Deepak M. Kamat, MD, PhD

A 14-year-old girl with systemic lupus erythematosus (SLE) was evaluated for worsening left leg pain of 1 week’s duration. A month earlier, she had presented with left knee arthritis and a vasculitic rash; the antinuclear antibody titer was positive. In addition, she had leukopenia, myositis, hypocomplementemia, and mild proteinuria. She had responded to treatment with corticosteroids and hydroxychloroquine. She was not taking any other medications.

On examination, the patient had left popliteal tenderness and plethoric engorgement of the left calf. A Doppler ultrasonogram revealed a venous thrombus from the distal femoral vein into the lesser saphenous vein.

Further workup revealed a negative result on testing for lupus anticoagulant, a low-positive result on anticardiolipin antibody studies (IgG, 17 GPL units; IgM, less than 10 MPL units; IgA, less than 12 APL units), homozygosity for the methylenetetrahydrofolate reductase genetic mutation, and normal homocysteine levels. A venogram (injection via the left popliteal vein with the patient prone) revealed a nearly occlusive process in the proximal portion of the left common iliac vein, consistent with May-Thurner syndrome.

This rare anatomic cause of thrombosis was likely responsible for this patient’s deep venous thrombosis (DVT). Although SLE is commonly associated with an increased risk of thrombosis, this patient did not have significantly positive, persistent results on antiphospholipid antibody studies, and her homocysteine levels were normal.

May-Thurner syndrome was anatomically defined in 1957 by May and Thurner

; however, isolated left lower extremity swelling secondary to left iliac vein compression was first described in 1908 by McMurrich.

 May-Thurner syndrome, also known as iliac vein compression syndrome, manifests as left lower extremity swelling, pain, venous stasis changes, and DVT. It results from compression of the left common iliac vein between the overlying right common iliac artery and the lumbar spine, usually at L5. This compression may lead to focal intimal proliferation of the vein, and hence venous stasis in the left lower extremity.

Although anticoagulation is standard therapy for affected patients, surgical intervention with angioplasty and stent placement is often necessary for recalcitrant thrombi.

 There are no current data comparing treatment modalities for this condition.

This patient was treated with anticoagulation, thrombectomy, and angioplasty of the left common iliac vein at the site of obstruction. The clot was described as hard in texture and thus chronic in nature. She had one recurrence of occlusive DVT. Since then, she has been anticoagulated well. The thrombus completely resolved and has not recurred. Homocysteine levels have remained normal; results of anticardiolipin studies have remained negative.

May R, Thurner J. The cause of the predominantly sinistral occurrence of thrombosis of the pelvic veins. 

Wolpert LM, Rahmani O, Stein B, et al. Magnetic resonance venography in the diagnosis and management of May-Thurner syndrome. 

Vyas S, Roberti I, McCarthy C. May-Thurner syndrome in a pediatric renal transplant recipient-case report and literature review. 

Articles

A 14-year-old girl with systemic lupus erythematosus (SLE) was evaluated for worsening left leg pain of 1 week’s duration. A month earlier, she had presented with left knee arthritis and a vasculitic rash; the antinuclear antibody titer was positive. In addition, she had leukopenia, myositis, hypocomplementemia, and mild proteinuria.

May-Thurner Syndrome

A 13-year-old boy was brought to the emergency department (ED) with a generalized itchy rash of 2 days' duration. For the past 3 days, he had dry, itchy eyes with a purulent discharge (

) and nonbilious emesis 2 or 3 times per day, with some blood streaks in the vomitus on the third day of illness. Chills developed on the third day, but the patient's temperature was not measured. His lips were swollen and cracked (

, which made it painful to eat or drink. About 6 months earlier, he had a similar episode that resolved with application of a topical cream to the lips. He also had painful urination without urgency or penile discharge. He denied recent use of medications and had no ill family members. He had been well before the onset of symptoms.


Figure 1 – About 30% of children with Stevens-Johnson syndrome have ocular involvement. This 13-year-old boy had mucopurulent conjunctivitis with episcleritis as a manifestation of the disease.


Figure 2 – Mucositis of the lips in this teenager was a manifestation of Stevens-Johnson syndrome. Oral lesions are the most common type of mucosal involvement in affected patients. They are extremely painful and limit oral intake.

The teenager was apathetic, mildly dehydrated, and appeared to be in pain. Oral temperature was 39.6ºC (103.2ºF); respiration rate, 20 breaths per minute; heart rate, 108 beats per minute; and blood pressure, 108/63 mm Hg. Physical examination revealed injection of the conjunctivae with sticky yellow discharge, swollen lips with erosion of the mucosa, hemorrhagic crusting, intraoral ulcers, dry oral mucous membranes, ulceration of the head of the penis, and a generalized rash that consisted of target lesions with central erosions. 

The white blood cell count was normal (6700/Î¼L), without a left shift; hemoglobin level was 14.3 g/dL. Results of coagulation studies were normal. The erythrocyte sedimentation rate and C-reactive protein level were markedly elevated (107 mm/h and 33.78 mg/L, respectively). Serum electrolyte levels were normal, blood urea nitrogen level was elevated (33 mg/dL), and creatinine level was 1.3 mg/dL. Liver function test results were normal; the albumin level was slightly below normal (3.3 g/dL). Urinalysis results showed a specific gravity of 1.028 and 1+ protein; all other parameters were within normal range. IgA was 183 mg/dL. Direct fluorescent antibody studies of lip vesicles for herpes simplex virus types 1 and 2 were negative. Fluorescein examination of the eye demonstrated no corneal uptake of dye. A blood sample for culture was obtained.

In the ED, the patient received intravenous saline, ceftriaxone (a single dose), acyclovir, diphenhydramine, and analgesia. A topical analgesic was applied to the ulcerated mouth, and emollients were applied to the rash. The ophthalmology consultant diagnosed mucopurulent conjunctivitis with episcleritis and recommended lubrication with artificial tears and erythromycin ophthalmic ointment. The dermatology consultant performed a biopsy of a target lesion, which demonstrated interface dermatitis with vacuolation of the basal layer and rare dyskeratotic cells in the epidermis suggestive of Stevens- Johnson syndrome (SJS) or erythema multiforme (EM).

Serological test results were negative for Mycoplasma; herpes simplex virus; Epstein-Barr virus; Cytomegalovirus; HIV; hepatitis A, B, and C viruses; and Treponema pallidum. Blood culture was negative.

Because of persistent vomiting and a steadily increasing elevated lipase level (from 713 U/L to a maximum of 1589 U/L), abdominal ultrasonography was performed. The size of the pancreas was at the upper limits of normal; there was a small amount of free fluid in the abdomen.

During the patient's 10-day hospitalization, intravenous hydration was maintained until he was able to tolerate oral feeds. At discharge, the eye and skin lesions had completely resolved and the oral ulcers had almost completely healed. The final diagnosis was SJS and acute pancreatitis.

SJS and toxic epidermal necrolysis (TEN) are severe mucocutaneous blistering disorders of acute onset that are associated with considerable morbidity and life-threatening complications. Like EM minor, both SJS and TEN may have oral mucosal lesions and ulcerated lesions; however, SJS and TEN are distinguished from EM by the involvement of 2 or more mucosal surfaces, more widespread lesions, systemic illness, and more extensive epidermal involvement on biopsy.

 first described EM as a self-limited disease in healthy young adults that is most commonly caused by herpes simplex virus, has the classic iris or target lesion, and is rarely associated with fever or systemic symptoms. Stevens and Johnson

 later described a severe, generalized skin infection, prolonged high fever, purulent conjunctivitis, and severe oral stomatitis in 2 children. They excluded the diagnosis of EM in these 2 children because of the presence of atypical target lesions and prolonged systemic symptoms.

The term "EM minor" became synonymous with von Hebra disease and "EM major" (EM with involvement of 2 mucous membranes) with SJS. TEN, first described by Lyell,

 is currently considered to be a severe form of SJS caused by a similar spectrum of drugs and characterized by full-thickness epidermal loss over a large extent of the body surface. The current thinking is that there are 2 groups of diseases:

 are primarily caused by herpes simplex virus, present with classic target lesions in an acral distribution, and have a benign course.

 are often druginduced, are characterized by the presence of atypical target lesions and purpuric macules, and cause severe morbidity.

The current classification of acute severe bullous disorders comes from Bastuji-Garin and colleagues

 and is based on the extent of body surface involvement and type of skin lesions. SJS has an estimated incidence of2.6 cases per million per year5 and affects all age-groups.

Drugs are the most common cause of SJS and TEN,

 although infectious agents and immunizations have also been implicated. Drugs that frequently cause SJS include antibiotics (particularly sulfonamides, aminopenicillins, and cephalosporins) and aromatic anticonvulsants- phenobarbital, phenytoin, and carbamazepine. 

 While NSAIDs and antigout medications frequently cause SJS in adults, they are rarely implicated in children. Drug-induced SJS typically occurs between 1 and 3 weeks of initiation of drug therapy. Persons with systemic lupus erythematosus and those who are infected with HIV are more susceptible to drug-induced SJS.

Among infectious causes, herpes simplex virus and

 are most strongly associated with SJS. Epstein-Barr virus, Cytomegalovirus, and streptococcal infections are also associated with SJS. Herpes simplex virus 1 infection was the suspected cause of SJS in this patient based on the presence and previous episode of lip lesions. However, given the negative serological results, this could not be proved conclusively.

SJS is believed to be an immunological disorder that causes perivasculitis of the superficial dermal vessels. Immunofluorescent examination of early skin lesions in SJS demonstrate IgM and C3 deposits in the vascular walls in most patients. Other histological changes include full-thickness necrosis of the epidermis and a scant mononuclear cell in the dermis. The dermoepidermal junction shows changes that range from vacuolar alteration to subepidermal blister formation. In the drug-induced form, it is believed that full-thickness epidermal necrosis is triggered by accumulation of the drug metabolites in the epidermis. Patients and their first-degree relatives are believed to have genetic defects in the drug metabolic pathway that leads to accumulation of the drug metabolites. Persons with HLAB12 (HLA-Bw44) antigen are at greater risk for the development of SJS.

 T-cell–mediated cytotoxicity is believed to be responsible for the epidermal necrosis in TEN.

SJS is usually preceded by a prodrome of fever, sore throat, and generalized malaise that lasts for several days and is often misdiagnosed as an infectious illness for which an antibiotic is prescribed. In a large case series from Toronto, 61% of children had mucous membrane involvement, most commonly oral, genital, and anal.9 Of those children, 95% had oral lesions that ranged from isolated vesicles or bullae to swelling, blistering, and ulceration of both lips. The mouth lesions seen in SJS are extremely painful and limit oral intake, as was the case in this patient.

Genital lesions include vesicobullous vulvovaginitis, ulcers, and anal and urethral erosions. About 30% of children have ocular involvement in the form of hemorrhagic conjunctivitis, corneal ulceration, blepharitis, or scleritis

These can lead to corneal erosions, pseudomembrane formation, and adhesions. Rarely, other mucous membranes, such as the esophagus, intestinal tract, respiratory epithelium, and nasal cavity, can also be affected.

The rash of SJS usually begins as purpuric macules that evolve within days into atypical targetlike bullae and erosions of the face, trunk, limbs, palms, and soles. The scalp is usually spared. Typical target lesions are usually less than 3 cm in diameter and round with a well-defined border. They have 3 zones with 2 concentric rings, 1 of which is palpably edematous and paler than the central disk. Atypical target lesions are also round, edematous, palpable lesions but have only 2 zones and an ill-defined border.

The rash tends to be more severe and extensive in patients with drug-induced SJS. It can progress to sheetlike loss of epidermis, especially in cases of TEN. The Nikolsky sign (formation of a blister with peeling of the superficial layers of skin from the lower layers, leaving wet, red, painful areas on application of horizontal, tangential pressure to the skin) is usually positive in TEN. The average duration of illness is usually 2 weeks. Resolution and healing occur between 1 and 2 weeks.

SJS is usually a clinical diagnosis. Abnormal laboratory findings may include an elevated sedimentation rate, hypoalbuminemia (as in this patient), mildly elevated liver enzyme levels, microscopic hematuria, and mild leukocytosis. Leukopenia is considered a poor prognostic sign and may indicate superinfection and sepsis. Serological test results may be positive in 

A skin biopsy is indicated only when the diagnosis is uncertain. Histopathological findings include a mononuclear perivascular cell infiltrate in the dermis, basal layer edema, subepidermal blister formation, and epidermal cell necrosis. TEN is characterized by epidermal necrosis with minimal evidence of inflammation. 

A mortality rate of up to 5% has been reported with SJS.

Patient age and extent of skin detachment have been proposed as the main prognostic factors. Early withdrawal of the causative agent, when one is involved, may decrease mortality.

The most common complication is sepsis (most often caused by 

Hypovolemic shock can occur from fluid loss and electrolyte imbalance secondary to extensive skin detachment. Sloughing and edema of the respiratory epithelium may lead to upper airway obstruction, pneumonia, or diffuse interstitial pulmonary disease. Urethral erosions can cause acute urinary retention, especially in younger children. GI erosions can lead to upper GI bleeding and bloody diarrhea. Less common sequelae include cutaneous scarring, palpebral synechiae with permanent visual impairment, and bronchiolitis obliterans.

In a review of the literature, there was no reported association between pancreatitis and SJS, although some of the drugs that cause SJS (such as valproic acid) also cause pancreatitis. We do not believe that the pancreatitis led to SJS in this patient.

SJS and TEN in children are dermatological emergencies. Diagnosis should prompt immediate discontinuation of all potential causative drugs. Older children with proven 

 infection can be treated with either an oral macrolide or oral doxycycline. Patients with extensive blistering or skin loss require care at a pediatric burn center. Those with extensive skin detachment require reverse barrier isolation and a sterile environment. Consultation with an ophthalmologist and dermatologist is recommended.

Supportive measures include isolation, fluid and electrolyte balance, nutritional support, eye and mouth care, pain management, and nonadherent protective dressings for skin lesions.

Because of poor oral intake, many children require nutritional support with either a nasogastric tube or parenteral alimentation for 1 to 2 weeks. While surgeons advocate extensive debridement, as in a burn patient, dermatologists recommend debridement of necrotic and peeled skin only. The value of topical antibiotics is unproved. No particular type of dressing (synthetic, biological, or petrolatum gauze) has been proved superior. Children often require an opioid analgesic for dressing changes.

Other than good supportive care, there is no effective and universally accepted treatment of SJS. Although prevention and early treatment of sepsis is indicated, prophylactic antibiotics are not recommended.

The role of corticosteroids in the treatment of SJS or TEN is controversial. Although earlier retrospective studies reported a longer hospital stay and a higher incidence of complications in children with SJS who were treated with corticosteroids, 

other studies reported an outstanding success rate with early and prompt treatment with highdose corticosteroids.

To date, no randomized controlled studies have shown a benefit from their use in the treatment of SJS. Moreover, SJS can be managed successfully with supportive care alone.

Although some case series reported improved outcomes in patients with SJS after a single infusion of intravenous immunoglobulin (IVIG),

 a prospective study failed to show reduction in mortality or progression of disease.

 Randomized controlled trials with large numbers of patients are needed before IVIG can be recommended as a standard treatment for children with SJS.

On Diseases of the Skin Including the Exanthemata.

 Fagge CH, trans. London: New Sydenham Society; 1866:285-289.


 Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia: report of two cases in children. 

 Lyell A. Toxic epidermal necrolysis. An eruption resembling scalding of the skin. 

 Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. 

 SchÃ¶pf E, StÃ¼hmer A, Rzany A, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome. An epidemiologic study from West Germany.

 Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. 

 Prendiville J. Stevens-Johnson syndrome and toxic epidermal necrolysis. 

 Mondino BJ, Brown SI, Biglan AW, et al. HLA antigens in Stevens-Johnson syndrome with ocular involvement. 

 Forman R, Koren G, Shear NH. Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a review of 10 years' experience. 

 Revuz J, Penso D, Roujeau JC, et al. Toxic epidermal necrolysis: clinical findings and prognosis in 87 patients.

 Garcia-Doval I, LeCleach L, Bocquet H, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? 

 Prendiville JS, Hebert AA, Greenwald MJ, Esterly NB. Management of Stevens-Johnson syndrome and toxic epidermal necrolysis in children. 

 Kim PS, Goldfarb IW, Gaisford JC, et al. Stevens- Johnson syndrome and toxic epidermal necrolysis: a pathophysiologic review with recommendations for a treatment protocol.

 Patterson R, Miller M, Kaplan M, et al. Effectiveness of early therapy with corticosteroids in Stevens- Johnson syndrome: experience with 41 cases and a hypothesis regarding pathogenesis. 

 Metry DW, Jung P, Levy ML. Use of intravenous immunoglobulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis.

 Prins C, Vittorio C, Padilla RS, et al. Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: a retrospective, multicenter study. 

 Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. 

A 13-year-old boy was brought to the emergency department (ED) with a generalized itchy rash of 2 days' duration. For the past 3 days, he had dry, itchy eyes with a purulent discharge (Figure 1) and nonbilious emesis 2 or 3 times per day, with some blood streaks in the vomitus on the third day of illness.

Stevens-Johnson Syndrome

A 4-year-old girl was brought to the emergency department after she sustained an injury to her jaw in a car accident. She had been restrained in the rear passenger seat with a seat belt. She had not lost consciousness and was not ejected from the vehicle.

Vital signs were stable. Her weight was 23 kg; height was 117 cm. She had swelling and ecchymosis of the left lower jaw and dried blood around her lips. Intraorally, a few blood clots were present on the gum line with an obvious step off anteriorly.

) CT scans revealed a left mandibular angle/body fracture that was displaced and open and a right mandibular body fracture between the deciduous canine tooth and first molar that was also open and widely displaced. The patient underwent open reduction with internal fixation. Recovery was uneventful.

Fractures of the mandible in children are complicated by the developing anatomy, particularly the presence of tooth buds and the eruption of deciduous and permanent teeth.

 Because of the presence of tooth buds and crypts, the fractures are often long and irregular, running inferiorly and anteriorly. They are associated with many complications, including growth disturbances with facial asymmetry, maloccusion and poor mastication, osteomyelitis, tooth bud damage, temporomandibular joint syndrome, salivary disorders, obstructive sleep apnea, and chronic pain.

The type of treatment depends on the severity of the fracture and the age of the patient.

 Referral to an oral surgeon is required in most cases.

This child's fracture might have been prevented if she had been in a booster seat. The American Academy of Pediatrics recommends the use of a booster seat for older children until adult seat belts fit correctly- usually until the child is about 144.8 cm (57 in) tall and between 8 and 12 years of age.

 Discussing the use of booster seats for older children with parents and caregivers during regular well child care visits could help raise awareness.

 McGuirt WF, Salisbury PL 3rd. Mandibular fractures. Their effect on growth    and dentition. 

 Rowe NL. Fractures of the jaws in children. J Oral Surg. 1969;27:497-507.  
  

  Schweinfurth JM, Koltai PJ. Pediatric mandibular fractures. 

Hardt N, Gottsauner A. The treatment of mandibular fractures in children.    

  Jamerson RE, White JA. Management of pediatric mandibular fractures.    

 American Academy of Pediatrics. Car Safety Seats: A Guide for Families    2008. 

http://www.aap.org/family/Carseatguide.htm#BoosterSeats

Mandible Fracture After a Motor Vehicle Accident

A previously healthy 16-month-old boy was hospitalized because of vomiting of 10 days' duration, fever of 4 days' duration (temperature up to 38.6°C [101.4°F]), and watery diarrhea. He also had had a maculopapular rash, which resolved the day before presentation. Family history was unremarkable.

Physical examination, including abdominal examination, was normal. No rash was noted. Weight was 12.5 kg (90th percentile), and development was appropriate for age. On the third hospital day, significant pitting edema (mainly on the trunk) and periorbital swelling developed; the albumin level was 1.8 g/dL, and total protein level was 3.5 g/dL.

Urinalysis results, liver enzyme levels, prothrombin time, partial thromboplastin time, urea nitrogen level, and creatinine level were normal. A protein-losing enteropathy/gastropathy was suspected. Gastroscopy revealed hypertrophic gastric folds and severe gastritis (A). Histopathological examination of the gastric mucosa showed foveolar hyperplasia and inflammatory changes (B), consistent with Mntrier disease, and Cytomegalovirus (CMV) inclusion bodies (C, arrows).

Mntrier disease in children is a rare, self-limited disorder that is characterized by marked protein-losing gastropathy associated with enlarged and thickened gastric folds.

 Abnormal regulation of gastric epithelial growth, probably triggered by an infectious agent (CMV or 

 In this case, enzyme immunoassay testing was positive for CMV-specific IgM antibody and urine culture was positive for CMV antigen.

The clinical, radiological, and histological features of Mntrier disease in children resemble those of the adult form. However, there are important differences. Generalized edema occurs in fewer than 25% of adult cases but is the most common finding in children. In addition, the clinical course is usually unfavorable in adults; many require partial or total gastrectomy for persistent symptoms. The prognosis for children, on the other hand, is excellent.

This patient was treated with omeprazole; within 3 weeks, his symptoms had resolved and the serum albumin level had normalized.

 Gormally S, Sherman PM, Drumm B. Gastritis and peptic ulcer disease. In: Walker WA, Durie PR, Hamilton JR, et al, eds. 

. 2nd ed. St Louis: Mosby; 1996:506-527. 
    

 Proujansky R. Protein-losing enteropathy. In: Walker WA, Durie PR, Hamilton JR, et al, eds.

2nd ed. St Louis: Mosby; 1996: 971-980. 
    

 Dempsey PJ, Goldenring JR, Soroka CJ, et al. Possible role of transforming growth factor alpha in the pathogenesis of MÃ©nÃ©trier's disease: supportive evidence from humans and transgenic mice. 

 BayerdÃ¶rffer E, Ritter MM, Hatz R, et al. Healing of protein losing hypertrophic gastropathy by eradication of 

 Hochman JA, Witte DP, Cohen MB. Diagnosis of cytomegalovirus infection in pediatric MÃ©nÃ©trier's disease by in situ hybridization. 

 Occena RO, Taylor SF, Robinson CC, Sokol RJ. Association of cytomegalovirus with MÃ©nÃ©trier's disease in childhood: report of two new cases with a review of literature. 

 Sferra TJ, Pawel BR, Qualman SJ, Li BU. MÃ©nÃ©trier disease of childhood: role of cytomegalovirus and transforming growth factor alpha. 

Deepak M. Kamat, MD, PhD

Articles

May-Thurner Syndrome

Stevens-Johnson Syndrome

Mandible Fracture After a Motor Vehicle Accident

Ménétrier Disease