CASE REPORT/CLINICAL TECHNIQUES Qiongyi Kang, MD,* Zhengwei Huang, PhD,* and Wentao Qian, MD† SIGNIFICANCE Nicolau syndrome is a rare but serious complication of injections, causing pain and skin discoloration. This case report describes a teenager who developed Nicolau syndrome after receiving a calcium hydroxide injection during root canal treatment. The calcium hydroxide accidentally leaked beyond the intended area, blocking blood flow and causing permanent facial scarring. This case emphasizes the importance of careful injection techniques by dentists to avoid this risk, especially when dealing with bleeding during root canal procedures. From the *Department of Endodontics, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, People’s Republic of China; and †Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, People’s Republic of China 680 Nicolau Syndrome with Severe Facial Ischemic Necrosis after Endodontic Treatment: A Case Report ABSTRACT Nicolau syndrome (NS) is a rare complication resulting from intramuscular injections. It is characterized by severe pain at the injection site and the development of purplish discoloration. Only a limited number of case reports have been published documenting the adverse effects associated with the injection of calcium hydroxide (CH) beyond the apex during endodontic treatment. Here, we present the case of a 16-year-old female with NS after the injection of CH during the root canal treatment. The radiography examination revealed distal occlusion of the right maxillary and facial arteries. This caused a substantial area of skin necrosis to develop on the patient’s face, resulting in permanent scarring. NS is associated with the displacement of CH beyond the apex. To minimize the risk of NS, dentists should exercise caution by avoiding forced injection of CH duringtreatment,particularly whentheroot canal is actively bleeding. (J Endod 2024;50:680–686.) KEY WORDS Calcium hydroxide; facial necrosis; nicolau syndrome Nicolau syndrome (NS) was initially documented in 1924 as a rare cutaneous adverse reaction occurring specifically at the site of an intramuscular or intra-articular injection of a specific medication. Clinically, NS is distinguished by intense pain immediately following the injection (eg, subcutaneous, intravenous, etc.), accompanied by the development of an erythematous reticular patch. Over time, this patch progresses into a necrotic ulcer, resulting in scarring at the injection site1,2. Due to its bactericidal effects on various bacteria within the root canal, calcium hydroxide (CH) can penetrate the dentinal tubules to inactivate endotoxin, thus exerting a significant antimicrobial effect. As a result, CH has become an intracanal medicament of choice for treating apical periodontitis in permanent teeth. However, if CH is mistakenly injected into soft tissues or blood vessels, it can cause severe damage and long-term consequences. To date, the adverse reactions resulting from the displacement of CH beyond the canal terminus during root canal treatment have been documented in a relatively small number of case reports and case series. This article aims to report a case of NS that occurred after the injection of CH beyond the apex of tooth #30 during endodontic treatment.Additionally, it seeks to review previous literature to analyze and summarize the treatment approaches for this condition. CASE REPORT A 16-year-old female visited the Department of Oral Surgery, Shanghai Ninth People’sHospital, complaining of swelling and pain on the right side of the her face for 1 week. The patient went to the local hospital for root canal treatment due to pain in a lower right posterior tooth. According to the dental history, a pulp polyp was visualized on the occlusal surface of tooth #30. The treatment was conducted using local anesthesia due to pulp inflammation. During the pulp extirpation procedure, the dentist encountered bleeding and subsequently applied CH. The patient experienced a sudden onset of headache, accompanied by nausea and vomiting. This was followed by a brief episode of unconsciousness lasting approximately 10 seconds. Upon regaining consciousness, the patient reported no improvement in her headache symptoms and developed cyanosis in the face and lips. The patient was sent to the emergency department (Fig. 1A), where a magnetic resonance imaging was performed. The emergency physician suspected cavernous sinus syndrome and prescribed anti-inflammatory treatment. The next day, the Kang et al. JOE Volume 50, Number 5, May 2024 FIGURE 1–Progressionof facial necrosis after endodontic treatment. (A ) Patient immediately after treatment with facial and lip cyanosis. (B ) Worsening facial cyanosis upon arrival at clinic. (C ) Erosion and necrosis of right hard palate, buccal mucosa, and corner of mouth. (D ) Extensive facial necrosis 2 weeks after treatment. (E ) Extensive mucosal necrosis and ulceration on buccal side. (F ) Increased area of mucosal necrosis in the palate. patient was transferred to a higher-level hospital and underwent a lumbar puncture examination, Address requests for reprints to Dr Wentao Qian, Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, People’s Republic of China. E-mail address: 589346567@139.com 0099-2399/$- see front matter Copyright © 2024 American Association of Endodontists. https://doi.org/10.1016/j.joen.2024.02.010 JOE Volume 50, Number 5, May 2024 ruling out the possibility of intracranial infection. The patient continued to receive anti inflammatory andneurotrophic treatment for her condition. After receiving treatment for 1 week, the patient’s facial cyanosis showed no signs of improvement and instead became more severe (Fig. 1B). Extensive ecchymosis ontheright side of the face, skin necrosis on the right nostril and nasal tip, swelling and cyanosis of the upper lip, and right cheek intraorally were noted. Additionally, erosion and necrosis of the mucosa were observed on the right sides of the hard palate, buccal mucosa, and oral commissure (Fig. 1C), causing significant pain on opening. As a result, the patient resisted oral examination. The patient lacked sensation in the cyanotic areas of the face. Tooth#30 had no mobility but erosion was present in the buccal gingival region. A panorama graph revealed a clearly visible high-density radiographic image along the pathway of the right mandibular canal (Fig. 2A), extending from the mental foramen to the region of the mandibular foramen. A computed tomography scan, revealed high-density images of the external carotid artery branches, including the inferior alveolar artery, facial artery, and infraorbital artery (Fig. 2B and C). Based on a thorough analysis of the patient’s medical history, clinical manifestations, and imaging findings, we diagnosed the patient as NS. A Nicolau Syndrome and Endodontic Treatment 681 DISCUSSION FIGURE 2– Imaging findings of patient. (A ) Panorama radiograph showing high-density radiolucency along right inferior alveolar nerve canal. (B ) Computed tomography scan with arrow highlighting high-density areas in facial and inferior alveolar arteries. (C ) Computed tomography scan with arrow highlighting high-density area in infraorbital artery. (D ) Digital subtraction angiography examination revealing occlusion in distal segments of maxillary and facial arteries. multidisciplinary team involving experts from neurology, plastic surgery, and oral surgery， recommended avoiding surgical debridement and prescribed a conservative treatment approach. A digital subtraction angiography examination was completed to accurately pinpoint the location of the embolism. The digital subtraction angiography revealed occlusion in the distal segments of the right maxillary and facial arteries (Fig. 2D) blocking the blood supply to the cheek and nasal regions (Fig. 1D–F). The multidisciplinary team, including vascular surgeons and neurosurgeons, concluded that revascularization interventions such as thrombolysis or thrombectomy were unlikely to 682 be successful in this case due to the significant time lapse (.1 week) since symptom onset, exceeding the established therapeutic window for these procedures. Our conservative management approach involved the use of anti-inflammatory, analgesic, and neurotrophic drugs with current psychosocial support. After 10 months, the patient experienced the shedding of necrotic tissue from the face, resulting in a tissue defect in the right nasal alar (Fig. 3A–D). Extensive scarring developed on the face, and the lower eyelid became everted due to the presence of the scar. This situation has been particularly challenging for the young woman, and as a result, she has developed depression. NS was first described by German and Romanian dermatologists Freudenthal and Nicolau in 1924 after bismuth injection in a patient with syphilis2. The first clinical case report documenting an adverse reaction to CH was published in 20003. Since then, several more cases have been reported4-7. We reviewed the literature on the association between endodontic treatment and the development of NS. NS, occurring subsequent to root canal treatment, commonly manifests in the molar area and is not constrained by gender, age, or race (Table 1). Our findings indicate a similarity among these cases: dentists encountered bleeding within the root canal during treatment and proceeded to directly inject CH without fully arresting the bleeding. Consequently, the CH entered facial vascular compromising the blood supply. Patients typically experience immediate facial pain and numbness following the injection, with whitening of the maxillofacial skin on the same day that eventually progressed to facial tissue necrosis. The pathogenesis of NS is unknown, though intra and periarterial injection of the drug is a possible cause8. The primary mechanisms implicated in skin necrosis following injection include the following9: Inflammatory vasculitis: Vascular or perivascular injectioncantriggeraninflammatory response leading to direct destruction of the arterial wall, compromising blood flow and causing skin ischemia and necrosis. Embolic occlusion: Inadvertent intra arterial injection can introduce emboli (dislodged material or medication precipitates) that occlude downstream small arteries, hindering perfusion and causing ischemic necrosis. Thrombotic occlusion: Periarterial injection with arterial wall perforation can initiate thrombus formation, occluding the vessel and leading to skin ischemia and necrosis. Vasospasm: Intra-arterial, periarterial, or perinervous injection can induce reflex sympathetic vasospasm, constricting nearby arteries and causing ischemic necrosis. It is important to note that these mechanisms often act in concert, with varying degrees of contribution depending on the specific circumstances of the injection mishap. Ultimately, all pathways converge on peripheral arterial occlusion and tissue ischemia, leading to skin necrosis. CH has gained popularity as an intracanal medicament since its introduction to dentistry by Hermann in 1920. Healing is observed in clinical situations with this medicamentwhich isduetoits antimicrobial property, induction of hard-tissue formation, and ability to promote periodontal Kang et al. JOE Volume 50, Number 5, May 2024 FIGURE 3– Follow-up after the complication occurred. (A ) One-month postevent: The right maxillofacial region exhibits an extensive area of necrotic eschar. (B ) Two months postevent: The right maxillofacial region exhibits a small area of necrotic eschar. (C ) Three months postevent: The right maxillofacial with significant recovery. (D ) Ten months postevent: Spontaneous escharolysis (shedding) of necrotic tissue has occurred, revealing a tissue defect involving the right alar base. Figure (B ) (arrow) shows a high-density blockage in the right facial artery on CT scan, indicating a blockage within the vessel. Similarly, Figure (C ) (arrow) reveals a blockage in the infraorbital vessels. These findings suggest occlusive material within both blood vessels. repair10. Due to the strongalkalinity of CH, it has a corrosive effect on the endothelial cells of blood vessels, causing vasoconstriction and thrombus formation, which in turn leads to the severe pain experienced by the patient. CH can sometimes result in the formation of an embolus in the blood. This embolization process occurs in a retrograde manner, starting from the apical blood supply, progressing to arterial branches, and finally reachingtheperipheral vesselssupplying the skin area. Consequently, it may lead to ischemic necrosis of the facial skin or mucosa. According to the literature3-7, the infraorbital artery, posterior superior alveolar artery, and anterior temporal artery are commonly reported embolized vessels in thesecases.Inthiscase,embolismoccurredat the distal branches of the maxillary facial arteries, resulting in extensive necrosis. Interestingly, despite the involvement of the mandible in our case and previous cases, no necrosis was observed in the region supplied by the inferior JOE Volume 50,