What we know today as Lemierre's syndrome was originally described in 1900. In 1936, Dr Andre Lemierre reported 20 cases of "anaerobic septicemias" with 18 deaths. He referred to it as "postanginal septicemia" and reported characteristic clinical manifestations that he believed made the diagnosis unmistakable:"To anyone instructed as to the nature of these septicemias it becomes relatively easy to make a diagnosis on the simple clinical findings. The appearance and repetition several days after the onset of a sore throat?of severe pyrexial attacks with an initial rigor, or still more certainly the occurrence of pulmonary infarcts and arthritic manifestations, constitute a syndrome so characteristic that mistake is almost impossible. Certain diagnosis is established by bacteriological examination. Bacteroides fundiliformis [now known as Fusobacterium necrophorum] is easy to discover. . . . Blood culture on anaerobic media . . . gives the earliest definite information."¹

Fewer than 160 cases of classic Lemierre's syndrome have been reported, with about one third occurring since 1988.² The syndrome was rarely reported during the 1960s and 1970s, when penicillin was frequently used to treat throat infections, and its subsequent reemergence may be related to more prudent use of penicillin in patients with acute tonsillitis as well as to improved anaerobic diagnostic techniques.³ A Danish retrospective study conducted between 1990 and 1995 found an incidence of 0.8 per million persons per year.⁴

Etiology

F necrophorum is an anaerobic, gram-negative bacillus of the genus Fusobacterium, which has been implicated in the etiology, pathophysiology, and complications of several conditions, including periodontal diseases, tropical skin ulcers, intraamniotic infections, and Lemierre's syndrome. Fusobacterium is part of the normal flora of the oral cavity, female genital tract, and gastrointestinal tract. F necrophorum can produce various toxins that differ from those of other anaerobic bacteria and include lipopolysaccharide endotoxin, leukocidin, hemolysin, coagulase, and platelet aggregating factor. This may explain the bacteria's ability to cause intravascular invasion and thrombosis.

Other causative organisms of Lemierre's syndrome include Bacteroides melaninogenicus, Eikenella corrodens, and anaerobic streptococci.

Diagnosis

The hallmark features of Lemierre's syndrome are (1) primary infection in the oropharynx, (2) septicemia documented by at least 1 positive blood culture, (3) radiographic or clinical evidence of internal jugular vein thrombosis, and (4) 1 or more metastatic focus.² Suspect the syndrome in young, previously healthy patients who either have an oropharyngeal infection with an unexpected course or who require hospitalization for sepsis and pulmonary symptoms after an acute pharyngotonsillar infection.³

The initial symptoms of Lemierre's syndrome are usually nonspecific and include sore throat, fever, rigor, and lateral neck tenderness. The disease usually begins as pharyngitis or tonsillitis. Spread of the infection to the deep pharyngeal tissue allows anaerobic organisms to drain into the lateral pharyngeal space, leading to internal jugular vein septic thrombophlebitis.⁵ Commonly, septic clots dislodge from the internal jugular vein thrombus, causing pulmonary infarcts. Other complications include sepsis, jaundice, abnormal liver function, pleural effusions, and empyema. Hematogenous seeding can also occur, resulting in septic arthritis, meningitis, endocarditis, or soft tissue infections.

In Dr Lemierre's day, the diagnosis was made clinically, based on the typical symptoms and signs. Many diagnostic modalities are now available to identify the internal jugular vein thrombophlebitis, including retrograde venography (the gold standard), gallium scan, ultrasonography, contrast-enhanced computed tomography (CT), and magnetic resonance venography.^6,7 The latter appears to be the most accurate and reliable noninvasive method of detecting the presence and extent of venous thrombosis, and its correlation with contrast venography is reportedly as high as 97%.⁸

Treatment

In the pre-antibiotic era, the only known treatment for Lemierre's syndrome was ligation of the affected internal jugular vein to prevent septicemia. Today, the mainstay of therapy is a 4-to 6-week course of an antibiotic with activity against F necrophorum, such as penicillin G, clindamycin (Cleocin), or metronidazole (Flagyl, Protostat). Intravenous (IV) antibiotic therapy is the standard of care initially, especially if the patient is compromised or septic. However, monotherapy with metronidazole is not recommended.³ Because of the emergence of beta-lactamase-producing bacteria, beta-lactamase-resistant antibiotics are becoming more popular as a treatment option.⁹ The mortality rate in untreated patients is as high as 30% to 90%, with an embolic event rate of 25% and endocarditis rate of 12.5%.³

The role of anticoagulant therapy is controversial, but several clinical studies have shown that heparin may be beneficial. One study showed rapid clinical improvement in 42 of 46 patients with septic pelvic thrombophlebitis when heparin was added to the antibiotic therapy.¹⁰ In one case, a patient with Lemierre's syndrome who had fever and chest pain that persisted for 3 days did not improve until he was given heparin.¹¹ Thus, anticoagulation should be considered in some cases. Because of the possibility of extending the infection, anticoagulation must be carefully monitored; some suggest it should be reserved for thrombosis retrograde to the cavernous sinus.^3,12

Ligation of the internal jugular vein is unnecessary unless there is persistent sepsis or recurrent pulmonary septic emboli. Surgical drainage of purulent collections may, however, be required.

Illustrative Case

A 42-year-old healthy Italian man was traveling to the United States on business. During the overseas flight, he noted what he thought was "the flu." Upon arrival in Chicago, he took aspirin but his symptoms did not improve. Two days later he sought medical attention, complaining of sore throat, right-sided neck pain, fever and chills, nausea, mild epigastric pain, diarrhea, and general weakness. Physical examination revealed a somnolent and very sick man. He was hypotensive (blood pressure, 92/61 mm Hg), and tachycardic (heart rate, 130 beats/min). His throat was erythematous and congested and his tonsils were mildly enlarged. His neck was supple, with cervical lymphadenopathy and tenderness over the right sternocleidomastoid muscle. Abdominal examination revealed splenomegaly. There were no meningeal signs or rash. The patient was admitted to the intensive care unit, where he received fluids, piperacillin sodium (Pipracil), and gentamicin (Garamycin). The initial chest x-ray was unremarkable. His condition did not improve. Two days later he developed left-sided pleuritic chest pain and dyspnea. A repeat chest x-ray revealed right middle lobe infiltrates and a left pleural effusion (Figure 1). A thoracentesis demonstrated an exudative effusion.

Four days after admission, his blood culture grew F necrophorum, and the antibiotic was changed to IV clindamycin. CT scans of the sinuses, abdomen, pelvis, and chest revealed septic pulmonary emboli and mild splenomegaly (Figure 2). Transesophageal echocardiography and ventilation/perfusion scans were negative.

Lemierre's syndrome was suspected, and a CT scan of the neck with contrast showed a thrombus in the right internal jugular vein and an enlarged right sternocleidomastoid muscle without evidence of retropharyngeal abscess (Figure 3).

Follow-up chest and neck CT scans after 10 days showed improvement of the pulmonary septic emboli and diminution of the right internal jugular vein thrombus. The patient was discharged after 14 days and prescribed a 4-week course of antibiotic therapy (oral clindamycin). He returned to Italy and followed up with his physician.

Conclusion

Lemierre's syndrome is an anaerobic suppurative thrombophlebitis involving the internal jugular vein, usually as a complication of pharyngeal, dental, or mastoidal infection by F necrophorum. Since the advent of antibiotics, this syndrome has become rare and is often overlooked. Life-threatening complications can occur, as was the case in our patient.

Early clinical suspicion is crucial so that appropriate antibiotic therapy can be started to avert metastatic complications.

SELF-ASSESSMENT TEST

1. Which of these statements about Lemierre's syndrome is NOT true?

1. Initial symptoms are typically nonspecific
2. Pulmonary infarcts can occur
3. Endocarditis is a potential complication
4. Ligation of the internal jugular vein is a common treatment

2. Which of the following is NOT characteristic of Lemierre's syndrome?

1. Pharyngitis
2. Laryngitis
3. Tonsillitis
4. Fever

3. Which organism is most commonly associated with Lemierre's syndrome?

1. Bacteroides melaninogenicus
2. Fusobacterium necrophorum
3. Eikenella corrodens
4. Anaerobic streptococci

4. Which of these techniques is considered the gold standard for diagnosing internal jugular vein thrombophlebitis?

1. Retrograde venography
2. Contrast-enhanced CT
3. Gallium scan
4. Ultrasonography

5. Which of the following is NOT an appropriate treatment for a patient with Lemierre's syndrome?

1. 4-week course of cefuroxime
2. 10-day course of clindamycin
3. Initial treatment with IV penicillin G
4. 6-week course of clindamycin

(Answers at end of reference list)