Multiple cortical brain abscesses due to Listeria monocytogenes in an immunocompetent patient

Abstract

Listeria monocytogenes is an intracellular organism which is well recognised for its ability to cause meningeal infections in neonates, immunosuppressed, debilitated and elderly individuals.¹ Other less common central nervous system (CNS) infections caused by Listeria spp. include rhomboencephalitis, cerebritis and abscesses in the brain, brain stem and spinal cord. The neuroradiological appearance of Listeria brain abscesses is similar to other types and may also mimic primary or metastatic brain tumours.^2,3 We report a case of Listeria brain abscesses in a patient who was being treated for atypical parkinsonism. A good clinical outcome was achieved after appropriate antimicrobial therapy.

Keywords

Listeria monocytogenes multiple brain abscesses Listeria brain abscess

Case Report

A 52-year-old woman, previously diagnosed with systemic hypertension and an extrapyramidal syndrome, presented with a one-week history of headache and gradual diminution of vision. She had been taking levodopa-carbidopa 400 mg/day in divided doses for an extrapyramidal syndrome and losartan 50 mg/day for hypertension over the previous two years. There had been a poor response to treatment and she had been referred for evaluation of autoimmune causes of atypical parkinsonism. Her headache started as a mild, holocranial, continuous, non-throbbing pain with no aggravating or relieving factors. This was associated with painless, progressive, diminution of vision in both eyes. At the time of admission, she could only make out fingers at a close distance. She had one seizural episode on the day of admission with clenching of teeth, frothing followed by tonic-clonic movements of all four limbs which lasted for 2–3 min, followed by post-ictal confusion and drowsiness. She did not give any past history of seizures, auras, limb weakness or bowel and bladder incontinence, and was not allergic to any medication. On examination, she was afebrile, had a normal pulse rate (72 beats/min) and blood pressure (140/90 mmHg). She was conscious, oriented and cooperative. She had a mildly impaired attention span with hypophonia. Her vision was markedly impaired in both eyes but with intact perception of light rays. Other cranial nerves were functioning normally. There was cog wheel rigidity in all four limbs, which were accentuated on the left side. Intentional tremors were seen in both upper limbs, more towards the left. Her tandem walking was impaired, with bradykinesia and postural instability, as well as oral dyskinesia.

Laboratory investigations revealed an elevated white blood cell count (13,200 cells/mm³) and C-reactive protein (292 mg/L). A magnetic resonance imaging (MRI) brain scan showed multiple ring-enhancing lesions in the right frontal, left parietal and bilateral occipital lobes (Figure 1). Intravenous ceftriaxone was commenced and the seizures were managed by intravenous fosphenytoin 150 mg/min. To track the primary source of brain abscess, cerebrospinal fluid (CSF) and blood cultures were ordered. Abdominal and transoesophageal echocardio ultrasonography were normal. After one week of antibiotic therapy, the MRI was repeated, showing an increase in lesion size. After consultation with neurosurgical specialists, a conservative management was decided upon by the patient’s relatives and so meropenem and linezolid were started along with amphotericin B intravenously to provide empirical cover for Gram-positive, Gram-negative and fungal aetiologies, respectively. In the meantime, blood cultures grew a Gram-positive bacilli which was sensitive to penicillin, gentamicin, linezolid, vancomycin, cotrimoxazole and resistant to cephalosporins. A provisional diagnosis of Listeria spp. was made and the isolate was sent for further work-up to a reference centre where the further tests were performed. Investigations for HIV in blood and CSF were negative; a PET scan was likewise normal.

Figure 1.

MRI of the brain showing multiple abscesses.

The organism was identified as Listeria monocytogenes by standard biochemical tests. The genomic DNA of the isolate was extracted using QIAamp DNA mini kit (Qiagen) as per the manufacturer’s protocol. DNA were stored at −20℃ for further use. Polymerase chain reaction (PCR)-based serogrouping of the isolates were performed by using the method developed by Doumith et al.⁴ The primers used for the PCR based serogrouping and in vitro pathogenicity were synthesized from Integrated DNA Technologies, USA (Table 1). The reaction mixture of 50 µl was prepared using 2× ready PCR master mix (Thermo Scientific), 10 nM of each primer (lmo0737, ORF2110, ORF2819 and prs) and 50 ng of template DNA. PCR products were held at 4℃ until gel electrophoresis.

Table 1.

Primers used for serogrouping and pathogenicity studies.

Primer	Sequence
For serogrouping
lmo0737	F- 5′ AGG GCT TCA AGG ACT TAC CC 3′
	R - 5′ ACG ATT TCT GCT TGC CAT TC 3′
ORF 2819	F - 5′ AGC AAA ATG CCA AAA CTC GT 3′
	R - 5′ CAT CAC TAA AGC CTC CCA TTG 3′
ORF2110	F- 5′ AGT GGA CAA TTG ATT GGT GAA 3′
	R- 5′ CAT CCA TCC CTT ACT TTG GAC 3′
PRS	F - 5′ GCT GAA GAG ATT GCG AAA GAA G 3′
	R - 5′ CAA AGA AAC CTT GGA TTT GCG G 3′
For virulence
plcA	F- 5′ CTG CTT GAG CGT TCA TGT CTC ATC CCC C 3′
	R- 5′ CAT GGG TTT CAC TCT CCT TCT AC 3′
prfA	F 5′ CTG TTG GAG CTC TTC TTG GTG AAG CAA TCG 3′
	R 5′ AGC AAC CTC GGT ACC ATA TAC TAA CTC 3′
iap	F- 5’ACA AGC TGC ACC TGT TGC AG 3′
	R- TGA CAG CGT GTG TAG TAG CA 3′
hlyA	F 5′ GCA GTT GCA AGC GCT TTG GAG TGA 3′
	R 5′ GCA ACG TAT CCT CCA GAGTGA TCG 3′
actA	F 5′ CGC CGC GGA AAT TAA AAA AAG A 3′
	R 5′ ACG AAG GAA ACC GGG CTG CTA G 3′

In vitro pathogenecity of the isolates was determined by PCR-based technique for the detection of virulence genes hlyA, actA, plcA, iap and prfA. A total of 10 nM of each primer (hlyA, actA, plcA, iapA) and 50 ng of template DNA was used. Electrophoresis was carried out using 7 µL of product which separated on 1.5% agarose gel, stained with Ethidium Bromide (0.5 mg/mL) (Figure 2a, b). Oral cotrimoxazole was given in view of difficult venous access and the patient’s refusal of a central line. A repeat MRI scan showed significant reduction in abscess size and the appearance of no new lesions. Our patient was discharged on oral antibiotics; a final MRI scan after three months showed significant reduction in the size of the ring-enhancing lesions. The risk of recurrence was explained to the patient along with detailed instructions regarding when to seek medical care.

Figure 2.

(a) PCR results. (b) In vitro pathogenicity.

Discussion

CNS Listeriosis is a rare entity with reported incidence of 7.4–16 cases per population of 1 million.⁵ Classically, it affects immunocompromised individuals and individuals in extremes of age. The organism invades the CNS by crossing the blood–brain or blood–choroid barriers within leucocytes, by direct invasion of endothelial cells by extracellular blood-borne bacteria or by retrograde migration into the brain within the axons of cranial nerves.^6,7 We could not elicit any history indicating a foodborne listeriosis in our case. By contrast, an association between ingestion of contaminated food and neurological symptoms is difficult to make because symptoms of CNS listeriosis may occur one month after exposure to the pathogen.⁸ Most Listeria monocytogenes infections reach the CNS via the gastrointestinal route. Meningitis ensues owing to the attachment of the organism to the epithelial cells of the choroid plexus. Abscess formation results from penetration of the brain parenchyma through the cerebral capillary endothelium via the middle cerebral artery.⁹ Consequently, as seen in our case, bacteraemia is a finding in the majority (86%) of Listeria brain abscesses.¹⁰ However, only 11% of brain abscesses due to other bacterial causes have positive blood cultures.¹⁰

Listeria monocytogenes has 13 serotypes that cause human disease. However, 90% of human disease is attributed to only three serotypes: 1/2a,1/2b and 4b.¹¹ The isolate in our case belonged to serotype 4b, which is responsible for 33–50% of sporadic human cases.¹¹ Most invasive outbreaks of listeriosis are attributed to this serotype, which has been established as the serotype of the highest invasion efficiency.¹² The clinical picture seen in this case can be attributed to the pathogenic potential of serotype 4b. Additionally, our isolate was positive for four virulence genes. Listeriolysin O is a major virulence factor of Listeria which is a haemolytic cytotoxin that promotes the intracellular survival of this organism. This is encoded by the hlyA gene which was seen in the isolate from the described case also. This gene is positively regulated by the transcriptional activator, prfA (positive regulating factor A). Mutations in prfA can lead to loss of listeriolysin production.¹³ Other virulence genes like iap (invasion associated protein), plcA (which encodes phosphatidylinositol phospholipase C) and actA (surface actin polymerization protein) were also detected from the isolated strain.¹⁴ Thus, this isolate contained the virulence genes cluster found in the Listeria pathogenicity island-1 which is essential for the intracellular survival of the bacteria.

The treatment of choice for Listeria brain abscesses consists of a combination of ampicillin (for a minimum of one month) and gentamicin (for two to four weeks). Trimethoprim-sulfamethoxazole can be used as a reasonable alternative in penicillin allergic individuals.^15,16 Mortality rates are high, ranging from 40% with single abscess to 44% in multiple abscesses.¹⁷ Despite these gloomy figures, our case demonstrates that early institution of appropriate antimicrobial therapy can result in good clinical outcomes without surgical intervention. Furthermore, the diagnosis of Listeriosis is impossible without microbiological confirmation. Therefore, it is imperative that samples for microbiological diagnosis should always be sent, keeping in mind the inability of empiric therapy to cover all causes of brain abscesses.

Footnotes

Acknowledgements

The authors thank Dr. Sudheeran Kannoth, Professor, Neurology, Amrita Institute of Medical Sciences; Dr. Shamsul Karim, Professor, Microbiology, Amrita Institute of Medical Sciences and Dr. Sukhdeo B Barbuddhe, Principal Scientist, National Institute of Biotic Stress Management, Raipur for the clinical and microbiological support rendered.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Government of India for DBT sponsored the project ‘Translational Centre for Molecular Epidemiology of Listeria monocytogenes (TransLis)’ (grant no. BT/01/CEIB/11/VI/13).

References

Disson

Lecuit

. Targeting of the central nervous system by Listeria monocytogenes. Virulence 2012; 3: 213–221.

Gellin

Broome

. Listeriosis. JAMA 1989; 261: 1313–1320.

Workman

Theal

. Rhomboencephalitis caused by Listeria monocytogenes. Can J Infect Dis 1997; 8: 113–116.

Doumith

Buchrieser

Glaser

et al.

Differentiation of the major Listeria monocytogenes serovars by multiplex PCR. J Clin Microbiol 2004; 42: 3819–3822.

Jubelt

Mihai

et al.

Rhombencephalitis—brainstem encephalitis. Curr Neurol Neurosci Rep 2011; 11: 543–552.

Drevets

Leenen

PJM

Greenfield

. Invasion of the central nervous system by intracellular bacteria. Clin Microbiol Rev 2004; 17: 323–347.

Drevets

Bronze

. Listeria monocytogenes: epidemiology, human disease, and mechanisms of brain invasion. FEMS Immunol Med Microbiol 2008; 53: 151–165.

Bart

. Listeria and atypical presentations of listeria in the central nervous system. Semin Neurol 2000; 20: 361–373.

Soares-Fernandes

Beleza

Cerqueira

et al.

Simultaneous supratentorial and brainstem abscesses due to Listeria monocytogenes. J Neuroradiol 2008; 35: 173–176.

10.

Eckburg

Montoya

Vosti

. Brain abscess due to Listeria monocytogenes: five cases and a review of the literature. Medicine (Baltimore) 2001; 80: 223–235.

11.

Ward

Gorski

Borucki

et al.

Intraspecific phylogeny and lineage group identification based on the prfA Virulence Gene Cluster of Listeria monocytogenes. J Bacteriol 2004; 186: 4994–5002.

12.

Wałecka-Zacharska

Kosek-Paszkowska

Bania

et al.

Salt stress-induced invasiveness of major Listeria monocytogenes serotypes. Lett Appl Microbiol 2013; 56: 216–221.

13.

Leimeister-Wächter

Domann

Chakraborty

. The expression of virulence genes in Listeria monocytogenes is thermoregulated. J Bacteriol 1992; 174: 947–952.

14.

Osman

Zolnikov

Ahmed

et al.

Prevalence, pathogenic capability, virulence genes, biofilm formation,and antibiotic resistance of Listeria in goat and sheep milk confirms need of hygienic milking conditions. Pathog Glob Health 2014; 108: 21–29.

15.

Michelet

Leib

Bentue-Ferrer

et al.

Comparative efficacies of antibiotics in a rat model of meningoencephalitis due to Listeria monocytogenes. Antimicrob Agents Chemother 1999; 43: 1651–1656.

16.

Moellering

Medoff

Leech

et al.

Antibiotic synergism against Listeria monocytogenes. Antimicrob Agents Chemother 1972; 1: 30–34.

17.

Goulet

Hebert

Hedberg

et al.

Incidence of listeriosis and related mortality among groups at risk of acquiring listeriosis. Clin Infect Dis 2012; 54: 652–660.