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Acute compartment syndrome of the forearm as a rare complication of toxic epidermal necrolysis: a case report
© Kamal et al; licensee BioMed Central Ltd. 2012
Received: 7 October 2011
Accepted: 20 March 2012
Published: 20 March 2012
Toxic epidermal necrolysis lies within the spectrum of severe cutaneous adverse reactions induced by drugs, affecting skin and mucous membranes. Toxic epidermal necrolysis is considered a medical emergency as it is considered to be potentially fatal and carries a high mortality rate. To the best of our knowledge the association of toxic epidermal necrolysis and compartment syndrome has been rarely mentioned in the literature. In this case we treated the compartment syndrome promptly despite the poor general condition and skin status of our patient. Despite the poor skin condition, wound healing was uneventful with no complications.
A 62-year-old Caucasian man with a generalized macular-vesicular rash involving 90% of his body surface area and mucous membranes, as well as impaired renal and hepatic functions following ingestion of allopurinol for treatment of gout, was admitted to our hospital. Skin biopsies were taken and he was started on a steroid infusion. Within hours of admission, he developed acute compartment syndrome of the dominant forearm and hand.
Despite its rare incidence, toxic epidermal necrolysis is a condition with a high incidence of complications and mortality. Patients with severe conditions affecting a large degree of the skin surface area should be treated as promptly and effectively as patients with burns, with close monitoring and the anticipation that rare musculoskeletal complications might arise. The association of compartment syndrome and toxic epidermal necrolysis might lead to a rapid deterioration and fatal systemic involvement and multiple organ failures.
Toxic epidermal necrolysis (TEN) lies within the spectrum of severe cutaneous adverse reactions (SCAR) induced by drugs, and affects the skin and mucous membranes [1, 2]. TEN is considered a medical emergency as it may be potentially fatal and carries a high mortality rate. It is characterized by mucocutaneous tenderness and typically hemorrhagic erosions, erythema and more or less severe epidermal detachment presenting as blisters and areas of denuded skin . In 1995, a case-control study assessed the medications that may be related to TEN . According to a more recent case-control study, several drugs were confirmed to be at 'high risk' of inducing TEN, including: anti-infectives such as cotrimoxazole and sulfonamides, allopurinol, carbamazepine, phenytoin, phenobarbital and non-steroidal anti-inflammatory drugs (NSAIDs) of the oxicam type. Other drugs with 'significant but lower risk' included acetic acid NSAIDs, macrolides, quinolones, cephalosporins and tetracyclines . Among these drugs, allopurinol is considered to be the most common cause of TEN in Europe [6, 7]. Many previous studies have reported cases of allopurinol-induced TEN, and some have noted that the outcome of allopurinol-induced TEN is particularly lethal [8, 9].
TEN syndrome is an uncommon, acute, life-threatening, medication-induced disorder with a reported mortality rate of up to 60% . Different variables have been identified as risk factors. Drug-induced TEN is the main documented cause of TEN. More than 100 different drugs are considered as having caused TEN, but only a minority of them accounts for the majority of cases. These principal culprits are anti-infectives such as cotrimoxazole and sulfonamides, allopurinol, carbamazepine, phenytoin, phenobarbital, NSAIDs of the oxicam type, acetic acid NSAIDs, macrolides, quinolones, cephalosporins and tetracyclines . The management of such patients is primarily supportive, with particular attention to body fluid balance, nutritional status, pain relief, early treatment of eventual sepsis, and meticulous skin care . Recently, high-dose intravenous immunoglobulins have been advocated to treat TEN in combination with optimal care in a burn unit , as sepsis is a serious complication in patients with TEN .
Acute compartment syndrome (ACS) is defined as the development of increased pressure in a confined anatomic space that compromises circulation and leads to ischemia of the contained muscles and nerves. Several theories have been proposed regarding the pathophysiology of ACS. The arteriovenous gradient theory is arguably the most popular. It states that increased tissue pressure increases local venous pressure. This increased venous pressure approaches the pressure in the supplying arteries thus decreasing the arteriovenous pressure gradient. Local blood flow decreases as the gradient decreases and oxygen delivery to the surrounding tissue drops below demand. Muscle ischemia results in myocyte lysis and the release of toxic intracellular chemicals into the extracellular space. Microvascular damage leads to capillary leak, edema, and an increased compartment pressure. Muscle ischemia eventually progresses to muscle death. Over time the muscle is replaced with dense fibrous tissue, which results in limb contracture. Ischemic contracture, first described by Volkmann in 1881, is one known endpoint of untreated increased pressure within a confined forearm compartment. This pathologic event results in an atrophic and severely contracted extremity with muscle and nerve fibrosis.
Immunopathological mechanisms of TEN include recruitment of cluster of differentiation 4 (CD4)+ T cells in the dermis and CD8+ T cells in the epidermis thus inducing a T helper (TH)1 cell reaction . Recruited memory CD4+ and cytotoxic CD8+ T cells produce interferon γ (IFNγ) and tumor necrosis factor α (TNFα), both triggering massive apoptosis of keratinocytes through one of two main mechanisms: the perforin/granzyme B mechanism and lytically active Fas ligand (Fas-L) mechanism . Moreover, the production of TNFα would increase the expression of major histocompatibility complex (MHC) class I antigens in keratinocytes, making them more sensitive to cytotoxic cells producing perforin and granzyme B . Recently in 2008, Chung et al. demonstrated that the cytolytic protein granulysin is probably the most important factor in epidermal apoptosis observed in TEN. Its concentration in the blister fluid was several orders of magnitude higher than that of other cytokines, such as perforin, granzyme B or Fas-L and this concentration was found to be positively correlated with disease severity . Later, functionally active cells carrying the killer effector receptor CD94/NKG2C were detected in the blister fluid and the peripheral blood of patients with TEN and the authors postulated that this receptor might be involved in triggering cytotoxic T cells in the acute stage of the disease . Some studies have shown that apart from acting as target cells in TEN, keratinocytes may also be cytolytically active through their further production of TNFα and Fas-L and hence trigger even more massive apoptosis .
On occasion, for reasons that are not entirely clear, the inflammatory response may spiral out of control, progressing until it involves the entire body. The circulatory system loses its integrity followed by the breakdown of the adherens junctions between the endothelial cells lining the capillaries, allowing fluid to leak into the tissue spaces. Trauma from electrical injuries and burns, and snakebite or envenomation injuries may cause a cascade of events that lead to the rapid formation of edema. Similarly, thermal and chemical burns may incite a cascade of events involving substantial tissue injury and systemic response with associated increases in vascular permeability and interstitial edema. It is important to recognize that compartment syndrome has been described in the uninjured limb of up to 2% of patients with burns, occurring as the result of a systemic inflammatory response and the requirement for extensive fluid resuscitation.
We believe that in the case of our patient, the combination of capillary endothelial damage with subsequent increase of capillary permeability and interstitial fluid edema in addition to the inflammatory response affecting the dermis associated with a certain degree of loss of skin elasticity predisposed our patient to compartment syndrome. Similar conditions have been noted in patients with burns and have suggested early limb escharotomies or fasciotomies in patients with full-thickness burns with close monitoring of peripheral circulation . To the best of our knowledge there have been no documented similar cases (investigated via PubMed searches or any associated references in dermatology textbooks (Rooks)).
TEN, despite its rare incidence, is a condition with a high incidence of complications and mortality. Patients with severe conditions with a large degree of affected surface area should be treated as promptly and effectively as patients with burns, with close monitoring and anticipation that rare musculoskeletal complications might arise. The association of compartment syndrome and TEN might lead to a rapid deterioration and fatal systemic involvement and multiple organ failures.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
- Mockenhaupt M: Severe drug-induced skin reactions: clinical pattern, diagnostics and therapy. J Dtsch Dermatol Ges. 2009, 7: 142-160.PubMedGoogle Scholar
- Mockenhaupt M: The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Exp Rev Clin Immunol. 2011, 7: 803-813. 10.1586/eci.11.66.View ArticleGoogle Scholar
- Torres MJ, Mayorga C, Blanca M: Nonimmediate allergic reactions induced by drugs: pathogenesis and diagnostic tests. J Investig Allergol Clin Immunol. 2009, 19: 80-90.PubMedGoogle Scholar
- Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, Auquier A, Bastuji-Garin S, Correia O, Locati F, Mockenhaupt M, Paoletti C, Shapiro S, Shear N, Schöpf E, Kaufman DW: Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995, 333: 1600-1607. 10.1056/NEJM199512143332404.View ArticlePubMedGoogle Scholar
- Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, Sidoroff A, Schneck J, Roujeau JC, Flahault A: Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008, 128: 35-44. 10.1038/sj.jid.5701033.View ArticlePubMedGoogle Scholar
- Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Bouwes Bavinck JN, Sidoroff A, Naldi L, Dunant A, Viboud C, Roujeau JC, EuroSCAR Study Group: Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol. 2008, 58: 25-32. 10.1016/j.jaad.2007.08.036.View ArticlePubMedGoogle Scholar
- Halevy S: Stevens-Johnson syndrome and toxic epidermal necrolysis--updates and innovations. Harefuah. 2010, 149: 186-190.PubMedGoogle Scholar
- Laurisch S, Jaedtke M, Demir R, Sorrentino SA, Kielstein JT, Rennekampff HO, Vogt PM, Meyer GP, Fuchs M, Klein G, Drexler H, Schieffer B, Napp LC: Allopurinol-induced hypersensitivity syndrome resulting in death. Med Klin (Munich). 2010, 105: 262-266. 10.1007/s00063-010-1037-3.View ArticleGoogle Scholar
- Ventura F, Fracasso T, Leoncini A, Gentile R, de Stefano F: Death caused by toxic epidermal necrolysis (Lyell syndrome). J Forensic Sci. 2010, 55: 839-841. 10.1111/j.1556-4029.2010.01338.x.View ArticlePubMedGoogle Scholar
- Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC: Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993, 129: 92-96. 10.1001/archderm.1993.01680220104023.View ArticlePubMedGoogle Scholar
- Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein PJ: SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. Invest Dermatol. 2000, 115: 149-153. 10.1046/j.1523-1747.2000.00061.x.View ArticleGoogle Scholar
- Nassif A, Bensussan A, Boumsell L, Deniaud A, Moslehi H, Wolkenstein P, Bagot M, Roujeau JC: Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. J Allergy Clin Immunol. 2004, 114: 1209-1215. 10.1016/j.jaci.2004.07.047.View ArticlePubMedGoogle Scholar
- Chung WH, Hung SI, Yang JY, Su SC, Huang SP, Wei CY, Chin SW, Chiou CC, Chu SC, Ho HC, Yang CH, Lu CF, Wu JY, Liao YD, Chen YT: Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med. 2008, 14: 1343-1350. 10.1038/nm.1884.View ArticlePubMedGoogle Scholar
- Morel E, Escamochero S, Cabañas R, Díaz R, Fiandor A, Bellón T: CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Allergy Clin Immunol. 2010, 125: 703-710. 10.1016/j.jaci.2009.10.030.View ArticlePubMedGoogle Scholar
- Li X, Liang D, Liu X: Compartment syndrome in burn patients. A report of five cases. Burns. 2002, 28: 787-789. 10.1016/S0305-4179(02)00190-0.View ArticlePubMedGoogle Scholar
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