The Laryngoscope C 2014 The American Laryngological, V
Rhinological and Otological Society, Inc.
Septic Thrombosis of the Internal Jugular Vein: Lemierre’s Syndrome Revisited Adrian D. Schubert, MD; Michel-Andre Hotz, MD; Marco D. Caversaccio, MD; Andreas Arnold, MD Objectives/Hypothesis: Study of the clinical evolution of a primary ear, nose, and throat infection complicated by septic thrombophlebitis of the internal jugular vein. Study Design: Retrospective case-control study. Patients and Methods: From 1998 to 2010, 23 patients at our institution were diagnosed with a septic thrombosis of the internal jugular vein. Diagnostics included microbiologic analysis and imaging such as computed tomography, magnetic resonance imaging, and ultrasound. Therapy included broad-spectrum antibiotics, surgery of the primary infectious lesion, and postoperative anticoagulation. The patients were retrospectively analyzed. Results: The primary infection sites were found in the middle ear (11), oropharynx (8), sinus (3), and oral cavity (1). Fourteen patients needed intensive care unit treatment for a mean duration of 6 days. Seven patients were intubated, and two developed severe acute respiratory distress syndrome. An oropharynx primary infection site was most prone to a prolonged clinical evolution. Anticoagulation therapy was given in 90% of patients. All 23 patients survived the disseminated infection without consecutive systemic morbidity. Conclusion: In the pre-antibiotic time, septic internal jugular vein thrombophlebitis was a highly fatal condition with a mortality rate of 90%. Modern imaging techniques allow early and often incidental diagnosis of this clinically hidden complication. Anticoagulation, intensive antibiotic therapy assisted by surgery of the primary infection site, and intensive supportive care can reach remission rates of 100%. Key Words: Lemierre’s syndrome, septic thrombosis, jugular vein, ENT infection. Level of Evidence: 3b. Laryngoscope, 00:000–000, 2014
INTRODUCTION Primary infections of the ear, nose, and throat area are common and are not infrequently associated with local complications such as a phlegmon or abscess. If the infection is not controlled spontaneously or by antibiotics and/or surgery, the inflammatory process may spread and involve tributary vessels. This process may cause thrombophlebitis or even septic thrombosis of the superficial and deep cranial and extracranial venous system. Although the combined thrombosis of the superficial and deep cranial venous system produces local symptoms such as headache, epileptic seizures, and focal neurological deficits due to venous infarction of cerebellar and cerebral structures, the extracranial septic thrombosis of the internal jugular vein remains locally silent and produces emboli-associated pathologies. Some authors call the occlusive thrombus and the subsequent swelling of the internal jugular vein a protective measure of the
From the Department of ENT, Head and Neck Surgery, Inselspital, University of Bern, Switzerland Editor’s Note: This Manuscript was accepted for publication October 2, 2014. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Michel-Andr e Hotz, MD, Department of ENT, Head and Neck Surgery, Inselspital, University of Bern, CH-3010 Bern, Switzerland. E-mail:[email protected] DOI: 10.1002/lary.24995
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body to block the inflammatory process from reaching the mediastinum and its vital structures.1 This statement may be true for the direct per continuitatem expansion in the neck and thorax (acute mediastinitis is rare in these patients) but not for the well-known embolic dissemination in the lung and other organ systems. As brought to a wider audience by Lemierre in 1936, this thrombophlebitis, described before by Courmant, Cade, Schottm€ uller, and Fraenkel, was often deadly in the pre-antibiotic era.2,3 Lemierre’s address reported 20 cases with a mortality of 90%, but no detailed patient data. After broad introduction of antibiotics in the 1950s and 1960s, Lemierre’s syndrome was considered a forgotten or an all-but-forgotten disease.4,5 Over the past 20 years, more than 400 articles on this topic have been published, and most were single case reports. Almost 80 years after the publication of Lemierre’s article, a clinical update seems necessary not only to revive old scientific and clinical discussions but also to include new diagnostic and therapeutic options introduced into medicine during this time.
PATIENTS AND METHODS This retrospective case control study reviews the records of 23 patients treated between 1998 and 2010 in a tertiary referral center for septic thrombosis of the internal jugular vein secondary to a primary infection of the ear, nose, and throat
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(ENT) region (Table I). The gender distribution was almost equal (48% males, 52% females), the mean age of the treated patients was 39.5 years (range: 10 months–79 years), and the mean follow-up time was 9.4 months (range: 1 week–46 months). Diagnostic tests included classic laboratory tests; microbiologic analysis of blood and pus; and compulsory chestX-ray and other imaging techniques such as computed tomography (CT) scan, magnetic resonance imaging (MRI), and ultrasound. The therapeutic protocol included broad-spectrum intravenous antibiotics, surgical approach of the primary infectious lesion, and postoperative anticoagulation with heparin and/or cumarin derivates. This study was approved by the local review board of clinical investigation (Reg. 10-01-11).
RESULTS Diagnosis
F1
The primary ENT infection was localized in the middle ear (11 patients, 48%), the oropharynx (eight patients, 35%), the ethmoid-maxillary sinus (three patients, 13%), and the oral cavity (one patient, 4%). Figure 1 shows the frequencies and species of identified pathogenic microbes. Microbiological analysis of the pus–blood specimen showed pathogenic microbes (aerobic, facultative aerobic, anaerobic) in 20 of the 23 patients. Most likely due to ongoing antibiotic therapy at the time of collection, the specimens of three patients remained sterile. In 10 patients, more than one pathogenic microbe was identified. Five patients presented the classical microbe Fusobacterium necrophorum, originally described as the main microbiological cause of the infection. The most frequent infection in our study was due to group A Streptococcus (n 5 6). In all patients, septic thrombosis of the internal jugular vein was diagnosed on CT scan. Sixteen patients (70%) presented with a complete occlusion, and seven patients (30%) presented with a partial occlusion of the internal jugular vein. Patients with a primary otogenic infection (n 5 11) showed intracranial and extracranial extension of the septic thrombosis from the sigmoid sinus to the internal jugular vein. For all other primary infection sites, thrombosis remained strictly extracranial. Only one-third of CT scan referral forms stipulated the eventuality of septic thrombosis of the internal jugular vein (STIJV). In two-thirds of cases, the STIJV diagnosis was unexpected for the clinician. The radiological follow-up of cases with complete occlusion of the internal jugular vein was feasible in 10 of 16 patients, of which four patients showed a recanalization of the internal jugular vein after 18 days to 6 months. After the disappearance of the acute infection, patients with persistent obstruction of the internal jugular vein showed no clinical symptoms.
Therapy All patients received intravenous followed by oral antibiotics for a mean duration of 35 days. The initial antibiotic choice was emergency-driven by the septic status of the patient. After receiving the microbiology results, the antibiotic therapy was adjusted accordingly. The antibiotics used included mostly penicillin derivatives, cephalosporins, macrolides, and quinolones; Laryngoscope 00: Month 2014
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whereas aminoglycosides, glycopeptides, lincosamides, and nitroimidazol were rarely used. Neither antibiotic resistance of the diagnosed microbes nor secondary side effects of the antibiotics were observed during the study. Seventeen of the 23 (74%) patients underwent surgical treatment of the primary infection site. The interventions included tonsillectomy, mastoidectomy, sinus surgery, and dental extraction. Ligation of the internal jugular vein was added to the aforementioned primary surgery in three patients because of relapsing septic episodes and/or pulmonary emboli under high-dose antibiotics. No postoperative complications were observed. Twenty-one of the 23 (91%) patients were anticoagulated with heparin followed by cumarin derivatives for several months (Table I). Two patients with only partial thrombosis of the internal jugular vein were not anticoagulated. Fourteen patients (61%) had to be hospitalized in the intensive care unit (ICU) for a mean duration of 6 days (range 2–21 days) (Table II). Five patients presented with septic shock or respiratory insufficiency; five patients suffered from neurological deterioration; and four patients were in the ICU for postoperative care and surveillance. One patient was admitted twice to the ICU. Eight of the patients in the ICU (57%) were intubated for a mean duration of 5 days (range 1–16 days). Five patients (36%) needed vasoactive treatment for septic hypotension. Two of the 14 ICU patients (14%) developed acute respiratory distress syndrome (ARDS). These two patients showed severe clinical evolution with ICU stays of 17 and 21 days, respectively. None of the ICU patients needed resuscitation. Interestingly, an oropharynx primary infection site predisposed patients to a longer ICU stay due to severe complications such as ARDS.
Evolution Seven of the 23 patients (30%) developed a septic embolism to the lung diagnosed 7 to 14 days after the onset of the primary infection. Of those, six patients had their primary site in the oropharynx. Four out of five patients found with Fusobacterium necrophorum had a septic embolism to the lung. One patient presented with osteomyelitis of the left elbow due to a septic embolus 7 days after onset of the first symptoms from the primary infection. One patient developed a cerebellar infarction with typical neurological symptoms only 2 days after the onset of the disease. Patients were discharged from hospital after a mean duration of 25 days (range 3–63 days). No patient death was observed. Postinfection morbidity included sensorineural and conductive hearing loss and chronic otitis media perforata. Neither recanalized nor durably blocked internal jugular veins showed any type of clinical morbidity.
DISCUSSION Lemierre’s syndrome is a child of the first 3 decades of the 20th century, when medical research first postulated a relationship between focal primary infections in the ENT region and secondary diseases in other organ systems. Authors such as Hunter, Oph€ uls, and Lemierre Schubert et al.: Lemierre’s Syndrome Revisited
TABLE I. Patient Overview: Patient Characteristics, Primary Site of Infection, Isolated Microbe, Details of the Antibiotic Therapy, Additional Therapy Such as Surgery and/or Anticoagulation, and Duration of Hospital Stay.
Patient
Age/Sex
Primary Site of Infection
Germ
Antibiotics (type)
Antibiotics (days)
Surgery
Anticoagulation (months)
Hospital Stay (days)
1
56/female
Dental extraction
Unknown
AMC, MTZ
12
2
0
3
2
20/female
Tonsillitis
Fusobacterium necrophorum
CLR, FEP, NET, MTZ, CLI, TZP, PEN
31
2
1
26
3
38/male
Tonsillitis
Fusobacterium necrophorum
CLR, AMC, CLI
66
1*
0.15
40
4
32/female
Peritonsillar abscess
Bacteroides species, Pseudomonas aeruginosa
AMC, TZP CLI, CIP
30
1*
3.5
24
5
57/female
Peritonsillar abscess
TZP, RIF, AMC
45
1
7
32
6
42/female
Pharyngitis
AMC, VAN
37
1
3
21
7
18/male
Pharyngitis
Streptococcus milleri, Peptostreptococcus species Group A beta-hemolytic streptococcus Streptococcus milleri, Fusobacterium necrophorum
No follow-up
min. 6
8
29/female
Pharyngitis
0
15
9
68/female
Retropharyngeal Group C beta-hemolytic abscess streptococcus
No follow-up
min. 25
10 11
79/male 13/male
12
66/female
13
71/male
14
No 2 follow-up
CRO, MTZ, AMC, CLI
43
FEP, PEN, AMC
2
No 1 follow-up
Streptococcus milleri AMC, MTZ MEM, CLI, Group A beta-hemolytic CRO, AMX streptococcus, Staphylococcus aureus AMC, CRO Mixed anaerobic flora, coagulase-negative staphylococci
42 14
1 2
6 6
16 15
22
1
3
31
Necrotizing external otitis
Pseudomonas aeruginosa
FEP, CIP
59
1
Lifelong
37
7/female
Otitis media
Group A beta-hemolytic streptococcus
MEM, AMX
17
1
2.5
17
15
79/male
Otitis media
Group A beta-hemolytic streptococcus
CRO, AMX
31
1
Lifelong
min. 14
16
40/male
Mastoiditis
Streptococcus milleri
29
1
24
18
17
11/female
Mastoiditis
Unknown
CRO, AMX, VAN, MEM FLU, CRO, MTZ, AMC
52
1
6.5
16
18
6/male
Mastoiditis
Streptococcus pneumoniae, Corynebacterium sp.
AMX
30
1
7.5
23
19
49/female
Mastoiditis
Group A beta-hemolytic streptococcus, Staphylococcus aureus
PEN
42
1
Lifelong
52
Fusobacterium necrophorum
CRO, AMX, VAN, MEM, MTZ, CLI
39
1
8
27
Unknown Fusobacterium nucleatum, coagulase-negative staphylococci Group A beta-hemolytic streptococcus, Staphylococcus aureus
AMC, MXF MEM, AMC, CIP, CAZ, FEP
32 42
2 1*
6.5 No follow-up
14 63
AMC
21
1
0.15
15
20
Sinusitis Sinusitis
Fusobacterium necrophorum
CRO, MTZ
Periorbital abscess
7 months/female Mastoiditis
21 22
58/male 63/male
Mastoiditis Mastoiditis
23
7/male
Gradenigo Syndrome
*Ligation of the internal jugular vein. AMC 5 amoxicillin/clavulanate; AMX 5 amoxicillin; CIP 5 ciprofloxacin; CLR 5 clarithromycin; CRO 5 ceftriaxone; FEP 5 cefepime; MEM 5 meropenem; MTZ 5 metronidazole, RIF 5 rifampicin; TZP 5 piperacillin/tazobactam; VAN 5 vancomycin; min. 5 minimum.
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Fig. 1. Microbiological data found in intraoperative swabs or in blood cultures. dark grey 5 aerobic; gray 5 facultative aerobic; light gray 5 anaerobic.
supported this pathophysiologic model, which incited important preventive surgical activity in ENT and dentistry over the decades.3,6,7 The introduction of antibiotics after World War II made the focal infection theory more and more obsolete from medical and scientific discussion. A remnant is the ongoing discussion concerning whether arteriosclerosis is related to chronic oral infections.8 In fact, there has never been a formal case definition for Lemierre’s syndrome. Propositions from Sinave in 1989 and Riordan in 2007 limited Lemierre’s syndrome to a oropharyngeal origin of infection.9,10 Looking at Lemierre’s original work, he describes Fusobacterium necrophorum-driven septicemias with primary ENT infections (oropharynx, middle ear, oral cavity) resulting
in STIJV and producing metastatic emboli to the lungs and the periphery.3 Absolutely respecting the work of the aforementioned authors, our clinical study focuses on the STIJV with or without cranial extension independently from microbiological status. Lemierre described peripheral but not cerebral complications of the STIJV, although he mentioned the occurrence of septic sinus vein thrombosis secondary to ear and mastoid infections. In our study, 11 patients had the primary infection site in the middle ear. Of these, 10 patients had superficial cranial thrombosis presenting with general clinical signs of sepsis 1 to 2 weeks after onset of the infection. One patient with combined superficial and deep cranial septic thrombosis already presented 2 days after the beginning of primary infection with specific central nervous symptoms due to radiologically confirmed cerebellar infarction. These two different clinical time patterns between superficial as well as superficial and deep septic thrombophlebitis may explain why Lemierre did not describe clinical signs of cerebral complications. Today, imaging techniques such as CT scans and MRIs are the harbingers of the correct but often accidental diagnosis of septic thrombophlebitis, which urges the clinician to look for peripheral septic emboli. Computed tomography and/or MRI of the primary ENT infection site should always include the neck. In the event of confirmed and/or suspected thrombophlebitis, the lung and cerebrum must be included in the examination. The fast communication of results from the radiologist to the clinician is crucial to launch effective therapeutic measures. Lemierre did not believe in ligation of the internal jugular vein as a therapeutic option, as proposed by his German colleagues at the time. Three of our patients who underwent ligation showed a good clinical outcome after an initially difficult disease evolution. The procedure seems to be indicated in the presence of persistent
TABLE II. Intensive Care Data of Patients: Indication for Intensive Care, Requirement of Intubation and Its Duration, Requirement of Vasoactive Medication or Reanimation, and Length of Stay in the ICU. Patient
Indication
Intubation (days)
Vasoactives
ICU Stay (days)
2
Respiratory failure
16
yes
17
3
Septic shock
3
yes
4
4 5
Respiratory failure Postoperative monitoring
1 no
no no
3 4
9
Respiratory failure
14
yes
21
11 12
Cardiovascular instability Neurological deterioration/meningismus
no 1
yes no
2 2
14
Neurological monitoring after mastoidectomy
no
no
2
15 16
Venous sinus thrombosis with mastoiditis 1. venous cerebellar infarction; 2. after craniotomy
no no
no no
2 (5 1 3) 8
18
Neurological monitoring after mastoidectomy
1
no
3
19 20
Neurological deterioration Neurological deterioration
no no
no no
3 5
22
Neurological deterioration
1
yes
4
ICU 5 intensive care unit.
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Schubert et al.: Lemierre’s Syndrome Revisited
sepsis under high-dose antibiotics. The veterinary literature describes ligation of the thrombophlebitic internal jugular vein as a straightforward, efficient, and costeffective procedure in horses.11 Antibiotics eventually associated with surgery stop and eradicate the infection. Over almost 80 years, the microbiological profile fortunately has not changed, which allows for an effective treatment by classical broad-spectrum antibiotics without substantial resistance. The early administration of antibiotics seems to be crucial for successful treatment. The wide choice of antibiotics is correlated with actual ICU antibiotic guidelines before obtaining the microbiological results. Once the microbe is confirmed by microbiology, therapy may be switched to cost-effective and targeted antibiotics. Antibiotics have also cured patients with persistent thrombosis. There are no data to support the idea that recanalization of the internal jugular vein provides an advantage and lowers morbidity and mortality. Microbiological data from this study identified the Streptococcus family and not Fusobacterium necrophorum as the most frequent microbe in STIJV (Fig. 1). This result contrasts the results from Lemierre’s study but highlights an old discussion in which Fischer and K€orner presented the streptococcus family as the main microbe in STIJV.12–14 The Fusobacterium necrophorum bias introduced by Lemierre incited a series of publications identifying STIJV as almost pathognomonic sign of Fusobacterium necrophorum infection.9,15–22 However, our study clearly shows that STIJV can be caused by a multitude of microbes, a circumstance recently noted by Syed et al.23 Furthermore, compared to other microbes found in our patient group, Fusobacterium necrophorum infection showed no distinctive differences in diagnosis, therapy, and prognosis. Due to the intact sensitivity of implicated microbes to broadband antibiotics as well as the time delay to obtain the microbe diagnosis, microbiology lost its diagnosis leadership position to radiology over the past few decades. The diagnostic power and routine use of modern imaging may explain the continuous increase in literature reports of Lemierre’s syndrome in the past decades.24 Anticoagulation is recommended in the literature. Evidence seems to be low for extracranial STIJV because of the still-maintained central venous blood flow, except in the presence of classical thrombosis risk factors.25 The presence of thrombophilia with elevated factor VIII and antiphospholipid antibodies is an absolute indication for therapeutic anticoagulation.26 For cranial venous thrombophlebitis, the literature indicates 3 to 12 months of intravenous, subcutaneous, and/or oral anticoagulation due to the risk of complete blockage of the superficial and deep cranial venous system.27 All patients with an otologic primary infection site (48%) showed intracranial and extracranial septic thrombosis, whereas extracranial primary ENT infection sites led to strictly extracranial thromboses. The phenomenon that extracranial primary site infections were never associated with intracranial thrombosis may be explained by the venous valvular system inhibiting venous reflux or by anticoagulation therapy initiated Laryngoscope 00: Month 2014
early after onset of the disease. At the end of the anticoagulation treatment, a full hemostasis examination is recommended to identify eventual risk factors, which make life-long anticoagulation necessary.27 Our data give no evidence that anticoagulation could be contraindicated in STIJV due to extension of the infection, as cited by Hagelskjaer et al.21 In the follow-up of STIJV regarding anticoagulation and antibiotic therapy, different imaging modalities compete with anticoagulation guidelines and laboratory and clinical inflammatory parameters. The use of ultrasound to follow up deep vein thrombosis in the lower extremities to determine duration of anticoagulation is controversially discussed in the literature.28,29 Therefore, it might be safer to follow clinical anticoagulation guidelines in STIJV.25–27 The duration of antibiotic therapy is not related to the presence of the thrombus, but guided by laboratory and clinical inflammatory parameters.10 Suspected intracranial pathologies associated with STIJV are best assessed with MRI. The analysis of the clinical data in our series showed an ICU stay for 61% of patients, an intubation rate of 30%, and an ARDS rate of 9% in all patients. These findings and the good clinical outcomes of our patients stress the importance of the availability of ICU care for the successful treatment of Lemierre’s syndrome. Patients suspected of having STIJV should be transferred to an institution with an ICU for further treatment. In an epidemiological study with 24 patients all affected by Fusobacterium necrophorum-induced Lemierre’s syndrome of the ENT region, Hagelskjaer et al. reported similar results with no mortality and no posttreatment morbidity.21 We confirmed their finding that the oropharynx primary infection site implied a more severe clinical evolution, characterized by prolonged ICU stay duration and higher emboli frequency, than the other primary infection sites. Furthermore, Hagelskjaer showed that Lemierre’s syndrome with primary infection sites caudal to the neck region and with concomitant diseases such as cancer had a worse prognosis, with a mortality of 24%.21 Almost 80 years after Lemierre’s publication, this infectious cascade may again gain importance by antibiotic prescription guidance, eventually leaving falsely, negatively diagnosed putrid-ENT infections untreated in significant numbers.2,24,30 Simple laboratory tests such as C-reactive protein and peripheral white cell count, as well as the consequent application of clinical skills to correctly diagnose and treat primary dental and ENT infections, are the best options to avoid Lemierre’s syndrome and at the same time to protect the imaging and antibiotic resources of our stressed healthcare systems.31
CONCLUSION Over the past 80 years, the diagnosis and therapy for Lemierre’s syndrome have been fundamentally improved with a highly effective reduction in the morbidity and mortality. Modern imaging techniques, antibiotics, and ICUs are the tools needed to avoid the Schubert et al.: Lemierre’s Syndrome Revisited
5
disastrous spontaneous evolution of the disease. The Lemierre’s syndrome of the 21st century remains a unique pathophysiological model of intravenous systemic spread of acute ENT infections, eventually resulting in metastatic embolic disease. The primary infection site includes the whole ENT region; the microbiology shows a wide range with a preponderance of streptococci, fusobacterium, and staphylococci—all still sensitive to broadspectrum antibiotics. The systemic infection may overactivate hemostasis and cause cranial and/or extracranial thrombosis. Although extracranial STIJV and cranial superficial septic thrombosis remain clinically silent and are followed by general septic signs after 7 to 10 days, the combined thrombosis of the superficial and deep cranial venous system already presents with specific neurologic signs 36 to 48 hours after the onset of the infection. Confronted with the serious clinical consequences of cranial thrombosis, anticoagulation is recommended in all cases of septic thrombosis of the ENT region.
BIBLIOGRAPHY 1. Glasscock ME, Shambaugh GE, Johnson GD. Surgery of the Ear. Philadelphia, PA: Saunders; 1990. 2. Syed MI, Baring D, Addidle M, Murray C, Adams C. Lemierre syndrome: two cases and a review. Laryngoscope. 2007;117:1605–1610. 3. Lemierre A. On certain septicaemias due to anaerobic organisms. Lancet 1936; 227:701–703. 4. O’Brien WT Sr, Lattin GE Jr, Thompson AK. Lemierre syndrome: an allbut-forgotten disease. AJR Am J Roentgenol 2006;187:W324. 5. Moore-Gillon J, Lee TH, Eykyn SJ, Phillips I. Necrobacillosis: a forgotten disease. Br Med J (Clin Res Ed) 1984;288:1526–1527. 6. Ophuls W. Arteriosclerosis and cardiovascular disease: their relation to infectious diseases. JAMA 1921;76:2. 7. Hunter W. The coming of age of oral sepsis. Br Med J 1921;1:859. 8. Sinanoglu H. Association Between Peridontitis and Coronary Heart Disease. Marburg, Germany: Philipps-University Marburg; 2010. 9. Sinave CP, Hardy GJ, Fardy PW. The Lemierre syndrome: suppurative thrombophlebitis of the internal jugular vein secondary to oropharyngeal infection. Medicine (Baltimore) 1989;68:85–94.
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10. Riordan T. Human infection with Fusobacterium necrophorum (Necrobacillosis), with a focus on Lemierre’s syndrome. Clin Microbiol Rev 2007; 20:622–659. 11. Russell TM, Kearney C, Pollock PJ. Surgical treatment of septic jugular thrombophlebitis in nine horses. Vet Surg 2010;39:627–630. 12. Schottmuller H. Ueber den angeblichen Zusammenhang zwischen Infektionen der Zahne und Allgemeinerkrankungen. Dtsch Med Wochenschr 1922;48: 181–182. 13. Fischer MH. Relation of mouth infection to systemic disease. Cincinnati,OH: Lancet-Clinic; August 7, 1915. 14. Korner O. Die otitischen Erkrankungen des Hirns, der Hirnhaute und der Blutleiter. Wiesbaden, Germany: Bergmann; 1908. 15. Alston JM. Necrobacillosis in Great Britain. Br Med J 1955;2:1524–1528. 16. Felner JM, Dowell VR Jr. "Bacteroides" bacteremia. Am J Med 1971;50: 787–796. 17. Henry S, DeMaria A Jr, McCabe WR. Bacteremia due to Fusobacterium species. Am J Med 1983;75:225–231. 18. Moreno S, Garcia Altozano J, Pinilla B, et al. Lemierre’s disease: postanginal bacteremia and pulmonary involvement caused by Fusobacterium necrophorum. Rev Infect Dis 1989;11:319–324. 19. Eykyn SJ. Necrobacillosis. Scand J Infect Dis Suppl 1989;62:41–46. 20. Leugers CM, Clover R. Lemierre syndrome: postanginal sepsis. J Am Board Fam Pract 1995;8:384–391. 21. Hagelskjaer LH, Prag J, Malczynski J, Kristensen JH. Incidence and clinical epidemiology of necrobacillosis, including Lemierre’s syndrome, in Denmark 1990–1995. Eur J Clin Microbiol Infect Dis 1998;17:561–565. 22. Golpe R, Marin B, Alonso M. Lemierre’s syndrome (necrobacillosis). Postgrad Med J 1999;75:141–144. 23. Syed MI, Baring D, Murray C. In reference to Lemierre’s Syndrome: a systematic review. Laryngoscope 2010;120:215. 24. Karkos PD, Asrani S, Karkos CD, et al. Lemierre’s syndrome: a systematic review. Laryngoscope 2009;119:1552–1559. 25. Bondy P, Grant T. Lemierre’s syndrome: what are the roles for anticoagulation and long-term antibiotic therapy? Ann Otol Rhinol Laryngol 2008;117:679–683. 26. Grunt S, Wingeier K, Wehrli E, et al. Cerebral sinus venous thrombosis in Swiss children. Dev Med Child Neurol 2010;52:1145–1150. 27. Einhaupl K, Stam J, Bousser MG, et al. EFNS guideline on the treatment of cerebral venous and sinus thrombosis in adult patients. Eur J Neurol 2010;17:1229–1235. 28. Meissner MH. Duplex follow-up of patients with DVT: does it have clinical significance? Semin Vasc Surg 2001;14:215–221. 29. Prandoni P, Prins MH, Lensing AW. Residual thrombosis on ultrasound to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med 2009;150:577–585. 30. Thompson PL, Spyridis N, Sharland M, et al. Changes in clinical indications for community antibiotic prescribing for children in the UK from 1996 to 2006: will the new NICE prescribing guidance on upper respiratory tract infections just be ignored? Arch Dis Child 2009;94:337–340. 31. Jones JW, Riordan T, Morgan MS. Investigation of postanginal sepsis and Lemierre’s syndrome in the South West Peninsula. Commun Dis Public Health 2001;4:278–281.
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Rhinological and Otological Society, Inc.
Septic Thrombosis of the Internal Jugular Vein: Lemierre’s Syndrome Revisited Adrian D. Schubert, MD; Michel-Andre Hotz, MD; Marco D. Caversaccio, MD; Andreas Arnold, MD Objectives/Hypothesis: Study of the clinical evolution of a primary ear, nose, and throat infection complicated by septic thrombophlebitis of the internal jugular vein. Study Design: Retrospective case-control study. Patients and Methods: From 1998 to 2010, 23 patients at our institution were diagnosed with a septic thrombosis of the internal jugular vein. Diagnostics included microbiologic analysis and imaging such as computed tomography, magnetic resonance imaging, and ultrasound. Therapy included broad-spectrum antibiotics, surgery of the primary infectious lesion, and postoperative anticoagulation. The patients were retrospectively analyzed. Results: The primary infection sites were found in the middle ear (11), oropharynx (8), sinus (3), and oral cavity (1). Fourteen patients needed intensive care unit treatment for a mean duration of 6 days. Seven patients were intubated, and two developed severe acute respiratory distress syndrome. An oropharynx primary infection site was most prone to a prolonged clinical evolution. Anticoagulation therapy was given in 90% of patients. All 23 patients survived the disseminated infection without consecutive systemic morbidity. Conclusion: In the pre-antibiotic time, septic internal jugular vein thrombophlebitis was a highly fatal condition with a mortality rate of 90%. Modern imaging techniques allow early and often incidental diagnosis of this clinically hidden complication. Anticoagulation, intensive antibiotic therapy assisted by surgery of the primary infection site, and intensive supportive care can reach remission rates of 100%. Key Words: Lemierre’s syndrome, septic thrombosis, jugular vein, ENT infection. Level of Evidence: 3b. Laryngoscope, 00:000–000, 2014
INTRODUCTION Primary infections of the ear, nose, and throat area are common and are not infrequently associated with local complications such as a phlegmon or abscess. If the infection is not controlled spontaneously or by antibiotics and/or surgery, the inflammatory process may spread and involve tributary vessels. This process may cause thrombophlebitis or even septic thrombosis of the superficial and deep cranial and extracranial venous system. Although the combined thrombosis of the superficial and deep cranial venous system produces local symptoms such as headache, epileptic seizures, and focal neurological deficits due to venous infarction of cerebellar and cerebral structures, the extracranial septic thrombosis of the internal jugular vein remains locally silent and produces emboli-associated pathologies. Some authors call the occlusive thrombus and the subsequent swelling of the internal jugular vein a protective measure of the
From the Department of ENT, Head and Neck Surgery, Inselspital, University of Bern, Switzerland Editor’s Note: This Manuscript was accepted for publication October 2, 2014. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Michel-Andr e Hotz, MD, Department of ENT, Head and Neck Surgery, Inselspital, University of Bern, CH-3010 Bern, Switzerland. E-mail:[email protected] DOI: 10.1002/lary.24995
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body to block the inflammatory process from reaching the mediastinum and its vital structures.1 This statement may be true for the direct per continuitatem expansion in the neck and thorax (acute mediastinitis is rare in these patients) but not for the well-known embolic dissemination in the lung and other organ systems. As brought to a wider audience by Lemierre in 1936, this thrombophlebitis, described before by Courmant, Cade, Schottm€ uller, and Fraenkel, was often deadly in the pre-antibiotic era.2,3 Lemierre’s address reported 20 cases with a mortality of 90%, but no detailed patient data. After broad introduction of antibiotics in the 1950s and 1960s, Lemierre’s syndrome was considered a forgotten or an all-but-forgotten disease.4,5 Over the past 20 years, more than 400 articles on this topic have been published, and most were single case reports. Almost 80 years after the publication of Lemierre’s article, a clinical update seems necessary not only to revive old scientific and clinical discussions but also to include new diagnostic and therapeutic options introduced into medicine during this time.
PATIENTS AND METHODS This retrospective case control study reviews the records of 23 patients treated between 1998 and 2010 in a tertiary referral center for septic thrombosis of the internal jugular vein secondary to a primary infection of the ear, nose, and throat
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(ENT) region (Table I). The gender distribution was almost equal (48% males, 52% females), the mean age of the treated patients was 39.5 years (range: 10 months–79 years), and the mean follow-up time was 9.4 months (range: 1 week–46 months). Diagnostic tests included classic laboratory tests; microbiologic analysis of blood and pus; and compulsory chestX-ray and other imaging techniques such as computed tomography (CT) scan, magnetic resonance imaging (MRI), and ultrasound. The therapeutic protocol included broad-spectrum intravenous antibiotics, surgical approach of the primary infectious lesion, and postoperative anticoagulation with heparin and/or cumarin derivates. This study was approved by the local review board of clinical investigation (Reg. 10-01-11).
RESULTS Diagnosis
F1
The primary ENT infection was localized in the middle ear (11 patients, 48%), the oropharynx (eight patients, 35%), the ethmoid-maxillary sinus (three patients, 13%), and the oral cavity (one patient, 4%). Figure 1 shows the frequencies and species of identified pathogenic microbes. Microbiological analysis of the pus–blood specimen showed pathogenic microbes (aerobic, facultative aerobic, anaerobic) in 20 of the 23 patients. Most likely due to ongoing antibiotic therapy at the time of collection, the specimens of three patients remained sterile. In 10 patients, more than one pathogenic microbe was identified. Five patients presented the classical microbe Fusobacterium necrophorum, originally described as the main microbiological cause of the infection. The most frequent infection in our study was due to group A Streptococcus (n 5 6). In all patients, septic thrombosis of the internal jugular vein was diagnosed on CT scan. Sixteen patients (70%) presented with a complete occlusion, and seven patients (30%) presented with a partial occlusion of the internal jugular vein. Patients with a primary otogenic infection (n 5 11) showed intracranial and extracranial extension of the septic thrombosis from the sigmoid sinus to the internal jugular vein. For all other primary infection sites, thrombosis remained strictly extracranial. Only one-third of CT scan referral forms stipulated the eventuality of septic thrombosis of the internal jugular vein (STIJV). In two-thirds of cases, the STIJV diagnosis was unexpected for the clinician. The radiological follow-up of cases with complete occlusion of the internal jugular vein was feasible in 10 of 16 patients, of which four patients showed a recanalization of the internal jugular vein after 18 days to 6 months. After the disappearance of the acute infection, patients with persistent obstruction of the internal jugular vein showed no clinical symptoms.
Therapy All patients received intravenous followed by oral antibiotics for a mean duration of 35 days. The initial antibiotic choice was emergency-driven by the septic status of the patient. After receiving the microbiology results, the antibiotic therapy was adjusted accordingly. The antibiotics used included mostly penicillin derivatives, cephalosporins, macrolides, and quinolones; Laryngoscope 00: Month 2014
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whereas aminoglycosides, glycopeptides, lincosamides, and nitroimidazol were rarely used. Neither antibiotic resistance of the diagnosed microbes nor secondary side effects of the antibiotics were observed during the study. Seventeen of the 23 (74%) patients underwent surgical treatment of the primary infection site. The interventions included tonsillectomy, mastoidectomy, sinus surgery, and dental extraction. Ligation of the internal jugular vein was added to the aforementioned primary surgery in three patients because of relapsing septic episodes and/or pulmonary emboli under high-dose antibiotics. No postoperative complications were observed. Twenty-one of the 23 (91%) patients were anticoagulated with heparin followed by cumarin derivatives for several months (Table I). Two patients with only partial thrombosis of the internal jugular vein were not anticoagulated. Fourteen patients (61%) had to be hospitalized in the intensive care unit (ICU) for a mean duration of 6 days (range 2–21 days) (Table II). Five patients presented with septic shock or respiratory insufficiency; five patients suffered from neurological deterioration; and four patients were in the ICU for postoperative care and surveillance. One patient was admitted twice to the ICU. Eight of the patients in the ICU (57%) were intubated for a mean duration of 5 days (range 1–16 days). Five patients (36%) needed vasoactive treatment for septic hypotension. Two of the 14 ICU patients (14%) developed acute respiratory distress syndrome (ARDS). These two patients showed severe clinical evolution with ICU stays of 17 and 21 days, respectively. None of the ICU patients needed resuscitation. Interestingly, an oropharynx primary infection site predisposed patients to a longer ICU stay due to severe complications such as ARDS.
Evolution Seven of the 23 patients (30%) developed a septic embolism to the lung diagnosed 7 to 14 days after the onset of the primary infection. Of those, six patients had their primary site in the oropharynx. Four out of five patients found with Fusobacterium necrophorum had a septic embolism to the lung. One patient presented with osteomyelitis of the left elbow due to a septic embolus 7 days after onset of the first symptoms from the primary infection. One patient developed a cerebellar infarction with typical neurological symptoms only 2 days after the onset of the disease. Patients were discharged from hospital after a mean duration of 25 days (range 3–63 days). No patient death was observed. Postinfection morbidity included sensorineural and conductive hearing loss and chronic otitis media perforata. Neither recanalized nor durably blocked internal jugular veins showed any type of clinical morbidity.
DISCUSSION Lemierre’s syndrome is a child of the first 3 decades of the 20th century, when medical research first postulated a relationship between focal primary infections in the ENT region and secondary diseases in other organ systems. Authors such as Hunter, Oph€ uls, and Lemierre Schubert et al.: Lemierre’s Syndrome Revisited
TABLE I. Patient Overview: Patient Characteristics, Primary Site of Infection, Isolated Microbe, Details of the Antibiotic Therapy, Additional Therapy Such as Surgery and/or Anticoagulation, and Duration of Hospital Stay.
Patient
Age/Sex
Primary Site of Infection
Germ
Antibiotics (type)
Antibiotics (days)
Surgery
Anticoagulation (months)
Hospital Stay (days)
1
56/female
Dental extraction
Unknown
AMC, MTZ
12
2
0
3
2
20/female
Tonsillitis
Fusobacterium necrophorum
CLR, FEP, NET, MTZ, CLI, TZP, PEN
31
2
1
26
3
38/male
Tonsillitis
Fusobacterium necrophorum
CLR, AMC, CLI
66
1*
0.15
40
4
32/female
Peritonsillar abscess
Bacteroides species, Pseudomonas aeruginosa
AMC, TZP CLI, CIP
30
1*
3.5
24
5
57/female
Peritonsillar abscess
TZP, RIF, AMC
45
1
7
32
6
42/female
Pharyngitis
AMC, VAN
37
1
3
21
7
18/male
Pharyngitis
Streptococcus milleri, Peptostreptococcus species Group A beta-hemolytic streptococcus Streptococcus milleri, Fusobacterium necrophorum
No follow-up
min. 6
8
29/female
Pharyngitis
0
15
9
68/female
Retropharyngeal Group C beta-hemolytic abscess streptococcus
No follow-up
min. 25
10 11
79/male 13/male
12
66/female
13
71/male
14
No 2 follow-up
CRO, MTZ, AMC, CLI
43
FEP, PEN, AMC
2
No 1 follow-up
Streptococcus milleri AMC, MTZ MEM, CLI, Group A beta-hemolytic CRO, AMX streptococcus, Staphylococcus aureus AMC, CRO Mixed anaerobic flora, coagulase-negative staphylococci
42 14
1 2
6 6
16 15
22
1
3
31
Necrotizing external otitis
Pseudomonas aeruginosa
FEP, CIP
59
1
Lifelong
37
7/female
Otitis media
Group A beta-hemolytic streptococcus
MEM, AMX
17
1
2.5
17
15
79/male
Otitis media
Group A beta-hemolytic streptococcus
CRO, AMX
31
1
Lifelong
min. 14
16
40/male
Mastoiditis
Streptococcus milleri
29
1
24
18
17
11/female
Mastoiditis
Unknown
CRO, AMX, VAN, MEM FLU, CRO, MTZ, AMC
52
1
6.5
16
18
6/male
Mastoiditis
Streptococcus pneumoniae, Corynebacterium sp.
AMX
30
1
7.5
23
19
49/female
Mastoiditis
Group A beta-hemolytic streptococcus, Staphylococcus aureus
PEN
42
1
Lifelong
52
Fusobacterium necrophorum
CRO, AMX, VAN, MEM, MTZ, CLI
39
1
8
27
Unknown Fusobacterium nucleatum, coagulase-negative staphylococci Group A beta-hemolytic streptococcus, Staphylococcus aureus
AMC, MXF MEM, AMC, CIP, CAZ, FEP
32 42
2 1*
6.5 No follow-up
14 63
AMC
21
1
0.15
15
20
Sinusitis Sinusitis
Fusobacterium necrophorum
CRO, MTZ
Periorbital abscess
7 months/female Mastoiditis
21 22
58/male 63/male
Mastoiditis Mastoiditis
23
7/male
Gradenigo Syndrome
*Ligation of the internal jugular vein. AMC 5 amoxicillin/clavulanate; AMX 5 amoxicillin; CIP 5 ciprofloxacin; CLR 5 clarithromycin; CRO 5 ceftriaxone; FEP 5 cefepime; MEM 5 meropenem; MTZ 5 metronidazole, RIF 5 rifampicin; TZP 5 piperacillin/tazobactam; VAN 5 vancomycin; min. 5 minimum.
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Fig. 1. Microbiological data found in intraoperative swabs or in blood cultures. dark grey 5 aerobic; gray 5 facultative aerobic; light gray 5 anaerobic.
supported this pathophysiologic model, which incited important preventive surgical activity in ENT and dentistry over the decades.3,6,7 The introduction of antibiotics after World War II made the focal infection theory more and more obsolete from medical and scientific discussion. A remnant is the ongoing discussion concerning whether arteriosclerosis is related to chronic oral infections.8 In fact, there has never been a formal case definition for Lemierre’s syndrome. Propositions from Sinave in 1989 and Riordan in 2007 limited Lemierre’s syndrome to a oropharyngeal origin of infection.9,10 Looking at Lemierre’s original work, he describes Fusobacterium necrophorum-driven septicemias with primary ENT infections (oropharynx, middle ear, oral cavity) resulting
in STIJV and producing metastatic emboli to the lungs and the periphery.3 Absolutely respecting the work of the aforementioned authors, our clinical study focuses on the STIJV with or without cranial extension independently from microbiological status. Lemierre described peripheral but not cerebral complications of the STIJV, although he mentioned the occurrence of septic sinus vein thrombosis secondary to ear and mastoid infections. In our study, 11 patients had the primary infection site in the middle ear. Of these, 10 patients had superficial cranial thrombosis presenting with general clinical signs of sepsis 1 to 2 weeks after onset of the infection. One patient with combined superficial and deep cranial septic thrombosis already presented 2 days after the beginning of primary infection with specific central nervous symptoms due to radiologically confirmed cerebellar infarction. These two different clinical time patterns between superficial as well as superficial and deep septic thrombophlebitis may explain why Lemierre did not describe clinical signs of cerebral complications. Today, imaging techniques such as CT scans and MRIs are the harbingers of the correct but often accidental diagnosis of septic thrombophlebitis, which urges the clinician to look for peripheral septic emboli. Computed tomography and/or MRI of the primary ENT infection site should always include the neck. In the event of confirmed and/or suspected thrombophlebitis, the lung and cerebrum must be included in the examination. The fast communication of results from the radiologist to the clinician is crucial to launch effective therapeutic measures. Lemierre did not believe in ligation of the internal jugular vein as a therapeutic option, as proposed by his German colleagues at the time. Three of our patients who underwent ligation showed a good clinical outcome after an initially difficult disease evolution. The procedure seems to be indicated in the presence of persistent
TABLE II. Intensive Care Data of Patients: Indication for Intensive Care, Requirement of Intubation and Its Duration, Requirement of Vasoactive Medication or Reanimation, and Length of Stay in the ICU. Patient
Indication
Intubation (days)
Vasoactives
ICU Stay (days)
2
Respiratory failure
16
yes
17
3
Septic shock
3
yes
4
4 5
Respiratory failure Postoperative monitoring
1 no
no no
3 4
9
Respiratory failure
14
yes
21
11 12
Cardiovascular instability Neurological deterioration/meningismus
no 1
yes no
2 2
14
Neurological monitoring after mastoidectomy
no
no
2
15 16
Venous sinus thrombosis with mastoiditis 1. venous cerebellar infarction; 2. after craniotomy
no no
no no
2 (5 1 3) 8
18
Neurological monitoring after mastoidectomy
1
no
3
19 20
Neurological deterioration Neurological deterioration
no no
no no
3 5
22
Neurological deterioration
1
yes
4
ICU 5 intensive care unit.
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Schubert et al.: Lemierre’s Syndrome Revisited
sepsis under high-dose antibiotics. The veterinary literature describes ligation of the thrombophlebitic internal jugular vein as a straightforward, efficient, and costeffective procedure in horses.11 Antibiotics eventually associated with surgery stop and eradicate the infection. Over almost 80 years, the microbiological profile fortunately has not changed, which allows for an effective treatment by classical broad-spectrum antibiotics without substantial resistance. The early administration of antibiotics seems to be crucial for successful treatment. The wide choice of antibiotics is correlated with actual ICU antibiotic guidelines before obtaining the microbiological results. Once the microbe is confirmed by microbiology, therapy may be switched to cost-effective and targeted antibiotics. Antibiotics have also cured patients with persistent thrombosis. There are no data to support the idea that recanalization of the internal jugular vein provides an advantage and lowers morbidity and mortality. Microbiological data from this study identified the Streptococcus family and not Fusobacterium necrophorum as the most frequent microbe in STIJV (Fig. 1). This result contrasts the results from Lemierre’s study but highlights an old discussion in which Fischer and K€orner presented the streptococcus family as the main microbe in STIJV.12–14 The Fusobacterium necrophorum bias introduced by Lemierre incited a series of publications identifying STIJV as almost pathognomonic sign of Fusobacterium necrophorum infection.9,15–22 However, our study clearly shows that STIJV can be caused by a multitude of microbes, a circumstance recently noted by Syed et al.23 Furthermore, compared to other microbes found in our patient group, Fusobacterium necrophorum infection showed no distinctive differences in diagnosis, therapy, and prognosis. Due to the intact sensitivity of implicated microbes to broadband antibiotics as well as the time delay to obtain the microbe diagnosis, microbiology lost its diagnosis leadership position to radiology over the past few decades. The diagnostic power and routine use of modern imaging may explain the continuous increase in literature reports of Lemierre’s syndrome in the past decades.24 Anticoagulation is recommended in the literature. Evidence seems to be low for extracranial STIJV because of the still-maintained central venous blood flow, except in the presence of classical thrombosis risk factors.25 The presence of thrombophilia with elevated factor VIII and antiphospholipid antibodies is an absolute indication for therapeutic anticoagulation.26 For cranial venous thrombophlebitis, the literature indicates 3 to 12 months of intravenous, subcutaneous, and/or oral anticoagulation due to the risk of complete blockage of the superficial and deep cranial venous system.27 All patients with an otologic primary infection site (48%) showed intracranial and extracranial septic thrombosis, whereas extracranial primary ENT infection sites led to strictly extracranial thromboses. The phenomenon that extracranial primary site infections were never associated with intracranial thrombosis may be explained by the venous valvular system inhibiting venous reflux or by anticoagulation therapy initiated Laryngoscope 00: Month 2014
early after onset of the disease. At the end of the anticoagulation treatment, a full hemostasis examination is recommended to identify eventual risk factors, which make life-long anticoagulation necessary.27 Our data give no evidence that anticoagulation could be contraindicated in STIJV due to extension of the infection, as cited by Hagelskjaer et al.21 In the follow-up of STIJV regarding anticoagulation and antibiotic therapy, different imaging modalities compete with anticoagulation guidelines and laboratory and clinical inflammatory parameters. The use of ultrasound to follow up deep vein thrombosis in the lower extremities to determine duration of anticoagulation is controversially discussed in the literature.28,29 Therefore, it might be safer to follow clinical anticoagulation guidelines in STIJV.25–27 The duration of antibiotic therapy is not related to the presence of the thrombus, but guided by laboratory and clinical inflammatory parameters.10 Suspected intracranial pathologies associated with STIJV are best assessed with MRI. The analysis of the clinical data in our series showed an ICU stay for 61% of patients, an intubation rate of 30%, and an ARDS rate of 9% in all patients. These findings and the good clinical outcomes of our patients stress the importance of the availability of ICU care for the successful treatment of Lemierre’s syndrome. Patients suspected of having STIJV should be transferred to an institution with an ICU for further treatment. In an epidemiological study with 24 patients all affected by Fusobacterium necrophorum-induced Lemierre’s syndrome of the ENT region, Hagelskjaer et al. reported similar results with no mortality and no posttreatment morbidity.21 We confirmed their finding that the oropharynx primary infection site implied a more severe clinical evolution, characterized by prolonged ICU stay duration and higher emboli frequency, than the other primary infection sites. Furthermore, Hagelskjaer showed that Lemierre’s syndrome with primary infection sites caudal to the neck region and with concomitant diseases such as cancer had a worse prognosis, with a mortality of 24%.21 Almost 80 years after Lemierre’s publication, this infectious cascade may again gain importance by antibiotic prescription guidance, eventually leaving falsely, negatively diagnosed putrid-ENT infections untreated in significant numbers.2,24,30 Simple laboratory tests such as C-reactive protein and peripheral white cell count, as well as the consequent application of clinical skills to correctly diagnose and treat primary dental and ENT infections, are the best options to avoid Lemierre’s syndrome and at the same time to protect the imaging and antibiotic resources of our stressed healthcare systems.31
CONCLUSION Over the past 80 years, the diagnosis and therapy for Lemierre’s syndrome have been fundamentally improved with a highly effective reduction in the morbidity and mortality. Modern imaging techniques, antibiotics, and ICUs are the tools needed to avoid the Schubert et al.: Lemierre’s Syndrome Revisited
5
disastrous spontaneous evolution of the disease. The Lemierre’s syndrome of the 21st century remains a unique pathophysiological model of intravenous systemic spread of acute ENT infections, eventually resulting in metastatic embolic disease. The primary infection site includes the whole ENT region; the microbiology shows a wide range with a preponderance of streptococci, fusobacterium, and staphylococci—all still sensitive to broadspectrum antibiotics. The systemic infection may overactivate hemostasis and cause cranial and/or extracranial thrombosis. Although extracranial STIJV and cranial superficial septic thrombosis remain clinically silent and are followed by general septic signs after 7 to 10 days, the combined thrombosis of the superficial and deep cranial venous system already presents with specific neurologic signs 36 to 48 hours after the onset of the infection. Confronted with the serious clinical consequences of cranial thrombosis, anticoagulation is recommended in all cases of septic thrombosis of the ENT region.
BIBLIOGRAPHY 1. Glasscock ME, Shambaugh GE, Johnson GD. Surgery of the Ear. Philadelphia, PA: Saunders; 1990. 2. Syed MI, Baring D, Addidle M, Murray C, Adams C. Lemierre syndrome: two cases and a review. Laryngoscope. 2007;117:1605–1610. 3. Lemierre A. On certain septicaemias due to anaerobic organisms. Lancet 1936; 227:701–703. 4. O’Brien WT Sr, Lattin GE Jr, Thompson AK. Lemierre syndrome: an allbut-forgotten disease. AJR Am J Roentgenol 2006;187:W324. 5. Moore-Gillon J, Lee TH, Eykyn SJ, Phillips I. Necrobacillosis: a forgotten disease. Br Med J (Clin Res Ed) 1984;288:1526–1527. 6. Ophuls W. Arteriosclerosis and cardiovascular disease: their relation to infectious diseases. JAMA 1921;76:2. 7. Hunter W. The coming of age of oral sepsis. Br Med J 1921;1:859. 8. Sinanoglu H. Association Between Peridontitis and Coronary Heart Disease. Marburg, Germany: Philipps-University Marburg; 2010. 9. Sinave CP, Hardy GJ, Fardy PW. The Lemierre syndrome: suppurative thrombophlebitis of the internal jugular vein secondary to oropharyngeal infection. Medicine (Baltimore) 1989;68:85–94.
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10. Riordan T. Human infection with Fusobacterium necrophorum (Necrobacillosis), with a focus on Lemierre’s syndrome. Clin Microbiol Rev 2007; 20:622–659. 11. Russell TM, Kearney C, Pollock PJ. Surgical treatment of septic jugular thrombophlebitis in nine horses. Vet Surg 2010;39:627–630. 12. Schottmuller H. Ueber den angeblichen Zusammenhang zwischen Infektionen der Zahne und Allgemeinerkrankungen. Dtsch Med Wochenschr 1922;48: 181–182. 13. Fischer MH. Relation of mouth infection to systemic disease. Cincinnati,OH: Lancet-Clinic; August 7, 1915. 14. Korner O. Die otitischen Erkrankungen des Hirns, der Hirnhaute und der Blutleiter. Wiesbaden, Germany: Bergmann; 1908. 15. Alston JM. Necrobacillosis in Great Britain. Br Med J 1955;2:1524–1528. 16. Felner JM, Dowell VR Jr. "Bacteroides" bacteremia. Am J Med 1971;50: 787–796. 17. Henry S, DeMaria A Jr, McCabe WR. Bacteremia due to Fusobacterium species. Am J Med 1983;75:225–231. 18. Moreno S, Garcia Altozano J, Pinilla B, et al. Lemierre’s disease: postanginal bacteremia and pulmonary involvement caused by Fusobacterium necrophorum. Rev Infect Dis 1989;11:319–324. 19. Eykyn SJ. Necrobacillosis. Scand J Infect Dis Suppl 1989;62:41–46. 20. Leugers CM, Clover R. Lemierre syndrome: postanginal sepsis. J Am Board Fam Pract 1995;8:384–391. 21. Hagelskjaer LH, Prag J, Malczynski J, Kristensen JH. Incidence and clinical epidemiology of necrobacillosis, including Lemierre’s syndrome, in Denmark 1990–1995. Eur J Clin Microbiol Infect Dis 1998;17:561–565. 22. Golpe R, Marin B, Alonso M. Lemierre’s syndrome (necrobacillosis). Postgrad Med J 1999;75:141–144. 23. Syed MI, Baring D, Murray C. In reference to Lemierre’s Syndrome: a systematic review. Laryngoscope 2010;120:215. 24. Karkos PD, Asrani S, Karkos CD, et al. Lemierre’s syndrome: a systematic review. Laryngoscope 2009;119:1552–1559. 25. Bondy P, Grant T. Lemierre’s syndrome: what are the roles for anticoagulation and long-term antibiotic therapy? Ann Otol Rhinol Laryngol 2008;117:679–683. 26. Grunt S, Wingeier K, Wehrli E, et al. Cerebral sinus venous thrombosis in Swiss children. Dev Med Child Neurol 2010;52:1145–1150. 27. Einhaupl K, Stam J, Bousser MG, et al. EFNS guideline on the treatment of cerebral venous and sinus thrombosis in adult patients. Eur J Neurol 2010;17:1229–1235. 28. Meissner MH. Duplex follow-up of patients with DVT: does it have clinical significance? Semin Vasc Surg 2001;14:215–221. 29. Prandoni P, Prins MH, Lensing AW. Residual thrombosis on ultrasound to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med 2009;150:577–585. 30. Thompson PL, Spyridis N, Sharland M, et al. Changes in clinical indications for community antibiotic prescribing for children in the UK from 1996 to 2006: will the new NICE prescribing guidance on upper respiratory tract infections just be ignored? Arch Dis Child 2009;94:337–340. 31. Jones JW, Riordan T, Morgan MS. Investigation of postanginal sepsis and Lemierre’s syndrome in the South West Peninsula. Commun Dis Public Health 2001;4:278–281.
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