Pearls & Oy-sters: Diagnosis and Subtyping of Listeria Ventriculitis in an Immunocompetent Host

Discussion

L. monocytogenes is a Gram-positive, facultative anaerobic intracellular rod-shaped bacterium, classically described to exhibit tumbling motility on light microscopy.² There are 17 species of the genus Listeria,² of which L. monocytogenes most commonly infects humans. Listeria was recognized as a food-borne pathogen in the 1980s, and although outbreaks are rare, it causes significant morbidity and mortality in susceptible hosts.³

Demographically, our patient was a young woman without any of the traditional risk factors of neurolisteriosis.⁴ In immunocompetent young patients, listeriosis typically manifests as a febrile gastroenteritis consisting mainly of self-limited diarrhea. Susceptible hosts consist of 3 groups: (1) those with immunosuppression, such as patients on medications that suppress cell-mediated immunity; (2) those at the extremes of age, including neonates and adults greater than 50 years old; and (3) pregnant women. In these individuals, Listeria infection can result in bacteremia and CNS infection. Because our patient was young, previously healthy, not immunosuppressed, and not pregnant, her recent exposure history to potentially undercooked meats was initially overlooked and was discovered only after the diagnosis of Listeria infection.

Clinically, CNS Listeria most commonly manifests as meningitis and meningoencephalitis and less commonly as rhombencephalitis (focal brainstem infection) and brain abscess.⁵ Like other forms of bacterial meningitis, fever and altered mental status are the most common findings in CNS listeriosis. Although our patient exhibited signs of meningeal irritation, patients with Listeria meningitis often do not exhibit specific meningeal signs, unlike meningitis caused by other bacteria.⁴ Ventriculitis, more commonly seen in postneurosurgery patients such as those with ventricular indwelling devices, may occur as a rare complication of meningitis. One case of Listeria ventriculitis has been reported in a 78-year-old immunocompetent patient⁶ and other cases in pediatric patients or neonates. However, ventriculitis by itself is not specific or unique to neurolisteriosis; thus, our initial empiric antibiotic coverage consisted of IV vancomycin and a third-generation cephalosporin,^7,8 which does not cover Listeria. Because of the emergent nature of this patient's progression in the ED, it would not be unreasonable to broaden her antibiotic coverage to include Listeria. Given her normal fundoscopic examination and absence of specific signs at presentation, elevated intracranial pressure (ICP) was initially not suspected. Once florid ventriculitis and elevated ICP were established, the priority became lowering of ICP through neurosurgical intervention while simultaneously addressing the underlying cause.⁹

Diagnosis of CNS listeriosis is typically performed using a combination of clinical, CSF, and MRI findings and confirmed using blood or CSF culture or PCR. Pleocytosis in the CSF indicates CNS inflammation and may be seen in a variety of infectious or autoimmune conditions.¹⁰ Our patient had a severe neutrophil-predominant pleocytosis suggestive of bacterial or early viral meningitis. However, it should be noted that pleocytosis may be absent in 1%–12% of bacterial meningitis cases, and neutrophil predominance has poor discriminatory power for bacterial vs viral meningitis.¹⁰ CSF glucose is related to the degree of pleocytosis¹⁰ and a CSF:serum glucose ratio <0.5, as seen in our patient, along with a CSF protein >1.5g/L and elevated CSF lactate dehydrogenase, is consistent with bacterial rather than viral meningitis. Of note, these classic CSF chemistry findings of bacterial meningitis (i.e., high protein, low glucose) are present in only 77% of cases of Listeria meningitis,¹¹ and Gram staining for Listeria misses about two-third of cases,^4,11 suggesting the need to have a relatively low threshold to treat at-risk patients who have an atypical presentation for bacterial meningitis.

Treatment for Listeria meningitis is ampicillin or penicillin G, or alternatively trimethoprim-sulfamethoxazole or meropenem, for at least 21 days.⁷ The addition of an aminoglycoside such as gentamicin may have a synergistic effect and could be considered, although the potential for renal failure limits its general use.⁸ In a large prospective study, adjunctive dexamethasone was associated with increased mortality in CNS listeriosis¹²; thus, it is no longer recommended. Despite the relatively available antibiotic therapies, globally neurolisteriosis remains highly morbid, with a mortality rate of around 30%.³ In our case, septic shock was the most likely cause of death.

The question remains as to why our patient, a healthy immunocompetent host, manifested with Listeria ventriculitis, whereas her friend was asymptomatic. Although genotyping Listeria subtypes is not typically performed in clinical practice because it has little implications for treatment or prognosis, we pursued genetic subtyping to further investigate pathogen factors that may contribute to the patient's presentation, which we briefly discuss below.

The mechanism by which Listeria infects the nervous system is unknown. One proposed mechanism involves hematogenous spread, whereby the bacteria invade intestinal mucosa and gain access to the bloodstream. From there, Listeria may use internalin (Inl) proteins InlA and InlB to interact with E-cadherins and Met proteins present on choroid plexus epithelial and brain endothelial cells to gain entry through the blood-brain barrier. An alternative hypothesis posits that bacterial cells are taken up by host phagocytes, escape from phagosomes using a pore-forming toxin listeriolysin O, and then move into the cell cytosol via actin assembly-inducing protein, thus gaining access to the CSF space through these phagocytes.^2,5

Phylogenetic studies have identified 4 evolutionary lineage of L. monocytogenes, of which isolates from lineages I (serotypes 1/2b, 3b, 4b, 4d, and 4e) and II (serotypes 1/2a, 1/2c, 3a, and 3c) are implicated in the majority of human outbreaks.¹³ In our genetic analysis using whole-genome sequencing and near-source species comparison, the 3 strains with the highest similarity to the patient's isolate are lineage II serotypes (strain NH1, serotype 1/2c, similarity 0.978268; strain SLCC2479, serotype 3c, similarity 0.978242; strain 2018TE5305-1-4, serotype 1/2a, similarity 0.978107). Animal studies suggest that lineage I serotypes exhibit greater virulence, possibly because lineage II serotypes overexpress truncated InlA proteins,¹⁴ whereas lineage II serotypes exhibit greater genomic plasticity.¹⁵ One might hypothesize that lineage II subtypes of Listeria may have a higher propensity for CNS invasion in otherwise healthy adults, such as in our case, although more systematic studies are needed to elucidate the mechanism.