TY - JOUR
AU - MD, Vikram C. Prabhu,
AB - Abstract The aim of this report is to describe the management of scalp toxic epidermal necrolysis (TEN) and cranial osteomyelitis complicating malignant glioma therapy. A 21-year-old man developed TEN while being radiated and receiving antineoplastic and anticonvulsant therapies for a malignant intracranial glioma. The strategy used to manage the above situation included withdrawal of the medications causing TEN, meticulous dermatological wound care, resection of residual glioma, debridement of scalp and bone, and reconstruction of the scalp and calvarial defect with a myocutaneous vascularized free flap. The scalp wounds have healed completely in a cosmetically acceptable fashion and the patient remains free of tumor recurrence approximately 18 months after surgery, having completed a course of systemic chemotherapy. TEN may complicate the use of anticonvulsant and antineoplastic medications in malignant glioma patients. Withdrawal of the offending agent and immune suppressant medications, skin care and infection control, tumor resection to diminish steroid use, and reconstruction of scalp and calvarial defects with a vascularized myocutaneous flap facilitate wound healing and permit resumption of antineoplastic therapies. Toxic epidermal necrolysis (TEN) is a rare, fulminant, drug-related dermatologic reaction characterized by mucous membrane sloughing of the face, upper trunk, and respiratory tract. Scalp involvement is relatively rare. Anticonvulsant medications are commonly implicated in the pathogenesis of toxic epidermal necrolysis. Radiation and chemotherapy administered for treatment of malignant gliomas may also precipitate or potentiate such dermatologic side effects that are thought to be immunologically mediated. We report a unique case of TEN complicating antiepileptic and antineoplastic drug use and radiation therapy that involved the scalp with resultant breakdown of tissues leading to cranial osteomyelitis. These effects may have been precipitated or aggravated by concomitant radiation and chemotherapy after partial resection of a left frontal glioblastoma multiforme and the use of antiepileptic medications. As a result, all such medications were withdrawn, leading to cessation of tumor treatment and seizure prophylaxis. A careful multidisciplinary strategy led to recovery from the TEN, allowing subsequent resection of the residual neoplasm, debridement of infected and necrotic scalp and calvarial tissues, and reconstruction with a serratus anterior free myocutaneous flap, resulting in a favorable functional and cosmetic outcome that allowed resumption of chemotherapy after an appropriate interval of healing. CASE REPORT History This 21-year-old right-handed Indian-American man presented with headaches, emesis, and diplopia to another facility. Findings of a neurologic examination were normal. Magnetic resonance imaging (MRI) demonstrated a left-frontal heterogeneously enhancing lesion with significant mass effect. Administration of phenytoin and dexamethasone was started. A left-frontal craniotomy was performed through a modified bicoronal incision and a subtotal resection was performed. Pathology confirmed glioblastoma multiforme. The postoperative course was complicated by CSF rhinorrhea, and he was taken back to the operating room for cranialization of the frontal sinus and packing with temporalis muscle. Discharged on phenytoin after an uneventful recovery from the second operation, he presented 2 weeks later with a generalized erythematous rash generally associated with phenytoin toxicity. The phenytoin was withdrawn, and treatment was started with phenobarbital, which led to resolution of the rash. Standard adjuvant radiation and temozolomide (75 mg/m2/day) chemotherapy were started approximately 3 weeks after surgery. Five weeks later, during radiation, the patient developed severe oral ulcers. He had received 25 fractions (45 Gy) of conformal external beam therapy. Skin blistering and sloughing began within the scalp flap, extending to the extremities over the palms and soles. In addition, mucosal sloughing of the upper aerodigestive tract was noted that prompted diagnostic esophagraphy. During this procedure, he aspirated the contrast material into his upper airways and right lung. He was intubated and antibiotic and antiviral therapy was initiated; he was then transferred to our institution's burn center for further management. On arrival, he was noted to move all four extremities and to have equal-size and reactive pupils. Because he was sedated and on a ventilator, the rest of his neurological examination was limited. The patient was febrile but had stable hemodynamic and respiratory parameters on mechanical ventilation. Blister formation with skin sloughing was noted on the scalp, face, neck, upper trunk, and upper extremities. A bronchoscopy with lavage of the upper airway and right lung permitted removal of the inspissated barium. Punch biopsies of affected areas demonstrated epidermal necrosis, subepidermal bullae, and lymphocytic infiltrate, consistent with toxic epidermal necrolysis. Extensive mucosal sloughing of the mouth and upper airway necessitated continued endotracheal intubation and ventilatory support. The patient was treated in the burn unit for 1 month according to the Loyola Burn Center Protocol for TEN Patients.5 Anticonvulsant, antineoplastic, and steroid medications were withdrawn. A tracheotomy and gastric feeding tube were placed, and nutrition was administered. Wound diagrams were recorded on admission and after any significant change. The wounds were cleaned, debrided, and dressed with nanocrystalline silver dressings (Acticoat, Smith & Nephew, Largo, Florida) on admission and every 3 days thereafter. No prophylactic antibiotics, steroids, or immunomodulatory agents were administered. With gradual resolution of the TEN involving the skin and mucosal surfaces, the tracheostomy was capped, and the patient was allowed to take food by mouth. Follow-up cranial MRI approximately 3 months after initial diagnosis demonstrated a residual and recurrent tumor within the left-frontal lobe with significant mass effect (Figure 1). The patient reported moderate to severe headaches, but his neurologic examination remained normal. The treating team was hesitant to restart radiation, chemotherapy, or steroids, given the severe dermatological problems that had been previously encountered. Because of these considerations and the patient's youth and good performance status, re-resection was offered. Figure 1. View largeDownload slide Preoperative MRI (T1-weighted with gadolinium) demonstrated a heterogeneously enhancing solid cystic lesion within the left-frontal lobe associated with significant vasogenic edema and mass effect. Figure 1. View largeDownload slide Preoperative MRI (T1-weighted with gadolinium) demonstrated a heterogeneously enhancing solid cystic lesion within the left-frontal lobe associated with significant vasogenic edema and mass effect. An awake craniotomy was performed, involving mapping of speech and motor function with somatosensory evoked potentials and direct cortical stimulation. The surgical exposure was difficult, given extensive scar formation from two previous operations and the subsequent radiation, but a gross total resection of the contrast-enhancing volume was achieved. The patient recovered headache-free without neurologic deficits. Four days after surgery, CSF rhinorrhea and subcutaneous emphysema beneath the skin flap were noted. A lumbar drain was placed and CSF was diverted for 5 days, but the fistula persisted. The patient became delirious. Broad-spectrum antibiotics were started for suspected meningitis, although lumbar CSF cultures remained negative. Concerns about infection involving the subgaleal space, cranial bone, and epidural space prompted consideration of tissue and bone debridement and a vascularized pedicled myocutaneous flap to obtain adequate and cosmetic skin closure and repair of the dural deficiencies. Seropurulence was immediately encountered upon incision into the subgaleal space, and the underlying bone was necrotic. The scalp and galea were debrided; the bone flap and previous synthetic dural graft were removed. A new dural substitute (Durepair, TEI Biosciences, Boston, MA) was placed and a serratus anterior myocutaneous flap was harvested and used to cover the temporalis muscle, bone, and scalp defects and to obliterate the frontal sinus with vascular anastomosis of the graft pedicle to the lateral neck vessels. An incision was made approximately 4 cm below the angle of the mandible, extending through the subcutaneous tissues and platysma. The external jugular vein was identified and the carotid sheath opened. The external carotid artery was followed rostrally to the facial artery. A subcutaneous tunnel connected the craniotomy and neck incisions. The left serratus anterior muscle was harvested, as described by Buncke and Whitney,6 through an incision beginning on the border of the posterior axillary fold extending along the eighth rib. The thoracodorsal vessels and nerve were identified and preserved. The lower three slips of the serratus muscle were transected off the costal origin and scapular tip (Figure 2). The chest wound was closed in layers over a drain. The free muscle flap covered the cranial defect, secured with horizontal mattress sutures. One slip of muscle was separated anteriorly for use in obliterating the left frontal sinus. An end-to-end anastomosis in the neck connected flap vessels to the facial artery and external jugular vein. The wound was closed in layers over a subgaleal drain. There were no immediate complications. Pseudomonas aeruginosa grew in cultures of specimens from the subgaleal space, and the patient was treated with ceftriaxone (Rocephin, Roche Pharmaceuticals, Nutley, NJ). Following three additional days of lumbar drainage, the patient recovered well and was ambulating without neurological deficits on discharge 12 days later. At 18 months follow-up, he is progressing well, with normal neurologic findings and no significant deficit with detailed neuropsychologic testing. His wounds are healed. He has completed 5 cycles of adjuvant therapy with Lomustine (CeeBU, Bristol- Myers Squibb, Princeton, NJ). MRI 18 months after initial diagnosis did not reveal any recurrence of tumor, and the patient continues to do well at the time of this report (Figure 3). Figure 2. View largeDownload slide Serratus harvesting and placement within the cranial defect. Figure 2. View largeDownload slide Serratus harvesting and placement within the cranial defect. Figure 3. View largeDownload slide Twelve-month postoperative MRI following gross total resection and wound reconstruction with serratus anterior free flap shows no radiographic evidence of tumor recurrence. Clinically, the skin lesions and incisions have healed and the patient is doing well. Figure 3. View largeDownload slide Twelve-month postoperative MRI following gross total resection and wound reconstruction with serratus anterior free flap shows no radiographic evidence of tumor recurrence. Clinically, the skin lesions and incisions have healed and the patient is doing well. DISCUSSION Toxic epidermal necrolysis is a rare, potentially fatal exfoliative hypersensitivity reaction related to drug administration that generally involves the mucous membranes and more than 30% of the TBSA.5,7 It is the most severe form of skin reactions, which include the Stevens-Johnson syndrome (SJS; 10% to 30% TBSA) and erythema multiforme (<10% TBSA). Drugs implicated in these reactions include sulfonamides, penicillin, and anticonvulsants.3,5,8 Toxicity is idiosyncratic, occurring regardless of medication dose, relating to abnormal drug metabolism that may induce immune-complex damage and cell-mediated cytotoxicity against keratinocytes. Fas ligand–mediated keratinocyte apoptosis is thought to be involved in the pathophysiologic process.4,5,9 The clinical syndrome can manifest within days or weeks of medication administration, starting with a prodrome of fever and malaise, followed by the development of erosive mucosal lesions, blisters, and skin sloughs.5,10 Target-like (morbilliform) eruptions start on the face and upper trunk, spreading to form large, confluent, flaccid bulla with denouement of the underlying skin. Mortality approaches 30% to 40%.5,7 Treatment strategies for SJS and TEN involve withdrawal of the inciting agent and management of open wounds to prevent infection, with airway protection and nutritional support critical in the recovery process. Glioblastoma multiforme is the most common malignant primary CNS neoplasm. Treatment involves removal of as much of the tumor as is safely possible while avoiding postoperative neurologic deficits, and adjuvant radiation and chemotherapy, which together may extend survival to 18 to 24 months from the time of initial diagnosis.1 Corticosteroids are frequently used to ameliorate symptoms associated with vasogenic edema, and antiepileptic drugs are used to either prevent or control seizures. Corticosteroids may impair tissue healing, and in the presence of chemotherapy and radiation, wound infections may occur. External beam radiation therapy and systemic chemotherapy are established modalities in the management of malignant brain tumors. Glioblastoma multiforme is generally treated with conformal external beam therapy delivered 5 days a week for 6 weeks, to a total dose of 60 Gray.13,14 However, radiation may sensitize a patient to toxic exfoliative skin conditions such as TEN, particularly in those receiving anticonvulsant therapy.15,16 Nine cases of true TEN have been reported involving patients undergoing cranial irradiation and concomitant anticonvulsant therapy.8,17,18 Of these, four occurred as a result of concomitant radiation and phenobarbital administration.17,19,20,21 The initial skin reaction presented within the confines of the irradiated field, later manifesting elsewhere to involve the mucous membranes of the upper respiratory and digestive tracts. As in previously reported cases, the risk of developing TEN with anticonvulsants even in the presence of radiation is independent of dose.8 The addition of a chemotherapeutic agent to radiation therapy confers a small survival benefit in patients with malignant gliomas.1 Temozolomide (Temodar, Schering-Plough, Kenilworth, NJ) is an oral alkylating agent used in the primary management of malignant gliomas concurrently with radiation therapy. It is usually continued as a maintenance regimen.1 Its mechanism of action includes formation of DNA adducts, inducing strand breakage and cell death. Advantages of its use include ease of administration, a minimal side effect profile, and its ability to cross the blood-brain barrier.22 Conventional dosing schedules include 150 to 200 mg per square meter of body surface area for 5 days of a 28-day cycle, and long-term daily therapy of 75 to 130 mg per square meter for up to 7 weeks. Dose-limiting side effects are predominantly hematologic: thrombocytopenia and neutropenia occur in approximately 7% of patients within the first few cycles of therapy. The most common nonhematologic side effect is fatigue, reported by 33% of patients. There is a 2% to 3% risk of pneumonia or other infection. Mild skin rashes and pruritus occur in 8% of patients. Temozolomide has not been implicated in the development of severe exfoliative skin reactions such as SJS or TEN, as reported here.1 Whether temozolomide alone precipitated this problem or contributed to the effects of the radiation therapy and anticonvulsant medications in our patient is undetermined. Antiepileptic drugs such as phenytoin, carbamazepine, and phenobarbital commonly cause dermatologic complications that may range from mild rashes to severe systemic reactions such as SJS.2 An extreme and rare side effect is TEN, characterized by epidermal sloughing of the face and upper trunk and mucous membranes of the upper respiratory tract, nasal-oral cavity, and orbit. Respiratory compromise is common, and superinfection with systemic sepsis may be fatal in 30% to 40% of cases.3 The pathophysiologic mechanism underlying TEN may be immunologically mediated and precipitated by radiation, chemotherapy, corticosteroids, and antiepileptic drugs alone or in combination. Skin reactions and other severe side effects associated with anticonvulsant medications have prompted careful reconsideration of their role in seizure prophylaxis.12 A meta-analysis of 12 studies demonstrated seizure occurrence to be 19% to 26% among patients with brain tumors.2 The study concluded that the risk of anticonvulsant-associated side effects outweighed any benefit in seizure reduction for patients with brain tumors. Patients who present with seizures or with cortical intra-axial primary or metastatic neoplasms are nonetheless candidates for therapy with an anticonvulsant medication. Among anticonvulsant agents implicated in TEN, the relative risk (RR) of SJS or TEN in patients receiving short-term (≤2 months) phenobarbital is 45 in comparison with nonmedicated, matched controls (Figure 4). This yields a prevalence of 1.2 cases per million users per week.3,11 The risk of developing TEN or similar severe dermatological side effects with other commonly used anticonvulsants varies (phenytoin RR, 53; valproic acid RR, 25; carbamazepine RR, 90). When all medications are considered as a whole, sulfonamides are associated with the highest risk of causing SJS and TEN (RR, 156). Other commonly prescribed nonanticonvulsant medications such as oxicam nonsteroidal antiinflammatory drugs (RR, 72), corticosteroids (RR, 54), and allopurinol (RR, 52) may also have similar dermatological side effects. Figure 4. View largeDownload slide Drugs implicated in TEN and their associated relative risks.3 Figure 4. View largeDownload slide Drugs implicated in TEN and their associated relative risks.3 Free myocutaneous flaps for craniofacial reconstructive surgery have been described mainly in the context of head and neck tumors.23,24 Although several donor sites have been used, the thoracodorsal axis (including latissimus dorsi and serratus anterior with the adjacent ribs) offers a variety of advantages, in particular, adequate graft bulk. Bone may be harvested if necessary, and there is minimal donor site morbidity. Vascular pedicle length and relative lack of atherosclerosis in these vessels facilitate anastomosis.25,26 Among thoracodorsal grafts, serratus anterior flaps have certain advantages that make them more suitable to cranial reconstructive surgery. Serratus flaps have a longer, more consistent vascular pedicle. Vessel length ranges from 9.6 ± 1.5 cm, and flaps can be used to reconstruct defects as large as 180 square cm.27,28 Vessels can be tunneled through a subcutaneous plane with ease, and multiple slips of the muscle allow for graft contouring to the cranial profile. Dead spaces, such as those created by the cranialized frontal sinus, may be obliterated. Donor site morbidity and functional effects on the shoulder and scapula are minimal.24,29,30 This patient experienced TEN after 5 weeks of concomitant administration of phenobarbital, radiation, and temozolomide. The initial management consisted of meticulous skin and wound care in a burn unit, and respiratory mucosal sloughing necessitated ventilatory support. The offending agents, presumably phenobarbital and temozolomide, were withdrawn, as was the radiation treatment. Given the mass effect and vasogenic edema associated with the tumor, it was believed that surgical debulking would allow minimizing the use of immune-suppressant medications such as corticosteroids. The denuded, compromised scalp tissues and infected cranial bone flap were completely removed and the defect reconstructed with a pedicle vascularized myocutaneous flap. With complete wound healing, therapy was started with an alternative antineoplastic agent, and he has remained without evidence of tumor progression 18 months from the time of surgery, with a good functional outcome. CONCLUSIONS TEN is a rare but serious dermatological complication that may complicate the use of anticonvulsant and other medications used in brain tumor patients. The concomitant use of radiation therapy with anticonvulsants or a chemotherapeutic agent may increase the risk. Careful appraisal of the need for each modality and consideration of alternate options, as with anticonvulsant and chemotherapy medications, are part of a multidisciplinary approach to the problem. In the event of TEN or a similar severe dermatological problem, the offending agent should be withdrawn, immune suppressant medication use minimized, and skin care and infection control (preferably in a burn unit) instituted. As in this instance, aggressive tumor resection can diminish steroid dependency. Reconstruction of scalp and calvarial defects with a vascularized myocutaneous flap expedites and facilitates wound healing, allowing resumption of adjuvant antineoplastic therapies. ACKNOWLEDGMENTS The authors graciously thank Dianne Martia, medical illustrator and editor, for her meticulous work on the manuscript. REFERENCES 1. Stupp R, Mason WP, Van den Bent MJ, et al.   Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med  2005; 352: 987– 96. 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TI - Management of Scalp Toxic Epidermal Necrolysis and Cranial Osteomyelitis With Serratus Anterior Myocutaneous Pedicle Flap: A Case Report
JF - Journal of Burn Care & Research
DO - 10.1097/BCR.0B013E318053DA97
DA - 2007-05-01
UR - https://www.deepdyve.com/lp/oxford-university-press/management-of-scalp-toxic-epidermal-necrolysis-and-cranial-UIsCQp1ffS
SP - 524
EP - 529
VL - 28
IS - 3
DP - DeepDyve
ER -