Nicolau syndrome following subcutaneous glatiramer acetate injection: A case report and review of the literature.

Nicolau syndrome is a rare serious drug reaction associated with the administering various injectable medications. It is often characterized by an acute and severe pain accompanying erythema that tends to rapidly evolve into the livedoid reticular or hemorrhagic patches and less commonly to ulcers and skin necrosis. Herein, we report a 34-year-old woman who presented with painful, tender discoloration over her abdominal skin following subcutaneous glatiramer acetate injection. Since the patient was diagnosed with multiple sclerosis 18 months ago, she had been on treatment with subcutaneous glatiramer acetate injections thrice weekly. The patient was diagnosed with Nicolau syndrome clinically and histopathologically. After 15-day treatment with topical betamethasone valerate and mucopolysaccharide polysulfate cream twice daily, the lesion completely regressed with only minimal hypopigmented irregular scarring. Nicolau syndrome should be considered in patients with severe pain, tenderness, and redness localized at the injection site following glatiramer subacetate.

Introduction

Nicolau syndrome is also known as livedoid dermatitis or embolism cutis medicamentosa and was first described as a rare cutaneous injection site reaction after intramuscular administration of bismuth.[1] It is a serious complication of injectable medications and characterized by severe pain, tenderness, and erythema. Lesions tend to progress rapidly to livedoid reticular, hemorrhagic patches, and subsequently to ulcers and skin necrosis. After several weeks or months, the lesions heal by leaving atrophic scarring.[1] Although the reaction has been historically associated with bismuth, more recently, presentations with injectable forms of β-lactam antibiotics, nonsteroidal anti-inflammatory drugs, corticosteroids, lidocaine, and fillers such as hyaluronic acid have been reported.[1]

Glatiramer acetate is an approved and first-line immune modulatory treatment for multiple sclerosis (MS). It is associated with a wide range of dermatological side effects in most patients (20%–60%). The most common side effects include transient mild localized skin reactions such as erythema, swelling, pain, irritation, and induration around the injection site.[12] Only a few cases of severe localized reactions known as Nicolau syndrome following glatiramer subacetate injection have been reported so far.[12345]

Herein, we describe a case of Nicolau syndrome following glatiramer subacetate injection in a patient with MS who rapidly improved with topical betamethasone valerate and mucopolysaccharide polysulfate within 15 days.

Case Report

A 34-year-old woman was referred to our outpatient clinic from the emergency service for a painful discoloration and sharp pain over her lower left abdomen. Her medical history was not remarkable except for MS. Glatiramer subacetate injections thrice weekly were her only medication since diagnosed with MS 18 months ago. She described tenderness, local heat sensation, and redness around the injection site with her recent injection, which then expanded with some purple blotches on the next day. The patient's dermatological examination revealed a large, erythematous patch with bizarre livedoid purpuric areas on the left side of the umbilical region 72 h after the injection [Figure 1a]. The patient had significant tenderness to gentle palpation on this area. She had no other cutaneous or systemic symptoms such as chilling, sweating, or fever. She had already ceased treatment after initial symptoms. The patient expressed that she performed the injections to the arms, legs, and abdomen by turns with the appropriate injection technique. She had never experienced similar lesions before.

Figure 1

Large erythematous patch with bizarre livedoid purpuric areas on the left abdomen (a). Healing of the lesion with minimal scarring after 15 days of therapy (b)

Laboratory analyses revealed that complete blood count, liver and renal function tests, inflammatory markers, and coagulation parameters were within normal limits except elevated serum creatine kinase level (714 U/L; normal range: 24–170). Superficial ultrasonography showed dermal edema without any collection of fluid. Histopathological examination of the lesion showed marked epidermal ischemia, necrotic keratinocytes, fibrin deposits within multiple capillaries, and no remarkable inflammation [Figure 2]. Clinical and histopathological findings were compatible with Nicolau syndrome. After 15 days of topical treatments with betamethasone valerate and mucopolysaccharide polysulfate twice daily, the lesion regressed completely with a minimal residue of hypopigmented irregular scarring [Figure 1b]. Besides, serum creatine kinase level reduced to normal limits (76 U/L).

Figure 2

Necrotic epidermal keratinocytes (blue arrows) and fibrin deposits within capillaries in the dermis (black arrow) (H and E, ×400)

Discussion

Nicolau syndrome, also referred to as embolia cutis medicamentosa, was first described by German and Romanian dermatologists Freudenthal and Nicolau in 1925 after bismuth injection in a patient with syphilis.[12] Nicolau syndrome has been associated with several intramuscular and less frequently subcutaneous injectable medications, mainly nonsteroidal anti-inflammatory drugs. However, this severe reaction following glatiramer subacetate injections has been reported in very few cases. Table 1 summarizes the clinical and demographic characteristics of the present cases in the literature in English written language available through MEDLINE/PubMed.

Table 1

Summary of the demographic and clinical findings of patients with Nicolau syndrome in the literature

	Gender/age	Location	Admission time after GA injection	Considerable clinical finding	Medical comorbidities	History of recurrence	Glatiramer subacetate	Treatment	Recovery time
Mott et al.[1]	Female/51 years	Right lower abdomen	Recent injection	7×5 cm indurated plaque with central necrosis	-	No	20 mg daily, 7 years	Local wound care, surgical excision	Longer than 3 months
Zecca et al.[2]	Female/58 years	Left abdomen	24 h	Hemorrhagic patch with central necrosis	-	Yes	N/A, 9 years	Local wound care, surgical excision	2 months
Kimbrough et al.[3]	Female/43 years	Left thigh	48 h	3.8-cm2 erythematous patch with eschar formation	Vitamin D insufficiency and migraine	No	20 mg daily, 2 years	Surgical debridement	9 months
	Female/34 years	Left thigh	-	Ulcerated livid patch (1.0×1.1×0.3 cm)	Hypertension, allergic rhinitis, codeine allergy	No	20 mg daily, 1 year	Local wound care, surgical debridement	N/A
Demircan et al.[4]	Female/26 years	Thigh	1 month	A purple, sclerotic, yellowish crusted plaque	-	No	40 mg thrice weekly, 4 years	Topical mupirocin	1 month
Koller et al.[5]	Female/39 years	Lower left abdomen	48 h	A palm-sized, indurated, plaque with purpuric center	-	No	20 mg daily, 2 years	-	10 weeks
Current case	Female/34 years	Lower left abdomen	72 h	Large erythematous patch with bizarre livedoid purpuric areas	-	No	40 mg thrice weekly, 18 months	Topical betamethasone valerate, mucopolysaccharide polysulfate	2 weeks

GA=Glatiramer acetate, N/A=Not applicable

Although the pathogenesis of the disease is still not fully understood, direct injury to vessels with unintentional injections (1) or vascular compression following thrombosis or embolism (2) is suggested to involve the main underlying pathogenetic events that cause skin necrosis. Furthermore, it is hypothesized that perivascular, intravascular, or perineural injections may also cause ischemic necrosis through sympathetic vasospasm due to the release of some vasoactive mediators (3). On the other hand, it is thought that neither the drug itself nor the administration route plays a role in the pathogenesis, and continuation of the ongoing medication is an accepted opinion and not contraindicated.[125] Nicolau syndrome is mainly associated with intramuscular injection; however, it can be observed after the subcutaneous administration route, as in our case. No specific body area or treatment duration has been associated with glatiramer acetate. Since the disease course is unpredictable and unavoidable, the appropriate injection technique seems to be the critical point for prevention.[45] To minimize the risk, the correct choice of needle length, negative aspiration before injection, administration at a constant rate, injection volume not more than 5 ml, rotation of injection sites for multiple and repeated treatments, and a Z-track injection are highly suggested when performing injections.[5]

Diagnosis of Nicolau syndrome is mainly based on the clinical and histopathological findings, excluding other possible diagnoses.[5] Although the disease can be distinguished by its typical clinical features and suggestive history of injectable medication, it may mimic several cutaneous conditions. The most commonly described differential diagnoses are infectious conditions such as cellulitis, necrotizing fasciitis or vasculitis, cutaneous cholesterol emboli, and compartment syndrome.

Due to the small number of cases, there is no standard care algorithm in the medical management of Nicolau syndrome.[12345] Various treatment methods have been used based on the ulcer's extent, including dressings, topical or systemic corticosteroids, heparin, and surgical debridement.[12] As the mucopolysaccharide gel chemically resembles heparin, it is thought to improve perivascular tissue microcirculation and nutrition by inhibiting microthrombus formation. Hence, in the current case, we recommended mucopolysaccharide gel and a topical steroid, which resulted in a fast recovery of the lesions with only minimal scarring along with regression of serum inflammatory markers. Considering the clinical characteristics of the patients as shown in Table 1, early diagnosis and rapid initiation of treatments including mucopolysaccharide gel, absence of concomitant medical comorbidity, or lack of skin lesions such as ulcer or necrosis were likely to positively affect the course of the current case.

Conclusion

Nicolau syndrome is a rare drug adverse reaction that may emerge out following subcutaneous glatiramer acetate injection, although the patient is on a long-lasting treatment.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written permission is available for review by the Editor of this journal.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.