Anesthetic Management of a Dental Patient With Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is a representative hereditary periodic fever syndrome inherited in an autosomal recessive manner. FMF is primarily characterized by recurrent fevers exceeding 38°C and abdominal pain due to serositis, with typical episodes lasting 12 to 72 hours.¹ Erysipelas-like erythema, commonly found in the ankle region or dorsum of the foot, is also a notable feature, and patients may present with arthritis, rashes, or scrotal pain.² In some FMF cases, chronic inflammation leads to the overproduction of serum amyloid A, resulting in amyloid deposition in organs and causing AA amyloidosis, which may progress to chronic renal failure.¹ FMF is classified into two types: type 1, characterized by periodic fever and peritonitis; and type 2, in which these symptoms are absent, but AA amyloidosis develops.²

Most FMF patients have mutations in the MEFV gene, which encodes pyrin. However, 10% to 20% of patients lack this mutation,³ suggesting genetic defects upstream or downstream of the MEFV metabolic pathway.⁴ Pyrin consists of 781 amino acids and is expressed in the membranes of granulocytes, eosinophils, monocytes, and fibroblasts as well as in synovial tissue where it forms and regulates the pyrin inflammasome. Mutations in pyrin lead to aberrant activation of the pyrin inflammasome, triggering increased IL-1β production through caspase-1 activation and enhancing inflammation.⁴ Colchicine is effective in many cases of FMF, suppressing symptoms by inhibiting neutrophil migration through its binding to tubulin and stabilization of microtubules. For patients resistant to colchicine, IL-1 receptor antagonists are employed.⁵

FMF is predominantly observed in Mediterranean populations, particularly among Jews from North African descent, Armenians, Turks, and Arabs.¹ Its prevalence is estimated to be as high as 1 in 700 in Israel and 1 in 1,400 in Turkey.⁹ In Japan, FMF was once considered rare, but cases often go undiagnosed for 5 to 10 years due to misdiagnosis as an acute abdomen.⁶ Thus, it is believed that a significant number of undiagnosed atypical FMF cases exist.

Here, we report the anesthetic management of a male dental patient with FMF confirmed to have a MEFV gene mutation. Written informed consent was obtained from the patient for the publication of this case report.

CASE PRESENTATION

The patient was a 32-year-old male (height, 174 cm; weight, 76.2 kg; BMI, 25.1 kg/m²). Since he was 26 years of age, he had experienced recurrent episodes of fever and abdominal pain that occurred once every few months with complete remission between episodes. His mother had a similar history of fever and abdominal pain since she was 26 years old. Blood tests performed at the time of initial symptoms revealed only an elevated C-reactive protein (CRP), with no abnormalities in other blood tests, upper and lower gastrointestinal endoscopy, abdominal ultrasound, or abdominal computed tomography scan leading to a diagnosis of enteritis.

He was later referred to another hospital where he was diagnosed with FMF based on criteria including recurrent fever exceeding 38°C for 2 hours to 3 days, nonlocalized abdominal pain due to peritonitis, and elevated inflammatory markers during episodes that normalized in the inter-episode period. Treatment with colchicine led to partial control of his FMF signs and symptoms. Genetic testing revealed a heterozygous M694I mutation in Exon 10 and a heterozygous E148Q mutation in Exon 2 of the MEFV gene, confirming the diagnosis of FMF. Despite ongoing colchicine treatment, the patient continued to experience febrile episodes once or twice per year.

The patient was diagnosed with periapical cysts in the right mandibular first molar and left mandibular second molar as well as a horizontally impacted third molar in the left mandible, so extractions and cystectomies under general anesthesia were planned. A consultation with the internal medicine physician regarding the patient’s FMF revealed that his symptoms were controlled by colchicine, and general anesthesia was deemed feasible accordingly. A preoperative chest radiograph, electrocardiogram (ECG), and blood tests were all performed in late March, approximately 3 weeks before the surgery. The chest radiograph and electrocardiogram (ECG) showed no abnormalities. Apart from elevated AST (35 IU/L) and ALT (62 IU/L), all other routine preoperative blood test results were within normal limits, including a C-reactive protein of 0.03 mg/dL (normal range, 0.3–1.0 mg/dL). No FMF signs or symptoms were observed preoperatively, and the patient’s axillary temperature was 36.9°C the day before surgery. Airway evaluation revealed that he was Mallampati class I, had a 3.5-finger mouth opening, and had no limitations in cervical spine mobility.

To avoid triggering an FMF recurrence due to cold exposure, surgery was scheduled for late April (∼3 weeks after the patient’s assessment and labs). Careful assessment and monitoring confirmed the absence of any symptoms or warning signs of an FMF attack before initiating general anesthesia. Standard anesthetic monitors that consisted of a noninvasive blood pressure cuff, pulse oximeter, ECG, thermometer, and capnography were applied, and after intravenous (IV) access was secured in the right forearm, a 1% dextrose-acetate Ringer’s solution infusion was started. General anesthesia induction was achieved with a remifentanil continuous infusion (0.2 µg/kg/min) and boluses of fentanyl (100 µg) and propofol (120 mg), followed by rocuronium (50 mg) for muscle relaxation. Mask ventilation and nasotracheal intubation were performed without complications. General anesthesia was maintained with sevoflurane (1.1%), oxygen (1 L/min), and air (2 L/min) along with the continuous remifentanil infusion. Local anesthesia for both surgical sites in the bilateral mandibular region was administered using 2 mL of 0.5% lidocaine with epinephrine (1:200,000) infiltrated per site for intraoperative analgesia and hemostasis (total dose, 20 mg of lidocaine and 0.02 mg of epinephrine). This dose was chosen to minimize systemic absorption and potential adverse effects while providing effective local anesthesia. Vital signs remained stable throughout the surgery, with no significant fluctuations.

Planned postoperative pain management included IV acetaminophen (1000 mg), flurbiprofen (50 mg), and fentanyl (100 µg) administered near the end of the procedure. The surgery lasted 1 hour with a total anesthesia time of 1 hour 55 minutes and minimal blood loss. Postoperative pain was well controlled with loxoprofen (60 mg) given orally after each meal on the first and second postoperative day.

The patient’s core temperature during the procedure was measured rectally and maintained between 37.4°C and 37.5°C using a warming device. Since a slight upward trend in body temperature was observed intraoperatively, the warming device was adjusted accordingly to prevent hyperthermia. The patient’s postoperative axillary temperatures ranged from 36.9°C to 37.2°C, and he was discharged on the second postoperative day without any FMF attacks. No febrile or painful episodes related to FMF were observed within the first 3 weeks postoperatively.

DISCUSSION

Regarding the anesthetic management of patients with familial Mediterranean fever (FMF), a critical objective is the prevention of acute inflammatory episodes and avoidance of perioperative triggers. Stringent control with colchicine is pivotal in mitigating such attacks; however, approximately 5% to 10% of patients exhibit resistance to colchicine and may require adjunctive or alternative therapy with IL-1 inhibitors.^5,7 Therefore, thorough preoperative evaluation in collaboration with the patient’s primary physician is essential to fully assess the patient's current condition. In the present case, while the patient experienced febrile episodes once or twice annually, consultation with his primary physician confirmed that colchicine effectively controlled his FMF signs and symptoms, ensuring the patient’s stability and fitness for undergoing general anesthesia.

Approximately 50% of patients diagnosed with FMF report experiencing prodromal symptoms,⁸ characterized by mild discomfort preceding attacks. These prodromal symptoms recur in the majority of episodes, with an average duration of 20 hours and presenting either as localized discomfort at the site of the impending attack (discomfort prodrome) or as a broader spectrum of physical, emotional, and neuropsychological manifestations (variant prodrome). Both types of prodrome are frequently accompanied by a variety of constitutional symptoms.⁸

In this case, we considered the possibility of postponing the planned dental surgery if any such symptoms were present prior to admission; however, none were observed. Given the rapid onset and progression of abdominal pain episodes that can develop within 1 to 2 hours,⁹ it was essential to continue monitoring the patient up until the initiation of general anesthesia to ensure that no changes in his condition occurred. In addition to information provided by the patient’s primary physician, we confirmed that there were no signs or symptoms of an FMF recurrence immediately before the induction of anesthesia.

Several factors have been reported to trigger or exacerbate FMF attacks, including emotional stress,^10,11 cold exposure,^10,12 seasonal changes,^11,13 fatigue,^10,11,13 menstrual cycles,^10,11,13 and prolonged travel.¹⁰ In addition, perioperative factors such as surgical trauma and pain may contribute to FMF exacerbations. These factors should be minimized throughout the perioperative period. Insufficient pain control may act as a stressor and potentially trigger an FMF episode, emphasizing the importance of an appropriate pain management strategy tailored to the surgical procedure. It may be beneficial to schedule surgery around the menstrual cycle for female patients. Additionally, cases have been reported where patients primarily experienced attacks during the winter months.¹⁴ This highlights the importance of avoiding cold exposure. In this case, we avoided winter and scheduled the surgery for late April.

There has been a report of a 20-year-old male patient with FMF who developed FMF-like abdominal pain after receiving high-dose bupivacaine for pilonidal sinus surgery but that resolved with the administration of IV diclofenac and fentanyl.¹⁵ Based on this report, preparations were made to administer IV diclofenac and fentanyl in the event of a perioperative FMF attack; however, no such recurrences were observed. Standard anesthetic management was sufficient, with careful maintenance of an appropriate depth of anesthesia and control of intraoperative stimuli. Multimodal pain management, including fentanyl, acetaminophen, and flurbiprofen provided effective postoperative analgesia and contributed to mitigating the risk of FMF attacks.

CONCLUSION

Successful anesthetic management in patients with FMF requires preoperative coordination with the primary physician and careful perioperative management to avoid triggering a recurrence. As long as an adequate depth of anesthesia is maintained, the choice of anesthetic technique does not appear to significantly influence outcomes. Moreover, patients with FMF who are undiagnosed may be encountered in dental or other surgical settings, and healthcare providers should remain vigilant for unexplained signs and symptoms that may warrant further investigation.