[Nicolau syndrome due to self-injectable drugs in multiple sclerosis]. / Síndrome de Nicolau por fármacos autoinyectables en la esclerosis múltiple.

INTRODUCTION AND AIMS: Nicolau syndrome, or embolia cutis medicamentosa, is a rare cutaneous complication of drug injection that has been rarely described in relation to medication used in multiple sclerosis. PATIENTS AND METHODS: We conducted a retrospective study of patients with Nicolau syndrome receiving self-injectable multiple sclerosis medication from 2010 to October 2022. RESULTS: From January 2010 to October 2022, 449 patients were followed up in our demyelinating pathology unit with self-injectable drugs - 317 with beta interferons and 132 with glatiramer acetate (GA). In this period of time, 10 episodes of Nicolau syndrome were recorded in seven patients (six men and one woman) receiving GA, which represents 5.3% of the total number of patients receiving this treatment. The most commonly affected areas were the buttocks (n = 4) and the arms (n = 3). Three patients (42.8%) suffered a second episode. CONCLUSION: Nicolau syndrome is a complication unique to GA and more frequent in men in our cohort of multiple sclerosis patients. This cutaneous complication frequently recurs in the same patient, which is a factor to be taken into account in the decision to maintain the drug or switch to another therapeutic strategy.

TITLE: Síndrome de Nicolau por fármacos autoinyectables en la esclerosis múltiple.Introducción y objetivos. El síndrome de Nicolau, o embolia cutis medicamentosa, es una complicación cutánea infrecuente de los fármacos inyectados que se ha descrito escasamente en relación con los fármacos empleados en la esclerosis múltiple. Pacientes y métodos. Es un estudio retrospectivo de pacientes afectos de síndrome de Nicolau que reciben fármacos autoinyectables para la esclerosis múltiple desde 2010 hasta octubre de 2022. Resultados. Desde enero de 2010 hasta octubre de 2022 se ha seguido en nuestra consulta de patología desmielinizante a 449 pacientes con fármacos autoinyectables ­317 con interferón beta y 132 con acetato de glatiramer (AG)­. En este período de tiempo se han recogido 10 episodios de síndrome de Nicolau en siete pacientes (seis hombres y una mujer) que recibían AG, lo que supone un 5,3% del total de pacientes bajo ese tratamiento. Las zonas más afectadas fueron el glúteo (n = 4) y el brazo (n = 3). Tres pacientes (42,8%) sufrieron un segundo episodio. Conclusión. El síndrome de Nicolau es una complicación exclusiva del AG y más frecuente en hombres en nuestra cohorte de pacientes con esclerosis múltiple. La recurrencia de esta complicación cutánea es frecuente en un mismo paciente, lo que es un factor que hay que tener en cuenta en la decisión de mantener el fármaco o cambiar a otra estrategia terapéutica.

Hyperbaric oxygen treatment in a rare complication of intramuscular injection: four cases of Nicolau syndrome.

Intramuscular injections are one of the most common clinical procedures. The objectives of this case series are to analyse the role, timing and efficacy of hyperbaric oxygen treatment (HBOT) in the management of Nicolau syndrome (NS), an extremely rare complication of this common intervention. Clinical, demographic, laboratory and microbiological data extraction were performed through retrospective analysis of the medical records of all patients with NS who were referred for HBOT over a 10-year period with wounds, ischaemia, infection or necrosis at the injection site following drug injection; four patients with NS were included. All injections were made via the intramuscular route; three adult cases followed a non-steroidal anti-inflammatory drug, diclofenac sodium and one in a child followed penicillin injection. The time between diagnosis/injection and HBOT ranged from five to 33 days. NS can develop despite all preventive measures based on injection technique guidelines. HBOT appeared beneficial to healing of NS when administered with other therapeutic approaches. Due to the missing pieces of the puzzle in pathogenesis, NS is rarely completely reversible; keeping the awareness high for undesirable complications stands out as the most effective approach.

Embolia Cutis Medicamentosa (Nicolau Syndrome) Secondary to Intramuscular Fulvestrant Injection: A Case Report.

PURPOSE: A case of embolia cutis medicamentosa (Nicolau syndrome) in a patient receiving monthly intramuscular fulvestrant injections is presented. SUMMARY: An 85-year-old woman receiving monthly fulvestrant injections in the outpatient setting developed a necrotic lesion at the fulvestrant injection site on her right buttock. Her medical history is notable for metastatic breast cancer with bone metastases. Prior to developing the necrotic lesion, the patient was receiving monthly fulvestrant injections for 6 years. Other potential causes such as infection and pressure necrosis were ruled out clinically. After 185 days of wound care involving multiple surgical debridements, topical therapy, and frequent follow-up appointments, the patient's wound resolved with 100% epithelialization. Nicolau syndrome has been reported with other non-vesicant, injectable medications such as antibiotics and corticosteroids; however, it has not been previously reported with fulvestrant. CONCLUSION: Nicolau syndrome developed in the right buttock of a patient with metastatic breast cancer following an intramuscular fulvestrant injection. Healthcare practitioners need to be cognizant of this adverse effect with intramuscular injections in order to recognize and refer patients for wound care evaluation early in the evolution of this syndrome. Proper injection technique is recommended to reduce the risk of this idiopathic adverse effect.

Nicolau Syndrome, Masquerader of Postinjection Sciatic Nerve Injury: Case Report and Review of Literature.

BACKGROUND: Sciatic nerve injury after inadvertent intramuscular gluteal injection is a well-described entity. We have presented a case of a rare and probably underdiagnosed pathological entity, Nicolau syndrome, which can be confused with injection palsy. CASE DESCRIPTION: We report the case of a 13-year-old boy who had presented with foot drop and urinary and fecal incontinence after an intramuscular injection of benzathine penicillin in the left gluteal region. On examination, the patient had multiple ecchymoses over the left gluteal region and back of the thigh, mild swelling of the left lower limb, and left foot drop. Meticulous examination also revealed a subtle weakness of the opposite limb. Nerve conduction studies revealed axonopathy involving multiple bilateral lower limb nerves. These unusual neurological-dermatological signs and electrophysiological findings raised the concern for an alternative pathology, which was later diagnosed as Nicolau syndrome. The patient experienced clinical and electrophysiological recovery after a course of oral steroids and physiotherapy during the next few months. CONCLUSIONS: Before diagnosing injection sciatic nerve injury, the possibility of medically treatable Nicolau syndrome should be considered. Neurosurgeons' familiarity with this pathology and a timely diagnosis is essential to plan appropriate treatment strategies.

[Severe pain and skin discolouration after injection: Nicolau syndrome, a rare complication]. / Hevige pijn en huidverkleuring na een injectie.

BACKGROUND Parenteral administration of medication is a frequent practice, but in rare cases, serious complications may occur. CASE DESCRIPTION A 33-year-old man experienced intense pain in his forearm immediately after administration of clemastine through a Venflon in his elbow crease. The pain was accompanied by white discolouration of some fingers and livid discolouration of the skin between the fingers. This reaction is typical for Nicolau syndrome, a rare skin reaction that may develop after intramuscular or intra-arterial administration of medication. Aetiology is unclear, but vascular spasms, blood vessel wall damage and thrombosis are the most important factors. Treatment consists of minimising complications. CONCLUSION In the worst cases of Nicolau syndrome, extensive necrosis and permanent injury may occur. It is important to recognise the symptoms. Preventing or minimising tissue necrosis is essential and attention should be paid to pain relief. Proper injection methods can prevent the occurrence of this syndrome.

Nicolau's syndrome: A rare but preventable iatrogenic disease.

Dear Editor, Nicolau's syndrome, also called embolia cutis medicamentosa or livedoid dermatitis, is a rare injection site reaction characterized by immediate intense pain at the injection site followed by erythema and a hemorrhagic patch with a livedoid reticular pattern after injections of non-steroidal anti-inflammatory drugs (NSAIDS), antiepileptics, antibiotics, antihistaminics, corticosteroids, etc. (1). To the best of our knowledge, only one case of Nicolau's syndrome has been reported after the use of triamcinolone acetonide. Herein we report two cases of Nicolau's syndrome caused by intramuscular injections of triamcinolone acetonide and diclofenac sodium, respectively. CASE 1 A 24-year-old male patient presented with severe pain and bluish discoloration of the right arm for 2 days, which he had noticed shortly after receiving an intramuscular injection of triamcinolone for recurrent episodes of urticaria by a local practitioner in the right deltoid region. On examination, there was a livedoid pattern of non-blanchable, violaceous discoloration extending from the deltoid area to the distal third of the forearm with associated induration (Figure 1, a, b). The local area was warm and tender to the touch. There was no regional lymphadenopathy, and the rest of the examination was normal. The patient's platelet count, bleeding and clotting times, prothrombin time, and international normalized ratio (INR) were unremarkable. There was no previous history of any bleeding disorder. The patient denied any intake of drugs like aspirin, warfarin, etc. Subsequently, the patient developed an ulcer on the forearm, which was managed by topical and systemic antibiotics to prevent any secondary infection of the wound. CASE 2 A 40-year-old female patient presented with complaints of pain and discoloration of the left gluteal region after receiving an intramuscular injection of diclofenac sodium for her arthralgia. A large ecchymotic patch with reticular borders was found on the gluteal region, extending to the lateral aspect of thigh (Figure 2). It was tender to the touch, non-indurated, and the local temperature was raised. There was no regional lymphadenopathy. No other abnormality was detected on examination. All routine investigations were within normal limits. Platelet count, bleeding, clotting and prothrombin times, and international normalized ratio (INR) were within normal limits. The lesions resolved within few weeks without any complications. Nicolau syndrome was first described in the early 1920s by Freudenthal and Nicolau as an adverse effect of using intramuscular injections of bismuth salts in the treatment of syphilis. Since then, several case reports of this disease occurring after intramuscular, intra-articular, intravenous, and subcutaneous injections have appeared in the literature associated with a variety of drugs like NSAIDs, vitamin K, penicillin, antihistamines, corticosteroids, local anesthetics, vaccines, polidocanol, and pegylated interferon alpha (1). The pathogenesis of Nicolau syndrome is unknown, though intra and periarterial injection of the drug is a possible cause. Stimulation of the sympathetic nerve due to periarterial injection causes spasms and consequent ischemia. Inadvertent intra-arterial injections may cause emboli and occlusion. A lipophilic drug may penetrate the vessel and produce physical occlusion like fat embolism. Cytotoxic drugs may produce perivascular inflammation and ischemic necrosis. NSAIDs are believed to additionally induce ischemic necrosis due to their inhibition of cyclooxygenase and, consequently, prostaglandins (2). The clinical features of the disease have been divided into three phases in a review by Kim et al. (3). The authors describe an initial phase characterized by intense pain with subsequent erythema. This is followed 1-3 days later by an acute phase, when an indurated, tender plaque with livedoid pattern develops. The final phase occurs between 5 days and 2 weeks later. Necrosis ensues in this stage, with possible ulceration. Diagnosis is chiefly clinical, and histopathology shows necrotic changes and vascular thrombosis. However, a biopsy was not performed in our cases because both lesions were painful. Management strategies are variable and range from conservative management with analgesics and antibiotics to active surgical debridement (4). Complications include deformities, contractures or even death. The patient in our first case developed ulceration which healed normally, while the second case resolved without any complications. Nicolau syndrome can be avoided by precautions such as aspirating the needle before injecting to check for blood, use of Z-track injection technique, proper site of injection, avoiding large doses at a single site, and regular change of sites if multiple injections are to be given (5). Nicolau syndrome is a rare disease. There are a few case reports of it occurring after diclofenac injection (1-5). We could only find one case report of this syndrome after intramuscular injection (IM) of triamcinolone in a patient with lichen planus (3), and our case is the second reported case of this syndrome as a result of triamcinolone acetonide injection, which adds to the significance to the present article.

Post-injection embolia cutis medicamentosa - Nicolau Syndrome: case report and literature review / Embolia cutis medicamentosa pós-injeção - Síndrome de Nicolau: relato de caso e revisão de literatura

We report on the case of a 40-year-old male who was admitted to the clinic with a large ulcer on his left buttock, 3 days after an intramuscular benzathine penicillin injection. The patient was diagnosed with Nicolau syndrome, a rare vascular complication in which a lesion develops after intramuscular injection. Symptoms are intense pain at the injection site, erythema, and livedoid dermatitis, which leads to necrosis of skin, subcutaneous tissue and muscle tissue. It was described by Nicolau after intramuscular injections of bismuth salt for syphillis therapy. Nicolau syndrome is rare, but its symptoms are devastating and healthcare professionals must be aware of this clinical entity, since intramuscular injections are common procedures for administration of drugs.

Relatamos o caso de um homem de 40 anos apresentando uma grande úlcera na nádega esquerda 3 dias após receber injeção intramuscular de penicilina benzatina. O paciente foi diagnosticado com síndrome de Nicolau, uma rara complicação vascular com lesão após injeções intramusculares. Os sintomas incluem dor intensa no local da injeção, eritema e dermatite livedoide, o que leva a necrose da pele, do tecido subcutâneo e do tecido muscular. Foi descrita por Nicolau após injeções intramusculares de sal de bismuto para o tratamento de sífilis. A síndrome de Nicolau é incomum, mas seus sintomas são devastadores. Portanto, os profissionais de saúde precisam conhecer essa entidade clínica, uma vez que as injeções intramusculares são procedimentos comuns para a administração de drogas.

Nicolau syndrome due to diclofenac sodium (Voltaren®) injection: a case report.

INTRODUCTION: Nicolau syndrome, also known as livedo-like dermatitis or embolia cutis medicamentosa, is a rare complication following the intramuscular or intra-articular injection of various drugs. CASE PRESENTATION: In our case report we report the case of a 45-year-old Turkish woman who developed Nicolau syndrome after an intramuscular injection in her right gluteal region of single-dose diclofenac sodium to treat a headache. A culture taken from the ulcer showed growth of methicillin-sensitive Staphylococcus aureus on the 10th day. The secondary staphylococcal infection was treated effectively with intravascular ampicillin-sulbactam (4 × 1.5 g/day). She was treated with surgical debridement, sterile dressings and analgesics. The ulcer healed completely within 12 weeks with scarring. CONCLUSIONS: Although Nicolau syndrome develops very rarely, it is an important cause for morbidity. It is an iatrogenic condition, treated mostly by health care workers. Thus, although it appears to be a very simple procedure for a health care worker, care must be taken during intramuscular injections. Although diclofenac sodium is a widely used non-steroidal anti-inflammatory drug, Nicolau syndrome following intramuscular diclofenac sodium injection has rarely been reported in the published literature. The application of a cold compress was considered to be an aggravating factor in our patient. This case highlights the need for awareness about this condition and the need to exercise utmost care during the administration of any parenteral injections by health workers.

[Nicolau syndrome after intramuscular injection]. / Complication d'une injection intramusculaire ou syndrome de Nicolau.

Nicolau syndrome is a rare, potentially severe complication that may occur after any drug injection, particularly after intramuscular injection. It is characterized by the acute onset of cutaneous and soft-tissue aseptic necrosis. Here, we report the case of a 14-year-old boy diagnosed with Nicolau syndrome on the right lower limb, after a benzathine-penicillin intramuscular injection for suspected rheumatic fever. The short-term progression was marked by uncomplicated rhabdomyolysis and the constitution of homolateral testicular torsion. The cutaneous-muscular disorders evolved favorably under symptomatic treatment. We discuss this insufficiently known complication of intramuscular injection, which may motivate reduced use of this route of drug administration in children and strict adherence to the procedure. Furthermore, it is important to note that Nicolau syndrome may evolve to homolateral testicular torsion, as, to the best of our knowledge, is reported for the first time in this case.