Acta Neurochir (2014) 156:1971–1976 DOI 10.1007/s00701-014-2170-1


Brain abscess associated with patent foramen ovale Hirokazu Sadahiro & Sadahiro Nomura & Akinori Inamura & Akiko Yamane & Kazutaka Sugimoto & Yuichi Fujiyama & Michiyasu Suzuki

Received: 25 March 2014 / Accepted: 5 June 2014 / Published online: 1 July 2014 # Springer-Verlag Wien 2014

Abstract Background Brain abscesses can develop with Tetralogy of Fallot and pulmonary anterior venous fistula with large rightto-left shunt. However, some patients exhibit cryptogenic brain abscess (CBA) in the absence of any such congenital disease or other infections. Patent foramen ovale (PFO) is a very common disease that exhibits right-to-left shunt. This study reports the potential for concern between CBA and PFO. Methods We enrolled patients with CBA in our hospital between January 2003 and January 2013. Patients underwent transesophageal echocardiography (TEE) with contrast medium to investigate the presence of PFO. Results Seven patients were included. Four were females, and the mean age was 67.7±9.2 years. In all patients, TEE failed to reveal any new findings, however, six patients had PFO, and another patient had pulmonary arteriovenous shunt. Four patients had odontopathy. Conclusion In this study, all CBA patients exhibited right-toleft shunt. CBA might be caused by paradoxical embolization of a bacterial mass via PFO. Thus, more patients with CBA need to undergo TEE to detect PFO.


Keywords Brain abscess . Patent foramen ovale . Transesophageal echocardiography . Pulmonary anterior venous fistula . Odontopathy

Material and methods

H. Sadahiro (*) : S. Nomura : A. Inamura : A. Yamane : K. Sugimoto : Y. Fujiyama : M. Suzuki Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, Japan e-mail: [email protected]

Brain abscess is an uncommon but potentially fatal infectious disease. Brain abscess frequently occurs as a result of an otorhinolaryngological infection [12, 14, 29], or due to congenital disease manifesting with right-to-left shunt, such as Tetralogy of Fallot [12, 17] or pulmonary anterior venous fistula (pAVF) [18, 20, 27]. In some cases, however, the primary source of the brain abscess remains unknown, which is known as cryptogenic brain abscess (CBA). In patients with right-to-left shunt, the accumulation of a bacterial mass without trapping in the pulmonary microcirculation may embolize to the cerebral microcirculation to cause a brain abscess. We hypothesize that patent foramen ovale (PFO), which is a wellknown right-to-left shunt disease [7, 22, 24], may be one of the etiologies of brain abscess. Several reports have described the presentation of brain abscesses with PFO, but all were reports of one or two cases, and there have been no reports as to whether or not PFO exists for a series of patients with CBA. Herein, we investigate whether or not several CBA patients exhibited right-to-left shunt using transesophageal echocardiography (TEE).

From January 2003 to 2013 March, we retrospectively enrolled patients with CBA. TEE was performed to determine the existence of PFO using contrast medium. Patients were excluded if they exhibited an otorhinolaryngological infection, infectious endocarditic, congenital heart disease or a post-operative infection, and if they or their family did not agree to undergo TEE. All study protocols followed the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all patients. The study was approved by our institutional review board.

Rt. thalamus Small PFO n.p F 76 7

TTE transthoracic echocardiography, TEE transesophageal echocardiography, pAVF pulmonary arteriovenous fistula, PFO patent foramen ovale, EV Eustachian valve, GR good recovery, MD moderate disability

GR None None Drainage 28 days

MD GR None None Periodontal disease Extraction of tooth Drainage Drainage 7 days 13 days 80 61 5 6


n.p n.p

Large PFO Medium PFO

Rt. occipital Lt. orbita

Eikenella corrodens Streptococcus intermedius Not revealed Fusovacterium nucleatum Actionomyces meyeri Streptococcus intermedius Lt. frontal Large PFO n.p 62 4


Not revealed Rt. occipital Medium PFO n.p 76 3


Lt. parietal Large PFO+EV n.p 61 2



GR None Periodontal disease Drainage 29 days

MD None Periodontal disease Drainage 35 days

MD None None Drainage 34 days

None None None 21 days

ABPC/MCIPC CTX MEPM CTX ABPC/MCIPC CTX PAMP/BP CTX Streptococcus intermedius Pseudomonas putida Streptococcus intermedius Rt. frontal pAVF n.p 58 1


Odontopathy Surgery Duration of antibiotic therapy Antibiotic(s) Pathogenic bacteria Location TEE TTE Sex Age Case

We initially enrolled 17 patients with brain abscesses. Eight patients were excluded; three patients exhibited otorhinolaryngological infections, two patients had congenital heart disease, and three patients had post-operative infections. Of nine patients with CBA, two patients could not undergo TEE. One patient had a serious illness that was complicated by brainstem hemorrhage and led to immediate death, and autopsy was not performed. Another patient was an 86-year-old woman and, because of her advanced age, her family did not agree to providing informed consent. Ultimately, seven patients with CBA were included. The baseline characteristics of the seven patients with CBA are presented in Table 1. Four were females, and the mean age (±SD) was 67.7±9.2 years. Of all patients, TTE did not reveal any new findings, however, TEE demonstrated PFO in six patients (86 %) and pAVF in another (Fig. 1). One patient with PFO had a Eustachian valve. The patient with pAVF had no clinical symptoms of

Table 1 Clinical characteristics of seven patients with cryptogenic brain abscess


Immunosuppression or other factors

The following clinical data were collected: (1) age and gender, (2) transthoracic echocardiography (TTE) findings, (3) TEE findings, (4) location of the abscess, (5) pathogenic bacteria, (6) surgical or conservative treatment, (7) what antibiotics were administered and for how long, (8) presence of odontopathy, (9) immunosuppression or other predisposing factors, and (10) outcomes. Patients were fasted for 4 h prior to TEE examination using a Prosound α-7 system (Hitachi-Aloka Medical, Japan) with a 2–8 MHz wideband multiplane transducer. The patients remained conscious during the study. Lidocaine spray was administered above the pharynx, but no premedication was used for the Valsalva maneuver. The patients were placed in the left lateral decubitus position during probe insertion. The probe was slowly advanced to the esophagus. A careful survey of the entire left atria, left ventricle, and valves was performed to detect infective endocarditis and other cardiopathies. The left atrium debris was investigated during and after the Valsalva maneuver. Contrast medium, a mixture of 9 ml saline and 1 ml air, was then infused via the right brachial vein during the Valsalva maneuver. When the contrast medium filled the right atrium, the patient performed the Valsalva maneuver. We diagnosed the patient as having PFO as the observation of contrast medium distinct from the debris in the left atrium within three cardiac cycles, and diagnosed the patient as having pulmonary arteriovenous fistula as the observation of contrast medium in the left atrial after three cardiac cycles [5, 22, 37]. PFO size was determined as follows: 1–5 contrast bubbles represented a small PFO, 6–25 represented a medium PFO, and 26 or more represented a large PFO [32].


Acta Neurochir (2014) 156:1971–1976 Outcome


Acta Neurochir (2014) 156:1971–1976


Fig. 1 Magnetic resonance imaging (a, b, and c) and transesophageal echocardiography (d and e) of case 2. Enhanced T1-weighted imaging (a) showed the abscess with ring enhancement of the left parietal lobe, 27 mm in diameter. Fluid-attenuated inversion recovery (b) showed brain edema around the abscess, and diffusion-weighted imaging (c) showed a

high-intensity signal. Transesophageal echocardiography showed patent foramen ovale (d, white circle), and contrast medium leak from the right atrium (RA) to the left atrium (LA) (e, white arrows) after the Valsalva maneuver

pulmonary disease, and plain chest radiography and thoracic computed tomography (CT) did not reveal any findings. Bacterial cultures were not obtained for two patients because empirical antibiotic therapy was introduced at a previous hospital. Pathogenic bacteria were identified in five patients, and three were polymicrobic. Streptococcus intermedius was confirmed in four patients and all others exhibited normal oral bacteria. The duration of antibiotic therapy (±SD) was 23.9± 10.7 days. Drainage was performed in six patients, and another patient (case 1) was treated with antibiotics alone. In this patient, the abscess perforated to the ipsilateral ventricle, and lumbar puncture was performed to identify the pathogenic bacteria. Odontopathy was confirmed in four patients, and three patients had periodontal disease. There was no patent with immunosuppression. Four patients exhibited good recovery and three patients continued to exhibit moderate disease.

Discussion This study demonstrated that all patients with CBA exhibited right-to-left shunt, and six of seven patients (86 %) also exhibited PFO. To our knowledge, there have been 19 cases of brain abscess associated with PFO reported in the literature, including our own [1, 4, 9, 11, 16, 19, 21, 23, 25, 33, 35] (Table 2). These reports each include one or two cases, and this study is the first series report of brain abscess with PFO. In our analysis of 19 cases, almost all patients were from middle to elderly age, and the mean age (±SD) was 58.2±11.6. Thirteen patients (68 %) had odontopathy, and most of the pathogenic bacteria were Staphylococci species, Streptococcus species, and other indigenous oral bacterium. Tetralogy of Fallot [12, 17] and pulmonary anterior venous fistula (pAVF) [18, 20, 27] can cause brain abscess; the right-to-left shunt allows the bacterial mass to circumvent restriction by the pulmonary capillary vessels, thus contributing to cerebral embolization of the bacterial mass and


Acta Neurochir (2014) 156:1971–1976

Table 2 Literature reporting brain abscess associated with patent foramen ovale Author

Year Age Sex Source of infection

Kawamata, T.

2001 63 2001 36 2003 58


2006 2006 2006 2006

67 63 43 43


Stathopoulos, G.T. 2007 53 Chen, F.C. 2008 51 Keith-Rokosh, J. 2008 51


Ariyaratnam, S. Walsh, K. Horiuchi, Y.

2010 53 2011 53 2012 55


61 76 62


80 61




Friedlander, R.M. Doepp, F. LaBarbera, M. Khouzam, R.N.

Present cases


Pathogenic bacteria

Γ-Streptococcus ? Streptococcus milleri Haemophilus aphrophilus Perianal abscess Multiple Esherichia coli Dental filling Cerebellar vermis Streptococcus intermedius – Lt. cerebellum Streptococcus intermedius Poor oral hygiene Lt. parieto-occipital Coagulase-negative Staphylococci Streptococcus varidans Periodontal-gingival sepsis Lt. occipital Staphylococcus haemolyticus Vegetation over PFO Rt. temporal Staphylococcus aureus – Lt. parieto-occipital Methicillin-resistant Staphylococcus aureus Dental root canal surgery Multiple Aggregatibacter paraphrophilus Extraction of tooth Lt. parietal Streptococcus constellatus Poor dental hygiene Lt. frontal Prevotella intermedia Bacteroides fragilis Peptostreptococcus micros – Lt. parietal Streptococcus intermedius Periodontal disease Rt. occipital ? Periodontal disease Lt. frontal Eikenella corrodens Streptococcus intermedius Periodontal disease Rt. occipital ? Extraction of tooth Lt. orbita Fusovacterium nucleatum Actionomyces meyeri – Rt. thalamus Streptococcus intermedius

Pyorrhea alveolaris Periodontal disease Dental filling

Lt. thalamus Lt. occipital Rt. frontal

PFO closure Outcome – – –


– Done Done –

GR GR GR Death

– Done –

GR GR Death

– – –


– – –


– –



PFO patent foramen ovale, GR good recovery, MD moderate disability

formation of the brain abscess. Only bacillemia of the Streptococcus and Staphylococcus species do not cause brain abscess, as these bacteria are 0.5–1.5 μm in diameter [10, 36] and easily pass thorough the cerebral capillary vessels, which are 4–7 μm in diameter [6]. Intravenous flow of the bacterial mass is usually prevented by the pulmonary capillary vessels, which are 7– 10 μm in diameter [26]. However, right-to-left shunt can allow direct embolization to the brain. Polymicrobic infection has been identified in some patients with brain abscess [11, 16, 17, 23, 29], which is consistent with this hypothesis. In cases of brain abscess, 20–30 % are identified as CBA [28, 29]. Our study indicates that almost all patients with CBA had PFO. PFO is known to occur with a high prevalence; it is found in approximately one in four adults during autopsy [15]. While odontopathy is one of the predisposing factors of brain abscess [12, 29], it is not obvious how this can actually lead to the development of brain abscess. Transarterial infection from the oral cavity cannot be assumed, and intravenous infection causes bacillemia; however, with these processes, brain abscess would not occur. We hypothesize that intravenous invasion of the bacterial mass from the oral cavity via PFO causes brain abscess. Age was the strongest factor related to periodontal disease [13]. In our study, the mean age was 67.7 years, three

patients (43 %) had periodontal disease and all detecting pathogenic bacteria were normal oral bacteria. Humans with PFOinduced periodontal disease are at risk of brain abscess. Streptococcus intermedius, a member of the “Streptococcus anginosus”, is one of the most pathogenic bacteria of brain abscesses [2, 3]. S. intermedius possesses the ability to bind the extracellular matrix and produces a wide variety of hydrolytic enzymes that may cause brain abscess [30]. S. intermedius is located on various mucosal membranes, i.e., the oral cavity, genitourinary system, and gastrointestinal tract [34], and mucosal erosion brings about intravenous invasion of S. intermedius, which may lead to brain abscess via PFO. In our study, all CBA patients without odontopathy were due to S. intermedius. Transcatheter closure of PFO is one of the therapeutic approaches for patients with cryptogenic stroke [8, 31]. In some CBA patients with PFO, PFO closure was performed to prevent recurrence [4, 25]. In our study, none of the patients underwent PFO closure. However, CBA patients with PFO and periodontal disease are considered to be at risk of recurrent brain abscess. Therefore, we should consider the need for PFO closure in such patients. The current study has some limitations, including the small number of patients and the fact that it was a single-center

Acta Neurochir (2014) 156:1971–1976

study. Pathogenic bacteria were not found in some patients and it was not clear where the bacteria came from in some patients. Within these limitations, we conclude that all CBA patients had right-to-left shunt and almost all had PFO. PFO is one of the risk factors of brain abscess. CBA might be caused from paradoxical embolization of the bacterial mass via PFO. Thus, more patients with CBA need to undergo TEE to detect PFO.

Conflicts of interest None.

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Comment About half of all brain abscesses are considered to be of hematogenous origin. Consequently, echocardiography and pulmonary evaluation are routinely used to evaluate a possible source of the infection.

Acta Neurochir (2014) 156:1971–1976 Patent foramen ovale (PFO) has not been considered an important source of brain abscesses. It is a common condition (approximately 25 % of adults) and requires contrast TEE to be reliably detected. The authors have collected a series of seven cases of cryptogenic brain abscesses in which six of the patients exhibited a PFO on TEE. Four of the six patients also had dental disease. Similarly to the situation of cryptogenic stroke where the contribution of a PFO is still under debate, the authors have not proven a correlation, but have highlighted a possible etiological mechanism that has received little attention in the literature. Zvi Harry Rappaport Petah Tiqva, Israel

Brain abscess associated with patent foramen ovale.

Brain abscesses can develop with Tetralogy of Fallot and pulmonary anterior venous fistula with large right-to-left shunt. However, some patients exhi...
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