Nicolau syndrome after administration of glatiramer acetate

Dear Editor:

Local complications associated with glatiramer acetate are frequent, especially at the injection site. The presence of pain, oedema, and local erythema is almost a given in areas where the drug is administered subcutaneously. However, the presence of cutaneous necrosis should alert doctors to the possibility of impairment of underlying vascular structures.

Nicolau syndrome or embolia cutis medicamentosa is an uncommon complication resulting from the intramuscular, intra-articular or, more rarely, subcutaneous administration of some drugs. Symptoms include cutaneous infarction due to damage to nearby small and medium-sized hypodermal-dermal vessels.¹ There are several documented cases involving administration of different drugs^2–4 or vaccines.^5,6

We present the case of a 45-year-old woman who developed painful cutaneous lesions following subcutaneous injection of glatiramer acetate.

Following diagnosis with relapsing-remitting multiple sclerosis, she had been treated with glatiramer acetate (20 mg/day) for 3 years. She was referred to the dermatology department due to the appearance of localised painful lesions in the lateral left thigh. Symptoms had begun to appear 7 days previously, after subcutaneous administration of the drug to this area. The patient's personal and family history did not reveal relevant findings. The examination revealed a purplish plaque with a hardened, infiltrative feel with no other relevant cutaneous or systemic findings (Figs. 1 and 2). A blood test showed haematological, haemostatic, and biochemical parameters within normal ranges. The blood test showed no autoimmune markers (ANAs, ANCAs, anti-DNA, anti-Ro, anti-La) and no lupus anticoagulants or cryoglobulins. The histopathological study of the lesion revealed coagulative necrosis of dermal collagen and nearby adipose tissue, as well as multiple hyaline thrombi inside small and medium-sized blood vessels. These were located throughout the dermis and hypodermis with no apparent perivascular inflammatory component. The study found no calcium deposits in vascular walls, no cholesterol crystals, and no intravascular fungal matter. A soft tissue ultrasound showed no damage to underlying muscular tissue.

Figure 1.

Violaceous purpuric livedoid plaque.

Figure 2.

Photograph of the same lesion showing foci of established cutaneous necrosis.

Given a diagnosis of Nicolau syndrome, doctors decided to continue injecting treatment in other sites while closely monitoring the lesions. The patient's cutaneous symptoms progressively improved; by 4 weeks, a depressed scar had formed in the lateral thigh.

The presence of retiform purpura (purpuric macules in a web-like pattern) is a fundamental clinical sign of vaso-occlusive processes causing skin damage. Affected vessels are found in the reticular dermis or subcutaneous cellular tissue, where they will be larger. When examining these patients, we must always consider processes involving extracutaneous damage, such as cholesterol embolism syndrome, calciphylaxis, arterial ischaemia due to arteriosclerosis, or systemic vasculitis.⁷ In addition, similar cutaneous signs may appear in cases in which vaccines and intramuscular, intra-articular or subcutaneous treatments are not administered properly. This too is known as embolia cutis medicamentosa or Nicolau syndrome. Although the pathogenesis of this condition is not clear, it seems that accidental intravascular or perivascular drug delivery may lead to vasospastic and/or thrombotic phenomena, resulting in ischaemia and tissue necrosis.^8,9 These cases rarely involve distant emboli although researchers have described patients with myofascial plane impairment.

While no standard treatment exists, some authors promote the use of low molecular weight heparin or even surgical debridement in extreme cases of skin and soft tissue necrosis.¹⁰

In summary, patients should be taught to administer subcutaneous treatments properly and know how to recognise early signs of complications resulting from those treatments.