Phenytoin in cutaneous medicine: Its uses, mechanisms and side effects
Department of Dermatology, St.-Lukes Roosevelt Hospital Center, New York
Phenytoin (diphenylhydantoin or Dilantin) is a highly effective and widely prescribed anticonvulsant agent used in the treatment of grand mal and psychomotor epilepsy. In dermatology, phenytoin has been used to treat ulcers, epidermolysis bullosa, and inflammatory conditions. Its mechanism appears to involve its ability to inhibit collagenase. Its topical use for the promotion of wound healing seems promising but requires further trials. The side effects of phenytoin continue to create significant morbidity. Common side effects include gingival hyperplasia, coarsening of the facies, and hirsutism. Rarer cutaneous side effects include drug-induced lupus, purple-hand syndrome, pigmentary alterations, and IgA bullous dermatosis. It can cause generalized cutaneous eruptions that include a maculopapular exanthem, Stevens-Johnson syndrome, generalized exfoliative dermatitis, toxic epidermal necrolysis, vasculitis, and fixed-drug eruptions. Phenytoin is linked to a hypersensitivity syndrome manifested by fever, rash, and lymphadenopathy. Patients receiving phenytoin may develop pseudolymphoma or, rarely, malignant lymphoma and mycosis-fungoides-like lesions. Phenytoin can effect clotting function. Phenytoin can alter vitamin and mineral levels. Prenatal exposure to phenytoin may result in a spectrum of structural, developmental, and behavioral changes known as the fetal hydantoin syndrome. After 60 years of use, phenytoin uses and mechanisms of action have yet to be fully defined; the drug remains a useful tool and an important subject for additional research.
In 1938, Merritt and Putnam published their noteworthy data using phenytoin to treat major, absence, and psychic equivalent seizures. Since that time, phenytoin (diphenylhydantoin or Dilantin) (Fig. 1) has been demonstrated to be a highly effective anticonvulsant. Even decades later, it continues to be a widely prescribed anticonvulsant and antiarrhythmic agent in the treatment of grand mal and psychomotor epilepsy. It is part of the hydantoin family that includes mephenytoin (Mesantoin), phenylethylhydantoin (Nirvanol), and fosphenytoin.
Phenytoin has been investigated as a treatment for more than 100 diseases. A Medline search in November of 2002 showed that 12,860 articles concerning it have been published since 1966. In dermatology, phenytoin has been investigated to treat ulcers, epidermolysis bullosa, and inflammatory conditions. Numerous allergic, and proliferative, idiosyncratic cutaneous side effects have been reported with its use. This review summarizes its uses, mechanisms, and cutaneous side effects.
Scientific basis and treatment of epidermolysis bullosa
Researchers have investigated the effects of phenytoin on a cellular level. In some patients with epidermolysis bullosa, levels of collagenase are increased. Phenytoin inhibits collagenase in-vitro. By inhibiting collagenase activity, phenytoin has been theorized to stabilize collagen fibrils and thus decrease blister formation. Phenytoin reduces the contraction of recessive dystrophic epidermolysis bullosa fibroblast populated collagen gels. Phenytoin modulates connective tissue metabolism and cell proliferation in human skin fibroblast cultures. When fibroblasts are embedded within freely contracting, relaxed, type I collagen matrices, they are insensitive to phenytoin. However, if fibroblasts are grown in collagen matrices that are nonretracting and under tension, phenytoin stimulates cell proliferation and inhibits collagenase activity. Patients with epidermolysis bullosa treated with phenytion had lower levels of inflammatory mediators such as arachidonic acid in plasma and erythrocyte phospholipids than did untreated epidermolysis bullosa patients.
Some studies have shown that phenytoin is useful in treating recessive dystrophic epidermolysis bullosa and in reducing its blister count.[9, 10] Such efficacy has been noted in case reports of single patients in Taiwan and Italy. It has been used in short- and long-term management of dystrophic epidermolysis bullosa. Phenytoin has been an adjunct in the management of esophageal stenosis in epidermolysis bullosa. The aforementioned studies not withstanding, however, a large study conducted by the Epidermolysis Bullosa Study Group did not find phenytoin effective in treating dystrophic epidermolysis bullosa.
Phenytoin appears more effective in the treatment of other epidermolysis bullosa variants. It has been used to treat junctional epidermolysis bullosa.[16, 17] In one case, it reduced blister formation by 50 percent after two months of treatment (2 mg/kg increased to 15 mg/kg/day with a serum level of 12-15 µg/ml). The disease flared 1 week after discontinuance. Another study found it effective in treating two patients with generalized atrophic benign EB (GABEB) and ineffective in treating two patients with Herlitz disease. Others have found it ineffective for treating junctional epidermolysis bullosa. It has been used to treat the Dowling-Meara variant of epidermolysis bullosa simplex. Topical phenytoin (2 %-5 % cream twice daily) has been found helpful in treating the ulcers of epidermolysis bullosa simplex.
Phenytoin has been studied (mostly with inadequate controls) in the healing of pressure ulcers, venous stasis ulcers, diabetic ulcers, traumatic wounds, and burns. Used topically, it appears to enhance healing without side effects. Its wound-related pharmacology has been investigated. Phenytoin increases gene expression of the platelet-derived growth factor B chain in macrophages and monocytes. Healthy granulation tissue appears earlier with phenytoin than with conventional saline dressings. Phenytoin may promote wound healing through multiple mechanisms, including stimulation of fibroblast proliferation, facilitation of collagen deposition, glucocorticoid antagonism, and antibacterial activity.
Phenytoin seems promising in enhancing the healing of decubitus ulcers. In a comparison involving 47 patients with stage II decubitus ulcers, treatment with phenytoin, DuoDerm® dressings or triple antibiotic ointment applications all resulted in reduction of the ulcers. However, the phenytoin group demonstrated more rapid results in all aspects of ulcer healing. Similarly, one study suggests that phenytoin may be superior to honey as a topical agent in the treatment of chronic ulcers.
Phenytoin has been used to treat ulcers that result from mycobacterial infections. It has been used orally and topically to treat the trophic ulcers of leprosy.[31, 32, 33] In such a role, it is more effective than saline. It can be used in the treatment of the Buruli ulcer of Mycobacterium ulcerans.
Topical phenytoin was used with good effect during the Iran-Iraq war when other resources were limited. In Iran, it was reported to have a role in treating 19 wounds caused by missiles and 6 refractory ulcers in civilians. In Iraq, it was reported that topical phenytoin in the treatment of war-related decubitus ulcers resulted in prompt pain relief, decreased wound exudate and bacterial contamination, in enhanced granulation-tissue formation, and in more rapid healing. Such results might make phenytoin a useful agent in countries with limited access to more expensive wound-care therapies.
Other inflammatory and genetic conditions
Phenytoin has been used to treat a variety of collagen vascular diseases, genetic, and inflammatory conditions. It has been used to treat linear scleroderma (en coup de sabre morphea) in children with good effect in the 1970s  and 1990s. It has been used in the treatment of discoid lupus erythematosus, but its effect was not confirmed in an evidence-based analysis. It can be used to treat the painful tonic-dystonic spasms in Sjögren syndrome. Phenytoin might have a role in treating pachyonychia congenita. It increases insulin sensitivity and might ameliorate acanthosis nigricans. Orally and topically, it has been used to treat lichen planus and oral lichen planus. It has been used with good effect to treat rheumatoid arthritis but appears to be less effective than gold salts. Its benefits can be sustained, and the usual dose is 300 mg/day for this condition. Phenytoin is not widely used for any of the aforementioned conditions.
Phenytoin has been used to treat neuropathic pain. It now appears, however, that gabapentin is preferred to treat such pain over other anticonvulsants. Carbamazepine and phenytoin were the first anticonvulsants to be used in controlled clinical trials and shown to relieve painful diabetic neuropathy and paroxysmal attacks in trigeminal neuralgia. However, an evidence-based review of these trials found them unproven in affect. Similarly, phenytoin was found ineffective in the treatment of diabetic symmetrical polyneuropathy.
Immune function and phenytoin
Phenytoin has complex effects on the immune system. Phenytoin suppresses cytotoxic activities of cells such as natural killer (NK) cells and cytotoxic T lymphocytes (CTL), but not lymphokine-activated killer (LAK) cells. Phenytoin treatment preferentially induces a Th2-type response. Phenytoin also significantly depresses interferon augmentation of NK cell cytotoxicity in a dose-dependent manner. Phenytoin suppresses the production of cortisol. Specifically, phenytoin induces the liver cytochrome P450 enzyme system and stimulates steroid clearance. It can also induce adrenal suppression. These effects may partially explain the side effects of phenytoin, which are forms of immune dysfunction.
Common side effects
There are a few common cutaneous side effects of phenytoin. About 50 percent of patients on long-term phenytoin therapy develop gingival hyperplasia. Long-term phenytoin can lead to a coarsening of the facies, enlargement of the lips, and thickening of the scalp and face. These changes occur in one-third of institutionalized patients on long-term therapy. Coarse facies develop in one phenytoin-treated sister of each of two pairs of identical twins.
Phenytoin can also cause hirsutism. It occurs in about 12 percent of children receiving phenytoin, usually within 3 months of initiating therapy. It occurs on the extensor surfaces of the extremities and on the trunk and face. It usually resolves within 1 year of discontinuing therapy but sometimes does not.
A variety of side effects have been noted in epileptics who have taken phenytoin or other convulsants both together or consecutively. A South African study compared cutaneous conditions occurring in 173 epileptics aged 6-19 compared with 211 age-matched controls. Anticonvulsants used singly or in combination were carbamazepine in 54.9 percent, phenytoin in 47.8 percent, barbiturates in 36.6 percent and ethosuximide in 11.2 percent. The most frequent combination was phenytoin and carbamazepine14 percent of males and 18.4 percent of females. Hirsutism was found in 43.9 percent of the female epileptics compared to 7.5 percent of controls. Punctate and linear scars on the dorsum of the hands of 27.7 percent epileptics compared to 3.8 percent nonepileptics. Both ephilides and nevocellular nevi occurred in 12.7 percent of the epileptics compared to 29.4 percent and 52.1 percent, respectively, of controls. Leukonychia was found in 52 percent of epileptics and 28.9 percent of nonepileptics. Acne incidence was 80.3 percent in epileptic compared to 30.2 percent in nonepileptic females. These results were roughly replicated in a Brazilian study. These results differ from a study that found no significant increase in the prevalence of acne nor the sebum excretion rate in 243 patients taking phenytoin or other convulsants compared with 2,167 unmedicated controls.
Collagen-vascular-like side effects
A number of reports have linked phenytoin to drug-induced lupus and collagen vascular disease. It has caused subacute lupus, dermatomyositis, systemic lupus with vasculitis, systemic lupus with arthritic manifestations, and alopecia linked with lupus. Lupus can occur in children taking phenytoin. One report has linked phenytoin to the development of a systemic sclerosis like disease, and one patient developed scleroderma while taking it. Phenytoin-induced pseudo-Sjögren syndrome that included infiltrated salivary glands has been noted.
Vitamin, minerals, and phenytoin
Phenytoin use can alter vitamin levels. Pellagrous dermatitis has been induced by phenytoin in children. This effect has been noted in combination with other medications in a mentally handicapped patient who promptly responded to vitamin therapy. Phenytoin can affect biotin metabolism. This effect has been marked with long-term therapy and has been speculated to be one cause of the eruptions induced by phenytoin and a subject of basic research. Phenytoin can decrease folic acid levels.
Phenytoin has a variety of effects on copper, zinc, and magnesium in the hair, skin, and serum of epileptics. In one study, the levels of serum copper, zinc, copper-zinc superoxide dismutase, and malondialdehyde were significantly increased, but the glutathione level was significantly decreased, in epileptic patients using phenytoin monotherapy compared with those of the controls. Others, too, have reported increases in serum copper levels. Some have reported zinc deficiency in users of phenytoin, and others have reported that zinc levels in controls and users are the same. The clinical effects of these alterations are unclear.
The effects of phenytoin on calcium are complex. In a study of institutionalized patients, those who took it had lower serum calcium than those who did not. In an American study, epilepsy, and its therapy, including the newer drugs, are risk factors for low bone density, irrespective of vitamin D levels. Skeletal monitoring with the institution of appropriate therapy is indicated in patients on chronic antiepileptic therapy. However, these effects were not replicated in a Brazilian study.
Phenytoins effects on blood chemistry are complex as well. High-density lipoprotein cholesterol (HDL-C) was significantly higher in the epileptic children than in two control groups: healthy non-epileptic children and epileptic children before starting anticonvulsant therapy.
Generalized cutaneous eruptions
The reported incidence of cutaneous eruptions with phenytoin use varies. Cutaneous reactions in patients with head injuries receiving phenytoin for seizure prophylaxis are seen in 19.4 percent. Another review estimated that 5-10 percent of patients have cutaneous reactions who take phenytoin; specifically, 5 percent of children have transient maculopapular exanthems often within 3 weeks of drug initiation; a higher percentage have these reactions if a high loading dose is given. Still another review stated 2-3 percent of patients taking phenytoin develop exanthems.
Phenytoin can induce a variety of generalized eruptions and systemic complications that include maculopapular eruptions, Stevens-Johnson syndrome, generalized exfoliative dermatitis, toxic epidermal necrolysis, vasculitis, follicular or pustular eruptions, erythema multiforme, angioedema, and fixed-drug eruptions. To understand the relative frequency of these eruptions, researchers reviewed the records of 42 hospitalized patients with phenytoin reactions. The cutaneous manifestations reported were maculopapular eruptions (71.4 %), Stevens-Johnson syndrome (14.3 %), fever (4 %), generalized exfoliative dermatitis (2.4 %), toxic epidermal necrolysis (2.4 %), vasculitis (2.4 %) and agranulocytosis (2.4 %). In a large study, 4 percent of fixed-drug eruptions were caused by phenytoin, many of which were generalized. Allergy to phenytoin can be assessed with patch testing in 60 percent of cases.
Some of the eruptions that phenytoin causes occur only in combination with other medications or treatments. This concept is suggested by a report of a man who developed acne-keloidalis-like lesions in the scalp during treatment with phenytoin and carbamazepine. Combined intake of phenytoin, corticosteroids, and H2-blockers has resulted in cases of toxic epidermal necrolysis, exanthematous eruption and hypersensitivity syndrome. The combination of radiation therapy, and pheyntoin appears to increase the incidence of Stevens-Johnson syndrome.
Phenytoin causes a hypersensitivity syndrome that manifests with fever, rash, and lymphadenopathy. Its incidence is one in 1,000-10,000 exposures. It is also seen with other aromatic antiepileptic drugs: carbamazepine, phenobarbital, and primidone, with frequent cross-sensitivity. Hypersensitivity syndrome usually occurs 2-8 weeks after initiation of therapy. In one case, hypersensitivity syndrome stimulated the reactivation of human herpesvirus 6. A report notes reactivation of cytomegalovirus.
Often its initial sign is fever with malaise and pharyngitis, sometimes with a strawberry tongue. An eruption follows and ranges from a macularpapular exanthem to toxic epidermal necrolysis. This eruption can manifest as erythroderma or can mimic the exanthem of staphylococcal toxic shock syndrome or infectious mononucleosis. It can manifest with a generalized pustular eruption, which can be follicular based. The liver is often involved. The kidney, central nervous system, or lungs may be involved in hypersensitivity syndrome. Hypothyroidism may occur about 2 months after initial symptom outbreak. Hypersensitivity syndrome usually manifests with elevated liver enzymes and eosinophilia. There can be a hepatitis that can manifest with jaundice.
Immediate discontinuation of phenytoin is the sine qua non of effective treatment of the hypersensitivity syndrome that it induces. Valproic acid can usually be substituted with minimal concern for cross-reactivity but should be used cautiously in the face of hepatitis. Gabapentin and lamotrigine do not generally induce hypersensitivity syndrome in those who suffer from phenytoin-induced hypersensitivity syndrome. Patients with phenytoin-induced hypersensitivity syndrome can somtimes be managed supportively with hydration, antihistamines, H2-receptor blockers, and topical corticosteroids. In the face of significant internal systemic reaction, systemic corticosteroids, starting at 1 mg/kg/day, should be used for at least 1 month. Tapering is often difficult without precipitating a flare. The use of intravenous immune globulin should be limited to severe cases in which Kawasaki disease or idiopathic thrombocytopenic purpura remain diagnostic concerns.
The etiology of hypersensitivity syndrome is complex. The aromatic anticonvulsants are metabolized 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 secondary immunological response. Anticonvulsant hypersensitivity syndrome has been linked to a defect in the enzyme epoxide hydrolase. It has been suggested that the incidence of this defect is highest in elderly black males. It appears to be familial.
Intravenous phenytoin (used most often to treat status epilepticus) can cause purple-hand syndrome. It is characterized by edema, discoloration, and pain distal to the site of intravenous administration. In one study of patients taking phenytoin, it occurred in 3 of 179 patients. In another study it occurred in 9 of 152 patients treated with phenytoin. Subacute local cutaneous reactions in patients receiving intravenous phenytoin occurred in 29 of 115 consecutive patients studied (25.2 %; 22 mild and 7 moderate); all resolved within 3 weeks. Cutaneous necrosis and multinucleate epidermal cells associated with intravenous phenytoin has been reported.
Fosphenytoin is a water-soluble disodium phosphate ester of phenytoin that is converted in plasma to phenytoin. Fosphenytoin is compatible with most common intravenous solutions and can be administered safely through the intramuscular route. An additional safety factor is the absence of propylene glycol in the fosphenytoin formulation. Propylene glycol is used as a vehicle 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. It causes more pruritus than phenytoin. In one study, it induced pruritus in 49 percent of cases. Further study of this ester of phenytoin will be needed to determine if it is a safer intravenous preparation to use in the long run.
Phenytoin can affect pigmentation. It can induce chloasma and melasma. Acquired acromelanosis has been caused by phenytoin. Universal cutaneous depigmentation following phenytoin-induced toxic epidermal necrolysis has been noted.
Phenytoin can induce porphyria. In one patient, phenytoin increased skin pigmentation and hirsutism, decreased serum IgA level, and apparently unmasked hereditary coproporphyria. It can also unmask acute intermittent porphyria.  Acute intermittent porphyria has occurred in patients on phentoin therapy with normal erythrocyte porphobilinogen deaminase activity. Phenytoin also can affect the development of porphyria cutanea tarda. It has also led to the development of unclassified porphyria. It can be part of the multifactorial development of porphyria.
Phenytoin rarely induces other types of inflammatory and disorders of keratinization. Phenytoin has been linked to drug-induced linear IgA bullous dermatosis. It may be linked to the development of sarcoidosis, specifically pulmonary sarcoidosis. Thickening of the heel pad associated with long-term phenytoin therapy has been reported.
Patients receiving phenytoin may develop benign lymphoid hyperplasia, pseudolymphoma, pseudo-pseudolymphoma, or, rarely, malignant lymphoma. Lymphoid hyperplasia can be localized in the cervical area. Enlargement of inguinal lymph nodes during chronic phenytoin therapy has been reported.
Pseudolymphoma has manifested with generalized nodular lesions. Obtaining a history of phenytoin use is crucial in the diagnosis of such patients. Southern blots, gene-rearrangement studies and chromosome studies are important tools in differentiating pseudolymphoma from malignant lymphoma in patients receiving chronic therapy.
Phenytoin-induced pseudolymphoma can have mycosis fungoides manifestations, sometimes with lymphocyte dysregulation. Mycosis-fungoides-like lesions associated with phenytoin and carbamazepine therapy have been noted elsewhere. Phenytoin resulted in a mycosis-fungoides-like eruption in cancer patient. Two localized erythematous plaques of mycosis fungoides were noted in a patient whose eruption resolved 3 weeks after phenytoin was discontinued. Other cases of mycosis-fungoides-like patches have been localized.
Lymphoma in several forms is associated with phenytoin. Cases have been reported of pseudolymphoma that resolved after phenytoin was discontinued only to recur as frank lymphoma. Other cases of malignant lymphoma have been associated with phenytoin. Phenytoin has been linked to Hodgkin disease as well. A history of prolonged phenytoin therapy was reported by 8 of 516 patients (1.6 %) with Hodgkin disease or non-Hodgkin lymphoma, as compared with 3 of 516 patients (0.6 %) with other cancers, and 2 of 516 (0.4 %) tumor-free individuals, showing a small increase of malignancy with phenytoin use. Another report found in phenytoin use in 2.3 percent of cancer patients compared to 0.6 percent of controls.
Phenytoin can effect clotting function and result in eruption. Dilantin-induced disseminated intravascular coagulation with purpura fulminans has occurred. A 12-year-old boy developed a clinical picture of high fever, scarlatiniform eruption, hemorrhagic (purpuric) skin lesions on his buttocks and neck, stomatitis, and conjunctivitis within 2 weeks after phenytoin administration, related to disseminated intravascular coagulation. Phenytoin has induced serum sickness with fibrin-platelet thrombi in lymph node microvasculature. It can also cause lupus anticoagulants and prothrombin deficiency, which can result in thrombotic eruptions. Some have suggested that vitamin K be given to mother taking phenytoin in third trimester to prevent hemorrhage. However, a policy of giving vitamin K throughout the last third of pregnancy to all women being treated with anticonvulsants, recently recommended, is not justified by the available evidence.
Prenatal exposure to phenytoin may result in a spectrum of structural, developmental, and behavioral changes known as the fetal hydantoin syndrome (FHS). Varied malformations caused by hydantoin (phenytoin) intake during pregnancy include digit and nail hypoplasia, growth retardation, typical facial appearance, rib anomalies, abnormal palmar creases, hirsutism, and low hairlines. Ambiguous genitalia are rarely associated with this syndrome. A patient with the dysmorphic characteristics of FHS has manifested with unusual hyperpigmentation of several fingernails. Another neonate manifested with gum hypertrophy, digitalization of the thumbs, hypoplasia of the distal phalanges and nails, epicanthal folds, pseudohypertelorism, epidermoid cyst, and geographic tongue. Onychopathy can be a monosymptomatic or mild form of this syndrome. This syndrome may be associated with neonatal acne.
One study noted an increase incidence of facial clefts among epileptic patients and their children with an uncertain relationship to therapy. Another study did not bear this relationship out. Environmental factors are important in the development of such clefts. In sum, epilepsy, and phenytoin use seem of minor importance in regard to cleft development.
Phenytoin increases the metabolism of ethinylestradiol and progestogens, necessitating oral contraceptive preparations containing at least 50 mcg of ethinylestradiol. It induces failure of levonorgestrel implants and mandates that medroxyprogesterone injections be given every 10 rather than 12 weeks.
After 60 years of use, phenytoin uses and mechanisms continue to be defined. The inhibition of collagenase by phenytoin gives it a real role in facilitating the healing of ulcers. As was the case with topical tacrolimus, optimizing the vehicle that contains the topical phenytoin might optimize its effects. Phenytoin also has complex effects on the immune system, in particular an induction of a Th2-type response, which might underlie its common induction of eruptions and immunologic effects. It can also be seen as an antagonist of cortisol and this might buttress its effects on wound healing and immune dysregulation. It probably is under used in hard-to-treat conditions that involve excessive or dysfunctional production of collagen, such as morphea and epidermolysis bullosa. As is true with most other medications, more randomized double-blind studies would enhance our understanding of therapeutic efficacy. Possible areas of research include structure manipulation to enhance desired therapeutic effects and minimize the adverse effects that continue to create significant morbidity and must be considered before therapy is instituted. Phenytoin and related drugs remain promising therapies and fertile fields for future investigation.
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