivity
syndrome (DHS) or drug rash with eosinophilia and
systemic symptoms (DRESS), is typically associated with
the development of skin rash, fever, and internal organ
dysfunction, which may include blood dyscrasias, hepa-
titis, nephritis, myocarditis, thyroiditis, interstitial pneu-
monia, and encephalitis.
AHS occurs most frequently 1–8 weeks after the first
exposure to drugs, with fever (ranging from 38–40C)
often associated with malaise and pharyngitis, followed 1
or 2 days later by skin rash and lymphadenopathy. For
phenytoin, the mean interval to onset of AHS is from 17–
21 days after initial exposure to the drug, and for carba-
mazepine the onset is generally between 21 and 28 days.
In previously sensitized individuals, AHS may occur
within 1 day of rechallenge.
Drug eruption occurs in approximately 90% of patients
with AHS and can range from an exanthematous eruption
to more serious reactions like Stevens-Johnson syndrome
or toxic epidermal necrolysis (Wolkenstein & Revuz,
1995). Generally, the cutaneous eruption starts as a macu-
lar erythema that often evolves into a red, symmetrical,
pruritic, confluent papular rash on the upper trunk and
face, with later involvement of the lower extremities;
pustules, either follicular or nonfollicular, may also be
present. Desquamation occurs with resolution. The liver is
the most frequently involved internal organ (reported in
43
Antiepileptic Drugs and the Immune System
50–90% of cases); this involvement can be dangerous, and
fulminant hepatic necrosis can occur. Other potentially
fatal internal organ involvement includes kidney (with a
spectrum of presentation from nephritis to acute renal fail-
ure), heart (with myocarditis, pericarditis or congestive
heart failure), lung (from pneumonia to respiratory dis-
tress syndrome), and vasculitis.
The most important therapeutic action is to immediately
discontinue the offending drug. Different approaches to
therapy include high-dose steroids, other immunotherapy,
and sometimes desensitization.
Future directions
The exact incidence of AHS is not known because of
underreporting cases, variability in presentation, and lack
of strict diagnostic criteria; probably AHS is often unrec-
ognized. An international definition of AHS is needed,
along with more accurate epidemiologic data.
The pathogenetic mechanisms of AHS are not com-
pletely characterized; probably, a complex immune reac-
tion, mediated by the toxic metabolites of the aromatic
AEDs leading to cell death, underlies this syndrome.
Likely, the patients with peculiar HLA haplotypes have
high relative risk for developing AHS, but these data
are lacking (Cumbo-Nacheli et al., 2008; Chung et al.,
2010).
The diagnosis depends on clinical recognition based on
clinical history and a comprehensive physical examina-
tion; however, a validated, gold standard test for diagnosis
or prediction of AHS is not yet available (Elzagallaai
et al., 2009a,b).
Finally, validated and more efficacious therapies are
needed. International guidelines for therapeutic interven-
tion and for the management of these patients are other
important unmet needs.
Additional Contributors
Philipp N. Patsalos, London, United Kingdom. Alberto Verrotti, Chi-
eti, Italy. Federico Vigevano, Rome, Italy.
Acknowledgments
The work undertaken by Simon Shorvon was undertaken at UCLH/
UCL who received a proportion of funding from the Department of
Health’s NIHR Biomedical Research Centres funding scheme. The work
undertaken by Professor Patsalos was undertaken at UCLH/UCL who
received a proportion of funding from the Department of Health’s NIHR
Biomedical Research Centres funding scheme.
Disclosures
Neither of the authors have conflicts of interest relevant to the topic of
this article. We confirm that we have read the Journal’s position on issues
involved in ethical publication and affirm that this report is consistent
with those guidelines.
Epilepsia, 52(Suppl. 3):40–44, 2011
doi: 10.1111/j.1528-1167.2011.03035.x
44
E. Beghi and S. Shorvon
References
Aarli JA. (2000) Epilepsy and the immune system. Arch Neurol
57:1689–1692.
Aronica E, Crino P. (2011) Inflammation in epilepsy: clinical observa-
tions. Epilepsia 52(Suppl. 3):26–32.
Bartoszek M, Brenner AM, Szefler SJ. (1987) Prednisolone and methyl-
prednisolone kinetics in children receiving anticonvulsant therapy.
Clin Pharmacol Ther 42:424–432.
Chung WH, Hung SI, Chen YT. (2010) Genetic predisposition of life-
threatening antiepileptic-induced skin reactions. Expert Opin Drug
Saf 9:15–21.
Cumbo-Nacheli G, Weinberger J, Alkhalil M, Thati M, Baptist AP.
(2008) Anticonvulsant hypersensitivity syndrome: is there a role for
immunomodulation? Epilepsia 49:2108–2112.
de Jonge ME, Huitema ADR, van Dam SM, Beijnen JH, Rodenhuis S.
(2005) Significant induction of cyclophosphamide and thiotepa
metabolism by phenytoin. Cancer Chemother Pharmacol 55:507–
510.
Elzagallaai AA, Knowles SR, Rieder MJ, Bend JR, Shear NH, Koren G.
(2009a) In vitro testing for the diagnosis of anticonvulsant hypersen-
sitivity syndrome: a systematic review. Mol Diagn Ther 13:313–330.
Elzagallaai AA, Knowles SR, Rieder MJ, Bend JR, Shear NH, Koren G.
(2009b) Patch testing for the diagnosis of anticonvulsant hypersensi-
tivity syndrome: a systematic review. Drug Saf 32:391–408.
Friedman A, Dingledine R. (2011) Molecular cascades that mediate the
influence of inflammation on epilepsy. Epilepsia 52(Suppl. 3):33–38.
Gilhus NE, Lea T. (1988) Carbamazepine: effect on IgG subclasses in
epileptic patients. Epilepsia 29:317–320.
Goto M, Ohnishi C, Yamashina H, Johno I, Kitazawa S. (1987) Effect of
valproic acid on pharmacokinetic active metabolites of cyclophos-
phamide in mice. J Pharmacobiodyn 10:8–14.
Hirsch LJ, Arif H, Nahm EA, Buchsbaum R, Resor SR Jr, Bazil CW.
(2008) Cross-sensitivity of skin rashes with antiepileptic drug use.
Neurology 71:1527–1534.
Ichiyama T, Okada K, Lipton JM, Matsubara T, Hayashi T, Furukawa S.
(2000) Sodium valproate inhibits production of TNF-a and IL-6 and
activation of NF-jB. Brain Res 857:246–251.
Johannessen Landmark C, Patsalos PN. (2010) Drug interactions involv-
ing the new second- and third-generation antiepileptic drugs. Expert
Rev Neurother 10:119–140.
Kim JE, Choi HC, Song HK, Jo SM, Kim DS, Choi SY, Kim YI, Kang
TC. (2010) Levetiracetam inhibits interleukin-1 beta inflammatory
responses in the hippocampus and pyriform cortex of epileptic rats.
Neurosci Lett 471:94–99.
Epilepsia, 52(Suppl. 3):40–44, 2011
doi: 10.1111/j.1528-1167.2011.03035.x
Lackner TE. (1991) Interaction of dexamethasone with phenytoin. Phar-
macotherapy 11:344–347.
Lawson LA, Brenner AM, Szefler SJ. (1981) Phenytoin-dexamethasone
interaction: a previously unreported observation. Surg Neurol 16:23–
24.
Moder T, Domeij H, Andurn I, Mustafa M, Brunius G. (2000) Effect of
phenytoin on the production of interleukin-6 and interleukin-8 in
human gingival fibroblasts. J Oral Pathol Med 29:491–499.
Pacifici R, Paris L, Di Carlo S, Pichini S, Zuccaro P. (1991) Immunologic
aspects of carbamazepine treatment in epileptic patients. Epilepsia
32:122–127.
Pacifici R, Zuccaro P, Iannetti P, Raucci U, Imperato C. (1995) Immuno-
logic aspects of vigabatrin treatment in epileptic children. Epilepsia
36:423–426.
Patsalos PN. (2005) Anti-epileptic drug interactions – a clinical guide.
Clarius Press, Guildford, UK.
Patsalos PN, Bourgeois BFD. (2010) The epilepsy prescriber's
guide to antiepileptic drugs. Cambridge University Press, Cam-
bridge, UK.
Patsalos PN, Froscher W, Pisani F, van Rijn CM. (2002) The importance
of drug interactions in epilepsy therapy. Epilepsia 43:365–385.
Riva M, Landonio G, Defanti CA, Siena S. (2000) The effects of anticon-
vulsant drugs on blood levels of methotrexate. J Neuro-Oncol
48:249–250.
Sasaki T, Maita E. (1998) Increased bFGF level in the serum of patients
with phenytoin-induced gingival overgrowth. J Clin Periodontol
25:42–47.
Schlienger RG, Shear NH. (1998) Antiepileptic drug hypersensitivity
syndrome. Epilepsia 39(suppl):S3–S7.
Shiah IS, Yatham LN, Yeh CB, Ravindran AV. (2005) Effect of valpro-
ate on plasma levels of interleukin-6 in healthy male humans. Int Clin
Psychopharmacol 20:295–298.
Sume SS, Kantarci A, Lee A, Hasturk H, Trackman PC. (2010) Epithelial
to mesenchymal transition in gingival overgrowth. Am J Pathol
177:208–218.
Thilo B, Stingele R, Knudsen K, Boor R, Bien CG, Deuschl G, Lang N.
(2009) A case of Rasmussen encephalitis treated with rituximab. Nat
Rev Neurol 5:458–462.
Verrotti A, Basciani F, Trotta D, Greco R, Morgese G, Chiarelli F. (2001)
Effect of anticonvulsant drugs on interleukins-1, -2 and -6 and mono-
cyte chemoattractant protein-1. Clin Exp Med 1:133–136.
Wei M, Li L, Meng R, Fan Y, Liu Y, Tao L, Liu X, Wu C. (2010) Sup-
pressive effect of diazepam on IFN-c production by human T cells.
Int Immunopharmacol 10:267–271.
Wolkenstein P, Revuz J. (1995) Drug-induced severe skin reactions: inci-
dence, management and prevention. Drug Saf 13:56–68.