Adverse Drug Reactions

Adverse Drug Reactions

Comparative Percutaneous Absorption of Lindane and Permethrin

Introduction.—Lindane has been the standard treatment for scabies since its introduction in 1948, but the drug’s potential for neurotoxic effects when misused or overused has been a cause of concern. An alternative to lindane, 5% permethrin cream, became available in 1989. Because little is known regarding the percutaneous absorption of permethrin and its potential for toxic effects, a study was designed to develop quantitative systemic exposure data for the 2 agents.

Methods.—Samples of 1% lindane lotion and 5% permethrin cream were purchased from a local pharmacy. In vitro absorption studies were conducted using dermatomed human thigh skin and guinea pig back skin. Applications of an overuse dose were measured using the finite dose technique. In vivo blood and brain levels of the scabicides were evaluated in guinea pigs after 3 daily applications without washing (manufacturers’ instructions specify a single application to. be washed off 8 hours later). Levels of lindane and permethrin were quantified by gas chromatography- mass spectroscopy.

Adverse Drug ReactionsResults.—In guinea pig skin, penetration of the 2 compounds was not significantly different. There was a slow rise to an apparent steady-state rate of penetration after 30 hours of topical exposure, and flux was consistently greater with lindane than with permethrin. In human cadaver skin, however, lindane showed a rapid rise to an apparent steady-state rate of penetration within 5 hours of application; permethrin showed no measurable penetration until 10-20 hours after application. In vivo studies showed guinea pig blood and brain levels of lindane 4 times greater than those of permethrin.

Conclusion.—Based upon these findings for systemic exposure during overuse conditions, the risk for toxic effects is estimated to be 40-400 times lower for 5% permethrin cream than for 1% lindane lotion. Factors favoring permethrin over lindane for the topical treatment of scabies include lower inherent toxicity, lower cutaneous absorption, and lower brain and blood levels. Physicians should still caution against overuse of topical scabicides, especially when applied to a child.

► For reasons such as those outlined in this nicely done study, in many countries permethrin has largely replaced lindane for the topical treatment of scabies. Unfortunately, the retail cost of permethrin is much higher, which may pose a significant problem for large-scale community control projects or in countries where public health funding is severely limited. Permethrin also appears to be more efficacious than lindane, and lindane treatment failures have been reported both in the United States and abroad. An oral drug, ivermectin, has recently been reported to be an effective treatment for scabies, although its safety also has been questioned.

Salicylate Intoxication Using a Skin Ointment

Introduction.—Although salicylate intoxication via accidental oral ingestion is the subject of many reports in the pediatric literature, acute percutaneous salicylate intoxication is rare in children. The case reported here shows that a skin ointment containing salicylate can cause potentially lethal intoxication.

Case Report.—Girl, 5 years, had been treated for lamellar ichthyosis and was admitted to a pediatric ICU when nausea and vomiting occurred. Inquiries revealed that the child—now with fever, hypotonic limbs, and in a comatose state and oculogyric crisis—had had 3 applications of 10% salicylate and urea skin ointment over her entire body. Symptoms started after the second application of ointment. Coagulation tests revealed a decrease in prothrombin time and reduced platelet aggregation. Sixteen hours after admission, salicylemia measured 2.61 mmol/L. Fluid therapy was started with 5% dextrose solution and sodium chloride. Improvement was noted the next day, and by the third day, the child was alert with no respiratory alkalosis. The salicylate level had been reduced to 0.06 mmol/L. On the fifth day, the child was discharged in good general health.

Discussion.—Transcutaneous salicylate intoxication is rare and occurs primarily in patients with skin diseases such as psoriasis and ichthyosis. Repeated applications of salicylate ointments on extensive skin lesions can result in intoxication, and interactions with other substances may facilitate absorption. Salicylic levels should be measured regularly in children treated with salicylate as a skin therapy.

► Absorption of topically applied substances occurs most readily through erythrodermic skin and other conditions in which the stratum corneum barrier function is compromised. Children are at especially high risk of side effects from absorbed substances, as are adults with underlying systemic diseases that prevent rapid clearance of such substances from their blood (i.e., underlying renal or liver disease).

Cutaneous Necrosis Associated With Recombinant interferon Injection: Report of Three Cases with Interferon Beta-1 b and Review of Literature

Background.—A common side effect of recombinant interferon beta-1 b (IFN β-1b) is inflammation at the injection site. These authors report 3 cases of another side effect, cutaneous necrosis, at the site of IFN β-1b injection.

Case Report.—Woman, 42, white, with multiple sclerosis began using subcutaneous injections of IFN β-1b at a dose of 9.6 X 106 U qOD. Two months later, a red macular lesion developed on her abdomen, which evolved into an ulcer with necrotic eschar. This ulcer healed without therapy. Continued dosing with IFN β-1b caused a local macular erythematous reaction at each injection site, which also healed without therapy. About 9 months later, another lesion developed; this lesion, although resolving without treatment, left a hyperpigmented, atrophic scar. The patient continues to use IFN β-1b without further ulcers, but the local erythematous reaction after each injection continues.

Conclusions.—These findings join other reports of cutaneous necrosis after IFN β-1b injection for treatment of multiple sclerosis. A possible pathologic mechanism may be thrombosis and necrosis of vessels in the skin. Therefore, changing the area of the injection could help avoid the skin reaction.

► Cutaneous necrosis has been reported both with α and β interferon. The pathogenesis of the cutaneous necrosis is unclear, although vascular thrombosis is a frequent finding.’ In the future, it may be possible to define groups in whom therapy may be continued at different injection sites and in whom therapy must be discontinued. Individuals who are predisposed to local thrombosis of dermal vessels as a result of an inherited or acquired coagulopathy may not be able to tolerate interferon therapy.

Lovastatin-induced, Acquired Ichthyosis

Objective.—Acquired ichthyosis (Al) is associated with certain malignancies and systemic diseases. The etiology and possible causative factors of Al in a renal transplant patient are discussed.

Case Report.—A woman, 28, was treated with lovastatin to decrease serum cholesterol 1 year after renal transplantation. She was receiving immunosuppressive therapy and ranitidine. One month later, she was admitted to a dermatology clinic with ichthyosis. She was treated with emollients for 6 months, and her condition improved. After 6 months, lovastatin was discontinued, and her condition resolved completely.

Discussion.—This rare, acquired condition has clinical features similar to those of autosomal dominant ichthyosis vulgaris, ichthyosis vulgaris, X-linked ichthyosis, and lamellar ichthyosis. Acquired ichthyosis has hypogranulosis like ichthyosis vulgaris but has dark brown scales and flexural involvement like X-linked ichthyosis. Acquired ichthyosis may be associated with a variety of conditions. Cholesterol-lowering drugs may cause skin dryness and may lead to the development of abnormal keratinization by affecting the metabolism of cholesterol.

Conclusion.—Cholesterol-lowering drugs may be associated with one development of Al.

► Ichthyosis has long been recognized as a complication of cholesterol- lowering drugs, and with more and more of these coming on the market, dermatologists must be aware of this possible side effect. Cholesterol is a major constituent of stratum corneum lipids and drugs affecting cholesterol metabolism may lead to abnormal keratinization.

Hydroxyurea Dermopathy: A Unique Lichenoid Eruption Complicating Long-term Therapy With Hydroxyurea

Objective.—Hydroxyurea treatment of myeloproliferative disorders works by inhibiting cell DNA synthesis and cell death in the S phase. Unique clinical, histologic, and immunologic cutaneous side effects in patients receiving long-term therapy are reported, and a case is discussed.

Case Report.—A man, 69, with chronic myelogenous leukemia treated with hydroxyurea, 500 mg 3 times daily for 5 years, had tender bright erythematous, scaling eruptions on his hands, elbows, and feet. Hydroxyurea was discontinued, and the patient was started on a regimen of interferon-α, dipyridamole, and aspirin. Although the eruption improved, his peripheral leukocyte count increased. When restarting hydroxyurea worsened his dermopathy, the drug was discontinued again, and his condition improved significantly within 3 months.

Methods.—This cutaneous reaction has been observed in 6 patients (3 men), age 56-69 years. Eleven biopsy specimens from 5 of these patients were collected, stained with hematoxylin-eosin, and examined by direct immunofluorescence.

Results.—Patients received hydroxyurea for an average of 61 months for chronic myelocytic leukemia (n = 2), essential thrombocytosis (n = 2), polycythemia vera (n = 1), and chronic granulocytic leukemia (n = 1) before having a cutaneous reaction. All biopsy specimens demonstrated orthohyperkeratosis, hypergranulosis, and focal to extensive desquamation with thickened basement membranes. All specimens showed hydropic degeneration and dyskeratotic cells and cytoids coated with immunoglobulins and complement. These late-developing cutaneous changes appeared on the dorsal hands; 3 patients had leg ulcers. Four patients improved when hydroxyurea was stopped.

Conclusion.—This cutaneous condition probably is related to cytostatic effects and perturbed gene expression but may also be the result of free radical damage by nitroxide intermediates. Keratinocyte damage is common with chemotherapeutic agents. Damage progresses to where mecha-nisms are no longer able to repair the injury.

► With the advent of more effective modalities, hydroxyurea has fallen out of favor as an alternative therapy for severe psoriasis. However, it is still commonly used in clinical oncology, and dermatologists who consult on such cases should be aware of this complication of long-term therapy.

Hydroxyurea-induced Leg Ulceration in 14 Patients

Objective.—Hydroxyurea, an antineoplastic agent that has been used to treat various forms of cancer and less commonly for management of sickle cell anemia and HIV, has dermatologic side effects that can include leg ulcers. A retrospective review was undertaken of medical records of 14 patients at the Mayo Clinic with leg ulcers related to hydroxyurea therapy.

Case 1.—Man, 69, acquired an ulcer on his calf after 3 years of continuous hydroxyurea therapy. The ulcer increased in size as the hydroxyurea dosage was increased. When the drug was discontinued, the ulcer resolved within 3.5 months. When therapy was restarted 3 years later, multiple painful ulcers developed on his ankles. When therapy was discontinued, the ulcers resolved completely within 6 months.

Results.—Between 1980 and 1995, 14 patients with hydroxyurea-induced leg ulcers were identified among 115 patients with myeloproliferative diseases and leg ulcers who had received hydroxyurea therapy. The 14 patients had 18 ulcers located over the medial malleolus (n = 10) and over the lateral malleolus (n = 8) (Figure). Ulcers resolved in 12 patients after cessation of hydroxyurea, therapy. Discontinuation of hydroxyurea therapy was necessary for resolution of the ulcers despite meticulous wound care.

Conclusion.—That leg ulcers were the result of hydroxyurea therapy was proved when ulcers developed again on rechallenge. Therapy must be discontinued to effect ulcer resolution, and should not be restarted if an alternative therapeutic agent is available.

► Occasionally patients with myeloproliferative disorders develop leg ulcers, and thus it is uncertain whether the ulcers in these patients were secondary to the underlying disease or its treatment with hydroxyurea. However, the temporal relationship with hydroxyurea therapy, the resolution in most patients after treatment was discontinued, and the recurrence in 2 patients after restarting treatment supports the possibility that hydroxyurea did indeed play a role in the pathogenesis of these ulcers.

Terbinafine-induced Acute Generalized Exanthematous Pustulosis Con-firmed by a Positive Patch-Test Result

Objective.—The clinical and pathologic findings of acute generalized exanthematous pustulosis are similar to those of pustular psoriasis. Acute generalized exanthematous pustulosis may be induced by drugs or viruses. A case of terbinafine-induced acute generalized exanthematous pustulosis with a positive patch test is reported.

Case Report.—Woman, 63, was being treated with terbinafine, 250 mg/day, for tinea corporis. She had a pustular eruption and fever starting after 2 weeks of treatment. An erythematous eruption covered with superficial, nonfollicular pustules developed on the trunk and proximal and distal extremities. Pustule cultures were negative for bacteria and fungi. On biopsy, there were subcorneal pustules with neutrophils and a perivascular infiltrate in the superficial dermis, which was made up of polymorphonuclear cells and lymphocytes. Management consisted of discontinuation of terbinafine and treatment with oral methylprednisolone. The fever and pustules resolved within 10 weeks. Patch testing was positive for terbinafine but negative for all other substances.

Discussion.—A patient with terbinafine sensitivity manifesting as acute generalized exanthematous pustulosis is reported. This eruption most often results from infection with enterovirus or other viruses, mercury in-toxication, or drugs, especially β-lactam and macrolide antimicrobials. The eruption usually develops within 2 or 3 days after administration of the antibiotic. Commonly implicated drugs are spiramycin, erythromycin, roxithromycin, and pristinamycin. Drugs other than antimicrobials are rarely involved. When they are, the interval to eruption is about 18 days.

► Differentiation between acute generalized exanthematous pustulosis and pustular psoriasis can be difficult.

Anticonvulsant Hypersensitivity: An Unfortunate Case of Triple Exposure to Phenytoin

Objective.—Anticonvulsant hypersensitivity in patients taking phenytoin, phenobarbital, or carbamazepine most often develops within 2-4 weeks but can start up to 3 months later. The reaction starts with a rash, progressing to erythema multiforme, toxic epidermal necrolysis, and multiorgan system involvement, as well as lymphadenopathy, facial edema, eosinophilia, and elevated transaminase levels. The incidence is 1 in 1,000 to 10,000 patients exposed to these drugs. It is more frequent among African Americans. A case of anticonvulsant hypersensitivity in a patient with repeated exposure to phenytoin was reported.

Case Report.—Woman, 62, came to the emergency department in status epilepticus. She received diazepam to halt her seizure activity, followed by phenytoin. The patient had dementia resulting from stroke, and could not tell the emergency department physician about her medical history or drug allergy. The next day, a fever and diffuse, warm erythema had developed. Anticonvulsant hypersensitivity was suspected, so phenytoin was stopped and prednisone started. However, the erythema continued to spread. By the fifth day, the patient had approximately 12 target lesions, mainly on her legs. She also had 2 bullous lesions with epidermal desquamation and Nikolsky’s sign, and drying, crusting, and fissuring of the lips. Her white blood cell count peaked at 10,100/mm3, with no eosinophilia. The skin lesions were clearing 17 days after phenytoin administration.

On review, the patient’s chart noted no drug allergies, except for a skin rash in response to an unknown anticonvulsant. However previous hospital records showed an episode of toxic epidermal necrolysis after a phenytoin bolus. During clinic follow-up, the patient was found to have been exposed to phenytoin again at another emergency department. This was followed by more extensive target lesions and epidermal sloughing. The patient’s family was not reliable in remembering her drug allergy or giving her anticonvulsant medication regularly. The authors obtained a MedicAlert identification bracelet for the patient’s protection. They also placed her in a daytime activity center to ensure that she received her anticonvulsant medication regularly.

Discussion.—This patient with anticonvulsant hypersensitivity had repeated and severe reactions to phenytoin, she was exposed at least 3 times. With each exposure, the surface area and number of sites involved increased dramatically. Anticonvulsant hypersensitivity is potentially fatal if liver involvement or toxic epidermal necrolysis occurs. Reactions must be recognized promptly so that the drug can be discontinued; repeated exposure can be prevented by continuity of care and by ensuring that the patient has a MedicAlert bracelet.

► This unfortunate woman had several exposures to phenytoin, each of which resulted in a severe drug reaction. Many patients receiving seizure medications have underlying neurologic disorders that prevent them from fully understanding the nature of their drug sensitivity. It is critical that drug sensitivities be appropriately documented in the patient’s medical chart and that the patient wear a MedicAlert bracelet to inform health care workers of this sensitivity should the chart be unavailable.

Phototoxic Properties of Neuroleptic Drugs

Background.—Many drugs used to treat psychiatric illnesses, including phenothiazines and thioxanthenes, are known to cause photosensitive reactions. Twenty-seven neuroleptics were examined to determine their phototoxicities.

Methods.—Twelve phenothiazines and 5 thioxanthenes were dissolved in methanol or ethanol and further diluted in buffer. These diluents were then incubated with human erythrocytes and irradiated to determine the percentage hemolysis. Only photohemolysis greater than 10% was considered significant and is reported. Irradiation was performed with a UVA-SUN lamp (maximum dose 100 J/cm2 UVA) and with TL 20 W/12 light bulbs (maximum dose 1,600 mJ/cm2 UVB).

Findings.—Even without UV irradiation, 14 of the drugs at concentrations of 10-3 mol/L caused significant hemolysis (more than 70%); the 3 drugs that did not were chlorprothixene, dixyrazine, and thiothixene. And at concentrations of 10-4 mol/L, 6 drugs still caused hemolysis without any irradiation (clopenthixol, fluphenazine, thioridazine, trifluoperazine, tri-flupromazine, and zuclopenthixol). Of the phenothiazines, UVA-rich irradiation caused photohemolysis with 10-3 or 10-4 mol/L concentrations of chlorpromazine, perazine, perphenazine, promazine, promethazine, prothipendyl, and dixyrazine. Irradiation that was UVB rich caused hemolysis with 10-3 or 10-4 mol/L concentrations of chlorpromazine, dixyrazine, and perazine. Of the thioxanthenes, UVA-rich irradiation caused photohemolysis with 10-3 or 10-4 mol/L concentrations of chlorprothixene and thiothixene. Ultraviolet B-rich irradiation of the thioxanthenes did not cause significant hemolysis. For all neuroleptics, the percentage hemolysis tended to increase as the irradiation dose increased.

Conclusions.—Most of the phenothiazines (10 of 12) and some of the thioxanthenes (2 of 5) showed phototoxicity at concentrations of 10-3 and 10-4 mol/L. This effect tended to be dose dependent, with greater UV exposure resulting in more hemolysis. Therefore, patients who use neuroleptics, particularly phenothiazines, should be advised to limit their exposure to the sun or other UV sources to avoid photosensitization.

► Drugs used to treat psychiatric illness are among the most common causes of photodermatitis. Although dermatologists are often well aware of this complication, we need to educate the prescribing physicians to counsel patients regarding sun protection and avoidance.

Acrosyringeal Concentration of Necrotic Keratinocytes in Erythema Multiforme: A Clue to Drug Etiology. Clinicopathologic Review of 29 Cases

Objective.—Erythema multiforme (EM) can be caused by drugs, or infectious agents and result in a wide variety of dermal and epidermal changes. Because several cases of EM have shown acrosyringeal concentration of necrotic keratinocytes, a retrospective investigation into 29 cases of EM was conducted to determine whether this pattern is clinically significant when attempting to identify the cause of the lesion.

Methods.—Biopsy specimens from the 29 patients were divided into 2 groups. Group 1 contained specimens with a prominent concentration of necrotic keratinocytes within and around the acrosyringium, and group 2 comprised specimens with necrotic keratinocytes scattered throughout the epidermis with no acrosyringeal concentration.

Results.—Substantially more group 1 specimens than group 2 specimens contained eosinophils (60% vs. 11%), whereas more group 2 patients than group 1 patients had moderate inflammation of the upper dermal layer (15 vs. 3). No confluent epidermal necrosis was found in any patient. Whereas in 10 cases (group 1), specimens had necrotic keratinocytes concentrated in and around the acrosyringeal epithelium, in 19 cases (group 2), specimens had necrotic keratinocytes scattered irregularly throughout the epidermis. Clinical correlation studies pointed to a drug as the cause of all EM cases in group 1 and 3 cases in group 2, for a sensitivity of 0.8 and a specificity of 1.0.

Conclusion.—Although this study was small and retrospective, histopathologic results showed that acrosyringeal concentration of keratinocyte necrosis, together with eosinophils and mild-to-moderate upper dermal inflammation, occurs in drug-related cases of EM.

► The authors demonstrate that necrotic keratinocytes concentrated within the eccrine duct can serve as a reliable marker for drug-induced EM. They propose that this phenomenon may occur because of concentration of drugs within the acrosyringeal unit, resulting in a direct toxic effect.

Erythema Multiforme and Toxic Epidermal Necrolysis: A Comparative Study

Objective.—Erythema multiforme (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN) may be different manifestations of the same disease. A series of evolving lesions of EM and TEN were histologically and immunochemically examined to evaluate possible links and dissimilarities in the pathogenesis.

Methods.—Punch biopsies were performed in 17 patients (7 females), age 17-69, with EM lesions in early erythematous nonbullous stage (n = 4), bullous EM lesions (n = 5), TEN lesions in the early erythematous nonbullous stage (n= 3), and bullous TEN lesions (n = 5). EM cases were idiopathic or postherpetic in etiology, whereas TEN cases were caused by piperacillin (n = 2), clindamycin (n = 2), amoxycillin, allopurinol, phenytoin, and carbamazepine. The quantity of inflammatory cells was graded from 0 (absence) to 4 (very dense).

Results.—The density and nature of the inflammatory cells suggest that EM and TEN are different entities. EM lesions are characterized by a cell infiltrate abundant with mononuclear cells and T-lymphocytes, whereas TEN lesions show a lack of inflammatory infiltrate but a predominance of macrophages and dendrocytes in the dermis and epidermis and deposits of TNF-a in the epidermis. Another study found that T-lymphocytes rather than macrophages were the predominant cell type in TEN lesions. It appears that macrophages and T-lymphocytes working together are responsible for epidermal destruction.

Conclusion.—There are histologic and immunochemical differences between EM and TEN that imply a distinct origin for these diseases.

► The authors describe the histologic and immunohistochemical differences between erythema multiforme and toxic epidermal necrolysis. Based on their findings, they propose that different pathogenic mechanisms underlie these conditions. Histologically, erythema multiforme is characterized by the accumulation of neutrophils within the superficial vascular plexus; toxic epidermal necrolysis is much less inflammatory. The inflammatory population in erythema multiforme is more densely populated by T lymphocytes, whereas the inflammatory population in toxic epidermal necrolysis is macrophage-predominant. Toxic epidermal necrolysis is also marked by prominent expression of tumor necrosis factor-a within both keratinocytes and macrophages. These findings suggest that toxic epidermal necrolysis and erythema multiforme occur through different pathogenetic mechanisms and are not simply a clinical spectrum based on severity.

Toxic Epidermal Necrolysis: An Analysis of Referral Patterns and Steroid Usage

Introduction.—An exfoliative disorder associated with mucosal slough and systemic toxicity, toxic epidermal necrolysis is characterized by malaise, high fever, epidermal detachment of more than 10% of total body surface area, and mucosal involvement of 2 or more surfaces. To prevent further epidermal loss, high-dose corticosteroid treatment was advocated for patients with toxic epidermal necrolysis. Care in burn centers was uncommon. These management protocols were refuted in the mid 1980s, and recommendations were made to withhold steroid treatment and to transfer patients early to a burn center. To determine whether patients were being administered steroids and whether they were being referred early to a burn center, patients with toxic epidermal necrolysis were reviewed.

Methods.—A retrospective review was conducted of 14 patients with toxic epidermal necrolysis to evaluate steroid usage and timing of burn center transfer. Records were reviewed for septic complications, deaths, and drug exposures.

Results.—In 10 patients (72%), transfer to a burn center was delayed more than 2 days; the mean delay was 4.4 ± 2.7 days. Steroids were administered to half the patients. Three (21%) died. In 5 patients (36%), pneumonia developed and in 3 patients (21%) urinary tract infections developed. Intubation was required in 7 patients (50%), and hemodialysis was required in 3 patients (21%). Nutritional supplementation was necessary in 13 patients (93%). In patients who received steroids or who were transferred late, no differences in mortality rates or infectious complications were noted. Septic complications occurred frequently in both groups.

Conclusion.—Referring institutions commonly delay transfer and initiate administration of steroids. A fivefold increase in the incidence of infection, a longer hospital stay, and increased mortality have been associated with the use of corticosteroids for more than 48 hours. At the level of the referring physician, the need for early burn center referral and avoidance of steroids needs to be reiterated.

► Although there were no differences in mortality rates or infectious complications between patients who did or did not receive systemic steroids, there was no obvious benefit from the use of these drugs. Clearly, the current standard of care for toxic epidermal necrolysis suggests that these patients are best cared for in a burn unit and that systemic steroids should be avoided. As infectious complications are especially common in patients with toxic epidermal necrolysis, avoidance of systemic steroids should be emphasized.

Plasmapheresis in Toxic Epidermal Necrolysis

Introduction.—-Toxic epidermal necrolysis (TEN) is a rare, life-threat-ening, usually drug-induced condition characterized by a rapidly progressive onset of painful, confluent, dusky erythema, and flaccid bullae that are easily detached to large sheets of necrotic skin and epithelia. Disease mortality ranges from 25% to 70%. The literature varies regarding the effectiveness of therapeutic plasmapheresis (plasma exchange [PE]) in the treatment of TEN. The therapeutic effect of PE was assessed in 7 patients with TEN.

Methods.—Seven patients with severe TEN covering 30% to 80% of body surface area and involving 2—4 mucous membranes underwent 1-4 PEs of 2.5 L performed on alternate days in 6 patients and daily in 1 patient.

Results.—All patients recovered from the disease. Most patients responded dramatically after the first PE. Four patients had no new lesions after the first PE. Relief of pain was the first sign of clinical improvement and occurred within a few hours after PE. There were no adverse reactions from PE or sequelae from TEN at long-term follow-up lasting up to 8 years.

Conclusion.—Plasmapheresis is expensive and requires easy venous access. It is safe, offers prompt pain relief, fairly rapid cessation of necrolysis, no early or late disease associated sequelae, and limited hospital stay. Sessions are recommended every other day rather than daily. Plasmapheresis may be considered a strong weapon in the armamentarium against TEN.

► The use of plasmapheresis for TEN has both its advocates and its detractors. A large scale, controlled study, adjusted for confounding factors, would help to resolve this controversy.