Phenytoin in cutaneous medicine: Its uses and side effects
Noah Scheinfeld, MD
Review/Editing 27 January 03

Abstract

Phenytoin (diphenylhydantoin; Dilantin) is a highly effective and widely prescribed anticonvulsant agent 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 in wound healing seems promising but requires further trials. Phenytoin's side effects continue to create significant morbidity. It commonly causes gingival hyperplasia, coarsening of the facies, and hirsutism. Rarer cutaneous side effect include drug induced lupus, purple hand syndrome, pigmentary alterations and IgA bullous dermatosis. It can cause generalized rashes that include: a maculopapular rash, Stevens-Johnson syndrome, generalized exfoliative dermatitis, toxic epidermal necrolysis, vasculitis and fixed drug eruptions. Phenytoin can alter vitamin and mineral levels. Phenytoin is linked to a hypersensitivity syndrome that manifests with fever, rash, and lymphadenopathy. Patients receiving phenytoin may develop pseudolymphoma or, rarely, malignant lymphoma and mycosis fungoides like lesions. Phenytoin can effect clotting function and result in rashes. 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 have yet to be fully defined. The mechanisms for its actions are not fully explicated, complicating it effective deployment. Its use as an oral medication should be reserved for conditions like epidermolysis bullosa that lack other effective therapies. Its topical use for the treatment of ulcers seems promising. After all six decades, phenytoin remains a tool to help patients and a subject for research.

Introduction

In 1938, Merritt and Putnam described their remarkable results using phenytoin to treat major, absence, and psychic equivalent seizures (Figure 1). Since then, phenytoin (diphenylhydantoin; Dilantin) has become a highly effective and 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), phenytoin and fosphenytoin.

Figure 1
Structure of phenytoin

Phenytoin has been suggested as a treatment in over 100 over conditions. A Medline search in November of 2002 showed that since 1966, 12,860 articles concerning it have been published. 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.[1] This review summarizes its uses, cutaneous side effects and some of its mechanisms.

Scientific basis and treatment of epidermolysis bullosa

Researchers have investigated phenytoin's cellular effects. In some patient with epidermolysis bullosa, levels of collagenase are increased.[2] Phenytoin inhibits collagenase in vitro.[3] By inhibiting collagenase activity, phenytoin has been theorized to stabilize collagen fibrils and thus decrease blister formation.[4] Phenytoin reduces the contraction of recessive dystrophic epidermolysis bullosa fibroblast populated collagen gels.[5] Phenytoin modulates connective tissue metabolism and cell proliferation in human skin fibroblast cultures.[6] 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 which are nonretracting and under tension, phenytoin stimulates cell proliferation, and inhibits collagenase activity.[7] Epidermolysis bullosa patients treated with phenytion had lower levels of arachidonic acid in plasma and erythrocyte phospholipids than did untreated epidermolysis bullosa patients suggesting that higher arachidonic acid may be related to its pathology.[8]

Some studies have shown phenytoin useful in treating recessive dystrophic epidermolysis bullosa[9] and in reducing its blister count.[10] Such efficacy has been noted in case reports of single patients in Taiwan[11] and Italy.[12] It has been used in short and long- term management of this disease.[13] Management of esophageal stenosis in epidermolysis bullosa has been noted to benefit from phenytoin.[14] However, a large study conducted by the Epidermolysis Bullosa Study Group did not find it effective.[15]

Phenytoin might have more of a role in the treatment of other epidermolysis bullosa variants. It has been used to treat junctional epidermolysis bullosa.[16] In Saudi Arabia, it has advocates for the treatment of junctional epidermolysis bullosa.[17] In one case, it reduced blister formation by 50% after two months of treatment (2mg/kg increased to 15mg/kg/day with a serum level of 12-15µg/ml) with a flare 1 week after discontinuance.[18] Another study found it effective in treating two patients with generalized atrophic benign EB (GABEB) and ineffective in treating two patients with Herlitz disease.[19] Others find it ineffective for junctional epidermolysis bullosa.[20] It has been used to treat the Dowling-Meara variant of epidermolysis bullosa simplex.[21] Topical phenytoin (2-5% cream twice daily) has been found helpful in epidermolysis bullosa simplex.[22]

Ulcers

Phenytoin has been studied (mostly with inadequate controls) in the healing of pressure ulcers, venous stasis and diabetic ulcers,[23] traumatic wounds, and burns. Used topically, it appears to enhance healing without side effects. Its wound pharmacology has been investigated.[24] Phenytoin increases gene expression for platelet-derived growth factor B chain in macrophages and monocytes.[25] Healthy granulation tissue appears earlier with phenytoin.[26] Phenytoin may promote wound healing by a number of mechanisms, including stimulation of fibroblast proliferation, facilitation of collagen deposition, glucocorticoid antagonism, and antibacterial activity.[27]

It seems promising in enhancing the healing of decubitus ulcers.[28] In a comparison involving 47 patients with stage II decubitus ulcers of phenytoin, DuoDerm® dressings or triple antibiotic ointment applications, all treatments shrank ulcers. However, the phenytoin group demonstrated more rapid results in all aspects of ulcer healing.[29] Similarly, a study suggests that phenytoin may be superior to honey as a topical agent in the treatment of chronic ulcers.[30]

Phenytoin has used to treat ulcers that result from mycobacterial infections. It has been used orally and topically to treat the tropic ulcers of leprosy.[31] In India, topical phenytoin has also been found useful in treating trophic ulcers of leprosy.[32] Other investigators have also reported this effect too.[33] In such a role, it is more effective than saline.[34] It can be used in the treatment of Buruli ulcer.[35]

Topical phenytoin was used to 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.[36] 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, enhanced granulation tissue formation, and more rapid healing. Such results might make phenytoin a useful agent in countries with limit access to more expensive wound care therapies.

Other conditions

Phenytoin has been used to treat a variety of collagen vascular diseases, genetic and inflammatory conditions. It has been used treat linear scleroderma in children with good effect in the 1970s[37] and 1990s.[38] It has been used in the treatment of discoid lupus erythematosus[39] but its effect was not proved in an evidence-based analysis.[40] It can be used to treat the painful tonic/dystonic spasms in Sjogren's syndrome.[41] Phenytoin might have a role in treating pachyonychia congenita.[42] It increases insulin sensitivity and might ameliorate acanthosis nigricans.[43] Orally and topically, it has been used to treat lichen planus[44] and oral lichen planus.[45] It has been used with good effect to treat rheumatoid arthritis[46] but is less effective than gold salts.[47] Its benefits can be sustained,[48] and it has been dosed at 300mg/day for this condition.[49] Phenytoin is not widely used for any of inflammatory condition.

Neuropathic pain

Some have used phenytoin 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.[50] However, an evidence-based review of these trials found them unproven in affect.[51] Similarly, phenytoin was found ineffective in the treatment of diabetic symmetrical polyneuropathy.[52]

Side effects

Incidence

The reported incidence of rashes with phenytoin use varies. Cutaneous reactions in head-injured patients receiving phenytoin for seizure prophylaxis was 19.4%.[53] Another review estimated 5-10% of patients have cutaneous reactions with 5% of children having transient maculopapular rashes often within 3 weeks of drug initiation and more if a high loading dose is given.[54] Still another review stated 2-3% of patient taking phenytoin develop rashes.[55]

Common side effects

There are a few but common cutaneous side effects of phenytoin. About 50% of patients on long term phenytoin therapy will develop gingival hyperplasia. Long-term phenytoin can lead to a coarsening of the facies, enlargement of the lip and/or thickening of the scalp and face.[56] This occurred in one-third of institutionalized patients on long-term therapy.[57] Coarse facies developed in one phenytoin treated sister of each of two pairs of identical twins.[58]

Phenytoin can also cause hirsutism.[59] It occurs in about 12% of children receiving phenytoin usually within 3 months of initiating therapy.[60] It occurs on extensor surfaces of the extremities and on the trunk and face. It usually resolves within one year of discontinuing therapy but sometimes does not.

A South African study compared cutaneous conditions occurring in 173 epileptics aged 6 to 19 years compared with 211 age-matched controls. Anticonvulants used, singly or in combination, were carbamazepine in 54.9%, phenytoin in 47.8%, barbiturates in 36.6% and ethosuximide in 11.2%. The most frequent combination was phenytoin and carbamazepine—14% of males and 18.4% of females. Hirsutism was found in 43.9% of the female epileptics compared to 7.5% of controls. Punctate and linear scars on the dorsum of the hands of 27.7% epileptics compared to 3.8% non-epileptics. Both ephilides and naevocellular naevi occurred in 12.7% of the epileptics compared to 29.4% and 52.1% respectively of controls. Leukonychia was found more in 52% of epileptics than and 28.9% of non-epileptics. 80.3% of epileptic females had acne compared to 30.2% of non-epileptic females. These results were roughly replicated in a Brazilian study.[61] This result differs 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 un-medicated controls.[62]

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,[63] dermatomyositis,[64] systemic lupus with vasculitis,[65] systemic lupus with arthritic manifestations,[66] and alopecia linked with lupus.[67] Lupus can occur in children taking phenytoin.[68] One report has linked phenytoin to the development of a systemic sclerosis like disease.[69] Phenytoin-induced pseudo-Sjogren's syndrome that included infiltrated salivary glands has been noted.[70]

Vitamin, minerals and phenytoin

Phenytoin use can alter vitamin levels. Pellagrous dermatitis has been induced by phenytoin in children.[71] This effect has been noted in combination with other medications in a mentally handicapped patient who promptly responded to vitamin therapy.[72] It can affect biotin metabolism.[73] This effect has been marked with long-term therapy[74] and has been speculated to be one cause of the rashes that phenytoin induces[75] and a subject of basic research.[76] Phenytoin can decrease folic acid levels.[77]

Phenytoin has a variety of effects on copper, zinc, and magnesium in the hair, skin and serum of epileptics.[78] In one study, the levels of serum copper, serum 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.[79] Others too have reported rises in serum copper levels.[80] Some have reported zinc deficiency in users of phenytoin and others have reported that zinc levels in controls and users are the same.[81] The clinical effects of these alterations are unclear.[82]

Phenytoin's effects on calcium are complex. In a study of institutionalized patients, those who took it had lower serum calcium than those who did not.[83] 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.[84] These effects were not replicated in a Brazilian study.[85]

Its 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.[86]

Generalized rashes

Phenytoin can induce a variety of generalized rashes and systemic complications that include: maculopapular eruptions, Stevens-Johnson syndrome, generalized exfoliative dermatitis, toxic epidermal necrolysis, vasculitis,[87] and fixed drug rashes. To understand the relative frequency of these rashes 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 (4.8%), generalized exfoliative dermatitis (2.4%), toxic epidermal necrolysis (2.4%), vasculitis (2.4%) and agranulocytosis (2.4%).[88] In a large study, 4% of fixed drug eruptions were caused by phenytoin, many of which were generalized.[89] Allergy to phenytoin can be assessed with patch testing in 60% of cases.[90]

Some of its rashes only occur 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.[91]

Combined intake of phenytoin, corticosteroids and H2-blockers resulted in cases of toxic epidermal necrolysis, exanthematous eruption and hypersensitivity syndrome.[92] The combination of radiation therapy and pheyntoin appears to increase the incidence of Stevens-Johnson-Syndrome.[93]

Hypersensitivity syndrome

Phenytoin causes a hypersensitivity syndrome that manifests with fever, rash, and lymphadenopathy.[94] Its incidence is 1,000 to 10,000 exposures. It is also seen with other aromatic antiepileptic drugs: carbamazepine, phenobarbital, and primidone, with frequent cross sensitivity.[95] Hypersensitivity syndrome usually occurs 2-8 weeks after initiation of therapy. Hypersensitivity syndrome is associated with the reactivation of human herpesvirus 6.[96] A report notes reactivation of cytomegalovirus.[97]

Often its initial sign is fever with malaise and pharyngitis sometimes with a strawberry tongue. Rash follows and ranges from a macular popular rash to toxic epidermal necrolysis. It can manifest as erythroderma.[98] It can imitate staphylococcal toxic shock[99] or infectious mononucleosis.[100] It can manifest with a generalized pustular rash,[101] which can be follicular based.[102] The liver is often involved. The kidney, CNS or lungs may be involved. Hypothyroidism may occur about 2 months after initial symptom outbreak. There can be elevated liver enzymes and eosinophilia. There can be a hepatitis that can manifest with jaundice.[103]

Immediate discontinuation of the suspected anticonvulsant is the sine qua non of treatment. Valproic acid can usually be substituted with minimal concern for cross reactivity but should be cautiously in the face of hepatitis. Gabapentin[104] and lamotrigine also do not generally cross-react. Patients usually are managed supportively with hydration, antihistamines, H2-receptor blockers, and topical corticosteroids. In severe cases, systemic corticosteroids may be used and might continue for more than a month. The use of intravenous immune globulin should be limited to severe cases in which Kawasaki disease or idiopathic thrombocytopenic purpura remain diagnostic concerns.[105]

Hypersensitivity syndrome's etiology is complex.[106] 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 epoxide hydrolase defect.[107] It has been suggested that its incidence is highest in elderly black males.[108] It appears to be familial in incidence.

Other rashes

Intravenous phenytoin (used most often to treat status epilepticus) can cause purple hand syndrome.[109] It is characterized by edema, discoloration, and pain distal to the site of intravenous administration. It incidence in one study was 3 of 179 patients treated;[110] in another study the incidence was 9 of 152 patients treated.[111] Subacute local cutaneous reactions in patients receiving intravenous phenytoin occurred in 29 of 115 patients consecutive patients studied (25.2%; 22 mild and seven moderate); all resolved within 3 weeks.[112]

Phenytoin can effect pigmentation. It can induce chloasma and melesma. In one patient, phenytoin increased skin pigmentation and hirsutism, manifested with decreased in serum IgA level, and apparently unmasked hereditary coproporphyria.[113] Acquired acromelanosis has been caused by phenytoin.[114] Universal cutaneous depigmentation following phenytoin-induced toxic epidermal necrolysis has been noted.[115]

It can induce porphyria. It can also unmask acute intermittent porphyria[116] and affect the development of porphyria cutanea tarda.[117] It has also led to the development of unclassified porphyria.[118] It can be part of multifactorial development of porphyria.[119] Acute intermittent porphyria has occurred in patients on phentoin therapy and with normal erythrocyte porphobilinogen deaminase activity.[120]

Phenytoin rarely induces inflammatory diseases. Cutaneous necrosis and multinucleate epidermal cells associated with intravenous phenytoin has been reported.[121] It has been linked to drug-induced linear IgA bullous dermatosis.[122] It may be linked to the development of sarcoidosis,[123] specifically pulmonary sarcoidosis.[124] Thickening of the heel-pad associated with long-term phenytoin therapy has been reported.[125]

Psuedolymphoma

Patients receiving phenytoin may develop benign lymphoid hyperplasia,[126] pseudolymphoma, pseudo-pseudolymphoma,[127] or rarely, malignant lymphoma.[128] Lymphoid hyperplasia can be localized in the cervical area.[129] Enlarged inguinal lymph nodes while receiving chronic phenytoin therapy have been reported.[130]

Pseudolymphoma has manifested with generalized nodular lesions.[131] Obtaining a history of drug use is crucial to diagnosising such patients. Southern blots, gene rearrangement studies and chromosome studies are important tools in differentiating pseudolymphoma from malignant lymphoma in patients receiving chronic therapy.[132]

Phenytoin-induced pseudolymphoma can have mycosis fungoides manifestations,[133] sometimes with lymphocyte disregulation.[134] Mycosis fungoides-like lesions associated with phenytoin and carbamazepine therapy have been noted elsewhere.[135] Phenytoin resulted in a mycosis fungoides like rash in cancer patient.[136] Two localized erythematous plaques of mycosis fungoides were noted in a patient who rash resolved 3 weeks after phenytoin was discontinued.[137] Other cases of mycosis fungoides like patches have been localized.[138]

Lymphoma in several forms is associated with phenytoin. Pseudo-pseudolympoma is pseudolymphoma that resolves when phenytoin is discontinued that later recurs as frank lymphoma. As stated above, it has been associated with phenytoin. Malignant lymphoma has been associated with phenytoin.[139] Phenytoin has been linked to Hodgkins disease as well.[140] A history of prolonged phenytoin 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%) tumor-free individuals showing a small increase of malignancy with phenytoin use.[141] Another report found in phenytoin use in 2.3% of patients compared to 0.6% of controls.[142]

Vascular Rashes

Phenytoin can effect clotting function and result in rashes. Dilantin-induced disseminated intravascular coagulation with purpura fulminans has occurred.[143] A 12 years old boy developed a clinical picture of high fever, scarlatiniform rash, a hemorrhagic (purpuric) skin lesion, on his buttocks and neck, stomatitis and conjunctivitis, within two weeks after phenytoin administration related to disseminated intravascular coagulation.[144] Phenytoin has induced serum sickness with fibrin-platelet thrombi in lymph node microvasculature.[145] It can also cause lupus anticoagulants and prothrombin deficiency, which can result to thrombotic rashes.[146] Some have suggested that Vitamin K be given to mother taking phenytoin in third trimester to prevent hemorrhage.[147] However, a policy of giving vitamin K throughout the last third of pregnancy to all women being treated with anticonvulsants, as recently recommended, is not justified by the available evidence.[148]

Fosphenytoin

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.[149] It causes more pruritus than phenytoin.[150] In one study, it induced pruritus in 49% of cases.[151]

Birth defects

Prenatal exposure to phenytoin may result in a spectrum of structural, developmental, and behavioral changes known as the fetal hydantoin syndrome (FHS). Varied malformations due to 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.[152] 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.[153] Onychopathy can be a monosymptomatic or mild form of this syndrome.[154] This syndrome may be associated with neonatal acne.[155]

One study noted an increase incidence of facial clefts among epileptic patients and their children if an uncertain relationship to therapy.[156] Another study did not bear this relationship out.[157] Environmental factors are important in the development of such clefts.[158] In sum, epilepsy and phenytoin use seem of minor importance in regard to cleft development.[159]

Conclusion

After 60 years of use, phenytoin uses have yet to be fully defined. The mechanisms for its actions are not fully explicated complicating it effective deployment. Like most other medications more randomized double blind studies would enhance it proven therapeutic repertoire. Its immunological and hematological side effects are complex. Its use as an oral medication should be reserved for conditions like epidermolysis bullosa that lack other effective therapies. Its topical use for the treatment of ulcers seems promising. Possible areas of research include a tweaking its structure to enhance its therapeutic effects. It also might have a role when combined with other immunomodulators. Phenytoin's side effects continue to create significant morbidity. As other agents become available, its use will probably decrease and this will decrease the side effects seen in patients. Minimization of side effects would also benefit from molecular engineering. After all six decades, phenytoin remains a tool to help patients and a subject for research.

References

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