Review

General

Impact of phenytoin therapy on

the skin and skin disease
Noah Scheinfeld
1. Introduction Department of Dermatology, St.-Lukes Roosevelt Hospital Center, 1090 Amsterdam Avenue, Suite 11D,
2. Immune function and New York, NY 10025, USA
phenytoin
Phenytoin (diphenylhydantoin; Dilantin®, ALZA Corp.) is a highly effective and
3. Cutaneous side effects
widely prescribed anticonvulsant agent used in the treatment of focal and
4. Psuedolymphoma tonic clonic generalised seizures. The side effects of phenytoin can occassion-
5. Collagen vascular-like ally engender significant morbidity. Phenytoin can induce generalised erup-
side effects tions that include: a maculopapular exanthem, Stevens–Johnson syndrome,
6. Intravenous phenytoin generalised exfoliative dermatitis, toxic epidermal necrolysis, vasculitis and
fixed drug eruptions. Phenytoin is linked to a hypersensitivity syndrome that
7. Fosphenytoin
manifests with fever, rash and lymphadenopathy. Patients receiving phenytoin
8. Birth defects
may develop pseudolymphoma or, rarely, malignant lymphoma and mycosis
9. Expert opinion and conclusion fungoides-like lesions. Rarer cutaneous side effects include drug-induced
lupus, purple hand syndrome, pigmentary alterations and IgA bullous derma-
tosis. Phenytoin can effect clotting function and alter vitamin and mineral lev-
els. Prenatal exposure to phenytoin may result in a spectrum of structural,
developmental and behavioural changes, known as the fetal hydantoin syn-
drome. Patients who use phenytoin in the long-term commonly manifest with
gingival hyperplasia, coarsening of the facies, and hirsutism.

Keywords: dilantin, fetal hydantoin syndrome (FHS), gingival hyperplasia, hypersensitivity

syndrome, phenytoin, pseudolymphoma, purple hand syndrome

Expert Opin. Drug Saf. (2004) 3(6):655-665

1. Introduction

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In 1938, Merritt and Putnam reported that phenytoin effectively treated focal onset
and secondarily generalised seizures [1]. Over the past 50 years, phenytoin (Figure 1)
(diphenylhydantoin; Dilantin®, ALZA Corp.) has been demonstrated to be a highly
effective anticonvulsant. Decades later, it continues to be used as an anticonvulsant
agent in the treatment of generalised and focal epilepsy. It is part of the hydantoin
family that includes, mephenytoin (Mesantoin®, Novartis Pharmaceuticals), pheny-
lethylhydantoin and fosphenytoin. Despite its effectiveness, because of the tolerability
issues addressed in this article, recent anti-epileptic drug expert guidelines consider
phenytoin as a second-line drug, particularly in women and children. In developing
countries, phenytoin continues to be a first-line agent due to its low cost.
Phenytoin has been investigated as a treatment for > 100 diseases. A Medline search
in August 2004 showed that since 1966, 13,384 articles mentioning phenytoin have
been published. In dermatology, phenytoin has been investigated to treat ulcers, epi-
dermolysis bullosa and inflammatory conditions. The use of phenytoin has been
linked with numerous allergic and proliferative idiosyncratic cutaneous side effects [2].
They have been reviewed recently [3], but are more extensively reviewed in this article.

2. Immune function and phenytoin

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The alterations in the immune system induced by phenytoin are manifold. Although
phenytoin does not effect lymphokine-activated killer (LAK) cells, it suppresses the
cytotoxic activities of cells such as natural killer (NK) cells and cytotoxic

10.1517/14740338.3.5.655 © 2004 Ashley Publications Ltd ISSN 1474-0338 655

Impact of phenytoin therapy on the skin and skin disease
H
N
O
N the children and was in the mesio-distal dimension of the gin-
H
O gival papillae [14].
Figure 1. The molecular structure of phenytoin.
T lymphocytes (CTLs) [4]. Phenytoin treatment preferentially
induces a TH2 type response [5]. In a dose-dependent manner,
phenytoin can robustly depress IFN augmentation of NK cell
cytotoxicity [6]. The production of cortisol is suppressed by
phenytoin. Importantly, phenytoin induces the liver cyto-
chrome P450 enzyme system and stimulates steroid clearance
[7]. Phenytoin is also able to induce adrenal suppression. These
alterations of immune and systemic function undoubtedly
underline the cutaneous side effects that phenytoin induces.
3. Cutaneous side effects
3.1 Incidence
The reported incidence of eruptions with phenytoin use var-
ies. One study noted the incidence of cutaneous reactions in
head injury patients that were receiving phenytoin, for sei-
zure prophylaxis, as 19.4% [8]. A different study suggested
that 5 – 10% of patients taking phenytoin experience a cuta-
neous reaction; specifically, 5% of children have a transient
maculopapular exanthems often within 3 weeks of drug initi-
ation. A higher incidence is observed if a high loading dose is
given [9]. Another review stated that 2 – 3% of patients tak-
ing phenytoin develop exanthems [10]. It seems likely that dif-
ferent subsets of patients have different incidences of
cutaneous side effects, although stratification of the inci-
dence of side effects requires further definition.
3.2Non-inflammatory side effects of long-term
use of phenytoin
There are a few common cutaneous non-inflammatory side
effects of chronic phenytoin use. The most important of these
are hirsutism, gingival hyperplasia and coarse facies. In a study
done in Addis Ababa University, Ethiopia, of the 89 patients
who were taking phenytoin for long periods, either singly or
combined with phenobarbitone, dysmorphic and idiosyn-
cratic side effects including gum hypertrophy, hirsutism, acne
and skin rash were observed in 37 patients (41.6%) [11].
Gingival hyperplasia can be painful and may interfere with
eating, speech and appearance. Based on studies of institu-
tionalised patients, between 13 – 50% of patients on
long-term phenytoin therapy will develop gingival hyperplasia
[12]. Some have found a lower incidence of gingival hyperpla-
sia and have attributed to the simultaneous use of phenobar-
bital or carbamazepine [13]. Thirty children aged 8 – 13 years
with epileptic disorders and receiving monotherapy with
656 Expert Opin. Drug Saf. (2004) 3(6)
phenytoin were selected from the Departments of Pediatrics
and Neurology of Post Graduate Institute of Medical Educa-
tion and Research, Chandigarh, India, to evaluate the devel-
opment of gingival overgrowth induced by phenytoin over a
period of 6 months. Gingival overgrowth occurred in 57% of
Proposed mechanisms of drug-induced gingival hyperpla-
sia include inflammation from bacterial plaque (poor oral
hygiene), increased sulfated glycosaminoglycans, immu-
noglobulins, gingival fibroblast phenotype population dif-
ferences, epithelial growth factor, pharmacokinetics and
tissue binding, collagenase activation, disruption of fibro-
blast cellular sodium/calcium flux, folic acid and combina-
tions of these factors [15]. Patients with gingival hyperplasia
secondary to phenytoin use are likely to have fibroblasts
that are growth sensitive to phenytoin [16]. Fibroblasts
derived from phenytoin-induced gingival hyperplasia syn-
thesised a greater amount of total protein and collagen than
the rest of the cell types, based on both the amount of total
protein and protein:micrograms DNA [17]. Phenytoin and
cyclosporin A specifically regulate macrophage phenotype,
and expression of platelet-derived growth factor (PDGF)
and IL-1 in vitro and in vivo; possible molecular mechanism
of drug-induced gingival hyperplasia. Specifically, the clini-
cal presentation of inflamed and hyperplastic gingival tis-
sues is associated with specific macrophages phenotypes,
which express the pro-inflammatory cytokine IL-1β in
inflamed tissues or the essential polypeptide growth factor
PDGF-B in phenytoin-induced hyperplastic tissues [18].
Some have speculated the proliferative inflammation
observed with drugs such as phenytoin, nifedipine and
cyclosporin may be initiated by the formation of reactive
metabolites and that the formation of these metabolites
may be catalysed by one or more cytochromes found in the
gingival. These metabolites may then cause cellular injury
and induce a reactive inflammatory response, followed by
fibroblastic proliferation, leading to the excess collagen
deposition observed with gingival hyperplasia [19].
Coarsening of the facies, enlargement of the lips and/or
thickening of the scalp and face can occur in patients who
take phenytoin for long periods [20]. In this study, one-third
of patients receiving phenytoin, all of whom were institution-
alised, had this side effect [21]. Coarse facies developed in one
phenytoin-treated sister of each of two pairs of identical
twins [22]. Phenytoin has been implicated in the induction of
rhinophyma [23].
Phenytoin has also been linked to the induction of hir-
sutism [24]. Hirsutism occurs in ∼ 12% of children receiving
phenytoin, usually within 3 months of initiating therapy [25].
It occurs on the extensor surfaces of the extremities and on the
trunk and face. It usually resolves within one year of discon-
tinuing therapy, but can on occasion persist.
A variety of other non-inflammatory cutaneous alterations
have been noted in epileptic patients who have taken

Table 1. Inflammatory eruptions and oral phenytoin.
Common Occasional
Maculopapular exanthem Toxic epidermal necrolysis
Stevens–Johnson syndrome
Generalised exfoliative dermatitis
(erythroderma)
Leukocytoclastic vasculitis
Fixed drug eruptions
Pseudolymphoma (hypersensitivity
syndrome)
Follicular or pustular eruptions
Angioedema
phenytoin or other convulsants, both together or consecu-
tively. A South African study compared cutaneous conditions
occurring in 173 epileptic patients aged 6 – 19 years com-
pared with 211 age-matched controls. Anticonvulsants used
alone or in combination, were carbamazepine in 54.9%,
phenytoin in 47.8%, barbiturates in 36.6%, and ethosux-
imide in 11.2%. The most frequent combination was pheny-
toin and carbamazepine, used by 14% of males and 18.4% of
females. Hirsutism was found in 43.9% of the female epilep-
tic patients compared to 7.5% of controls. Punctate and linear
scars on the dorsum of the hands of 27.7% epileptic patients
compared to 3.8% non-epileptic patients. Both ephilides and
naevocellular nevi occurred in 12.7% of the epileptic patients
compared to 29.4 and 52.1%, respectively, of controls. Leu-
konychia was found in 52% of epileptic patients and 28.9%
of non-epileptic patients. Acne occurred in 80.3% of epileptic
female patients compared to 30.2% of non-epileptic female
patients. These results were roughly replicated in a Brazilian
study [26]. These results differ from a study that found that
neither the prevalence of acne nor the sebum excretion rate
significantly increased in 243 patients taking phenytoin or
other convulsants, compared with the 2167 non-medicated
controls [27]. Alopecia has also been linked to anticonvulsant
and phenytoin use [28].
The non-inflammatory alterations that phenytoin induces
are likely to have a complex basis. As stated above, phenytoin
alters the functioning of fibroblasts. In addition, phenytoin
promotes early and marked angiogenesis, resulting in
increased collagen deposition [29].
3.3 Vitamins, minerals and phenytoin
Alterations of vitamin levels can occur with the use of pheny-
toin. In children, pellagrous dermatitis has been induced by
the use of phenytoin [30]. This effect has been noted in combi-
nation with other medications in a mentally handicapped
patient who promptly responded to vitamin therapy [31].
Biotin is a water-soluble vitamin that acts as an essential
cofactor for four carboxylases, each of which catalyses an
Expert Opin. Drug Saf. (2004) 3(6)
Scheinfeld
Rare Very rare
Pigmentary alterations Disseminated intravascular
coagulation with purpura fulminans
Drug-induced lupus Malignant lymphoma
Porphyria (induction or Mycosis fungoides
unmasking)
Linear IgA disease
Dermatomyositis
Systemic sclerosis
Pseudo-Sjogren's syndrome
essential step in intermediary metabolism (e.g., acetyl-CoA
carboxylase catalyses the rate-limiting step in fatty acid elonga-
tion), and biotin deficiency causes a variety of eruptions [32]. In
infants, children and adults it results in alopecia and a distinc-
tive scaly, erythematous mucosal dermatitis resembling the
eruption of zinc deficiency from which Candida albicans can
often be cultured. There is evidence that impaired fatty acid
metabolism secondary to reduced activities of the
biotin-dependent carboxylases (especially acetyl-CoA carboxy-
lase) plays an aetiologicol role in the dermatological manifesta-
tions of biotin deficiency. Candida infections secondary to
impaired immune function might also contribute to the der-
matitis of biotin deficiency. Phenytoin can affect biotin metab-
olism [33]. This effect has been marked with long-term therapy
[34] and has been speculated to be one cause of the eruptions
that phenytoin induces [35] and has been a subject of basic
research [36]. Phenytoin can decrease folic acid levels [37].
Copper, zinc and magnesium in the hair, skin and serum
of epileptic patients can be affected by the use of phenytoin
[38]. In one study, the levels of serum copper, serum zinc, cop-
per/zinc superoxide dismutase and malondialdehyde were
significantly increased, but the glutathione level was signifi-
cantly decreased in epileptic patients using phenytoin mono-
therapy, compared with those of the controls [39]. Others too
have reported increases in serum copper levels [40]. Some have
reported zinc deficiency in users of phenytoin and others
have reported that zinc levels in controls and users are the
same [41]. The clinical effects of these alterations in mineral
levels are unclear [42].
3.4 Inflammatory and generalised eruptions
Phenytoin can induce a variety of inflammatory and general-
ised skin changes and systemic complications (Table 1) that
include: maculopapular eruptions, Stevens–Johnson syn-
drome (SJS), generalised exfoliative dermatitis, toxic epider-
mal necrolysis, vasculitis [43], follicular or pustular eruptions,
erythema multiforme, angioedema and fixed drug eruptions.
To understand the relative frequency of these eruptions,
657
Impact of phenytoin therapy on the skin and skin disease
researchers reviewed the records of 42 hospitalised patients
with phenytoin reactions. The cutaneous manifestations
reported were maculopapular eruptions (71.4%), SJS
(14.3%), fever (4.8%), generalised exfoliative dermatitis
(2.4%), toxic epidermal necrolysis (2.4%), vasculitis (2.4%)
and agranulocytosis (2.4%) [44]. In a large study, 4% of fixed
drug eruptions were caused by phenytoin, many of which
were generalised [45].
There might be role for patch testing to test for allergy to
phenytoin. In a Spanish study of 15 patients with reactions to
anticonvulsant medications, 12 produced positive patch tests
(done with 5% medication preparations in petrolatum and
aqueous preparations, respectively) – 6 with carbamazepine,
3 with phenytoin and, 1 each with lamotrigine, sodium val-
proate and phenobarbital [46]. One article states allergy to
phenytoin can be assessed with patch testing in 60% of cases,
thus patch test is a useful tool in confirming the diagnosis of
drug rashes and warrants further studies [47]. In a case of an
infectious mononucleosis-like drug reaction that occurred as a
manifestation of carbamazepine-induced anticonvulsant
hypersensitivity, patch testing to carbamazepine and pheny-
toin were positive, but negative to phenobarbital, suggesting
that patch testing might be useful in the diagnosis of anticon-
vulsant hypersensitivity syndrome [48]. Exposing the lym-
phocytes of patients with anticonvulsant syndrome to
phenytoin, phenobarbital and carbamazepine anticonvulsant
drug metabolites generated in vitro by a murine hepatic micro-
somal system demonstrated cytotoxicity (% dead cells) that
exceeded three standard deviations above the mean result for
controls [49]. This study shows that, at least in terms of anti-
convulsant syndrome, the effects of phenytoin can be repro-
ducibly assessed. Despite these reports, standard textbooks on
patch and allergy testing do not explicate the role of patch and
allergy testing in assessing for anticonvulsant allergy.
Some of the eruptions induced by phenytoin only occur in
combination with other medications or treatments. This con-
cept is suggested by a report of a man who developed acne
keloidalis-like lesions in the scalp during treatment with
phenytoin and carbamazepine [50]. Combined intake of
phenytoin, corticosteroids and H2-blockers resulted in cases
of toxic epidermal necrolysis, exanthematous eruption and
hypersensitivity syndrome [51]. A number of cases have been
noted in which serious adverse drug reactions, such as toxic
epidermal necrolysis and SJS, have occurred following pheny-
toin exposure.
The use of radiation and phenytoin has been seen to
increase the risk of cutaneous side effects, such as erythema
multiforme or toxic epidermal necrolysis. The combination of
radiation therapy and pheyntoin appears to increase the inci-
dence of SJS [52]. Ahmed et al. [53] suggested using the acro-
nym ‘EMPACT’ (E: erythema; M: multiforme; associated
with P: phenytoin; A: and; C: cranial, radiation; T: therapy)
to best describe such cases. They reviewed 24 cases and noted
that the mean patient age was 44 years (range: 23 – 67) and
no sexual predisposition was noted. All patients had taken
658 Expert Opin. Drug Saf. (2004) 3(6)
phenytoin for variable time periods (range 16 – 80 days;
mean: 40) and were on the medication when the skin lesions
first appeared. These lesions developed within the port site
during the radiation treatments (11 cases) or soon after
(9 cases) its completion (mean: 16 days; range: 2 – 35). Subse-
quent disease evolution to erythema migrans major occurred
in all cases (SJS developed in 73% of patients). No relation-
ship was identified between the extent and the severity of the
skin lesions with the phenytoin and radiation dosages, and
with the histological type and origin of the intracranial malig-
nancy. None of the patients demonstrated the requisite fea-
tures of the phenytoin hypersensitivity syndrome. Although, a
systemic steroid taper was employed in 10 out of the
14 patients before the development of the skin lesions, the
subsequent progression of the skin lesions was not influenced
by the use of systemic steroid therapy. Complete recovery
occurred in all but two patients typically within 1 – 8 weeks
of phenytoin discontinuation. Some reports have noted the
effect of radiation therapy and the tapering of steroid dose on
the pathogenesis of these reactions [54].
Altuntas et al. [55] presented a case of phenytoin-induced
cholestatic hepatotoxicity in a 47-year-old woman who had
exfoliative dermatitis, an increase in liver enzymes with a
cholestatic pattern and eosinophilia after 25 days of pheny-
toin therapy. Clinical evaluation admitted no other possible
causes, and the results of a percutaneous liver biopsy were
consistent with drug-induced toxic hepatitis. Within three
weeks after discontinuing phenytoin therapy, her liver func-
tion tests returned to normal values.
3.5 Hypersensitivity syndrome
Phenytoin causes a hypersensitivity syndrome that manifests
with fever, rash and lymphadenopathy [56]. This syndrome can
also occur with an increase in the count of eosinophils. The
incidence of phenytoin hypersensitivity syndrome is 1 in
1000 – 10,000 exposures [57]. Such a hypersensitivity syndrome
can also occur with the use of other aromatic anti-epileptic
drugs: carbamazepine, phenobarbital and primidone. There is
frequent cross sensitivity between the aforementioned agents as
it pertains to the induction of hypersensivity syndrome [58].
Hypersensitivity syndrome usually occurs 2 – 8 weeks after ini-
tiation of therapy and is associated with the reactivation of
human herpesvirus 6 [59]. It has also been linked to seroconver-
sion to human herpes virus 6 [60]. A report has noted co-inci-
dent reactivation of cytomegalovirus [61].
Often, its initial sign is fever with malaise and pharyngitis,
sometimes with a strawberry tongue. An eruption follows.
This eruption can manifest almost any type of rash from a
bland macularpapular exanthem to toxic epidermal necrolysis.
This eruption can manifest as erythroderma [62] or can mimic
the exanthem of staphylococcal toxic shock syndrome [63] or
infectious mononucleosis [64]. It can manifest with a general-
ised pustular eruption [65], which can be follicular based [66].
Systemic involvement is common in this syndrome. The
liver, kidney, CNS or lungs may be involved in hypersensitivity

syndrome. Hypothyroidism may occur ∼ 2 months after the
initial symptom outbreak of the syndrome. In most cases,
hypersensitivity syndrome usually manifests with elevated liver
enzymes and eosinophilia. The syndrome can demonstrate a
hepatitis that presents with jaundice [67].
Hypersensitivity syndrome is most effectively treated by
immediate discontinuation of phenytoin – this is the essential
element of effective therapy. Valproic acid can usually be sub-
stituted with minimal concern for cross-reactivity, but should
be cautiously in the face of hepatitis. Gabapentin [68] and
lamotrigine [56] do not generally induce hypersensitivity syn-
drome in those who suffer from phenytoin-induced hypersen-
sitivity syndrome. Patients with phenytoin-induced
hypersensitivity syndrome can sometimes be managed sup-
portively with hydration, antihistamines, H2-receptor block-
ers, and topical corticosteroids. Usually, systemic
corticosteroids (1 mg/kg/day) should be used for at least
one month. Some state that use of intravenous immunoglob-
ulin should be limited to severe cases in which Kawasaki dis-
ease or idiopathic thrombocytopenic purpura remain
diagnostic concerns [69]. Some have found intravenous immu-
noglobulin very effective in the treatment of this disease [70].
The aetiology of hypersensitivity syndrome is complex [71].
The aromatic anticonvulsants are metabolised to hydroxylated
aromatic compounds, such as arene oxides. If detoxification of
this toxic metabolite is insufficient, the toxic metabolite may
bind to cellular macromolecules, causing cell necrosis or a sec-
ondary immunological response. Anticonvulsant hypersensitiv-
ity syndrome has been linked to a defect in the enzyme epoxide
hydrolase [72]. It has been suggested that its incidence is highest
in elderly black males [73]. It appears to be familial in incidence.
Anticonvulsant hypersensitivity seems to be much more aggres-
sive in patients undergoing concomitant radiotherapy [74].
Anticonvulsant hypersensitivity syndrome was reported in a
patient with a previous history of Hodgkin’s lymphoma [75].
3.6 Other eruptions
Cutaneous pigmentation can be effected by the use of pheny-
toin. Phenytoin can induce chloasma and melasma. In one
patient, phenytoin increased skin pigmentation and hir-
sutism, manifested with a decrease in serum IgA level, and
apparently unmasked hereditary coproporphyria [76].
Acquired acromelanosis has been caused by phenytoin [77].
Universal cutaneous depigmentation following pheny-
toin-induced toxic epidermal necrolysis has been noted [78].
Phenytoin can induce porphyria. It can also unmask acute
intermittent porphyria [79] and affect the development of por-
phyria cutanea tarda [80]. It has also led to the development of
unclassified porphyria [81]. It can be part of the multifactorial
development of porphyria [82]. Acute intermittent porphyria
has occurred in patients on phentoin therapy and with normal
erythrocyte porphobilinogen deaminase activity [83].
Inflammatory skin diseases are rarely induced by pheny-
toin. Cutaneous necrosis, which demonstrated multinucleate
epidermal cells on biopsy, associated with intravenous
Expert Opin. Drug Saf. (2004) 3(6)
Scheinfeld
phenytoin has been reported [84]. Phenytoin has been linked
to drug-induced linear IgA bullous dermatosis [85]. It may be
linked to the development of sarcoidosis [86], specifically pul-
monary sarcoidosis [87]. Thickening of the heel-pad associated
with long-term phenytoin therapy has been reported [88].
Phenytoin-induced linear IgA dermatosis, mimicking toxic
epidermal necrolysis, has been reported to occur [89].
4. Psuedolymphoma
Pseudolymphoma associated with phenytoin use has a variety
of cutaneous manifestions. Patients receiving phenytoin may
develop benign lymphoid hyperplasia [90], pseudolymphoma,
pseudo-pseudolymphoma [91], or rarely, malignant lymphoma
[92]. Lymphoid hyperplasia can be localised in the cervical area
[93]. Enlarged inguinal lymph nodes while receiving chronic
phenytoin therapy have been reported [94]. Generalised nodu-
lar lesions can occur as a manifestation of pseudolymphoma
[95]. To diagnose such patients, documentation of their history
of phenytoin use is necessary. Southern blots, gene rearrange-
ment studies and chromosome studies are important tools in
differentiating pseudolymphoma from malignant lymphoma
in patients receiving chronic therapy [96].
In an important study, Choi et al. studied clinicopatholog-
ical and genotypic aspects of anticonvulsant-induced pseudo-
lymphoma syndrome (this is likely a variation of
hypersensitivity syndrome) [97]. The causative agents were
carbamazepine (four cases), phenytoin (two cases), pheno-
barbital (one case) and valproic acid (one case). A cross-reac-
tion between phenobarbital and phenytoin was observed in
one case. The eruptions were generalised maculopapular
eruptions in all cases, including one case accompanied by
vesiculopustular lesions and occurred 3 – 24 weeks (mean:
7 weeks) after initiation of treatment. The frequencies of the
associated features were as follows: facial oedema (88%),
fever (75%), lymphadenopathy (63%) and hepatomegaly
(25%). Laboratory findings revealed leukocytosis, atypical
lymphocytes, eosinophilia, monocytosis, neutrophilia,
lymphocytosis and abnormal liver function. Histopathologi-
cally, there was similarity between pseudolymphoma syn-
drome and mycosis fungoides, in that epidermotrophism of
atypical lymphocytes (100%) and Pautrier’s microabscess-
like structures (38%) were observed. However, pseudolym-
phoma syndrome has some differences from mycosis fun-
goides, including moderate-to-marked spongiosis (75%),
necrotic keratinocytes (63%), infiltration of eosinophils
(25%) in the epidermis and in the dermis, papillary dermal
oedema (100%), extravasated erythrocytes (100%), lym-
phocytes within the dermis larger than those within the epi-
dermis (63%), and infiltration of various inflammatory cells
including neutrophils (50%). Genotypic analysis showed a
rearrangement of the T cell receptor-γ gene in one of eight
cases studied. In Choi’s series, there were no deaths and all
cases were improved at two to nine weeks (mean six weeks)
after the cessation of the anticonvulsant, systemic and topical
659
Impact of phenytoin therapy on the skin and skin disease
corticosteroid therapy, and symptomatic therapy. When
comparing agents, there were no significant differences in
clinical, laboratory and histological findings.
Phenytoin-induced pseudolymphoma can present as myco-
sis fungoides [98]. Such presentations can be associated with
lymphocyte dysregulation [99]. Mycosis fungoides-like lesions
associated with phenytoin and carbamazepine therapy have
been noted [100]. In a cancer patient, phenytoin resulted in a
mycosis fungoides-like eruption [101]. Two localised erythema-
tous plaques of mycosis fungoides were noted in a patient
whose eruption resolved three weeks after phenytoin was dis-
continued [102]. Other cases of mycosis fungoides-like patches,
which were in fact manifestations of the use of phenytoin,
have been localised [103].
Other forms of lymphoma have been associated with
phenytoin use. Pseudo-pseudolympoma is pseudolymphoma
that resolves when phenytoin is discontinued and that later
recurs as frank lymphoma. As stated above, it has been associ-
ated with phenytoin. Malignant lymphoma has been associ-
ated with phenytoin [104]. Phenytoin has been linked to
Hodgkin’s disease as well [105]. A history of prolonged pheny-
toin therapy was reported by 8 of 516 patients (1.6%) with
Hodgkin’s disease or non-Hodgkin’s lymphoma, as compared
with 3 of 516 patients (0.6%) with other cancers, and 2 of
516 (0.4%) tumour-free individuals showing a small increase
of malignancy with phenytoin use [106]. Another report found
a history of phenytoin use in 2.3% of lymphoma patients
compared to 0.6% of controls [107].
5. Collagen vascular-like side effects
Drug-induced lupus and collagen vascular diseases have been
associated with phenytoin use. Phenytoin has been said to
induce subacute lupus [108], dermatomyositis [109], systemic
lupus with vasculitis [110], systemic lupus with arthritic mani-
festations [111], and alopecia linked with lupus [112]. Lupus can
occur in children taking phenytoin [113]. One report has linked
phenytoin to the development of a systemic sclerosis-like dis-
ease [114] and a patient developed scleroderma while taking it
[115]. Phenytoin-induced pseudo-Sjogren’s syndrome, which
included infiltrated salivary glands, has been noted [116].
5.1 Vascular eruptions
Phenytoin can affect clotting function and result in eruptions
that are vascular in nature. Dilantin-induced disseminated
intravascular coagulation with purpura fulminans has
occurred [117]. A 12 year old boy developed a clinical picture
of high fever, scarlatiniform eruption, a haemorrhagic (purpu-
ric) skin lesion, on his buttocks and neck, stomatitis and con-
junctivitis, within 2 weeks after phenytoin administration
related to disseminated intravascular coagulation [118]. Pheny-
toin has induced serum sickness with fibrin-platelet thrombi
in lymph node microvasculature [119]. It can also cause lupus
anticoagulants and prothrombin deficiency, which can result
in thrombotic eruptions [120].
660 Expert Opin. Drug Saf. (2004) 3(6)
The effects of phenytoin have important implications in
pregnant women who are taking phenytoin to control their
seizures. Some articles note that vitamin K can be given to
females taking phenytoin in the third trimester of pregnancy in
order to prevent haemorrhage [121]. However, a policy of giving
vitamin K to all pregnant women being treated with anticon-
vulsants throughout the last third of pregnancy, as recently rec-
ommended, is not justified by the available evidence [122].
6. Intravenous phenytoin
Intravenous phenytoin (used most often to treat status epilep-
ticus) can cause purple hand syndrome [123]. Purple hand syn-
drome is characterised by oedema, discoloration, and pain
distal to the site of intravenous administration. In one study
of patients taking phenytoin, it occurred in 3 of 179 patients
treated [124]; in another study it occurred in 9 of 152 patients
treated with phenytoin [125]. Subacute local cutaneous reac-
tions in patients receiving intravenous phenytoin occurred in
29 of 115 patients studied (25.2%; 22 mild and 7 moderate);
all resolved within 3 weeks [126].
O’Brien et al. [126] prospectively examined the occurrence
of subacute local cutaneous reactions in patients receiving
intravenous phenytoin over a 12 month period at a general
hospital; local cutaneous reactions were detected in 29 of
115 patients (25.2%; 22 mild and 7 moderate). All resolved
within three weeks. Patients with local cutaneous reactions
were older (median: 68 versus 54.5 years; p = 0.004), were
more likely to be in a general ward (86 versus 66%;
p = 0.04), and had larger catheters (median: 16 G versus
18 G; p = 0.05). O’Brien et al. concluded that local cutane-
ous reactions are common in routine hospital practice, but
are generally mild and benign.
7. Fosphenytoin
Fosphenytoin is a water-soluble disodium phosphate ester of
phenytoin that is converted in the plasma to phenytoin.
Fosphenytoin is compatible with most common intravenous
solutions and can be administered safely through the
intramuscular route. An additional safety advantage of
fosphenytoin is the absence of propylene glycol in the
fosphenytoin formulation. Propylene glycol is used as a vehi-
cle in the intravenous phenytoin preparation and by itself may
produce serious cardiovascular complications. Fosphenytoin
administration resulted in significantly less venous irritation
and phlebitis compared with an equimolar dose of phenytoin
[127]. Fosphenytoin causes more pruritus than phenytoin [128].
In one study, it induced pruritus in 49% of cases [129].
8. Birth defects
Anticonvulsants taken in pregnancy are associated with an
increased risk of malformations and developmental delay in
the children [130]. The spectrum of structural, developmental
 Scheinfeld

and behavioural changes that may result from prenatal expo-
sure to phenytoin is known as fetal hydantoin syndrome
(FHS). A variety of malformations may be due to hydantoin
(phenytoin) intake during pregnancy. These malformations
include: growth retardation, digit and nail hypoplasia, typi-
cal facial appearance, rib anomalies, hirsutism, low hairlines,
and abnormal palmar creases. FHS is rarely associated with
ambiguous genitalia. A patient with the dysmorphic charac-
teristics of FHS has manifested on several fingernails with
unusual hyperpigmentation [131]. Another neonate mani-
fested with gum hypertrophy, digitalisation of the thumbs,
hypoplasia of the distal phalanges and nails, epicanthal
folds, pseudohypertelorism, epidermoid cyst, and geo-
graphic tongue [132]. Onychopathy can be a monosympto-
matic or mild form of this syndrome [133]. This syndrome
may be associated with neonatal acne [134]. Another report
observed two children of a mother treated with phenylhy-
dantoine for post-surgical epilepsy and noted the hand mal-
formation in one of them was indicative for a vascular
disruption sequence [135].
The relationship of phenytoin use and midline defects such
as facial clefts is unclear. A study reported an increase inci-
dence of facial clefts among epileptic patients and their chil-
dren [136]. However, another study did not bear this
relationship out [137]. Environmental factors are important in
the development of such clefts [138]. Until better evidence is
assembled, maternal epilepsy and phenytoin use seem of
minor importance in regard to cleft development [139].
9. Expert opinion and conclusion
The side effects of phenytoin continue to create significant
morbidity and must be assessed before therapy is instituted.
As noted above, despite its effectiveness, because of the tolera-
bility issues addressed in this article, most recent anti-epileptic
drug expert guidelines consider phenytoin as a second-line
drug, particularly in woman and children. In developing
countries, phenytoin continues to be a first-line agent due to
its low cost. Phenytoin can induce generalised eruptions that
include: a maculopapular exanthem, SJS, generalised exfolia-
tive dermatitis, toxic epidermal necrolysis, vasculitis and fixed
drug eruptions. Rare cutaneous side effects include
drug-induced lupus, purple hand syndrome, pigmentary
alterations and IgA bullous dermatosis. Phenytoin can induce
a hypersensitivity syndrome that manifests with fever, rash,
eosinophilia and lymphadenopathy. Patients receiving pheny-
toin may develop pseudolymphoma or, rarely, malignant lym-
phoma and mycosis fungoides. Phenytoin can alter clotting
function, vitamin levels and mineral levels. Prenatal exposure
to phenytoin may result in a spectrum of structural, develop-
mental, and behavioural changes known as FHS. Patients who
use phenytoin for long periods commonly manifest with gin-
gival hyperplasia, coarsening of the facies, and hirsutism. An
understanding of the cutaneous effects of phenytoin enhances
it appropriate use. Phenytoin is an important and effective
anticonvulsant that has a variety of cutaneous side effects that
must be fully understood for it to be used safely.

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Affiliation
Noah Scheinfeld MD
Department of Dermatology, St.-Lukes Roosevelt
Hospital Center, 1090 Amsterdam Avenue,
Suite 11D, New York, NY 10025, USA
Tel: +1 212 523 3888;
E-mail: Scheinfeld@earthlink.net.
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