Fatal Course of Cutaneous Cholesterol Embolization Syndrome: A Case Report

Introduction

Cutaneous Cholesterol Embolization Syndrome (CES) is an increasing but often unrecognized diagnosis due to its poor clinical recognition. ¹ Cholesterol embolism may occur after the start of anticoagulant or thrombolytic therapy or after endovascular procedures or may occur spontaneously.^2–5 Atherosclerotic plaques are lined along the great and intermediate great vessels. ⁶ The effect of the embolism depends on the position of the plaque in the aorta. ⁷ Plaques along the descending aorta mostly affecting the lower extremities, kidneys, intestine, or skin. Skin involvement results in blue toes syndrome or livedo reticularis in the upper legs and buttocks, in 88% of cases. From these patients, around 40% develop ulcers or necrosis. ⁸ In patients with CES, with only cutaneous involvement, a mortality of 33% is reported.^2,8 In this case report, we present a severe and fatal course of CES.

Case Description

A 62 years old male with a medical history of ischemic cerebrovascular accident, dyslipidemia, hypertension, adiposity, and peripheral arterial vascular disease, consulted the outpatient clinic because he had progressive ulcers of both feet (chronic limb ischemia grade 5). The ulcers had developed two months before the consultation. An ankle/arm index showed 28% on the left and 38% on the right leg. The diagnosis of arterial ulcers was made. Magnetic Resonance Angiography (MRI) showed an atherosclerotic wall plaque lining along the aortic wall and multiple occlusions in the iliac and crural arteries [Figure 1]. The patient was admitted twelve days after the first presentation due to progressive worsening of the wounds and endarterectomy of the left common femoral artery was performed followed by a Percutaneous Transluminal Angioplasty (PTA) from the external iliac artery to the crural arteries. Subsequently, a necrotectomy of the left foot was performed. After one week a PTA recanalization at the right side of the superficial femoral artery was performed followed by a wound debridement of the right foot with top “amputation” digits 4 and 5. Postoperatively, the ankle/arm index was 100% on the right and 92% on the left leg. The patient was discharged after 37 days in reasonably good condition.

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Figure 1.

Radiographs from the aortic plaque.

Ten days after discharge, the patient presented with progressive and infected wounds on the left leg, following which the left lower leg was amputated. After seven days, a forefoot amputation of the right foot was carried out because of progressive worsening of necrosis and infection. Five days later, multiple necrotic plaques surrounded by livedo reticularis and retiform purpura developed over the trunk and upper legs [Figure 2]. Due to skin abnormalities and progressive deterioration of wounds, four 3 mm punch skin biopsies (for pathology) and one 4 mm punch skin biopsies (for direct immunofluorescence) were taken with the differential diagnosis of cholesterol embolisms, vasculitis, septic embolisms, calciphylaxis, and heparin necrosis. In the pathological examination, perivascular lymphocytic infiltrative reactions and discrete fibrin thrombi were seen with no evidence of cholesterol crystals, vasculitis or calciphylaxis. In laboratory evaluation, C-Reactive Protein was increased when extend necroses was present and infection of the wounds occurs, furthermore, a slight rise of serum creatinine was seen with mild renal insufficiency and there was eosinophilia. A Computed Tomography Angiogram (CT-A) was performed showing the known aortic plaques but no features of embolism were seen. Heparin-Induced Skin Necrosis was considered. The heparin was then converted to Anti-Xa therapy, but without positive results in stabilizing the necrotic area. Also, there was no biochemical evidence for heparin-induced skin necrosis as IgG antibodies against Heparin Platelet Factor-4 were negative. Despite patent arteries without significant stenoses on duplex ultrasonography, progressive worsening of the wounds on both legs, amputation of the upper leg followed on both sides. New larger elliptical incision biopsies were taken at the edge of the necrotic lesions because of sampling error in the small punch biopsies. Pathological examination this time showed necrosis with cholesterol crystals. Therefore the diagnosis of Cutaneous Cholesterol Embolism Syndrome was confirmed. Due to the delay in diagnosis and the rapid progression of necrotic wounds and deterioration in condition, and despite the use of high-dose corticosteroids, the patient was no longer eligible for endovascular treatment. He died 4.5 months after the first presentation in our outpatient clinic because of his extensive skin necrosis with sepsis resulting in multi-organ-failure.

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Figure 2.

Pictures from different time periods in the progression of skin necrosis.

Discussion

Cholesterol embolism syndrome is an increasingly common disease. Since the start of endovascular treatments and the possibilities for thrombolytic therapies, the incidence of CES has increased. It is more common in men than women, with the classic age being 60 years and older. Risk factors are smoking, hypertension, peripheral- and central vascular disease. Laboratory findings such as acute renal insufficiency, eosinophilia and, increased erythrocyte sedimentation rate can be found in CES.^2,9 Skin involvement mostly results in blue toes syndrome (74%) and 50% of patients with visceral manifestation have skin lesions. Early recognition of skin necrosis is essential in the management and prevention of the high morbidity and mortality of this disease. Cutaneous necrosis is often a symptom of broad sequelae of pathologies, one of which is CES. ¹⁰ Histology confirms the diagnosis of CE with a sensitivity of 86% to 92%.^6,8 In our case, the first histological biopsies were negative for cholesterol crystals, possibly due to the small biopsy size of 3 mm and 4 mm with a higher risk of sampling error. Therefore, a larger elliptical incision biopsy should be taken to prevent misdiagnosis [Figure 3].

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Figure 3.

Pathology: second biopsy shows cholesterol crystal embolisms.

Differential diagnostically, heparin-induced skin necrosis was considered (HISN). Necrotic skin lesions occur in 0.2%-7.5% of patients receiving heparin, however the most common lesions are minor lesions on the injection side, a minority of cases with extended lesions are caused by unfractionated heparin and anecdotal described in distant lesions from low molecular weight heparin. There are no reports describing the incidence of such extend necrotic lesions under heparin therapy as described in this case report.^11–13 Heparin-induced skin necrosis usually develops with erythematous painful subcutaneous nodules that rapidly increase in size. After this, blisters and ulcerations form. Skin biopsies of these lesions show necrosis, infarcts, or vasculitis. ¹⁴ Heparin-induced skin necrosis usually occurs after 5 to 10 days and occurs mainly in women. ¹⁰ Unlike CES, there are laboratory tests for HISN. Although HISN is associated with HIT, however, a reduced platelet count is not always found. Diagnosis of HISN is confirmed by the presence of IgG antibodies against Heparin Platelet Factor-4. These antibodies were not found and there was no evidence of vasculitis.^15,16

Heparin-induced skin necrosis or HIT normally improves upon withdrawal of the heparin. ¹⁵ In our case, there was no improvement in skin lesions despite discontinuation of heparin and switching to fondaparinux and a course of high-dose prednisone. During admission in our hospital patient received nadroparin prophylaxes and was discontinued during one month without any improvement in skin lesions. The blood tests were negative for HISN or HIT. A second larger histological biopsy was taken to confirm the CES diagnoses. Our case was treated in a multidisciplinary manner with the dermatologist and internal medicine.

The treatment of CES is based on three characteristics of this disease. First, establishing the aortic plaque with cardiovascular risk management using statins, blood pressure regulation, and lifestyle changes. Statins are beneficial in improving cutaneous manifestations and renal outcomes.^17,18 Further, reducing the inflammatory response of cholesterol crystals was high-dose prednisone, and colchicine is effective in reducing symptoms and extend of necroses in cutaneous manifestation.^19,20 Despite the high dose of prednisone in our case, no improvement was seen in his cutaneous lesions. New perspectives for the treatment of CES is targeting the inflammatory response by inhibition of interleukin 1 and 5 which are mediators in the inflammation in CES. Pharmaceutical treatments should started in an early stage of disease in targeting these inflammatory responses are colchicine, canakinumab, cyclophosphamide, and corticosteroids, in our case there was no positive effect on high dose of corticosteroids. ²¹ Surgical intervention can be considered to remove or bypass the embolization source. In one study endarterectomies and bypass surgeries for CES documented survival of 89% of patients after one year of follow-up. ²² Nowadays, new techniques with endovascular stents are promising in covering the aortic plaques to prevent further embolization.^23,24 After the diagnosis of CES was confirmed in our case, stent placement covering the aortic wall plaque was considered. Due to the rapid progression of necrosis in the groin, buttocks, and legs, it was no longer possible to access the groin for endovascular treatment. The lesson learned from this case is when arterial revascularization is performed and progression in skin necrosis occurs despite optimal arterial vascular status the diagnosis CES should be considered.