Lemierre’s disease: a typical presentation in two diabetic patients

INTRODUCTION

Lemierre disease (LD) or postanginal syndrome, was initially reported by Courmont and Cade in 1900 and best described by French microbiologist Andre Lemierre in 1936, hence the name.^1,2 Typically, the disease is of young immunocompetent persons in the age group 15-25 years. The condition carried high morbidity and mortality due to metastatic systemic infection, lung being the most typical site. With introduction of antibiotics, the overall mortality has decreased to less than 2%.^1,3 In recent times many cases of LD have been reported in the middle aged and elderly group of patients.^4-6

The possible causes include increase in comorbidities such as diabetes, use of immunosuppressive drugs and prevalence of drug resistance bacteria.⁷

In this article, we present two such interesting cases of LD in diabetic patients with atypical presentations with a review of the literature. In one such case, clivus involvement with lower cranial nerve paralysis and mass nasopharynx mimicked nasopharyngeal malignancy. Clival osteomyelitis has rarely been reported in the LD. The delayed presentation posed a diagnostic and therapeutic challenge.

CASE REPORT

Case 1

A 64-year-old male diabetic (type II NIDDM), and hypertensive presented to the ENT outpatient clinic with gradually increasing history of throat pain, fever, odynophagia and right otalgia of two weeks duration. He had no past history of recurrent sore throat. On clinical examination, he looked dehydrated, febrile; (38.50 ⁰C), blood pressure of 160/90 and pulse rate of 80/minute. On examination, he had mild trismus, right tonsil congested and pushed medially with supratonsillar bulge. He was diagnosed as right peritonsillar abscess. Neck examination revealed small tender jugulodigastric lymph node on right side (level II). Ear examination revealed normal ear canal and tympanic membrane. Rest of examination was normal. His random blood sugar (RBS) recorded as 17.2 mmol/L. Incision and drainage of abscess was performed and pus swab sent for culture and sensitivity. He was treated with IV fluids, intravenous amoxiclav 1.2 gm thrice daily, analgesics and chlorhexidine mouth gargle. Blood sugar controlled with insulin injection-isophane (N)-30 IU split doses to control his blood sugar. He was started on antihypertensive medication lisinopril 10 mg OD. Blood investigations revealed leukocytosis WBC 17,900 cells/µL (4-11), Hb-11.9 g/L, with neutrophil-83%, lymphocytes-12%, monocytes-2% and atypical lymphocytes 3%. Peripheral smear showed neutrophilic leukocytosis with leukocytes showing toxic granulations. Renal function showed Na-138.8 mmol/L (137-148), K-4.49 mmol/L (3.6-5), chloride-97.3 (101-111), urea 8.5 mmol/L (2.5-7.5) and serum creatinine 70.28 umol/L (60-120). Urine examination was negative for ketone bodies. hemoglobin A1C-9.8 reflecting poor glycemic control. Pus culture sensitivity revealed moderate growth of Klebsiella pneumonae sensitive to gentamycin, amoxiclav, cephradine, ceftazidime.

He showed progressive clinical improvement in next 24-48 hours with the resolution of trismus and local findings. He was continued on intravenous amoxiclav for 5 days and discharged on oral amoxiclav for next seven days. He had complete resolution of signs and symptoms with no fever, neck pain/swelling. He was further advised further follow up with his primary care physician for diabetic management.

Two months later he was again referred for right otalgia, headache, pain right upper neck and tinnitus, heaviness in tongue and difficulty in swallowing liquids for 1 month. There was no history of fever, neck trauma, aspiration or symptoms suggestive of cerebrovascular accident. On clinical examination, he was conscious, fully oriented. Local ENT examination revealed tongue deviated to the right side (right XII paresis), absent gag reflex and absent right palatal movement (IX nerve involvement). Both tonsils looked healthy. Flexible fiberoptic examination revealed a bulge in the posterior wall of right-side nasopharynx with fullness and obliteration of right fossa of Rosenmuller. The nasopharyngeal mucosa looked intact with no ulcerative lesion. Clinically a suspicion of nasopharyngeal malignancy was made. Both true vocal folds were mobile and normal with no pooling of secretions in both pyriform fossae. Left ear examination was the normal. Right ear examination revealed wide canal, dull tympanic membrane which was suggestive of otitis media with effusion. Neck examination revealed generalized fullness and tenderness in right side level II and III with no definite lump palpable. Rest of cranial nerves were intact and normal.

He was initially suspected to have nasopharyngeal malignancy. High resolution CT scan (HTCT) of nasopharynx and neck revealed thrombosis of right internal jugular vein (IJV) and asymmetrical bulge in right nasopharynx with obliteration of fossa of Rosenmuller.

There was evidence of significant erosion of right side clivus with increased prevertebral soft tissue edema (Figure 3).

No cervical lymphadenopathy. MRI reported high signal intensity in T2W1 flair in right mastoid air cells (fluid) with obliteration of right fossa of Rosenmuller and right internal IJV, right parapharyngeal space and erosion of right side clivus. He underwent EUA of nasopharynx, biopsy and myringotomy grommet insertion right ear under general anesthesia. Histopathological examination of nasopharyngeal tissue revealed inflammatory tissue with no evidence of malignancy. ESR (112 mm/hr) and C-reactive protein (68 mg/L) were raised. Bone scan (Tc99 scintigraphy) and Gallium 67 scintigraphy also showed increased radiotracer uptake in right temporal bone. X-ray chest was normal. These findings confirmed the diagnosis of right skull base-clivus osteomyelitis with IX and XII cranial nerve involvement.

He was treated with triple antibiotics intravenously; ceftazidme (1 gm twice daily (33days) amikacin 500 mg twice daily (25 days) and tazocin (piperacillin and tazobactum) 4.5 gm thrice daily (33 days) and control of blood sugar with insulin. He was regularly monitored for nephrotoxicity and ototoxicity. Amikacin trough and peak serum level were also measured periodically. He was also treated with 24 sessions of hyperbaric oxygen therapy (HBOT).

He was discharged after 33 days of antimicrobial therapy and placed on oral ciprofloxacin 750 mg BID for next 12 weeks. At three month and one-year follow-up, he showed complete recovery of IX and XII cranial nerve paralysis. Gallium 67 scintigraphy was normal. Inflammatory markers, ESR reduced serially from 122, 118, 70, 49 to 16 mm/hr and CRP value from 68 mg/L to 2 mg/L.

Case 2

A 68 years old retired gentleman, diabetic and hypertensive on medications, was referred to ENT clinic from the emergency department with a history of headache, neck pain and fever for more than one-week duration. One day later, he complained of left-sided upper neck pain with no restriction of movements. The headache started over both temporal regions, more on the left side, severe and associated with nausea. He had no history of head injury or convulsions. No photophobia, phonophobia, or alteration of mental status, or vision abnormalities was recorded.

The patient also gave history of sore throat and runny nose two weeks before the present complaints which had resolved.

On examination, he was febrile (38°C), conscious and alert. Vitals were normal. The pharynx was mildly congested with neck tenderness over the left upper neck side behind angle of the mandible. There was no neck swelling.

Nasal endoscopy and fibro-optic laryngoscopy showed normal nasal mucosa with no discharge but congested pharyngeal mucosa. Blood count showed marked leukocytosis-WBC count of 21, 100 cells/µL (neutrophils of 19,100 cells/µL), C-reactive protein of 234 mg/L, and normal electrolytes. Chest X-ray was normal. Computed tomography (CT) brain and sinus revealed no evidence of intracranial pathology but reported incidental finding of opacification of right maxillary sinus with hyperdense shadow suggestive of fungal ball. The rest of sinuses were normal.

He was started on intravenous ceftriaxone for two days. With no significant improvement in headache and neck pain, subsequent CT neck with contrast revealed extensive thrombosis of left IJV, jugular bulb and sigmoid sinus, along with bilateral lymphadenopathy (Figure 4 and 5).

He was diagnosed as LD. After consultation with infectious diseases team, intravenous tazocin 4.3 gm, clindamycin 200 mg 8 hourly and anticoagulants including warfarin and low molecular weight heparin (LMWH) at dosage of 1mg/kg body weight was started. By the 4^th-day blood culture grew Hemophilus influenza, sensitive to ampicillin, thus tazocin was replaced by ampicillin 1 gm 6 hrly. He responded to treatment by 3^rd day with no more headache or neck pain and no fever. Intravenous amoxiclav continued for 2 weeks. He was carefully monitored for his general condition and any evidence of spread of disease and septic emboli. His chest remained normal both clinically and radiologically. He was discharged from hospital after two weeks and advised to continue oral amoxiclav 375 mg thrice daily for a total of 4 weeks. Warfarin was also continued for three months with monitoring of his INR and diabetic treatment at local health center. There was no evidence of systemic disease after three months of follow up. He was advised to undergo functional endoscopic sinus surgery (FESS) for right maxillary sinus lesion.

DISCUSSION

LD is characterized by septic thrombophlebitis of IJV commonly from the oropharyngeal source of infection often due to Fusobacterium necropharum.² Still, anaerobic septicemia can originate from other diverse sources such as gastrointestinal and genitourinary tract.⁹ The causative organisms in our cases were identified as Klebsiella pneumonae and Haemophilus influenzae, and the latter has not been reported so far in the LD.

In recent times many cases have been reported in the middle age and elderly individuals with pre-existing immunocompromised conditions such as diabetes mellitus, cancer etc.^5,6 The lung is considered to be the most common site of septic emboli followed by other organs such as liver, spleen, joints, heart and central nervous system.^10-17 Involvement of clivus and cranial nerves in LD is infrequent. In the review of the literature, we could find 8 reported cases (including our case) of clivus osteomyelitis in LD with varied neurological involvement (Table1).

Cranial nerve involvement with clivus osteomyelitis may not always be present. In only two instances, typical "clival syndrome" with VI, XII cranial nerve involvement has been reported.^18,19 In three cases, no lower cranial nerve involvement has been reported.^20-22 In contrast, isolated XII cranial nerve involvement is found in two patients.^23,24 However clival osteomyelitis has also been associated with extensive thrombosis of the cavernous sinus, transverse sinus including internal carotid and vertebral artery. Extension of disease into cavernous sinus thrombosis has been reported to be accompanied by higher intracranial complications such as meningitis, brain abscess and subdural empyema, possibly as a result of spread from the same primary focus of infection.²⁵

Our case of clival osteomyelitis with IX, XII cranial nerve involvement mimicking nasopharyngeal malignancy is a very unusual presentation in LD. The ipsilateral bulge in nasopharynx both clinically and radiologically with otitis media with effusion further raised suspicion of nasopharyngeal malignancy. The pathogenesis in our case is likely to be due to the retrograde spread of septic emboli through the IJV and spread of inflammation to parapharyngeal space, prevertebral soft tissue and skull base producing smooth bulge in nasopharynx and misinterpreted as nasopharyngeal malignancy initially. This was further compounded with involvement with lower cranial nerve IX and XII. However, nasopharyngeal examination and biopsy is essential to rule out malignancy.

The atypical and rare display of clival osteomyelitis with lower cranial nerves involvement IX and XII, sparing X and XI in the jugular foramen is also unusual. Osteomyelitis of clivus with the involvement of IX and XII cranial nerve should be considered as “clival syndrome” and a feature of LD. Similar atypical clinical presentation has also been reported in skull base osteomyelitis (SBO).²⁶ Our patient did not have any otogenic or sinugenic source of infection to explain the clival osteomyelitis.

This case was also unusual, as he did not have postanginal pyrexia during the first month and had complete clinical recovery after treatment of peritonsillar abscess drainage and antibiotics. However, he complained of persistent mild neck pain at a local hospital, which was probably missed. This is to highlight the importance of a high clinical index of suspicion of underlying internal jugular thrombophlebitis. Underlying diabetes also perhaps modified the clinical presentation.

The course of the disease varies. A high index of clinical suspicion, early diagnosis of IJV thrombophlebitis and management would perhaps help in the prevention of metastatic septic emboli/abscess. A high leukocytosis and raised CRP value, absence of any neurological signs, persistent pyrexia and tenderness over neck should further raise clinical suspicion of IJV thrombophlebitis. Our second case reflects the importance of the early diagnosis and appropriate management of the condition. Isolation of Haemophilus influenza in blood culture as a causative organism in LD was unusual in this case, extremely rare and not reported in the literature so far. Early diagnosis of the condition and appropriate antimicrobial therapy helped to prevent septic emboli and resolution of the disease. Riordan et al also emphasized the red flag symptoms of pyrexia, headache, unilateral neck pain/swelling along with sternocleidomastoid muscle indicative thrombosis of IJV in 26-45% cases before significant metastatic spread has occurred.¹⁷

The management of the condition is multidisciplinary. While giving antibiotic therapy, close observation for the signs of continued sepsis, propagation of thrombus and septic emboli is vital.²⁷ The role of anticoagulants is controversial and reserved for a select group of patients not responding to antibiotics or if there is a progression of the thrombus to cavernous sinus Moore et al reported addition of anticoagulants proved to be beneficial in clinical improvement in 11 out of 41 cases of extensive thrombosis of IJV in LD.^28-30 In our second case, anticoagulants were used effectively for extensive thrombosis of IJV and sigmoid sinus.

HBOT has been used successfully in treating the skull base osteomyelitis as an adjuvant to antimicrobial therapy.³¹ The beneficial effect of HBOT therapy is improvement of tissue oxygenation and amplification of oxygen gradient along the periphery of ischemic wounds created due to diabetic microangiopathy. This enhances the penetration of antimicrobial agent and phagocytic activity of macrophages, neovascularization and enhances wound healing.^32,33 In using HBOT with antimicrobials, we could treat clival osteomyelitis successfully with recovery of IX and XII cranial nerve weakness.

CONCLUSION

LD can occur in middle age though young adults are commonly affected.

Diabetes mellitus, a global health problem should be considered as a predisposing factor for LD in modern clinical practice. A high index of suspicion is needed by the clinician as primary oropharyngeal infection could have resolved by the time the patient presents. CT neck, with contrast, is confirmatory. Early diagnosis and appropriate antibiotics help to prevent the dissemination of septic emboli. clivus osteomyelitis with neurological complications secondary to septic thrombophlebitis poses a diagnostic and therapeutic challenge.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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