White thrombus as a possible feature of atypical stroke etiology: Coxiella burnetii as the primary cause of acute ischemic stroke

Abstract

Acute ischemic stroke (AIS) is the most common neurologic complication of infective endocarditis. We describe a singular case report of a 62- year-old male with AIS related to the occlusion of the left middle cerebral artery. Thrombus-aspiration allowed retrieving a 6 millimeters white thrombus. The real-time polymerase chain reaction performed on the thrombus detected Coxiella Burnetii allowed the diagnosis of infective endocarditis (IE) and the identification of the specific pathogen. Coxiella Burnetii is an endemic, small, intracellular, gram-negative coccobacillus and it is a rare cause of IE. The management of AIS caused by IE remains controversial, although in the cases of major occlusion mechanical thrombectomy is associated with better clinical outcomes. IE patients could not present symptoms and signs related to the infection, therefore we underline the importance of the microbiological analysis of the retrieved thrombi especially when atypical etiology is suspected.

Introduction

Acute ischemic stroke (AIS) is the most common neurologic complication of infective endocarditis (IE). ¹ Coxiella burnetii represents the responsible pathogen in 3 to 5% of all cases of endocarditis.^2,3 Herein we describe a peculiar case of AIS secondary to Coxiella burnetii related in whom the analysis of the retrieved thrombus allowed the precise definition of the etiology of the IE.

Case report

Acute phase management

A 62-year-old male, without relevant medical history, was admitted to a spoke hospital for the acute onset of right hemiparesis and global aphasia (baseline NIHSS 20). The emergency serological tests showed the alteration of the brain natriuretic peptide (BNP) and cardiac troponin values (respectively 2.5 and 15 folds higher than the reference values). Almost 80 minutes after the onset MRI was performed (Figure 1) showing an extended left middle cerebral artery (MCA) territory AIS (ASPECTS: 5) due to a carotid siphon occlusion. The clot was not visible in the gradient-echo sequence (Figure 1). Intravenous thrombolysis (Actilyse, Boehringer Ingelheim, Ingelheim, Germany) was administered 110 minutes after the onset of symptoms and the patient was secondarily transferred to our comprehensive stroke center for mechanical thrombectomy. Groin puncture was performed (onset-to-groin: 240 minutes) and the left carotid angiogram showed clot migration in the proximal M1-MCA (Figure 1). Collateral circulation was scored as intermediate (ASITN grade: 2). ⁴ Through a tri-axial system, a reperfusion catheter (ACE 68, Penumbra, Alameda, CA) was brought in contact with the clot in 10 minutes. At the moment of the withdrawal of the thrombus-aspiration system, the clot was found neither in the aspiration pump nor in the reperfusion catheter. However, resistance at the moment of the injection through the balloon occlusion catheter (BOC; MERCI 9 F, Stryker Neurovascular, Fremont, CA) had been remarked. For that reason, the BOC was removed but the clot was not found inside. Therefore, we removed the 9 F-femoral sheath and on its tip a 6 millimeters, white, elastic and “encapsulated” thrombus was retrieved (Figure 1). A control angiogram performed after contralateral groin puncture showed complete revascularization of the left ACM (TICI 3) (Figure 1). The thrombus was then collected and frozen according to the internal protocol of the institution.

Figure 1.

Baseline MRI: diffusion-weighted imaging sequence (a) showing the acute ischemic lesion in the left MCA territory, slightly visible in the FLAIR sequence (b); the Gradient-Echo sequence (c) did not reveal the presence of a left ICA terminus-MCA clot. Pre-treatment Digital Subtraction Angiography (DSA) showing a left proximal MCA occlusion (d, white arrow). Post mechanical thrombectomy DSA (e) documented the complete recanalization of the left MCA. The retrieved 6-millimeters white thrombus (f) was dissected showing its encapsulated aspect (g). The 24-hour follow-up MRI (h) showed the constituted ischemic core in the FLAIR sequence (h) without further extension of the ischemic area.

Post-procedural management

Two days after mechanical thrombectomy, a transesophageal echocardiography was performed showing the presence of 4 mm mitral vegetation and the blood cultures resulted negative. The patient remained clinically stable and the 24-hours Angio-MRI follow-up showed a patent left MCA, an aspect of laminar necrosis of the left superficial MCA territory, without further recent ischemic lesions in other territories, vascular anomalies or hemorrhagic evolution. The patient was retransferred to the referring spoke center with a triple empiric antibiotic therapy (i.e. Amoxicillin 2000 mg ×6/die, Cefazolin 2000 mg ×4/die and Gentamicin 240 mg/die). However, the finding of endocarditis on a native mitral valve with negative blood cultures immediately prompted further laboratory investigations. The serologic investigation highlighted the presence of an important increase of the anti-Coxiella burnetii IgG1 and IgG2 amount (> 16,000 mg/dl) associated with persistent Q-fever. ⁵ Simultaneously, real-time polymerase chain reaction (RT-PCR) analysis performed on the frozen thrombus revealed the presence of Coxiella burnetii. Under adapted therapeutic protocol (i.e. Doxycycline 100 mg ×2/die et Hydroxychloroquine 200 mg ×3/die), the patient was then addressed to a rehabilitative center. He was discharged with NIHSS 1 and after 3 months he was functionally independent (modified Rankin Scale 2). The antibiotic protocol was administered for 18 months.

Discussion

Q-fever is a zoonosis caused by a small, intracellular, gram-negative coccobacillus, the Coxiella burnetii, whose reservoirs are several animals, both domestic and wild. ⁵ Q-fever is endemic worldwide. Spain, France and Germany are the European countries with the higher amount of cases.^2,3 Endocardial involvement is the most frequently reported form of persistent Coxiella burnetii infection. ⁵ Pre-existing valvular disease is the main risk factor for the development of endocarditis with an estimated incidence of 39%. ⁵ The clinical presentation of Coxiella burnetii IE is nonspecific, AIS is the primary manifestation in almost 15%. ⁶ Although AIS management in IE remains controversial, in case of large vessel occlusions mechanical thrombectomy is associated with better clinical outcomes and lower risk of hemorrhagic infarction compared to IV thrombolysis and combined treatment.^1,7

However, the overall prognosis of stroke caused by IE is usually unfavorable if an early diagnosis is not made. ⁸ Septic embolization (SE) from IE is a rare case of AIS, nevertheless Fernandez et al. ⁸ observed that the incidence of SE was 6.2%, which may suggest that the rate of AIS secondary to SE could be underestimated. In our case, we were able to retrieve a 6 millimeters white thrombus. The atypical macroscopic aspect of the thrombus was suspected from the absence of the visualization of the clot in the gradient-echo sequence. ⁹ Recently, it has been discussed that white thrombi may be associated with atypical etiologies and in particular with IE. ¹⁰ The white macroscopic aspect may be related to a higher proportion of fibrin/platelet and white blood cells, despite the cardioembolic thrombi are more consistently formed by red blood cells. ¹¹ For that reason, in our case, the macroscopic characteristics suggested a possible atypical etiology, and the thrombus was subsequently analyzed allowing the detection of the Coxiella burnetii.

The clot analysis is rarely performed in the current clinical practice as reported in few case report^12,13 and in a recent systematic review ¹ that described the microbiological examination of the retrieved thrombi in only 28 patients after an extensive review of the literature. In particular, although IE patients may not present symptoms and signs related to the infection, these patients could benefit from the early diagnosis and reduce the morbidity and mortality rate. Despite IE is a rare clinical condition in AIS, particular attention should be paid to those patients with white retrieved clots, especially in younger patients as described previously. ¹²

Conclusion

To the best of our knowledge, this is the first reported case of Coxiella burnetii isolation in a retrieved thrombus in a patient with IE and AIS. This singular case report underlines the importance of the microbiological analysis of the retrieved thrombi especially when atypical etiology is suspected.