CNS listeriosis …

Sudhir Kothari MD

Infectious Disorders

Updated 11.21.2023
Released 09.21.1998
Expires For CME 11.21.2026

CNS listeriosis

Author: Sudhir Kothari MD

See Contributor Disclosures

Editor: Christina M Marra MD

CNS listeriosis

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Introduction

Overview

Listeriosis is a rare but important disease, usually causing a mild self-limited gastroenteritis, but rarely an invasive dangerous bacteremia, meningitis, or meningoencephalitis. Pregnancy-associated listeriosis can be missed as a minor infection in the mother but can cause miscarriage or severe illness in the fetus or infant.

CNS listeriosis has the second highest case fatality rate amongst food-borne diseases. Almost one third of all patients die despite adequate therapy, and hardly one third survive unscathed.

It is very important to realize that this preventable and treatable disease is almost always acquired (99% of cases) by eating infected food (72).

This fascinating bacillus can tenaciously survive adverse environments, biding time for years in a dormant form like a saprophyte. When conditions are right, it can awaken, multiply rapidly, silently invade the host, and suddenly transform into a dangerous pathogen targeting infants and elderly, pregnant women, or sick and immunocompromised persons, with a particular affinity for the brain, causing meningitis, meningoencephalitis, or abscesses (80). It uses unique mechanisms to breach defenses, evade the immune system, reach the bloodstream, and travel backward to the brainstem via the vagus and trigeminal nerves.

Pregnancy by itself puts women at a very high risk of getting Listeria infection. A deceptively minor-looking febrile illness in the mother may target and severely affect the unborn or newborn baby (72). One must know about the uncommon Listeria rhombencephalitis, which presents as a benign-looking illness in healthy young adults. If it is missed at this early stage or there is a delay in diagnosis, it rapidly progresses to bulbar and respiratory paralysis, and often death.

Finally, it is important to remember that Listeria responds mainly to certain older antibiotics like penicillins, aminoglycosides, or trimethoprim-sulfamethoxazole. Most newer antibiotics, like cephalosporins, fail.

We can ignore Listeria only at our peril. I have been extremely lucky to escape an attack of Listeria rhombencephalitis.

Key points

	• CNS listeriosis is a rare but important disease with the second highest case-fatality rate amongst food-borne diseases.
	• Almost all cases are caused by eating contaminated food.
	• In most exposed persons, it only causes a self-limited gastroenteritis.
	• Persons at risk of invasive disease include the elderly and infants, immunocompromised persons, diabetics, and cancer patients.
	• One third with invasive disease die, and another one third have major disability. Hardly one third escape without any major disability.
	• Pregnant women are at very high risk of listeriosis. The illness in women is mild and looks like an innocuous flu-like illness, but it can seriously hurt or even kill the fetus.
	• Listeria has the unique ability to silently evade various defense mechanisms, cross barriers, and move intracellularly and within axons.
	• Rhombencephalitis is a deceptive but extremely dangerous form, often seen in healthy and young persons.
	• Those at high risk need to know particularly about food choices and food handling.
	• Risky foods include dairy products, fruits and vegetables, meat products, fish products, and even hospital foods.
	• A high index of suspicion and early treatment are the key to success.
	• The therapy of choice for CNS listeriosis is combination therapy. The first choice is a beta-lactam (ampicillin or benzylpenicillin), combined with gentamicin or with TMP-SMX. If beta-lactam is contraindicated, then one uses TMP-SMX plus gentamicin. Meropenem comes in only when both beta-lactams and gentamicin are contraindicated.
	• The duration of therapy in CNS listeriosis should be at least 3 to 4 weeks in immunocompetent and 6 to 8 weeks in immunosuppressed persons.
	• Studies suggest that steroids, when started with the antibiotics, are beneficial.

Historical note and terminology

Listeria monocytogenes has long been recognized as a veterinary pathogen causing basilar meningitis and stillbirth in sheep and cattle. It was first described as human pathogen in a patient with a mononucleosis-like syndrome in 1929 (89).

Meningitis due to L. monocytogenes was described in 1936, but the first authentic isolation came from a World War I soldier in 1918. His meningitis was attributed to a diphtheroid species. However, the original culture was preserved at the Pasteur Institute in Paris and was identified 20 years later as L. monocytogenes. This historical note provides an important reminder that L. monocytogenes is sometimes confused and dismissed as a diphtheroid contaminant because of morphological, colonial, and biochemical similarities. A 1949 German epidemic of “granulomatosis infantisepticum” led to the discovery that L. monocytogenes caused this severe neonatal infection (45). Brainstem encephalitis or rhombencephalitis due to Listeria was first described in 1957 (33). The first foodborne listeriosis outbreak was attributed to infected vegetables in a Boston Hospital in 1979 (38).

This gram-positive bacterium has been known by many names, including Listerella hepatolytica, Corynebacterium infantisepticum, Corynebacterium parvulum, and Erysipelothrix monocytogenes. In 1940, taxonomists reached a general agreement to call the species Listeria monocytogenes in honor of the father of antisepsis, Lord Lister (103).

Clinical manifestations

Presentation and course

	• In healthy persons, Listeria usually causes a self-limited gastroenteritis.
	• Listeriosis primarily affects pregnant women, newborns, older adults, and people with weakened immune systems.
	• The bacteremia in pregnant women is mild and mimics a simple urinary infection or a “flu.” If untreated, even this “minor” illness may lead to spontaneous abortion or dangerous neonatal infection.
	• Otherwise healthy pregnant women with Listeria do not get CNS involvement.
	• In other predisposed persons, Listeria causes a deadly invasive disease in the form of bacteremia, CNS invasion, or various focal infections.
	• CNS listeriosis can cause anything from a mild fever with some mental change to frank coma. Meningoencephalitis is more common than pure meningitis. Almost all have fever, and most have headache. Neck stiffness is seen in about two thirds of patients.
	• A small percentage (4%) of otherwise healthy and young persons can get the deceptive but extremely dangerous subtype affecting the brainstem called rhombencephalitis.
	• The key to successful treatment is suspecting and treating early.
	• Despite treatment, CNS listeriosis has a very high morbidity and mortality.

Listeria gastroenteritis. Healthy and immunocompetent children and adults tend to get a self-limited gastroenteritis with diarrhea, fever, and body aches, typically within 24 hours of ingesting contaminated food; it is self-limited with recovery within a couple of days due to a robust immune response. Diagnosis is usually presumptive in a person with gastroenteritis soon after exposure in a known Listeria outbreak (71; 37).

Invasive listeriosis. Invasive listeriosis can take the form of bacteremia, with subsequent CNS or various focal infections, including peritonitis, cholecystitis, hepatitis, pleuritis, splenic abscesses, pericarditis, osteomyelitis, endophthalmitis, and others. Most cases of invasive disease occur in immunocompromised people or the elderly or pregnant women. The average incubation period is 10 days (range: 0 to 21 days) (03). It is an insidious illness with a long incubation period. Symptoms are severe, and it often leaves behind significant sequelae (72).

In pregnant women, the bacteremia is much milder, tending to invade the placenta rather than the CNS or other organs. In fact, CSF assessment should not be performed in otherwise non-immunosuppressed pregnant women with maternal-neonatal listeriosis (23).

Invasive listeriosis has the following types (23):

(i)	Pregnancy-associated and neonatal listeriosis 14%
(ii)	Bacteremia 52%
(iii)	Central nervous system infection 31%
(iv)	Less common focal infections account for the remaining.

Listeria bacteremia. Bacteremia is the most common invasive form of listeriosis (52% above) but can be difficult to recognize. It looks like any other bacteremia with a continuum, ranging from nonspecific symptoms, such as fever, diarrhea, chills, and muscle or joint pain, to septic shock, multiorgan failure, and death. The MONALISA study of 427 cases found that more than 90% of patients with bacteremia presented with fever and elevated C-reactive protein (21).

In pregnant women, the bacteremia is mild and may be passed off as a mild “flu” or a uriunary tract infection (86).

CNS listeriosis. L. monocytogenes involving the CNS most often presents as meningoencephalitis. Less common are cerebritis, abscess, and brainstem infection. Clinically, it may range from a mild fever with minor mental changes to frank coma (85).

Unlike the other common pathogens that cause bacterial meningitis, L. monocytogenes tends to attack the brain (70), so pure meningitis is less common than meningoencephalitis (13% versus 84%) (21).

Fever is seen in 91% to 100% of patients with CNS listeriosis, and headache is seen in 75% (09). Between 25% and 42% of patients may not show signs of meningeal irritation (85; 21; 06).

Meningoencephalitis. This is the most common type of CNS listeriosis and is seen in 84% of cases (212 of 252). Fever is seen in almost all, neck stiffness in 163 of 252 cases (65%), seizures in 46 of 252 (18%), and limb paresis in 31 of 252 (12%). Headache is very common (21).

Cranial nerve palsies, especially 7th and 6^th, were common in other series too. One series of 100 cases showed some cranial nerve involvement in 19%, 6th and 7th nerve involvement in 9% of cases each, and multiple cranial nerves in 5% (07). Another review of 82 cases found nearly half had some cranial nerve palsy at admission, with facial nerve palsy in 37% (06).

Meningitis. Meningitis alone without encephalitic features is seen in only 13% to 15% of cases (21; 06).

The onset may not be abrupt as seen with pneumococcal or meningococcal meningitis, and neck stiffness may be absent in up to 20%, but one cannot reliably distinguish it from other causes of meningitis on clinical grounds alone. In the elderly, neck stiffness, headache, or fever may be absent in up to 40%, and they may present only with altered consciousness (85; 93). Thus, the absence of meningeal signs does not rule out Listeria meningitis or meningoencephalitis.

Movement disorders occur in 15% to 20% of cases, and seizures in 25% (70; 85). Hydrocephalus can be an occasional complication (56).

Worldwide, Listeria monocytogenes is amongst the top ten causes of bacterial meningitis (3.4% of cases) (109).

Rhombencephalitis. L. monocytogenes can cause a brainstem encephalitis, called rhombencephalitis, involving the pons and medulla. It is probably underrecognized but reported in 9% to 17% of cases of CNS listeriosis (09; 04; 21). This is the main form of CNS listeriosis in ruminant animals like cattle or sheep and causes unilateral hemiparesis or ataxia, leading to the animal walking in circles, making it the so-called “circling disease.”

Most (70% to 92%) patients are healthy young adults and not elderly or immunocompromised (05; 55). It typically has a biphasic presentation, with an initial deceptively benign-looking phase with nonspecific symptoms like malaise, fever, headache, vomiting, and sweating. Early recognition in this prodromal stage of 4 to 15 days is challenging (111; 91). Meningeal signs and fever may be absent in 15% of cases; therefore, one may not think of a life-threatening brain infection (09; 102). At this stage, diagnosis can be difficult and missed even after CSF examination and MRI.

It is crucial to diagnose early because if missed, the next stage sets in rapidly with progressive brainstem deficits, including asymmetric cranial nerve palsies (facial paresis, diplopia, dysphagia, palatal palsy, dysarthria, and paresthesias in the trigeminal region), as well as long tract signs in the form of cerebellar ataxia, motor or sensory deficits in the limbs (hemiparesis or tetraparesis, spasticity, or increased tendon reflexes), and impaired consciousness, including coma, and seizures. Almost one half of patients develop respiratory failure (111; 09; 91).

In a review of 123 cases, fever was seen in most (82.7%) at onset, and most (74%) had prodromal symptoms, but only 44.3% had meningeal symptoms (55). The other symptoms were an eye movement disorder, headache, altered mental status, limb ataxia, nausea or vomiting and nuchal rigidity, dysarthria, dizziness or vertigo, or dysphagia. Patients were between the ages of 14 to 87 years, with 16 patients younger than or equal to 29 years.

Listerial rhombencephalitis has even sometimes presented as a fairly sudden hemiparesis, mimicking a stroke (74).

Cerebritis and abscess. Cerebritis and abscess formation are rare (about 1% of patients with listeriosis). Immunosuppression is the major risk factor. Men are more often affected than women, with a ratio of 6:1. Mortality is nearly three times higher than nonlisterial brain abscesses (26).

Unlike other bacteria, listerial brain abscess coexists with bacteremia in nearly all cases and with meningitis in one fourth of cases; in addition, abscesses are often subcortical (21).

Spinal cord abscess has also been reported (57; 100), and acute cervical myelitis from L. monocytogenes was described in immunocompetent patients (88; 53).

Non-neurologic syndromes. L. monocytogenes can cause several non-neurologic syndromes, including cutaneous and conjunctival listeriosis in veterinary or lab workers; bacterial endocarditis in persons with valvular disease, hepatitis, and liver abscess; and peritonitis in persons undergoing continuous ambulatory peritoneal dialysis and those with biliary tract infection, osteomyelitis, or septic arthritis. Most of these infections also occur in immunocompromised persons (102).

Prognosis and complications

	• CNS infection is almost always fatal if untreated and around 30% with treatment, going up to 50% in rhombencephalitis or brain abscesses.
	• One third need artificial ventilation.
	• Two thirds survive with significant neurologic disability.
	• Prognosis is better in healthy individuals.
	• Factors associated with mortality include old age, ongoing malignancy, bacteremia, monocytopenia, immunocompromised status, and steroid therapy.
	• Complications include focal deficits, hydrocephalus, infarcts, and seizures.

Mortality. Listeriosis is the third leading cause of death amongst foodborne illnesses, with about 260 deaths per year in the United States. The case-fatality rate is about 20%. Compared with other pathogens causing CNS infections, L. monocytogenes mortality remains among the highest (109; 115; 13).

Nearly one quarter of pregnancy-associated cases result in fetal loss or death of the newborn. More information can be accessed at the following website: www.cdc.gov/foodborneburden/questions-and-answers.html.

The MONALISA study showed the 3-month mortality was 45% in patients with bacteremia (194 of 427 patients) and 30% in those with CNS infection (75 of 252 patients); there were no deaths in 107 pregnant patients (21). Untreated CNS infection is almost universally fatal (21; 37). The MONALISA study found the following factors associated with mortality: older age, female sex, ongoing malignancy, multiple organ failure, worsening of prior organ disease, weight loss, monocytopenia less than 200 cells/µL, elevated neutrophil count, bacteremia, and dexamethasone administration. A newer study suggests steroids are beneficial, though (14). Neurolisteriosis patients with encephalitis had three times higher mortality than those without encephalitis (33% vs. 9%) (21).

Prognosis is better in those without serious underlying disease, those who are not immunocompromised, those who are not pregnant, and in younger adults (19; 99). In two series of 281 and 74 patients, there were no deaths in otherwise healthy patients compared with an overall mortality rate of 22% to 32% in patients with underlying health conditions (106; 42).

Mortality in rhombencephalitis or abscess is high, between 30% and 50% (05; 55; 102). Mortality in Listerial brain abscess is nearly three times higher than nonlisterial brain abscesses (26).

A retrospective study of 100 cases of CNS listeriosis found that seizure and delay in treatment were most significantly associated with mortality (07).

Community-acquired Listeria meningitis in an analysis of 92 cases in the Netherlands comparing those from 1998 to 2002 with those from 2006 to 2012 showed unfavorable outcomes to have increased from 27% to 61% (60).

Morbidity. Morbidity in survivors is high, with significant residual disability in over two thirds (21; 06). Neurologic sequelae were most likely to be experienced in patients whose treatment was delayed beyond 7 days (07). Long-term neurologic sequelae included limb motor deficiencies, cerebellar symptoms, and eighth nerve palsy (21).

Rhombencephalitis or abscess also had up to 61% of survivors having significant residual deficit (34; 55; 102).

Although pregnant women with listeriosis generally do not have CNS involvement, systemic infection during pregnancy can lead to amnionitis, premature labor, or, rarely, stillbirth.

Complications. The course of the illness may be complicated by focal deficits, hemiparesis, quadriparesis, bulbar palsy, and a need for artificial ventilation, as well as seizures, hydrocephalus, and increased intracranial pressure. Cerebral vasospasm with subsequent infarction can occur days or weeks after initial presentation (58). Almost one third need artificial ventilation (21).

Clinical vignette

Case 1. A 50-year-old man developed a severe headache, lethargy, and fever over 2 days. He came to medical attention when his wife found him disoriented and combative. In the emergency room, he had a generalized seizure followed by ventricular tachycardia requiring cardioversion. His past medical history was remarkable for adult-onset diabetes mellitus, active pulmonary sarcoidosis treated with 30 mg prednisone daily, alcoholic cirrhosis, and splenectomy after a gunshot wound. Before the seizure, he was arousable only by a loud voice. He was disoriented to place. Vital signs included a temperature of 39.2°C, blood pressure of 108/70 mmHg, regular pulse of 98 per minute, and respirations of 12 per minute. He had a small liver with abdominal distention and shifting dullness. His neurologic exam exhibited meningismus, withdrawal of all four limbs to painful stimulus, and normal cranial nerves. Deep tendon reflexes were normal.

A non-contrast head CT scan was unremarkable. Lumbar puncture showed an opening pressure greater than 30 cm of water, cloudy fluid, and 8400 white blood cells per mm3 with 90% neutrophils and 10% lymphocytes. Red blood cells were 986 per mm3. Glucose was 291 mg/dL (serum 410 mg/dL) and protein measured 291 mg/dL. The CSF Gram stain was unremarkable. Blood and CSF cultures showed growth after 2 days, and L. monocytogenes was identified at day 3. The patient initially received intravenous vancomycin, ceftriaxone, and ampicillin. After bacterial identification, the treatment was switched to a combination of ampicillin and gentamicin and continued for 3 weeks. Recovery was complete within 10 days.

Case 2. A 52-year-old mildly hypertensive neurologist had a history of occasional migraine headaches once a month or so for many years. He had a hectic month with a lot of travel, including Europe and Uzbekistan. He had a dental extraction of an upper molar on the left side done 1 month previously, but the area was still raw and occasionally bled a little when brushing.

Two weeks after returning home, after a late night, he started getting a headache. It did not respond to his usual paracetamol, so on day two, he took naproxen. The headache worsened, and he could no longer see patients in his clinic.

On the morning of day three, the headache continued; additionally, he felt a little dizzy and developed a mild fever of 100.5° F. There were no focal signs or meningeal signs.

The brain MRI showed a lesion on FLAIR sequence, mainly in the posterior left pons, extending down to the medulla. The left trigeminal nerve was slightly enhanced as it exited the pons. The CSF showed 350 cells, mainly polymorphonuclear leucocytes, with glucose 75 mg% and protein 61 mg%.

Listeria rhombencephalitis (1)

Brain MRI on day 3 shows a lesion on FLAIR sequence, mainly in the posterior left pons, extending down to the medulla. There is slight enhancement of the left trigeminal nerve as it exited the pons. (Contributed by Dr. Sudhir K...
Listeria rhombencephalitis (2)

Brain MRI on day 3 shows a lesion on FLAIR sequence, mainly in the posterior left pons, extending down to the medulla. There is slight enhancement of the left trigeminal nerve as it exited the pons. (Contributed by Dr. Sudhir K...

His hemogram showed a normal hemoglobin, with about 14000 WBCs, 75% polys, and 5% monocytes. The ESR and CRP were normal. TB PCR was negative. The CSF HSV and VZV tests were scheduled. He was started on empirical valacyclovir, cefotaxime, steroids 4 mg every 12 hours, and paracetamol, but he continued to worsen.

On day 4, the fever and headache were initially less but returned in the evening, and he started feeling dizziness on moving his head and unsteadiness while walking; he also felt numbness and altered sensation over the left face, scalp, and left hand. There was no weakness or limb ataxia. And no Horner syndrome.

On day 5, the numbness and ataxia further worsened, and the headache continued as did the low-grade fever. After discussing with a fellow neurologist in the United States, he diagnosed himself with listeria rhombencephalitis. He stopped all the earlier treatments and started ampicillin with gentamicin in appropriate doses.

On day 6, he continued to worsen, and the ataxia and dysarthria worsened. He would lurch while walking and also developed left finger-nose ataxia. He started getting early bulbar palsy with a change in his voice and had difficulty moving his tongue, though he could still swallow.

The MRI repeated on day 7 showed partial resolution of the pontine lesions, but there were confluent ring-enhancing lesions in the medulla with surrounding edema. There was a little hemorrhage seen within the medullary lesions on GRE sequence.

Listeria rhombencephalitis (3)

MRI repeated on day 7 shows partial resolution of the pontine lesions, but now there are confluent ring-enhancing lesions in the medulla with surrounding edema. There is a little hemorrhage seen within the medullary lesions on ...
Listeria rhombencephalitis (4)

MRI repeated on day 7 shows partial resolution of the pontine lesions, but now there are confluent ring-enhancing lesions in the medulla with surrounding edema. There is a little hemorrhage seen within the medullary lesions on ...

Treatment was continued; TMP-SMX was substituted for the gentamicin.

From the 8th day onward, he started feeling better. The fever and headache started to subside. The ataxia and dysarthria took a few weeks to reduce.

Repeat MRIs continued to show enhancement, but the edema was reduced. Full treatment was continued for 2 months. The patient was much better at the end of 2 months, but oral moxifloxacin was given for 2 more months, and the ampicillin and TMP-SMX were stopped.

At 6 months, some enhancement persisted, but all treatment was stopped.

A repeat MRI done at 1 year showed almost total resolution. At 1 year, there was no neurologic deficit.

Biological basis

Etiology and pathogenesis

	• L. monocytogenes is a gram-positive rod, with flagella giving it a peculiar tumbling motility.
	• It can survive for years in extremely adverse environments, such as food processing and storing facilities.
	• It can switch from a peaceful saprophyte form to a dangerous pathogenic form in mammals.
	• On ingestion, it causes a minor gastroenteritis.
	• In certain susceptible persons, it gets past the gut into the bloodstream and to the brain or placenta.
	• Various virulence factors, like internalins and listeriolysin, give it the unique ability to silently evade various defense host mechanisms, cross barriers, survive, and move within cells, hijacking various host processes to its own cause.
	• In some healthy persons, it can spread retrogradely to the brainstem within axons of certain cranial nerves.
	• Once in the brain, it can spread along axons and cause inflammation and progressive disease.

Microbiology. L. monocytogenes is the only Listeria species recognized as a human pathogen. Listeria ivanovii causes abortion, septicemia, and enteritis in ruminants but is very rarely isolated from humans. There are many nonpathogenic species (61).

L. monocytogenes is a gram-positive rod with flagella or “whips,” which gives it the characteristic tumbling motility. It can mimic other less dangerous bacteria as it can be gram-variable, and the rods may be short-looking like cocci. Thus, they can be mistaken for gram-positive cocci like enterococci or pneumococci, for gram-negative coccobacilli like H. influenzae, or gram-negative bacilli like various enteric bacteria. It is easily confused with harmless diphtheroids found on the skin or found as contaminants in blood culture. Thus, the possibility of Listeria should always be considered when "diphtheroids" are reported to be growing from blood or CSF cultures (37). The microbiologist should be alerted to the possibility of Listeria and specifically look for the tumbling motility of Listeria at 25°C, which distinguishes it from the similar-appearing diphtheroids (16). Listeria grows well on most routine culture media and usually forms a narrow zone of beta-hemolysis on blood agar (50).

Listeria is a very flexible and adaptive organism, easily switching from a saprophytic mode of life in the soil to one where it causes infection in animals and humans (41; 97).

It is found widely in soil, water, vegetation, and food. It is a very adaptive and flexible organism, can survive in aerobic or anaerobic environments, and can resist environmental stresses like temperatures, acidic pH, and dryness (97; 102).

In the cold and harsh food-processing environment, it enjoys a competitive advantage over other microorganisms and can survive for even years due to its ability to endure various stresses, such as sanitizers, pH, temperature, UV light, and drying (52) and by forming biofilms, or thin sticky films attached to various surfaces, thereby evading various eradication measures and disinfectants (77).

It can bide time and multiply rapidly once conditions become conducive, for example, warmer (30°C to 37°C) or more alkaline.

Like its survival strategy in the environment, even inside the cell, it can temporarily adopt a dormant but viable vacuolar form, undetected by culture, evading the immune system and resisting antibiotics (11).

Pathobiology. Listeria infection progresses in three stages. It first has to get past the intestinal barrier and then, via the bloodstream, reach the “primary target organs,” namely the liver and spleen. In these early two stages, the patient is asymptomatic or has just a nonspecific fever or gastroenteritis. In most healthy individuals, the cell-mediated immune system clears the infection at these stages. Only when that fails does it go to the third stage of invasive disease, reaching the “secondary target organs,” that is brain or placenta. The course depends on the number of bacteria ingested, the virulence of the strain, and, most importantly, the immunological status of the host. In a host with good immunity, even a large dose usually stops at the stage of febrile gastroenteritis. For unknown reasons, in some immunocompetent individuals, Listeria can invade the brainstem directly, bypassing the above hurdles (61). The primary virulence strategy of L. monocytogenes is the ability to invade, survive, and replicate within various mammalian cells. Internalins are surface proteins for host cell attachment; listeriolysin O and phospholipase allow it to escape from host cell vacuoles; actin polymerization (ActA) helps the bacteria move within and between cells (51).

Almost a billion bacteria must be ingested to cause gastroenteritis in a normal person. However, in a predisposed person, just a couple thousand can become invasive and reach the blood or brain (97).

After ingestion, Listeria has to overcome acid and bile salts in the stomach and later overcome competition by the intestinal microbiota before it reaches the portal of entry in the small intestine (61). It thrives when the acid in the stomach is reduced and pH goes above 3.5. It easily neutralizes bile salts and disrupts the protective gut microbiome with Listeriolysin S, a bacteriocin (96; 50).

The next task is to get past the intestinal barrier, which it does efficiently, even within 15 minutes, by invading the intestinal epithelium using its internalins. There is also an inefficient way whereby it waits to get taken up passively by M-cells lining the Peyer’s patches.

The internalins bind to receptors and induce uptake into vacuoles. The vacuoles are punctured by listeriolysin O (LLO) and two phospholipases, and Listeria escapes into the cytoplasm (97). Within the cytosol, Listeria multiplies rapidly and uses the host actin to develop actin tails, propel itself within the cytoplasm, break the cell membrane, and reach the adjacent cell, evading the immune system and continuing the cycle in the next cell. During this intestinal phase, everything is silent, or there is just mild gastroenteritis (97).

Once past this barrier, it spreads to the draining mesenteric lymph nodes and then into the bloodstream. Within minutes of getting into the blood, 90% is cleared by the liver and, only a fraction, in the spleen. They multiply in both liver and spleen.

Cell mediation usually clears this infection, even in healthy persons.

It can go from the liver and spleen to cross further barriers--the fetoplacenta in pregnant women and the blood-brain barrier in immunocompromised persons.

L. monocytogenes crosses the blood-brain barrier and infiltrates the CNS by three possible mechanisms: invasion of the endothelium of the cerebral vasculature via vacuoles as in the intestine; via infected leukocytes, the “Trojan Horse mechanism” (122); and the very peculiar and almost unique method of retrograde spread through various cranial nerves (08).

Because extracellular host defenses, such as antibodies, complement, and neutrophils, do not have access to the intracellularly spreading Listeria bacteria, defense and later recovery depend on cytosolic innate immunity and the cell-mediated immune response (61). The CD8 T-cell response, crucial in resolving the infection, also provides protective immunity to reinfections (97; 50).

Listeria spreads and causes progressive brain damage, despite a good intrathecal immune response (12; 43; 08; 119). Even within the brain, Listeria seems to use its actin tail to spread along white matter tracts inside axons. While spreading along the axons, Listeria attracts neutrophils and phagocytes to chase them, leading to a track of inflammation and microabscesses.

There is evidence in sheep and other domestic animals, as well as pathological and radiological evidence in humans, suggesting retrograde spread of the bacterium along certain cranial nerves, particularly from injured oropharyngeal and periodontal tissue via the trigeminal nerve and from the gut mucosa via the vagus nerve (08; 119). The highly prevalent problem of dental disease may explain why the trigeminal nerve is much more frequent than the vagus. The longer incubation period of nearly one month may be explained by the longer course of the vagus (08; 119).

This invasion via nerves directly to the brainstem is seen particularly in immunocompetent individuals and in ruminants. Most humans with Listeria have impaired immunity (due to extreme age, disease, drug, or pregnancy), and the hematogenous route is preferred in them (08). In one large series (MONALISA), only 10 (4%) of 252 patients with neurolisteriosis were younger than 40 years and had no comorbidity or ongoing pregnancy and no report of substantial infection before listeriosis (21).

Neonates can become infected transplacentally from maternal bacteremia. The organism can also be acquired during vaginal delivery.

Epidemiology

	• Listeria is ubiquitously distributed and often contaminates certain food products.
	• Listeria remains one of the main three causes of foodborne disease leading to hospital admissions in North America and Europe.
	• Though rare, listeria still has the second highest case-fatality rate amongst food-borne diseases.
	• Invasive listeriosis is reducing but still is among the top ten causes of meningitis worldwide and among the top ten causes of death due to meningitis.
	• In the immunocompromised, listeria is the second highest cause of CNS infections.
	• Persons at risk are those in the extremes of age, pregnant women and the immunocompromised, diabetics, alcoholics, and persons with malignancy or chronic illness.
	• Rhombencephalitis is a variety that affects immunocompetent healthy young adults.

With the ubiquitous distribution and frequent contamination of various food items, humans are frequently exposed to small numbers of L. monocytogenes, with approximately five to nine exposures per person-year. Illness occurs only when the dose is large or the host is susceptible (102).

Human listeriosis is a relatively rare disease, with an estimated incidence ranging between 0.1 and 11.3 cases per million population per year, depending on geographical location and surveillance system (61). It is important due to its deadly nature, with the second highest case-fatality rate of food-borne illnesses, and is responsible for 19% to 28% of all food-borne disease-related deaths. It has the highest hospitalization rate of 99% among the foodborne diseases (52). Listeria remains one of the top 10 most common pathogens of CNS infections in the world and is second among patients with diabetes or alcohol dependence and in those on immunosuppressive therapies.

In 2010, listeriosis caused an estimated 23,150 illnesses, 5463 deaths, and 172,823 disability-adjusted life-years worldwide (31).

The highest incidence of disease was found in Mexico, Central America, and the West Indies. The lowest disease incidence was found in Eastern Europe, Caucasus, and Central Asia. Of all cases, roughly 80% were non-perinatal infections, of which 31% were CNS infections; 26% of non-perinatal cases were fatal (31).

The latest review of December 2021 estimates that 1600 serious infections and 260 deaths occurred in the United States due to L. monocytogenes infection, and the annual incidence of laboratory-confirmed listeriosis in the United States was about 0.24 cases per 100,000 population (20).

Most cases of listeriosis are sporadic rather than part of an outbreak. Most sporadic cases are likely due to consumption of contaminated food. Despite all efforts by government and food agencies, L. monocytogenes causes major foodborne outbreaks globally (116; 31; 52). A high proportion of cases are linked to outbreaks, maybe up to 50% (61). Seasonal trends are seen, with peak incidence of invasive listeriosis cases in the summer months (118; 72).

Gastroenteritis. Listeria is an uncommon cause of gastroenteritis, mainly affecting healthy children and adults in outbreaks and uncommonly as sporadic cases. Attack rates during outbreaks have ranged from 52% to 100%.

Invasive listeriosis. Invasive listeriosis has been declining due to various control measures. It decreased by 42% from 1996 to 2012 (49). Listerial meningitis decreased by 46% between 1998 and 2007.

Most cases are sporadic (18). Of nonpregnant individuals who develop L. monocytogenes bacteremia, 97% have at least one underlying immunodeficiency, either due to one or more medical conditions or due to immunomodulating medications (21). Similarly, only 10 (4%) of 252 patients with neurolisteriosis were younger than 40 years, had no comorbidity or ongoing pregnancy, and had no report of substantial infection before listeriosis (21).

Listeria is the tenth most common cause of bacterial meningitis (36). Approximately one third of listerial meningitis occurs in the newborn. In people aged 50 years or more, the percentage of Listeria goes up to 9% (93). In infants, E. coli, S. agalactiae, and L. monocytogenes are the most common causes of bacterial meningitis (02).

Listeria is the second most common cause of meningitis in immunocompromised persons. These are patients on immunosuppressive medications or long-term steroids or who have solid organ tumors, lymphomas, or an organ transplant (114).

Rhombencephalitis is probably underrecognized but still reported in 9% to 17% of CNS Listeria cases (09; 21). In contrast to other forms of listerial infection, rhombencephalitis strikes healthy adults; only about 8% are immunocompromised (05). In a literature review of 120 patients, ages ranged from 14 to 87 years, with 16 patients less than or equal to 29 years old, 59.3% of the patients were men. Of the 96 patients with known immune status, 69.8% (n = 67) were immunocompetent (55).

Rhombencephalitis caused by L. monocytogenes developed in a patient without severe lymphocytopenia treated with dimethyl fumarate (101).

Cerebritis and abscess formation occur in about 1% of patients with listeriosis. Immunosuppression is the major risk factor. Men are more often affected than women, with a ratio of 6:1.

Biodiversity of Listeria. Various methods have been used for subtyping Listeria to help trace outbreaks, understand virulence and antibiotic resistance, etc. Methods based on genetic properties are lineage, clonal complexes, and sequence types. Lineage tells us the big picture about how Listeria strains are related, clonal complexes take a closer look within a lineage, and sequence type reveals the unique genetic identity of an individual strain within a complex. Listeria serovars or serological subtypes are based on the antigenic properties of the bacterium's cell surface and are determined through serological tests. The serovar classification focuses on the antigenic properties and is more used in Asia. Europe and North America use more of MLST. There have been efforts to harmonize subtyping with common comparative databases to make it easier to detect and trace foodborne outbreaks (61).

Listeria has four lineages. Lineage I is responsible for most human listeriosis, at least two thirds of cases cases, and is considered the most virulent. Lineage II is commonly found in food processing environments and causes fewer cases, maybe less than one third. Lineage III and Lineage IV are less frequently associated with human infections.

Out of the 13 serovars, serovars 1/2b and 4b within lineage I and serovar 1/2a within lineage II cause 95% of human listeriosis cases. As we saw earlier, lineage II is mainly found in food or environment surveys (serovars 1/2a), whereas most listeriosis cases are caused by lineage I serovar 4b strains. Within serovar 4b, clonal complexes CC1, CC2 (from lineage I), CC4, and CC6 (from lineage II) are considered “hypervirulent” as they are more often found in invasive listeriosis (61).

The vast majority of human listeriosis cases are caused by three serotypes: 1/2a, 1/2b, and 4b (28). 1/2a and 1/2b are responsible for most cases of febrile gastroenteritis, whereas serotype 4b more commonly causes invasive diseases (71).

Various clones lead to tremendous diversity in virulence, geographical distribution, etc. Certain clones are most likely to cause disease, infect dairy products, affect meat, and tend to cause rhombencephalitis. The genotype clonal complex CC6 or ST6 has resistance to benzalkonium in disinfectants and so tends to grow preferentially and has become the major cause of Listeria meningitis in the Netherlands (60; 59; 75; 76).

Patient groups at risk. Invasive disease mainly occurs in predisposed persons, including the elderly and infants, pregnant women, and persons with a compromised immune system. Most normal and healthy persons do not get an infection on exposure, and even if they do, it is usually a self-limited gastroenteritis. Still, around 4% of otherwise healthy young persons (less than 40 years of age) can get invasive disease without any identifiable risk factors like age, immunocompromised state, or pregnancy (21). They may have genetic susceptibility or are exposed to a higher bacterial inoculum. Extremes of age are a risk, with both neonates and the elderly being at particular risk. Incidence in persons over 75 years of age is nearly 20 times greater (0.98 cases out of 100,000) than in individuals younger than age 65 years (0.05 cases out of 100,000) (40). Listeriosis caused 16% of cases of community-acquired bacterial meningitis in patients over age 80 (113).

Neonatal listeriosis incidence is between 1.3 and 25 per 100,000 live births. In the 1990s, it was the second leading cause of bacterial meningitis in patients younger than 1 month (22%). But now it has come down to between 1.5% and 5% of children, infants, and neonates in various countries (61). Pregnant women have a 10- to 18-fold higher risk in relation to the overall population and a 100-fold increased risk compared to nonpregnant women of reproductive age. Pregnancy accounts for almost one sixth of all invasive listeriosis cases (27). Pregnant Hispanic women and those with low socioeconomic status have been identified as high-risk groups (105; 87).

The MONALISA study showed 93% of individuals with CNS listeriosis had some immunosuppressive comorbidity with an 8-fold increased risk in patients with a history of immunosuppressive therapy. Active cancer, both solid and hematological malignancies, was seen in almost one third of cases (21). Apart from cancer, the underlying conditions included kidney disease, cirrhosis, diabetes mellitus, giant cell arteritis, organ transplantation, AIDS, chronic corticosteroids, or other immunosuppressants, including tumor necrosis factor-alpha antagonists (82; 63; 95).

Individuals with alcohol use disorder or a history of chronic liver disease have a 5-fold increased risk of brain infection (61). L. monocytogenes meningitis has been reported in patients with multiple sclerosis treated with alemtuzumab (98) and rhombencephalitis treated with dimethyl fumarate (101).

Even proton pump inhibitors increase the risk of developing invasive infection (48). Inflammatory bowel disease has been found to be a risk factor, probably due to TNF inhibitors usage (104).

All of the above categories of patients at risk should be warned about dietary practices and precautions for listeriosis.

Foods at risk. L. monocytogenes is ubiquitously distributed and grows in various environments, including soil, water, plant matter, diverse food items, and the intestinal tract of mammalian hosts (91). Surface contamination of meat and vegetables is found in up to 15% of samples (102).

Listeriosis has been documented to occur from various foods.

The commonest offenders are meat products, especially delicatessen-style ready-to-serve meats; dairy products (eg, ice creams, cheeses, butter), especially unpasteurized soft cheeses; fruits and vegetables; and fish products (102). Even hospital foods like sandwiches have been implicated (105).

Due to their eating preferences, two groups of elderly persons were identified to be at the highest relative risk: those who preferred fruits, vegetables, and cheeses; and those who preferred cereals, milk, and yogurt (117).

Tracking listeriosis cases and linking to food products is now done by pulsed-field gel electrophoresis and whole-genome sequencing, which have largely replaced older methods, such as serotyping (28).

Whole‐genome sequencing (WGS) has revolutionized the detection of outbreaks. As Listeria attack rates are low and retail processed food is often widely and even internationally distributed, what would have been interpreted as unrelated sporadic cases are now identified as common source outbreaks (61). This rapid identification allows recall and other measures to stop the spread of outbreaks, for example, outbreaks involving contaminated salmon (65) and frozen vegetables (73). WGS is also used to predict various genetic traits related to virulence, stress, or antimicrobial resistance (66).

Prevention

	• Awareness, regulation, and testing at the food-processing level are very important.
	• Some precautions need to be taken by everyone to prevent food-borne illnesses.
	• Persons at high risk include the elderly, pregnant women, infants, and anyone with a compromised immune system for any reason.
	• Those at high risk need to be educated about their risk, and precautions need to be taken about food choice and food handling.
	• Trimethoprim-sulfamethoxazole prophylaxis effectively prevents listeriosis in high-risk patients, for example, those with HIV.
	• Infected patients do not need to be isolated.
	• A healthy gut microbiome may be protective.
	• On possible exposure to Listeria-contaminated food, asymptomatic persons do not need treatment but need to keep a watch for 2 months for fever or muscle aches or fatigue, especially the high-risk category.

Steps at the food processing level. L. monocytogenes is one of the most dangerous foodborne pathogens, able to survive and grow under various stressful conditions and form biofilms in the food production environment, including low and high temperatures, variable pH, osmotic stress, nutrient deficiency, and contact with disinfectants.

It can cross-contaminate other food products (120).

This contamination of food products is particularly important for ready-to-eat foods, including vegetables and fruits, as they are eaten directly without heating or other disinfection (52; 99; 73).

Guidelines have promoted universal awareness of the problem in the food-processing industry, which has undertaken hazard analysis at critical control points and microbial risk assessment programs to reduce contamination of foods with L. monocytogenes and other pathogens.

One has to balance efforts to avoid contamination because of the high risk to the consumer against the inconvenience and cost of food recall. A debate continues between zero-tolerance advocates and those supporting a risk-assessment approach to Listeria food contamination (32). The U.S. Food and Drug Administration has a zero-tolerance policy for L. monocytogenes in its industry sampling programs, whereas other countries allow a small amount of contamination in an attempt to balance the protection of public health and wastage of otherwise edible food (102). European regulations allow up to 100 CFU/gram, whereas the U.S. FDA has a zero-tolerance policy on the grounds that low contamination levels involve a risk to highly susceptible people, causing around 3.5% of human listeriosis cases. Maybe one needs to tailor zero tolerance to dangerous serotypes or clonal complexes to reduce the economic burden of the control measures (61).

Surveillance for Listeria is being done using sophisticated techniques like electrochemical biosensors (78) and whole-genome sequencing. Bacteriophages may be a promising treatment to limit L. monocytogenes on food products or food contact surfaces (120).

As more cases are associated with drug-resistant strains, studies are being done to identify factors that promote resistance, akin to the study of antibiotic resistance.

General measures to be taken by everyone. These recommendations help to prevent any foodborne illness and include:

	• Proper washing and handling food
		- Thoroughly cook raw food from animal sources
		- Thoroughly wash, scrub if needed, and dry raw vegetables and produce like cucumbers and melons
	• Food choices
		- Use precooked or ready-to-eat food as soon as possible and do not store beyond the expiry date
		- Use leftovers within 3 to 4 days
		- Avoid raw (unpasteurized) milk or foods made from raw milk
	• Keep kitchen safe
		- Wash hands, knives, and cutting boards after handling uncooked foods
		- Keep refrigerator free of spills and temperature below 40°F and freezer below 0°F

Special precautions for high-risk individuals. People at high risk, which include immunocompromised persons due to various diseases or drugs, pregnant women, the elderly, and parents of infants, need to be educated about listeria and about foods that are at risk of being contaminated with listeria. Recognition and education of subset populations at even higher risk, such as pregnant Hispanic women in the United States, should be prioritized (37). Similarly, elderly people must be careful about certain foods and food habits. They should consider the following (37):

	• Cheeses
		- Avoid soft cheeses and Mexican-style cheese
	• Meats and seafood
		- Avoid from delicatessen counters unless thoroughly reheated or steaming hot before eating
		- Avoid refrigerated meats and seafood unless thoroughly cooked again
		- Separate raw meat and poultry from ready-to-eat food
	• Melons
		- Wash hands properly before and after handling
		- Scrub surface and dry melons properly and sanitize the brush after each use
		- Consume melon immediately after cutting or refrigerate promptly and eat within a week
		- Discard cut melons left at room temperature for more than 4 hours
	• Raw sprouts
		- Do not eat any kind of raw sprouts and inform when eating out
		- Cooking sprouts thoroughly can reduce the risk

Listeriosis is effectively prevented by trimethoprim-sulfamethoxazole given as Pneumocystis prophylaxis to organ transplant recipients, those receiving corticosteroid immunosuppression, or individuals infected with human immunodeficiency virus.

Second episodes of neonatal listerial infection are virtually unheard of, and intrapartum antibiotics are not recommended for women with a history of perinatal listeriosis. Except for transmission from infected mother to fetus, human-to-human transmission of listeriosis does not occur; patients do not need to be isolated.

Recommendations on food handling to avoid infections from L. monocytogenes have been published by the CDC. More information can be accessed at the following sites: CDC and US Health Department.

High-risk foods should not be served in hospitals catering to immunocompromised patients (eg, cancer). Excluding high-risk foods from being served in settings that care for patients with immunocompromising conditions may reduce the risk of listeriosis for these patients, including out-patients (44).

Role of the gut microbiome. Despite frequent exposure, very few persons actually get listeriosis, and a healthy gut microbiome probably plays a key role in protecting against listeriosis. Studies suggest that it may be possible to enhance this protection by promoting healthy bacteria, such as by using probiotics (10). If proven, this could be a simple strategy for augmenting prevention in individuals at high risk apart from paying attention to food habits, as explained above.

Recommendations for possible exposure to Listeria-contaminated food. On possible exposure to food known to be contaminated with Listeria, for example, during an outbreak, certain steps need to be taken depending on the person’s risk category and symptoms.

Most normal and healthy persons will either not get any illness or may get a self-limited gastroenteritis. They do not need any tests or any specific treatment. They should be counseled and monitored for 2 months, watching for any fever, muscle ache, headache, or fatigue. This is particularly important in the high-risk category: the elderly, pregnant, or immunocompromised.

In the high-risk category, if there is fever, it is advised to get blood cultures done and start intravenous ampicillin. If diagnosis is proven, treatment should be continued for 2 weeks. Adding gentamicin is controversial. Most authorities recommend trimethoprim with sulfamethoxazole if there is allergy to ampicillin (25).

In the high-risk category, one may still consider sending blood cultures and observing very closely if they have mild symptoms without fever. More information is found at the following site: https://www.cdc.gov/listeria/faq.html.

Differential diagnosis

Associated or underlying disorders

We need to keep a high index of suspicion for listeriosis and even start empirical treatment until the disease is ruled out, in view of the possibility of rapid worsening and high mortality and morbidity (102).

It should be suspected in the following clinical scenarios, especially if the patient has recently ingested milk, soft cheeses, cold deli meats, or hot dogs.

	• Meningitis or parenchymal brain infection in persons greater than or equal to 50 years of age with hematologic malignancy, solid-organ malignancy, organ transplant, or AIDS or on immunosuppressive therapies
	• When the meningitis is subacute or there is a concomitant infection of the brain parenchyma
	• Subcortical brain abscesses
	• A young, healthy person presents with an acute brainstem disorder within days or weeks of having eaten “risky” food, even in the absence of fever or headache

Listeriosis should also be thought of in every neonate with respiratory distress, sepsis, or meningitis; in fever during pregnancy, especially in the third trimester; and in foodborne outbreaks of febrile gastroenteritis with negative stool cultures (50; 102; 99).

Meningitis and meningoencephalitis. Rather than pure meningitis, a meningoencephalitis or combination of simultaneous meningeal and brain parenchyma infection is more common with listeriosis than in other forms of bacterial meningitis (70; 74; 21).

Based on the clinical presentation or CSF picture, Listeria meningitis is indistinguishable from that due to more common bacterial pathogens, though it may be more subacute (94). The chances of Listeria being the cause are higher in the elderly and in neonates (93; 02). Diagnosing meningitis in the elderly may be difficult, as they may have nonspecific confusion without any fever, headache, or nuchal rigidity. Up to one third of the normal elderly may seem to have a stiff neck (29).

Patients with a prior history of receiving immunosuppressive therapy within 1 month and chronic liver disease have an 8.1-fold and a 5-fold increased risk of meningitis by L. monocytogenes compared to S pneumoniae, respectively (69).

Listeria meningitis can be mistaken for viral, tubercular, fungal, or syphilitic meningitis and, in patients with cancer, for leptomeningeal carcinomatosis (01).

Focal cerebral lesions are detected by CT or MRI in 23% to 26%, ventriculitis in about 10%, and hydrocephalus in 10% to 15% of adult neurolisteriosis patients (61).

Listeria abscess or abscesses. Subcortical abscess caused by L. monocytogenes should be added to the list of more frequently occurring polymicrobial, streptococcal, and staphylococcal brain abscesses, particularly in the immunosuppressed or with simultaneous meningitis.

The abscesses tend to spread along white matter tracts, creating characteristic worm-like enhancing MRI lesions.

Listeria rhombencephalitis. This must be considered in any acute or subacute brainstem lesion, especially if there is fever or known consumption of risky food, even in normal and young persons, even if not many systemic signs and gross CSF abnormalities (30; 102).

The most common cause of rhombencephalitis is listeriosis, but it has a number of differentials, including other infections like enterovirus 71, the various herpes viruses, autoimmune diseases like Behcet disease, and less commonly, lupus, relapsing polychondritis, and paraneoplastic syndromes, especially with anti-Yo(PCCA), anti-Tr, anti-Hu(ANNA1), anti-Ri(ANNA2), anti-Ma, and anti-amphiphysin antibodies, with underlying small cell lung cancer. It can be mistaken for and even occur in persons with demyelinating CNS diseases, such as multiple sclerosis or neuromyelitis optica. Other disorders to be kept in mind are intra-axial brainstem tumors, strokes, central pontine myelinolysis, and CLIPPERS (54; 24; 119).

Some pointers may help in narrowing down the causes:

	• Cerebellar ataxia is common in infectious and paraneoplastic syndromes.
	• Long tract signs are common with Behcet disease and Listeria, but not other infections.
	• Altered consciousness may be seen in infectious cases and in some types of Behcet disease.
	• Fever is common with infections and Behcet disease.
	• Meningismus is seen in infections.

The MRI is also very helpful, and an abnormal MRI is a must in Listeria rhombencephalus, multiple sclerosis, and Behcet disease, whereas a normal MRI is highly suggestive of paraneoplastic or possibly viral etiologies (54; 83; 17).

Diagnostic workup

	• CSF abnormalities are characteristic of pyogenic meningitis but may also mimic viral, tuberculous, or fungal meningitis.
	• MRI is abnormal in almost 90%, usually nonspecific, but sometimes it might be characteristic as in rhombencephalitis or worm-like brain abscesses.
	• A normal MRI does not rule out CNS listeriosis.
	• Culture from CSF or blood is the mainstay of diagnosis, but it takes time.
	• PCR is faster and may be positive, even in partially treated cases.
	• Serological testing and stool culture are not useful in individual cases.

Hemogram. The peripheral blood usually shows polymorphonuclear leukocytosis and lymphopenia, especially in nonperinatal cases. Despite its name, L. monocytogenes infections rarely produce a monocytosis in humans (21).

CSF findings. CSF usually shows a pleocytosis around 500 to 600 with neutrophil predominance and often (but not always) low glucose (85; 15; 21).

Only one third of cases showed Listeria on gram stain (85; 21). Caution is needed because it may appear as gram-negative or look like short rods or elliptical cocci; therefore, it may be mistaken for diphtheroids, streptococci, H influenzae, enterococci, or enteric bacteria (16).

MRI. MRI has clear advantages to CT (06). It shows various combinations of neuroradiological findings, none being specific. In one study of 71 cases, MRI was abnormal in 87%. Meningeal enhancement was seen in 35%, abscesses or nodular lesions in 14%, and contrast-enhancing ventricles or hydrocephalus in 10%.

CNS listeriosis is often thought to involve the brainstem. In fact, brainstem involvement narrows the differential diagnosis and is more specific, but only about 10% of CNS listeriosis cases show radiological signs of rhombencephalitis. Somewhat unexpectedly, hemorrhagic lesions are frequent (15%).

This brings us to a clinical pearl: one may start empirical anti-Listeria therapy when neurolisteriosis is suspected, even when MRI does not show rhombencephalitis, brain abscess, or meningeal enhancement (22).

Listeria monocytogenes abscesses frequently present as markedly irregular formations, revealing characteristic worm-like tubular patterns of chaotic curvilinear arrangement. This “tunnel sign” or “worm-like sign” can be considered very typical.

Listeria monocytogenes should be remembered in cases wherein brainstem or cerebellar involvement is detected on cranial MRI, particularly abscess or contrast enhancement (06). Almost all cases of Listeria rhombencephalitis have an abnormal MRI (54; 83; 17).

Culture of CSF or blood. CSF culture reveals the organism in five of six cases, whereas blood cultures are positive in more than half of patients. One in six may show a positive blood culture in the absence of a positive CSF culture. In the appropriate clinical setting, neurolisteriosis may be diagnosed with positive blood cultures alone (21). Cultures may be negative if patients received empirical antimicrobial treatment before sample collection.

PCR. A real-time PCR assay has high sensitivity and specificity for CNS listeriosis, even where CSF culture was negative, for example, due to previous treatment. It is rapid and reliable. This real-time quantitative PCR has sometimes been used to monitor therapy and detect bacterial persistence, for example, in ventriculoperitoneal shunts (68). Multiplex PCR testing for CSF for an array of viruses, bacteria, including L. monocytogenes, and fungi, is now commercially available (The BioFire® FilmArray® Meningitis/Encephalitis Panel, QIAstat-Dx Meningitis/Encephalitis Panel) (107).

It should be noted that in one series of listerial rhombencephalitis cases, 22% did not have an elevated CSF cell count. Moreover, the sensitivity of CSF culture is lower in rhombencephalitis, where only 41% and 61% of reported patients had positive CSF and blood cultures, respectively (05). PCR might prove useful in such culture-negative cases (90).

Management

	• Prompt and appropriate antibiotics are the key.
	• A delay of even a few hours can be fatal.
	• The therapy of choice is ampicillin or benzylpenicillin combined with either aminoglycoside or TMP-SMX.
	• In patients with intolerance to ampicillin or penicillin, one may use a combination of gentamicin with TMP-SMX.
	• If both penicillin and TMP-SMX are contraindicated, one may try meropenem plus gentamicin.
	• Cephalosporins do not work.
	• The duration of therapy should be at least 3 to 4 weeks in immunocompetent and 6 to 8 weeks in immunosuppressed persons.
	• Studies suggest that steroids benefit patients with L. monocytogenes meningitis as they do for other forms of bacterial meningitis.

Some important points to be considered are the following:

We need to keep in mind the following facts (46; 62; 11):

	• Most antibiotics have only bacteriostatic activity against listeria.
	• Only a few can reach the intracellular environment of listeria.
	• For CNS listeriosis, the antibiotic has to be able to cross the blood-brain barrier.
	• Listeria can form subpopulations of dormant, antibiotic-tolerant persisters (46; 62; 11).

There are no controlled head-to-head clinical trials for the choice of antibiotic therapy in Listeria infection; therefore, the recommendations are mainly based on observational and in vitro studies.

For example, the large MONALISA study in France showed a beta-lactam like amoxicillin or an aminoglycoside were each associated with reduced 3-month mortality on multivariate analysis compared with regimens that did not include each of those agents.

Penicillin and ampicillin. Penicillin, amoxicillin, and ampicillin work well because, in addition to reaching inside the CSF and the intracellular environment, they are able to bind to penicillin-binding protein 3 (PBP-3) of Listeria and cause it to die (108; 94). However, at the concentrations reached, penicillins are mainly bacteriostatic and so need to be combined with another bactericidal drug.

The dose recommended in adults is ampicillin 2 g intravenously every 4 hours or penicillin G 4 million units intravenously every 4 hours.

Infants and children also are treated similarly with ampicillin and gentamicin. In general, the dose is higher if there is either proven or possible CNS listeriosis. If CNS listeriosis has not been ruled out, the recommended dose of ampicillin is 300 mg/kg/day in four divided doses for babies from birth until age 60 days. In the first week, they are given in three divided doses. In infants and children after the age of 60 days, the dose is increased to 300 to 400 mg/kg/day in four to six divided doses, with a maximum of 12 g per day.

If CNS infection has been ruled out, the dose of ampicillin advised in the first week of life is 100 mg/kg per day intravenous in two divided doses for those with weight less than or equal to 2 kg or 150 mg/kg per day intravenous in three divided doses for infants with weight greater than 2 kg. Between 8 to 28 days, the dose is 150 mg/kg/day divided into three doses. After the age of 29 days, the dose is 200 mg/kg/day intravenous in four divided doses, up to a maximum of 8 g per day (37).

Gentamicin. Despite its poor CNS penetration (81; 07), gentamicin, which is bactericidal, enhances the killing rate with ampicillin in vitro (85; 94).

Amoxicillin-aminoglycoside combination therapy longer than 3 days had an independent protective effect on survival compared with no combination therapy (80% vs. 20%; OR 0.35, 95% CI 0.22-0.56) (21).

The combination of ampicillin with gentamicin is recommended by the European guidelines and even considered the treatment of choice by some authorities (37). The downside of gentamicin is nephrotoxicity and ototoxicity; therefore, patients should be monitored for nephrotoxicity and ototoxicity (110; 112). Also, it cannot be used in persons whose renal function is already impaired.

Gentamicin is advised in adults with normal renal function in a dose of 5 mg/kg per day intravenous in three divided doses. In infants, gentamicin is advised along with ampicillin until the infant is clinically improved and the CSF is sterile, whereas ampicillin is given for 14 to 21 days.

For infants less than 60 days old, depending on the gestational and postnatal age, the dose of gentamicin is as follows:

	• Gestational age less than 30 weeks:
		- Postnatal age less than or equal to 14 days: 5 mg/kg intravenous every 48 hours
		- Postnatal age greater than 14 days: 5 mg/kg intravenous every 36 hours
	• Gestational age 30 to 34 weeks:
		- Postnatal age less than or equal to 10 days: 5 mg/kg intravenous every 36 hours
		- Postnatal age greater than 10 to 60 days: 5 mg/kg intravenous every 24 to 36 hours
	• Gestational age greater than or equal to 35 weeks:
		- Postnatal age less than or equal to 7 days: 4 mg/kg intravenous every 24 hours
		- Postnatal age greater than 7 to 60 days: 5 mg/kg intravenous every 24 hours

For infants and children greater than 60 days of age, the dose advised is 7.5 mg/kg per day intravenous in three divided doses.

Trimethoprim-sulfamethoxazole (TMP-SMX). TMP-SMX is associated with a favorable outcome, probably due to good CNS penetration (94). Regimens with TMP-SMX were associated with reduced 3-month mortality (OR 0.49, 95% CI 0.26-0.92) compared to regimens without TMP-SMX (21).

The dose advised is 15 to 20 mg/kg intravenous per day of the trimethoprim component divided into four daily doses. TMP-SMX plus ampicillin is the choice when gentamicin cannot be used because of impaired renal function or concomitant use of nephrotoxic drugs. In fact, a small study of 22 patients suggested this combination may be more effective than ampicillin plus gentamicin (79).

In penicillin-allergic patients, TMP-SMX plus gentamicin combination is advisable.

Meropenem. Meropenem has excellent in vitro activity against Listeria and has been used successfully to treat listeriosis. However, there are reported failures, and a retrospective study showed higher mortality compared to penicillin (110).

Therefore, only when neither penicillin nor TMP-SMX can be used, one may use the combination of meropenem with gentamicin.

The dose of meropenem is 2 g intravenously every 8 hours in adults and 120 mg/kg per day in three divided doses in children; the maximum dose is 6 g/day (37).

Other second-line drugs. Quinolones have excellent tissue and cell penetration and are rapidly bactericidal for Listeria, but their clinical activity is not as high as expected. Newer quinolones may have a role, but it has yet to be elucidated.

Linezolid and rifampicin seem useful based on experimental studies, but there is not much clinical data (94).

Antibiotic agents to avoid. Certain antibiotics are ineffective against Listeria and should, therefore, be avoided (84; 37).

	• Vancomycin has been used as an alternative agent, but failures have been reported. It may be used in pregnant patients when other agents cannot be used.
	• Erythromycin and tetracyclines are bacteriostatic; their clinical efficacy is uncertain, and resistance has been reported.
	• Chloramphenicol is less effective and should be avoided.
	• Cephalosporins are inactive in vitro and ineffective clinically.

Duration of treatment. There are no definitive answers on the duration of therapy; therefore, one may decide based on the seriousness of the illness and on the status of the patient, whether immunocompetent, healthy, young, or otherwise. Response to therapy may be used to monitor clinical response, serial brain imaging, and possibly quantitative PCR or even CSF culture to confirm eradication in CSF (68; 37).

For immunocompetent patients with CNS disease, at least 3 to 4 weeks of treatment is recommended (112; 37).

Immunocompromised patients have had recurrences after 2 weeks of treatment (71), so 4 to 8 weeks of therapy is suggested (05; 70; 71; 85).

Cerebritis or brain abscesses are advised with longer treatment, for at least 6 to 8 weeks (70; 85).

Gentamicin is generally continued until the patient improves (usually 7 to 14 days) or, in poor responders, for up to 3 weeks if there is no nephrotoxicity or ototoxicity (37).

Steroids. It used to be recommended to avoid or stop steroids once one diagnosed meningitis to be due to Listeria. For example, the MONALISA study found steroid therapy to be associated with increased mortality (21).

A study from the Netherlands showed that adjunctive dexamethasone benefits patients with L. monocytogenes meningitis when given with the first dose of antibiotics in a dose of 10 mg four times daily for 4 days. Thus, they favor a full 4-day course of dexamethasone in all patients with community-acquired bacterial meningitis (14).

Outcomes

	• Untreated meningoencephalitis or rhombencephalitis has almost 100% mortality.
	• Mortality depends on immune status, site of infection, and how early or late diagnosis and appropriate therapy are initiated.
	• Mortality is 45% with bacteremia and 30% with CNS listeriosis.
	• Mortality is higher in those who received steroids.
	• CNS infection is an important risk factor for mortality and morbidity.
	• Adults with no underlying disease almost always do well.
	• Older patients with Listeria meningitis may need to be screened for cancer.
	• Outcomes for pregnant patients with Listeria are typically good.
	• Fetal and neonatal infections can be severe, leading to fetal loss, preterm labor, neonatal sepsis, meningitis, and death.

Special considerations

Pregnancy

	• Listeriosis has a specific tropism for the placenta.
	• It can reach and silently and efficiently invade the placenta and induce devastating consequences on the developing fetus.
	• Pregnant women are particularly prone to listeriosis, with an estimated 17-fold increase in incidence (10 to 100 times) compared to the general population.
	• One in seven cases of listeriosis occurs in pregnant women.
	• It causes a minor illness often mistaken for a urinary tract infection or a flu-like viral infection.
	• Only 5% of pregnant women with maternal listeriosis experience uneventful subsequent pregnancy and delivery.
	• Fetal infection has serious implications, with fetal loss in about 20% and newborn death in about 8% of cases.
	• Neonatal listeriosis can manifest in three forms: early-onset sepsis syndrome, late-onset meningitis, and the rarer granulomatosis infantiseptica.
	• Most pregnant women are unaware of listeriosis and precautions to be taken, and there is a need to educate them.
	• There needs to be a low index of suspicion for maternal listeriosis and a low threshold to begin empiric treatment in women with suspected infection.

Pregnancy-associated listeriosis. One in seven cases of listeriosis occurs in pregnant women. Compared with nonpregnant females, the risk is increased between 10 to 100 times higher according to rough estimates (23), and almost 17-fold by most authorities (27). The hypervirulent strains belonging to clonal complexes 1, 4, and 6 are the most associated with maternal-neonatal infections (23).

Possibly due to dietary habits, there is an even higher incidence of pregnancy-associated listeriosis in certain ethnic minorities, for example, American Hispanic women in the United States compared to the general population (30.0% vs. 3.5%, respectively) (27).

Pregnancy-associated listeriosis mainly affects otherwise healthy women. Most cases occur in the third stage of gestation.(61). The cause is thought to be the physiologic suppression of immunity, which is maximum in the third trimester and is necessary to avoid rejection of the fetus by the body’s immune system. This physiologic immunosuppression leads to increased susceptibility to intracellular pathogens such as L. monocytogenes, Coxiella burnetii, and Toxoplasma gondii (27).

Despite invading the bloodstream, listeriosis in pregnancy presents as a relatively mild illness with nonspecific or subtle symptoms like mild fever (in 12% to 85%) and myalgia. It may be mistaken for flu or a urinary tract infection (70; 86; 35; 21; 27). There is often a delay in diagnosis--a median time of 4.8 days in one study (64). Despite this frequent delay in diagnosis, maternal morbidity and mortality are rare, and almost all patients recover, sometimes even without treatment (21). Pregnant women do not usually get severe disseminated disease or CNS listeriosis (86), unless there are other risk factors causing immunosuppression (47). It is not necessary to do CSF assessment routinely in maternal listeriosis (23; 61).

This benign maternal course contrasts with the dubious distinction of being one of the infections associated with the highest fetal and neonatal morbidity, and over 95% of pregnant women with listeriosis experience some adverse outcome (21; 61). Despite being such a dangerous problem for pregnant women, most pregnant women are not aware of it. A national survey of 403 pregnant women from the United States found that only 18% were familiar with listeriosis, and less than 30% of those knew how to prevent ingesting contaminated foods (27).

Fetal and neonatal listeriosis. Despite not having many signs or symptoms themselves, almost all women (96%) with maternal Listeria transmit the infection to the fetus (27).

L. monocytogenes can invade the placenta, get past the fetoplacental barrier, and infect the fetus, causing chorioamnionitis, spontaneous abortion, stillbirth, preterm labor, and neonatal infection in the majority (27). There is no specific information about teratogenicity (27).

Fetal loss is more common (between 20% to 30%) than neonatal death (8%) (39). In the MONALISA study of 107 pregnant women with listeriosis, only five did not experience some adverse outcome. Ten neonates (12%) had normal physical examinations without signs of infection at birth; subsequently, six of these 10 neonates went on to develop late-onset disease (21).

The earlier in gestation the infection, the worse the outcome. The risk of miscarriage is 65% for infection in the first trimester as compared to 26% in the second or third trimester (19). Another series of 166 cases acquired in the first, second, and third trimesters documented fetal survival at 0%, 29.2%, and 95.3%, respectively (35). In the MONALISA study, all fetal losses occurred when the infection was acquired before 29 weeks (21).

Listeriosis has been one of the top causes of severe bacterial infection in the neonatal period, but in recent decades, there has been a reduction, possibly due to improved food safety and antenatal screening and prophylaxis with penicillin or amoxicillin for group B Streptococcus (67).

Listeria is the third leading cause of neonatal meningitis worldwide (121).

Neonates can get infected transplacentally or during vaginal delivery, and the earlier the onset, the more severe the illness. Neonatal listeriosis can manifest in three forms: granulomatosis infantiseptica, early-onset sepsis syndrome, and late-onset meningitis syndrome (70).

Granulomatosis infantiseptica and early-onset listeriosis are acquired by transplacental infection in utero, leading to the delivery of an often premature and severely ill infant.

Granulomatosis infantiseptica is a rare, rapidly fatal disseminated infection in utero presenting at birth with widespread microabscesses and granulomas within the liver, spleen, and sometimes, skin.

Early-onset listeriosis presents mainly as sepsis in a neonate (days 1 to 7) and has a high mortality rate. It presents with pneumonia, respiratory distress, and fever. Neurologic involvement, like meningitis, is less common (24%).

As against the sick and premature infant born to a woman with symptoms in early-onset listeriosis, the late-onset variety leads to a healthy infant born to an apparently healthy woman. The infant is usually term and healthy at delivery, and the mother is often just an asymptomatic gastrointestinal carrier of L. monocytogenes without sepsis. Infection is picked up by the infant in the colonized birth canal or later by aspiration or swallowing. Such infants present 7 to 14 days later with meningitis, in almost 94%, with fever and irritability. Thus, CNS involvement is the predominant clinical syndrome in late-onset listeriosis. The mortality rates are significantly lower as compared to the ones with early-onset neonatal infection (86).

Management of maternal listeriosis. There are no randomized trials of antibiotic treatment, and most data are based on reports of clinical experience. The diagnosis of listeriosis in pregnancy is particularly difficult, as up to 30% of infected mothers are asymptomatic. There are no rapid confirmatory tests, and placental or maternal blood cultures have a low sensitivity. When listeriosis is suspected, the recommendation is to start treatment before confirmation of diagnosis (27).

When a pregnant woman has a presumptive exposure, for example, having eaten food known to be contaminated or having a risk of being contaminated, the approach depends on the clinical presentation:

	• If asymptomatic, no treatment nor fetal surveillance is warranted. They should be advised to return if symptoms develop.
	• If there is unexplained fever greater than or equal to 38.1°C, empiric antibiotic therapy (ampicillin 2 g intravenously every 4 hours) should be initiated while diagnostic studies are pending. If blood cultures become positive, further management is discussed below. If blood cultures are negative, some authorities give a 7-day course of oral amoxicillin or oral TMP-SMX. TMP-SMX is to be avoided in the first trimester. Fetal surveillance also may be prudent.
	• With mild symptoms but without fever greater than or equal to 38.1°C (100.6°F), some suggest empiric oral amoxicillin or TMP-SMX unless blood culture comes positive.
	• If blood culture comes positive in any of the above categories, they should be treated as Listeria bacteremia as usual with intravenous ampicillin or penicillin for 14 days. Gentamicin is not preferred in pregnancy. As with Listeria infection in nonpregnant persons, penicillin-allergic patients may be given TMP-SMX, except during the first trimester. In those who cannot take TMP-SMX, meropenem or vancomycin may be appropriate (25; 37).

A website on Listeria is available for pregnant women and can be accessed at the following site: USFDA fact sheet.

Media

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Sudhir Kothari MD

Dr. Kothari of Poona Hospital and Research Centre has no relevant financial relationships to disclose.
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Editor

Christina M Marra MD

Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.
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Former Authors

Stephen F Overcash
Karen L Roos MD FAAN
Paul Auwaerter MD (original author), Samineh Khosrowshahi MD, Vitor Pacheco MD, John B Selhorst MD, and John N Ratchford MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: Elderly

Immune-compromised

Neonates
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Meningitis in other bacterial diseases classified elsewhere: 320.7

Listeriosis: 027.0
ICD-10: Meningitis in other bacterial diseases classified elsewhere: G00

Listeriosis: A32

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CNS listeriosis

Associated Disorders

Alcoholism
Bacterial meningitis
Brain abscess
Cancer
Cerebritis
- HIV
- Meningitis
- Neonatal meningitis
- Rhombencephalitis

Differential Diagnosis

S pneumonia
Neisseria meningitidis
tuberculous meningitis
fungal meningitis
syphilitic meningitis
- leptomeningeal carcinomatosis
- viral brainstem encephalitis
- Herpes simplex virus
- arboviral CNS infections
- brainstem-oriented infections
- Epstein-Barr virus
- adenovirus
- echovirus
- rabies
- stroke
- vasculitis
- multiple sclerosis
- neurosarcoidosis
- Behçet disease
- Bickerstaff brainstem encephalitis
- neoplasms
- paraneoplastic syndromes
- subcortical abscess
- polymicrobial brain abscesses
- streptococcal brain abscesses
- staphylococcal brain abscesses

Also Relevant

Ataxia
Bacterial meningitis
Cryptococcal meningitis
Diagnosis of CNS infections
Neonatal meningitis
- Recurrent meningitis
- Viral meningitis

CNS listeriosis …

CNS listeriosis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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CNS listeriosis

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Prion diseases

Rabies

Malaria

Neuropathies associated with cytomegalovirus infection

Genital herpes: neurologic complications

Neurocysticercosis

Trichinosis

Zika virus: neurologic complications

This is an article preview.
Start a Free Account
to access the full version.