Downbeat Nystagmus as a Presenting Manifestation of Neurolisteriosis in a Pregnant Woman

ABSTRACT

Listeria monocytogenes has tropism towards two immunologically ”privileged” sites, the fetoplacental unit in pregnant women and the central nervous system (neurolisteriosis) in immunocompromised individuals. We report a case of neurolisteriosis in a previously asymptomatic pregnant woman from rural West Bengal, India, who presented with a subacute onset febrile illness with features of rhombencephalitis and a predominantly midline-cerebellopathy (slow and dysmetric saccades, florid downbeat nystagmus, horizontal nystagmus, and ataxia). With timely detection and the institution of prolonged intravenous antibiotic therapy, both the mother and the fetus were saved uneventfully.

Introduction

Listeria monocytogenes (LM), an uncommon human pathogen, is a highly opportunistic, Gram-positive, facultative intracellular bacterium.¹ The gastrointestinal tract serves as the natural route of infection following the ingestion of food contaminated with LM which crosses the blood-intestine barrier by active endocytosis mediated by epithelial cells.¹ Then, it disseminates through the enteric lymphatic system to the primary target organs, i.e., the liver and spleen.^1,2 In immunocompetent adults, cell-mediated immunity efficiently clears this infectious process; hence, the infection remains largely subclinical.³ However, invasive listeriosis tends to occur in certain groups with somewhat impaired cellular immune responses, i.e., those with immunosuppressive comorbidities or who are on long-term immunosuppressive treatments.⁴ In these immunocompromised patients, secondary invasive tropism may stem from inadequate resolution of the primary infection.⁴ Specifically, LM has tropism towards two immunologically ‘privileged’ sites, the fetoplacental unit in pregnant women, and the central nervous system (CNS) (neurolisteriosis) in immunocompromised individuals.^5,6

We herein report a case of neurolisteriosis in a previously asymptomatic pregnant woman who presented with a subacute onset febrile illness with features of rhombencephalitis and a predominantly midline-cerebellopathy. With timely detection and the institution of prolonged intravenous antibiotic therapy, both the mother and the fetus were saved uneventfully.

Informed consent statement

The patient provided written informed consent to the publication of this case report.

Case report

A 23-year-old previously healthy primigravida (period of gestation 25 weeks) from rural West Bengal, India presented with fever, headache, and unsteadiness of gait. The fever had been there for the previous 5–6 days, was high grade, continuous, with chills and rigours, with an average recorded temperature of 40.3 ºC. It was associated with a few initial episodes of vomiting and a non-localising holocranial headache. She also complained of severe dizziness and difficulty getting up from the bed and tended to sway from side to side and fall. She also had slurred speech and was finding it difficult to speak fluently. Her personal, menstrual, and addiction history were unremarkable. General examination was normal except for fever and tachycardia. Neurological examination revealed preserved cognitive abilities, normal motor and sensory systems, and no autonomic dysfunction. Cerebellar examination showed slow and dysmetric saccades, florid downbeat nystagmus (online supplement Video), horizontal nystagmus, and ataxia (truncal and gait ataxia more than appendicular ataxia). She also had ataxic speech. The clinical diagnosis was of an infective rhombencephalitis.

Initially, she was empirically put on intravenous ceftriaxone (4 g/day), vancomycin (1.5 g/day), acyclovir (1.5 g/day), and oral doxycycline (200 mg/day) and a single dose of intravenous dexamethasone (8 mg) as per the regional protocol for the management of acute meningoencephalitis syndromes.

A complete blood cell count revealed a neutrophilic leukocytosis (total leucocyte count was 18,000/μL, with 80% neutrophils; normal range [NR] 4000–11,000/μL) with a raised erythrocyte sedimentation rate (80 mm/hr; NR 0–22 mm/hr). Her C-reactive protein level was high (50 mg/L; NR < 10 mg/L ), and her serum sodium concentration was low (128 meq/L; NR 135–145 meq/L). Her liver, kidney, and thyroid function tests and coagulation profiles were within normal limits. Serological tests for malaria, dengue, Japanese encephalitis, scrub typhus, Lyme disease, leptospirosis, syphilis, hepatitis (A, B, C, E), and human immunodeficiency virus (HIV) (1,2) were negative. Magnetic resonance imaging of the brain revealed hyperintense lesions on T2-weighted and fluid-attenuated inversion recovery sequences in the midbrain, pons, medulla, cerebellar vermis, and bilateral cerebral hemispheres without any contrast enhancement, suggestive of rhombencephalitis with cerebellitis (Figure 1). A cerebrospinal fluid (CSF) study revealed a normal opening pressure, a high leukocyte count (400 cells/μL; 80% polymorphonuclear cells), a raised protein level (98 mg/dl; NR 15–45 mg/dL), but a normal glucose level; it was negative for relevant neuroviruses, cryptococcosis, tuberculosis, Tropheryma whipplei, neurosarcoidosis, or Borrelia burgdorferi. CSF and blood cultures, however, confirmed the presence of LM. Antibiotic sensitivity testing revealed excellent sensitivity to ceftriaxone; hence, it was continued for three weeks without any signs of the development of adverse events. The vancomycin, acyclovir, and doxycycline were stopped after 5 days (when the CSF culture confirmed the presence of neurolisteriosis). Her pregnancy parameters were strictly monitored; fortunately, no adverse pregnancy event occurred. She was discharged after 4 weeks of hospital stay in a haemodynamically and neurologically stable condition and returned for periodic follow-ups. At 2 months of follow-up she had no clinically demonstrable neurological deficits, and repeat neuroimaging revealed only residual lesions (Figure 2).

Figure 1.

Magnetic resonance imaging of the brain revealing non-enhancing hyper-intense lesions on fluid-attenuated inversion recovery images involving bilateral posterior limbs of the internal capsules (red arrows), the crus of the midbrain (brown arrows), the vermis, the dentate nuclei, and bilateral cerebellar hemispheres (yellow arrows), suggestive of rhombencephalitis.

Figure 2.

Convalescent magnetic resonance imaging of the brain revealing non-enhancing residual hyperintense lesions on fluid-attenuated inversion recovery images asymmetrically involving bilateral cerebellar hemispheres (yellow arrows).

Discussion

Listeriosis is a rare but extremely severe foodborne infection representing a public health concern and a challenge to food safety. In the host LM colonises the gastrointestinal tract, crosses the intestinal barrier, and disseminates through the blood to target organs.¹ In immunocompromised subjects, the elderly, and pregnant women, LM can cross the blood-brain and placental barriers, leading to invasive listeriosis.⁶ Invasive listeriosis is divided into three subtypes: bacteraemia; neurolisteriosis; and maternal-neonatal listeriosis. Localised forms are also reported.⁶ Risk factors for invasive listeriosis include age, innate and cellular immune defects, cancers, HIV infection, cirrhosis, diabetes mellitus, alcoholism, and immunosuppressive therapies.^7–10 Raw or unpasteurised milk-based food products pose a risk, even in immunocompetent children.⁹

CNS invasion by LM can cause meningoencephalitis and, rarely, ventriculitis and rhombencephalitis.⁶ Although neurolisteriosis most commonly affects individuals with known risk factors, CNS infection is possible in otherwise healthy young patients.¹¹ Neurolisteriosis is easily misdiagnosed, especially in healthy adults with atypical symptoms, and its mortality rate can be up to 50%.⁷ The median time between the initial symptoms and their detection is 7 days, with many patients having already developing cerebral abscesses by this time.⁸ Suspicion should be raised in patients with an exposure history who do not improve with empiric antibiotics.¹¹

Maternal-neonatal listeriosis is mostly reported during the second and third trimesters of pregnancy, as sporadic cases or in the context of outbreaks.⁵ Pregnancy-associated listeriosis can lead to devastating consequences to premature and newborn babies.⁵ Timely diagnosis and treatment should be performed in neonates.⁵ Early detection of LM-infected cases, particularly in the prenatal stage, remains a major challenge.⁵ Strains belonging to clonal complexes 1, 4, and 6, classified as hypervirulent clones, are mostly associated with maternal-neonatal listeriosis.⁵ Maternal-neonatal listeriosis is a direct consequence of LM-specific placental tropism, which is mediated by the conjugated action of two proteins of LM, the Internalins A and B, at the placental barrier.⁵ Other key virulence factors of LM, such as the actin assembly-inducing protein and the listeriolysin O, are also involved in LM replication in the placental and dissemination into fetal tissues in a non-specific manner, as is Internalin P.⁵ LM pathogenicity island 4 is also involved in placental and CNS infection by unknown mechanisms.¹⁰

Classic CSF findings of bacterial meningitis (i.e., high protein and low glucose levels) are present in only 77% of cases of LM meningitis, and Gram staining for LM misses approximately two-thirds of cases, indicating the need to have a relatively low threshold to treat at-risk patients who have an atypical presentation for bacterial meningitis. Neurolisteriosis is usually diagnosed when CSF cultures or a polymerase chain reaction are positive for LM.¹¹

Neurolisteriosis usually presents as a combination of non-specific neuroradiological features, such as meningeal enhancement, abscesses, or nodular changes evocative of abscesses, haemorrhage, contrast-enhancing ventricles, hydrocephalus, white-matter changes, dilated Virchow-Robin spaces, cerebral atrophy, and brainstem involvement (meningeal enhancement, abscesses).^12,13 Radiological signs of rhombencephalitis are infrequent, whereas haemorrhagic lesions are frequent.¹² Parenchymal lesions are associated with lower three-month survival.¹²

Unfortunately, the prognosis for listeriosis has not improved over the past decades. Listeriosis has been a notifiable disease since 1999, with mandatory notification of culture-confirmed cases and submission of isolates to the National Reference Center for Listeria. In the prospective Multicentric Observational National Study on LISteriosis and ListeriA (MONALISA),⁷ neurolisteriosis presented as meningoencephalitis in 212 (84%) out of 252 patients; brainstem involvement was present in 42 (17%) patients. Three-month mortality was higher for bacteraemia than for neurolisteriosis.⁷ Neurolisteriosis mortality was higher in blood-culture-positive patients or those receiving adjunctive dexamethasone.⁷

Treatments for neurolisteriosis are ampicillin, penicillin G, trimethoprim-sulfamethoxazole (cotrimoxazole) or meropenem for at least 21 days.¹⁴ Adding an aminoglycoside, such as gentamicin, may have a synergistic effect and can be considered. However, the potential adverse impact of renal failure limits its use.¹¹ Ampicillin is currently the drug of choice for treating listeriosis.¹⁴ In a large prospective study adjunctive dexamethasone was associated with increased mortality in neurolisteriosis; thus, it is no longer recommended.⁷

Our patient presented with downbeat nystagmus, a type of central positional nystagmus that is believed to reflect an abnormal integration of semicircular canal-related signals by the cerebellar nodulus, uvula, and tonsil, ultimately providing an erroneous estimation of the head tilt and eye position coordinates. The direction of the nystagmus is often downward in head-hanging or apogeotropic in lateral supine positions; combinations of both forms also occur.¹⁵ As far as we know, this is the first reported case of downbeat nystagmus as a presenting manifestation of neurolisteriosis. Table 1 shows all previous reported cases of neuro-ophthalmological presentations in neurolisteriosis.^16–23 Hence, downbeat nystagmus should be included in the list of presentations of neurolisteriosis to obtain a prompt diagnosis and rapid initiation of antibiotic therapy. In addition, our case also shows that multifaceted manifestations of neurolisteriosis may be subtle and misleading. Specifically, the CSF analysis in the present case revealed a predominance of neutrophils and not lymphocytes.

Table 1.

Previous cases of neuro-ophthalmological presentations in neurolisteriosis.

Author and Year	Sex	Age	Neuro-ophthalmological signs at admission	Neuroradiological findings	Clinical-radiological presentation	Treatment	Outcome
Ricard D, et al. (2008)16	Male	63 years	Parinaud's syndrome	Left peduncle abscess, which descended deep into the brain, reaching the internal capsule	Rhombencephalitis	Steroids	Right hemiparesis and left III cranial nerve palsy
Miranda González G, et al. (2009)17	Female	36 years	III cranial nerve palsy	Lesions in the posterior brainstem (floor of the fourth ventricle)		Not specified	Not specified
		40 years
		55 years
Pelegrín I, et al. (2014)18	Male	65 years	VI cranial nerve palsy	Hydrocephalus			Death (aspiration pneumonia after neurological recovery)
		34 years		Not specified		Dexamethasone	Good
	Female	48 years		Hydrocephalus			Death (hydrocephalus leading to a vegetative state)
	Male	59 years	III + VI cranial nerve palsies	Not specified		Not specified	III and VI cranial nerve palsies
	Female	74 years	VI cranial nerve palsy				VI cranial nerve palsy
		53 years					VI cranial nerve palsy plus hemiparesis
		84 years		Hydrocephalus		Dexamethasone	Death (hydrocephalus and intracerebral haemorrhage due to external ventricular drain)
Acewicz A, et al. (2017)19		52 years	III + VI cranial nerve palsies	Ischaemic lesions involving cerebral peduncles, thalami, internal capsules, and the left globus pallidus		Intravenous ampicillin	Death (sudden cardiac arrest)
Arslan F, et al. (2020)20	Not specified (two patients)		IV cranial nerve palsy	Not specified			One patient was favourable, and another one was unfavourable
	Not specified (23 patients)		Not specified nystagmus				21 patients were favourable, and two were unfavourable
Brisca G, et al. (2020)21	Male	11 months	VI cranial nerve palsy	Ventriculitis and severe decompensated communicating hydrocephalus	Rhombencephalitis	Ampicillin, gentamicin, levetiracetam, and a ventriculoperitoneal shunt	Resolution
Zhao Y, et al. (2021)22	Male	68 years	III + VI cranial nerve palsies and right-sided horizontal nystagmus	Previous lacunar cerebral infarction in the right frontal lobe, GQ1b antibody positivity and multiple intracranial haemorrhages in the brainstem and cerebellum	Rhombencephalitis	Immunoglobulin, meropenem, electrolyte correction therapy, and methylprednisolone	Resolution
Percuoco V, et al. (2022)23	Male	37 years	VI cranial nerve palsy	Multiple ring-enhancing lesions within the brainstem, radiologically consistent with abscesses	Listeria monocytogenes-induced brainstem abscesses	Surgical abscess drainage	Deterioration with progression to a severe sensorimotor tetraparesis, with bilateral loss of sensation. Brainstem-mediated deficits, including central hypoventilation syndrome, had greatly subsided, with the patient only requiring nightly continuous positive airway pressure. Up to the article publication, the patient could mobilise with a Zimmer frame.

Finally, this case highlights the importance of considering LM as a cause of meningoencephalitis in any patient showing signs of brainstem involvement, which should prompt specific LM treatment (e.g., ampicillin) until the microbiological results are returned, since LM is the most frequent infectious cause of rhombencephalitis and delay of diagnosis can have detrimental consequences for the patient.¹⁸ In our case, the diagnosis was delayed. Fortunately, she responded to cephalosporins (ceftriaxone). However, this is frequently not the case because LM usually shows intrinsic cephalosporin resistance.²⁴

Funding Statement

J. Benito-León is supported by the National Institutes of Health, Bethesda, MD, USA (NINDS #R01 NS39422), the European Commission (grant ICT-2011-287739, NeuroTREMOR), the Ministry of Economy and Competitiveness (grant RTC-2015-3967-1, NetMD—platform for the tracking of movement disorder), and the Spanish Health Research Agency (grant FIS PI12/01602 and grant FIS PI16/00451).

Author contributions

All authors contributed significantly to the creation of this manuscript; each fulfilled criteria as established by the ICMJE.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/01658107.2023.2186431.