Lemierre's Syndrome Caused by Streptococcus milleri Group

Abstract

A 64-year-old woman was transported to the emergency room with a headache and fever. She presented with a right ocular protrusion, hyperemia, and tenderness in the neck. Contrast-enhanced MRI of the head showed a high DWI signal in the bilateral sphenoid sinuses and contrast defects along the bilateral internal jugular and superior ophthalmic veins. Blood and CSF cultures revealed Streptococcus milleri group. Surgery was performed for Lemierre's syndrome secondary to sphenoid sinusitis. The patient was treated with antibiotics and anticoagulant therapy, but a duodenal ulcer and brain abscess thereafter developed. However, multidisciplinary endoscopic and surgical treatment saved her life.

Introduction

Lemierre's syndrome, first described in 1936, was named after Lemierre, who reported 20 cases of bacteremia caused by anaerobic bacteria after a sore throat, accompanied by internal jugular vein thrombosis and multiple abscesses in other organs. It is an infectious syndrome caused by Fusobacterium spp. Although Fusobacterium is often identified as the causative organism, cases caused by Streptococcus species have also been reported (1). We herein report a case of Lemierre's syndrome involving sinusitis caused by Streptococcus milleri group.

Case Report

On February X, a 64-year-old woman noticed a throbbing headache involving the right temple. On day X+3, her headache worsened and her appetite decreased. On day X+5, she visited family physician A, who prescribed acetaminophen, naratriptan, and sumatriptan, and the patient returned home. On day X+8, she noticed swelling in her right eye and visited ophthalmologist B. She had a high right intraocular pressure and was prescribed acetazolamide, potassium _l-aspartate, and latanoprost eye drops. On day X+9, she developed fever, and despite oral administration of acetaminophen, the symptoms did not subside. On day X+10, she visited a fever outpatient clinic, tested negative for coronavirus disease 2019 (COVID-19) antigen, and was prescribed loxoprofen. The patient was administered loxoprofen as directed and her condition was carefully observed, but when her symptoms did not improve, she requested an ambulance and was transported to our hospital. Her medical history included hypertension, diabetes, and dyslipidemia. Her regular medications included telmisartan 40 mg/day, pitavastatin calcium 1 mg/day, canagliflozin 100 mg/day, acetaminophen 1,500 mg/day, loxoprofen 180 mg/day, rebamipide 300 mg/day, naratriptan 2.5 mg/day headache, sumatriptan 50 mg/day headache, acetazolamide 500 mg/day, potassium _l-aspartate 600 mg/day, and latanoprost ophthalmic solution 0.005% once daily in the right eye. She had no allergies, and no history of either smoking or alcohol consumption. She had received the COVID-19 vaccine twice. She had no history of trauma.

Diabetes is an immunosuppressed disease. The patient was 160 cm tall and weighed 64 kilograms. Consciousness was Glasgow coma scale (GCS) 14 E4V4M6, body temperature was 36.8°C, blood pressure was 173/149 mmHg, pulse was 89 beats/min, respiratory rate was 24 beats/min, and SpO₂ was 94% (ambient air). No anemia was noted in the palpebral conjunctiva. Hyperemia in the right bulbar conjunctiva, protrusion of the right eyeball, and neck stiffness were also observed. There was no redness or warmth on either side of the neck; however, tenderness was noted. Breath and heart sounds were within the normal limits. The abdomen was flat, soft, and non-tender, and the intestinal peristaltic sounds were good. No Kernig's sign, leg edema, eruptions, or tenderness of the joints were noted. Blood tests revealed leukocytosis and high C-reactive protein and procalcitonin levels. Cerebrospinal fluid examination revealed an increase in multinuclear cells (Table 1). Cranial contrast-enhanced magnetic resonance imaging (MRI) revealed bilateral internal jugular vein thrombosis (Fig. 1a), epidural abscess (Fig. 1b), abscess in the bilateral masticatory muscle space (Fig. 1c), sphenoid sinusitis (Fig. 1d), bilateral superior ocular vein thrombosis (Fig. 1e), and right parotid gland abscess (Fig. 1f). We diagnosed sphenoid sinusitis accompanied by Lemierre's syndrome, purulent superior ocular vein thrombosis, epidural empyema, and a parotid gland abscess. The patient had GCS14 and hoarseness at the time of treatment, suggesting concomitant meningoencephalitis. Cerebrospinal fluid examination revealed an increase in the number of cells, predominantly polynuclear cells, and bacterial meningitis was diagnosed. Antibiotic therapy with meropenem (MEPM) and vancomycin (VCM) was prescribed. Dexamethasone (DEX) was also prescribed for pneumococci. Considering the possibility of fungal sinusitis caused by Aspergillus or Mucor owing to an extensive invasion of the tissues around the sinuses, liposomal amphotericin B (L-AMB) was used in combination. Continuous intravenous infusion of unfractionated heparin (UFH) was administered for bilateral internal jugular vein thrombosis and bilateral superior ocular vein thrombosis. On day X+11, otolaryngology was requested, and endoscopic sinus surgery was performed. White pus was found in the right sphenoid sinus, and a white mass of less than 1 cm was found in the left sphenoid sinus. A pathological examination revealed hyphae branching with a septum from the white mass, suggesting Aspergillus infection (Fig. 2). Because serum Aspergillus antigen and β-D-glucan were negative and no fungi were detected in the blood or cerebrospinal fluid cultures, we diagnosed a local fungal infection of the paranasal sinuses, and the administration of L-AMB was discontinued. Organisms of the Streptococcus milleri group were detected in blood and cerebrospinal fluid cultures. On day X+12, anemia and black stool were observed and the continuous intravenous infusion of UFH was discontinued. Upper gastrointestinal endoscopy was performed, and hemostasis was achieved as a rough mucous membrane with a small amount of blood was found to adhere to the descending duodenum. On day X+21, the fever resolved. Thereafter, the headache persisted. When no black stool or melena was confirmed, UFH was resumed on day X+23. On day X+24, the cerebrospinal fluid was clear and colorless, initial pressure of 19.5 cmH₂O, cell count of 39 /μL, polygonal cells of 6 /μL, mononuclear cells of 33 /μL, protein level of 67 mg/dL, and sugar level of 56 mg/dL. On day X+25, the protrusion of the right eyeball disappeared. A brain abscess was found in the right temporal lobe on contrast-enhanced MRI on day X+38 of the follow-up. Because it was thought to be the cause of the dull headache, the administration of UFH was discontinued (Fig. 3). On day X+45, we requested a neurosurgeon to perform craniotomy for brain abscess removal and drainage. The causative bacteria could not be identified by culturing. As the causative bacterium could not be identified by culture, abscess formation was observed after the administration of antibiotics; MEPM and VCM were combined from day X+46. On day X+68, the headache resolved. On day X+76, contrast-enhanced MRI of the head revealed bilateral internal jugular vein thrombosis, an epidural abscess, an abscess in the bilateral masticatory muscle space, bilateral superior ocular vein thrombosis, and the disappearance of the right parotid gland abscess (Fig. 4). Cerebrospinal fluid normalization was also observed. The cerebrospinal fluid was found to be clear and colorless, with an initial pressure of 14.5 cmH₂O, cell count 2 /μL, polygonal cells 0 /μL, mononuclear cells 2 /μL, protein 19 mg/dL, and sugar 58 mg/dL. Therefore, the antibiotic administration was discontinued. On day X+78, the patient was discharged (Fig. 5).

Table 1.

Laboratory Findings. Blood Leukocytosis and High CRP and PCT Levels Were Observed. Multinuclear Cell-predominant Proliferation was Observed in the Cerebrospinal Fluid.

Hematology

CK

218

IU/L

Coagulation

WBC

32,900

/mm3

UA

5.1

mg/dL

PT

15.3

s

Neut

89.6

%

Ca

9.1

mg/dL

APTT

35

s

Lym

4.1

%

IP

3.1

mg/dL

D-dimer

2

μg/mL

Mon

5.8

%

Na

138

mEq/L

FDP

15.4

μg/mL

Eos

0

%

K

3.1

mEq/L

D-dimer

4.7

μg/mL

Bas

0.5

%

Cl

105

mEq/L

Fib

960

mg/dL

RBC

479×104

/μL

Glu

161

mg/dL

Hb

14.9

g/dL

HbA1c

6.7

%

Infection

Plt

24.5×104

/μL

Cryptoco ccus Ag

(-)

Serology

Aspergillus Ag

(-)

Biochemistry

CRP

35.8

mg/dL

β-D-Glucan

10.3

AST

34

IU/L

PCT

5.63

ng/mL

HIV-1,2Ab

(-)

ALT

31

IU/L

T-SPOT

(-)

LDH

405

IU/L

TP

6

g/dL

Alb

2.3

BUN

41

mg/dL

Cr

0.72

mg/dL

Blood gas

Cerebral fluid

Urinalysis

pH

7.446

Appearance

Colorless and transparent

Protein

(-)

PaCO2

25.3

mmHg

Pressure

21

cmH2O

Glucose

2,000

mg/dL

PaO2

71.3

mmHg

Cell count

32

/μL

Ketone

3+

HCO3-

17

mmol/L

poly

19

/μL

Ocult blood

(-)

cLac

1.2

mmol/L

mono

13

/μL

Glucose

74

mg/dL

Protein

48

mg/dL

HSV PCR

(-)

VZV PCR

(-)

Figure 1.

The imaging conditions were DWI in the upper row and 3D-SPGR in the lower row. Fluid retention and mucosal thickening with a high DWI signal were observed in the sphenoid sinus, extending into the cavernous sinuses on both sides (d, white arrow). High-intensity DWI and poorly enhanced areas were found along the medial side of the middle cranial fossa, suggesting an epidural abscess (b, white arrow). An abscess was also found in the bilateral masticatory muscle space (c, white arrow) and medial side of the right pa- rotid gland (f, white arrow). High-intensity DWI and contrast-enhanced areas along the bilateral internal jugular veins were observed, and the lumen of the veins was poorly visualized. Intravenous thrombosis or abscess extension along the vein was suspected (a, white arrow). In the orbit, high DWI signals were observed along the bilateral superior ocular veins and contrast enhancement was poor, thus suggesting thrombotic occlusion (e, white arrow).

Figure 2.

The collected specimen was identified as a necrotic fungal mass. The outline of the hypha indicated branching with septa, suggesting the possibility of Aspergillus (white arrow).

Figure 3.

Imaging conditions were 3DSPGR. An abscess measuring approximately 2 cm in diameter appeared in the right temporal lobe, with extensive surrounding edema.

Figure 4.

Bilateral internal jugular vein thrombosis, an epidural abscess, an abscess in the bilateral masticatory muscle space, bilateral superior ocular vein thrombosis, and an right parotid gland abscess had disappeared.

Figure 5.

Treatment course from admission to discharge. WBC and CRP improved with treatment intervention.

Discussion

We herein report a case of Lemierre's syndrome with bilateral sphenoid sinusitis, internal jugular vein thrombosis, superior ocular vein thrombosis, an epidural abscess, parotid abscess, meningitis, and brain abscess.

In 1936, Lemierre reported 20 cases of bacteremia due to an anaerobic bacterial infection after a sore throat, accompanied by internal jugular vein thrombosis and multiple abscesses in other organs. At that time, Lemierre's syndrome was a fatal condition, with a mortality rate of 90%; however, with the eventual widespread use of antibiotics to treat pharyngitis, it has since become very rare (2). However, the number of reports of Lemierre's syndrome has increased since the 1990s, probably because of the decreased use of antibiotics to treat pharyngitis and tonsillitis, which are considered to be viral and mild conditions (3-8).

As a general pathogenic mechanism, pharyngeal infection spreads to the parapharyngeal space and carotid sheath, causing thrombophlebitis of the internal jugular vein, which spreads to the parotid gland and orbit (9). In this case, the inflammation spread from the sphenoid sinus and ethmoid sinus to the orbit, carotid sheath, and parotid gland, and thrombosis was thought to occur in the superior ocular and internal jugular veins. In terms of diagnostic criteria, some clinicians propose an anaerobic infection of the oropharynx, bacteremia, thrombophlebitis in the internal jugular vein, and at least one remote infection site. The prevalence of Lemierre's syndrome has declined markedly, and, as such, there are no established criteria. Most of the causative organisms are of the genus Fusobacterium, including F. necrophorum, but there have been reports of cases in which the S. milleri group of bacteria was found to be the causative organism, as in this case. Linares et al. compared 14 cases of Lemierre's syndrome (1). Compared to F. necrophorum, a common bacterium, the syndrome reportedly occurs more frequently in middle-aged to older individuals (median age of onset 49 years vs. 19 years, p=0.007, interquartile range 36-58 years). To the best of our knowledge, this is the 15th such reported case (Table 2) (10-22).

Table 2.

Fifteen Cases of Lemierre’s Syndrome Caused by Streptococcus milleri Group Bacteria.

Age		Sex		Nidus		Aetiology
64★		F		Sphenoid sinusitis		S. milleri
56		F		Parapharyngeal abscess (1)		S. constellatus, culture-negative anaerobe
70		F		Bezold’s abscess (15)		S. constellatus
89		M		Sphenoid sinusitis (16)		Staphylococcus intermedius, Staphylococcus warneri
50		F		Deep neck abscess (17)		S. constellatus
59		M		Oesophageal squamous cell ca (18)		Streptococcus anginosus
27		M		Parapharyngeal abscess (19)		Fusobacterium spp., S. milleri
76		M		Retropharyngeal abscess (20)		S. constellatus
45		M		Orbital abscess (21)		S. milleri
15		F		None (22)		Fusobacterium necrophorum, S. constellatus
51		F		None (23)		S. constellatus
48		M		Parapharyngeal abscess (24)		Fusobacterium necrophorum, Prevotella sp., S. constellatus
36		F		Tonsillitis (25)		S. milleri, Eikenella corrodens
36		M		Parapharyngeal abscess (26)		S. intermedius, Bacteroides fragilis
13		M		Frontal sinusitis/empyema (27)		Haemophilus influenzae type b, S. constellatus

The star mark is this case.

In this case, acute fungal sinusitis was suspected and antifungal drugs were administered. However, the present case was atypical in that it demonstrated an acute course in which a fungal mass was observed, and no exacerbation of symptoms due to Aspergillus was observed even after the antifungal drug was discontinued after surgery. A chronic course was observed in this case (23,24). In this case, bacterial sinusitis could have developed due to the presence of S. milleri group in the tissue weakened by chronic Aspergillus sinusitis.

However, whether anticoagulant therapy should be used for thrombophlebitis remains unclear. It is often used in combination to prevent and treat sinus thrombosis. Some clinicians believe that anticoagulant therapy should be performed only when symptoms do not improve within 48-72 hours after starting antibiotics or when thromboembolism progresses. According to Kobayashi et al., anticoagulant therapy was administered in 64% of the reported cases in Japan (25), and anticoagulant therapy was administered to 30% of the 124 patients reported by Karkos et al. (26). The concomitant use of anticoagulant therapy is not uncommon, and many successful cases have been reported without any side effects, such as bleeding. None of the articles on Lemierre's syndrome clearly indicate a relationship between anticoagulant therapy and mortality. Gore compared 394 cases of Lemierre's syndrome while focusing on the effects of anticoagulant therapy (27). The odds ratio for recanalization of anticoagulant therapy was 1.6 (95% confidence interval 0.3-9.4; p=0.6). The mortality rate was 0.6 (95% confidence interval 0.1-2.9; p=0.5). No significant difference was observed in either case, and antibiotic treatment (and, if necessary, surgical treatment) was therefore considered to be the standard treatment for this disease. The patient in the present case also developed a duodenal ulcer, and UFH may have had an effect. However, if UFH is to be used, it should be administered carefully, with careful attention paid to adverse events. Although no consensus has been reached regarding the use of UFH, if it is used, it may lead to an early improvement of symptoms due to the disappearance of the thrombus, as was observed in this case.

It is significant that we suspected a head and neck infection, central nervous system infection, or thrombosis based on the patient's symptoms and we were thus able to successfully diagnose and treat Lemierre's syndrome.

The authors state that they have no Conflict of Interest (COI).