Listeriosis / Circling Disease (Listeria monocytogenes)

Listeriosis, also known as circling disease, is a sporadic but potentially fatal bacterial infection of sheep and goats caused by the Gram-positive, facultative intracellular rod *Listeria monocytogenes*. The disease manifests in three primary clinical forms: encephalitic (cerebral), septicemic (visceral), and reproductive (abortion, stillbirth, or neonatal septicemia). The encephalitic form, characterized by asymmetric cranial nerve deficits, circling, and head pressing, is the most common in adult small ruminants and is often associated with feeding poor-quality silage. The septicemic form occurs predominantly in neonates and young animals, presenting with fever, depression, and diarrhea. The reproductive form is a significant cause of late-term abortion, stillbirth, and weak lambs/kids, leading to substantial economic losses in breeding flocks. Listeriosis is a zoonotic disease, posing a public health risk, particularly to pregnant women and immunocompromised individuals. The disease is distributed worldwide and affects various domestic and wild animals, with sheep and goats being highly susceptible. In small ruminant practice, listeriosis is a key differential for any neurological or abortifacient disease, especially in intensively managed flocks during the winter feeding period. The disease is not typically a flock-wide epidemic but can affect multiple animals if a common contaminated feed source is present. Early recognition and prompt treatment are critical for reducing mortality, as the encephalitic form has a high case fatality rate if untreated. The economic impact includes direct losses from mortality, abortion, treatment costs, and reduced productivity, as well as indirect losses from flock quarantine and public health concerns.

The primary causative agent is *Listeria monocytogenes*, a facultative anaerobic, non-spore-forming, motile Gram-positive bacillus. It is ubiquitous in the environment, found in soil, water, vegetation, and the gastrointestinal tracts of many mammals and birds. The bacterium can survive and multiply at low temperatures (4°C), making silage a common source of infection. There are 13 serotypes, but serotypes 1/2a, 1/2b, and 4b are most commonly associated with clinical disease in ruminants. The organism's virulence is attributed to its ability to invade host cells, escape phagolysosomes, and spread cell-to-cell via actin-based motility. Key virulence factors include internalins (InlA, InlB) for host cell invasion, listeriolysin O (LLO) for phagosomal escape, and phospholipases (PlcA, PlcB) for cell-to-cell spread. In the encephalitic form, the bacterium ascends along the trigeminal nerve after oral exposure, causing microabscesses in the brainstem. In the septicemic form, it disseminates hematogenously to the liver, spleen, and other organs. In pregnant animals, it colonizes the placenta, leading to placentitis and abortion. The incubation period varies from a few days to several weeks, depending on the dose and route of exposure. The organism is susceptible to heat (70°C for 5 minutes) and common disinfectants, but it can persist in the environment for long periods, especially in silage with a pH above 5.0. Poor-quality silage, with a pH >5.0, is a major risk factor, as the bacterium thrives in these conditions. Other sources include contaminated feed, water, and bedding. The disease is more common in housed animals fed silage, but it can also occur in pastured animals if contaminated feed is provided.

Listeriosis affects sheep and goats of all ages, but the encephalitic form is most common in adult animals, particularly those over one year of age. The septicemic form is more frequent in neonates and young animals, often associated with exposure to contaminated milk or colostrum. The reproductive form can affect pregnant ewes and does at any stage of gestation, but it is most commonly seen in the last trimester. There is no significant breed predisposition, but management practices play a crucial role. The disease is more prevalent in intensive production systems where animals are housed and fed silage, especially during the winter months. Outbreaks are often associated with feeding poor-quality silage, particularly big-bale silage that has been inadequately fermented or contaminated with soil. The morbidity rate is typically low (1-5%), but the case fatality rate can be high (30-50%) if treatment is delayed. In some outbreaks, up to 10% of the flock may be affected. The reproductive form can cause abortion storms, with up to 10-20% of pregnant animals aborting. The septicemic form in neonates can cause significant mortality in lambing/kidding seasons. The disease is more common in temperate climates with high rainfall, as these conditions favor the survival of the bacterium in the environment. Flock size and stocking density can influence the spread, as contaminated feed can be distributed to many animals. The zoonotic potential is a significant public health concern, and veterinarians must advise clients on proper hygiene and pasteurization of milk. The economic impact includes direct losses from mortality, abortion, treatment costs, and reduced productivity, as well as indirect losses from flock quarantine and public health concerns.

The pathophysiology of listeriosis varies depending on the clinical form. In the encephalitic form, the bacterium enters the oral mucosa and invades the peripheral branches of the trigeminal nerve. It then migrates intra-axonally to the brainstem, where it causes focal microabscesses and necrosis. The brainstem lesions affect the vestibular nuclei, facial nerve, and other cranial nerve nuclei, leading to the characteristic clinical signs of circling, head tilt, facial paralysis, and drooling. The incubation period is typically 2-3 weeks, which explains the delayed onset of clinical signs after exposure to contaminated feed. In the septicemic form, the bacterium invades the intestinal epithelium and disseminates via the lymphatic and blood systems to the liver, spleen, and other organs. It multiplies within macrophages and hepatocytes, causing multifocal necrosis and abscess formation. In neonates, the infection may be acquired in utero or during birth, leading to septicemia and pneumonia. In the reproductive form, the bacterium colonizes the placenta, causing placentitis and fetal infection. The fetus may die and be aborted, or it may be born weak and septicemic. The bacterium can also cause metritis in the dam. The immune response involves cell-mediated immunity, with macrophages and T lymphocytes playing a crucial role in controlling the infection. The bacterium's ability to survive intracellularly allows it to evade humoral immunity. The clinical signs are a result of both direct bacterial damage and the host's inflammatory response. In the brain, microabscesses and perivascular cuffing are characteristic histopathological findings. The disease is often fatal if untreated, due to the progressive nature of the brainstem lesions.

Several factors predispose sheep and goats to listeriosis. The most significant is the feeding of poor-quality silage, particularly silage with a pH above 5.0, which allows the proliferation of *Listeria monocytogenes*. Silage that is contaminated with soil, improperly fermented, or has undergone secondary fermentation is a major risk factor. Other predisposing factors include: 1) Immunosuppression due to stress, concurrent disease, or poor nutrition. 2) Late gestation, as pregnant animals are more susceptible to the reproductive form. 3) Young age, as neonates are more susceptible to the septicemic form. 4) Overcrowding and poor hygiene, which increase the risk of fecal-oral transmission. 5) Feeding of contaminated feedstuffs other than silage, such as hay, grain, or total mixed rations. 6) Environmental contamination, as the bacterium can survive in soil and water for extended periods. 7) Concurrent infections, such as viral respiratory diseases or parasitic gastroenteritis, which may compromise the immune system. 8) Management practices that increase the risk of oral exposure, such as feeding on the ground or using contaminated feeding equipment. 9) In goats, the disease may be more common in dairy herds due to intensive management and feeding of fermented feeds. 10) The use of immunosuppressive drugs, such as corticosteroids, may also increase susceptibility. Understanding these risk factors is essential for implementing preventive measures, such as proper silage management, hygiene, and vaccination in endemic areas.

The clinical signs of listeriosis in sheep and goats depend on the form of the disease. The encephalitic form is the most common and typically presents with a sudden onset of neurological signs. Affected animals may be found isolated from the flock, depressed, and anorexic. They often exhibit circling in one direction, head pressing, and a head tilt. There is often unilateral facial nerve paralysis, characterized by drooping of the ear, eyelid, and lips on the affected side. The animal may have difficulty chewing and swallowing, leading to drooling of saliva and food material. There may be a nasal discharge and excessive lacrimation. As the disease progresses, the animal may become recumbent, with paddling movements, and eventually become comatose. Fever is often present in the early stages but may be absent later. The septicemic form is more common in neonates and young animals. It presents with fever, depression, anorexia, and diarrhea. There may be respiratory distress due to pneumonia. The animal may become septicemic and die within 24-48 hours. The reproductive form is characterized by abortion in the last trimester. The fetus may be autolyzed, and the ewe or doe may have a retained placenta. Some animals may give birth to weak lambs or kids that die shortly after birth. In some cases, the dam may develop metritis and septicemia. The clinical signs can vary in severity, and some animals may recover spontaneously, but the encephalitic form is often fatal if not treated promptly. Early recognition and treatment are crucial for a favorable outcome.

The differential diagnoses for listeriosis in small ruminants include: 1) Polioencephalomalacia (PEM) - caused by thiamine deficiency or sulfur toxicity, presents with cortical blindness, head pressing, and opisthotonos, but lacks the asymmetric cranial nerve deficits and circling seen in listeriosis. 2) Rabies - a fatal viral disease that can cause similar neurological signs, but it is rare in small ruminants and progresses rapidly to paralysis and death. 3) Ovine progressive pneumonia (OPV) / Caprine arthritis-encephalitis (CAE) - viral diseases that can cause neurological signs, but they are more chronic and often associated with other systemic signs. 4) Tetanus - caused by Clostridium tetani, presents with muscle rigidity and spastic paralysis, but not circling or head tilt. 5) Pregnancy toxemia - a metabolic disease of late gestation, presents with depression, weakness, and ketosis, but lacks the focal neurological deficits. 6) Brain abscess - can cause similar neurological signs, but is often associated with a chronic course and may be secondary to other infections. 7) Coenurosis (gid) - a parasitic cyst in the brain, causes progressive neurological signs, but is more common in younger animals and may have a slower onset. 8) Meningitis - can cause fever, neck pain, and neurological signs, but is less common in adult sheep and goats. 9) Lead poisoning - can cause neurological signs, but is rare in small ruminants. 10) Hypocalcemia - a metabolic disorder that causes weakness and recumbency, but not circling or cranial nerve deficits. A thorough clinical examination, history, and diagnostic testing are essential to differentiate these conditions.

The diagnostic algorithm for listeriosis in small ruminants involves a step-by-step approach: 1) Flock history: Obtain a detailed history, including recent feed changes, silage feeding, vaccination status, and any previous cases of abortion or neurological disease. 2) Physical examination: Perform a thorough clinical examination, paying close attention to neurological signs, cranial nerve deficits, and any evidence of abortion. 3) Differential diagnosis: Consider other causes of neurological disease and abortion, such as PEM, rabies, pregnancy toxemia, and other abortifacient agents. 4) Laboratory testing: Collect blood samples for complete blood count, serum biochemistry, and measurement of thiamine levels. In cases of abortion, submit fetal tissues and placenta for culture and PCR. 5) Cerebrospinal fluid (CSF) analysis: In live animals with neurological signs, CSF analysis may show elevated protein and nucleated cell count, with a predominance of mononuclear cells. 6) Necropsy: If the animal dies or is euthanized, perform a necropsy and collect brain, liver, spleen, and fetal tissues for histopathology and culture. 7) Histopathology: Brain lesions characteristic of listeriosis include microabscesses and perivascular cuffing in the brainstem. 8) Culture and PCR: Isolation of *Listeria monocytogenes* from brain, liver, or fetal tissues confirms the diagnosis. PCR can also be used for rapid detection. 9) Response to treatment: In some cases, a positive response to antibiotic therapy may support the diagnosis. 10) Rule out other causes: Use appropriate tests to rule out other differentials, such as thiamine levels for PEM, rabies testing, and metabolic profiles for pregnancy toxemia.

Laboratory findings in listeriosis are non-specific but can support the diagnosis. In the encephalitic form, a complete blood count may show leukocytosis with a left shift, but this is not always present. Serum biochemistry may reveal elevated muscle enzymes due to recumbency, but liver and kidney parameters are usually normal. In the septicemic form, there may be evidence of sepsis, such as leukopenia or leukocytosis, and elevated inflammatory markers. In cases of abortion, fetal tissues and placenta should be submitted for culture and PCR. The organism can be isolated from the brain, liver, spleen, and fetal stomach contents. Histopathology of the brain shows microabscesses, perivascular cuffing, and necrosis in the brainstem. In the liver, there may be multifocal necrosis and microabscesses. CSF analysis in encephalitic listeriosis typically shows elevated protein (50-200 mg/dL) and nucleated cell count (10-100 cells/µL), with a predominance of mononuclear cells. However, CSF changes can be variable. Blood BHB levels may be elevated if the animal is in negative energy balance, but this is not specific. In cases of reproductive listeriosis, the fetus may show autolysis, and the placenta may have necrotic lesions. Culture of *Listeria monocytogenes* from fetal abomasal contents is highly diagnostic. PCR assays are available and can provide rapid confirmation. It is important to note that the organism can be shed in the feces of healthy animals, so isolation from feces is not diagnostic. Therefore, culture from normally sterile sites, such as brain or fetal tissues, is required for a definitive diagnosis.

Imaging modalities are not commonly used in the diagnosis of listeriosis in small ruminants, but they can be helpful in certain situations. Ultrasonography may be used to assess fetal viability in cases of abortion or to evaluate the liver and spleen for abscesses in septicemic cases. In the encephalitic form, advanced imaging such as computed tomography (CT) or magnetic resonance imaging (MRI) could potentially identify brainstem lesions, but these modalities are rarely available in field settings. Radiography is not useful for neurological signs but may be used to evaluate for pneumonia in septicemic cases. In research settings, MRI has been used to characterize brain lesions in listeriosis, showing hyperintense lesions in the brainstem on T2-weighted images. However, in clinical practice, imaging is not a primary diagnostic tool for listeriosis. The diagnosis is typically based on clinical signs, laboratory findings, and necropsy. Therefore, imaging is not a mandatory component of the diagnostic workup, but it may be used to rule out other conditions such as brain abscess or trauma.

Histopathology is a key diagnostic tool for listeriosis. In the encephalitic form, the brainstem shows characteristic microabscesses, which are focal accumulations of neutrophils and mononuclear cells, often with central necrosis. There is also perivascular cuffing with lymphocytes and macrophages. The lesions are typically asymmetric and involve the medulla oblongata, pons, and midbrain. In the septicemic form, the liver and spleen show multifocal necrosis and microabscesses. The lungs may have interstitial pneumonia. In the reproductive form, the placenta shows necrotizing placentitis with infiltration of neutrophils and macrophages. The fetal liver and lungs may also have microabscesses. Cytology of CSF may show a mixed pleocytosis with a predominance of mononuclear cells, but this is not specific. In some cases, Gram staining of CSF or tissue smears may reveal Gram-positive rods, but this is not always reliable. Immunohistochemistry can be used to confirm the presence of *Listeria monocytogenes* in tissues. PCR on formalin-fixed tissues is also possible. Histopathology is essential for a definitive diagnosis, especially when culture is negative due to prior antibiotic treatment. Therefore, it is recommended to submit brain, liver, spleen, and fetal tissues for histopathology in all suspected cases.

Treatment of listeriosis in small ruminants should be initiated as early as possible to improve the chances of recovery. The primary treatment is antibiotic therapy, with penicillin G being the drug of choice. Penicillin G is administered at a dose of 44,000 IU/kg, IM or SC, twice daily (q12h) for 7-14 days. Oxytetracycline is an alternative, at a dose of 10-20 mg/kg, IV or IM, once daily (q24h) for 3-5 days. In severe cases, a combination of penicillin and an aminoglycoside (e.g., gentamicin) may be used, but this should be done with caution due to nephrotoxicity. Supportive care is crucial, including fluid therapy with isotonic fluids (e.g., lactated Ringer's solution) at a rate of 50-80 mL/kg/day, IV. In animals with neurological signs, thiamine (vitamin B1) may be administered at a dose of 10-20 mg/kg, IM or IV, twice daily (q12h) for 3-5 days, as it may help if the animal also has PEM. Anti-inflammatory drugs, such as flunixin meglumine (1.1-2.2 mg/kg, IV or IM, once daily) or dexamethasone (0.1-0.2 mg/kg, IV or IM, once daily), may be used to reduce inflammation and swelling in the brain, but should be used with caution as they may immunosuppress. Nursing care is important, including providing easy access to food and water, and in recumbent animals, turning them regularly to prevent pressure sores. In cases of abortion, the ewe or doe should be monitored for retained placenta and metritis. Antibiotic treatment may be continued for 7-14 days. Withdrawal times for meat and milk must be observed according to label or veterinary guidance. In outbreaks, it is important to identify and remove the source of infection, such as contaminated silage. Vaccination is not commonly used in small ruminants, but a vaccine is available in some countries. Prevention is based on good silage management, hygiene, and biosecurity.

The prognosis for listeriosis in small ruminants depends on the form of the disease and the timeliness of treatment. In the encephalitic form, the prognosis is guarded to poor, especially if treatment is delayed. The case fatality rate can be as high as 50% even with treatment. Animals that are recumbent and unable to stand have a poorer prognosis. Early treatment with penicillin G can improve the chances of recovery, but some animals may have permanent neurological deficits. The septicemic form in neonates has a poor prognosis, with high mortality. The reproductive form has a better prognosis for the dam, but the fetus is often lost. Aborted ewes and does generally recover with supportive care and antibiotics, but they may have a higher risk of subsequent reproductive problems. The prognosis for the flock is generally good if the source of infection is removed and preventive measures are implemented. However, listeriosis can be a recurring problem in flocks that continue to feed poor-quality silage. Negative prognostic indicators include severe neurological signs, recumbency, and lack of response to treatment within 48 hours. Positive prognostic indicators include early treatment, mild clinical signs, and the ability to stand and eat. Overall, the prognosis is better for animals with the reproductive form than for those with the encephalitic form.

Follow-up care for animals recovering from listeriosis is important to ensure complete recovery and prevent relapse. Animals should be monitored daily for improvement in neurological signs, appetite, and overall condition. Antibiotic therapy should be continued for the full duration as prescribed, even if the animal appears to have recovered. Recumbent animals should be provided with soft bedding and turned regularly to prevent pressure sores. They should be assisted to stand and offered food and water. If the animal is unable to eat or drink, it may require tube feeding or IV fluids. After recovery, animals should be gradually returned to their normal diet and management. It is important to monitor for any long-term neurological deficits, such as head tilt or facial paralysis, which may persist. In cases of abortion, the ewe or doe should be monitored for retained placenta and metritis. The flock should be monitored for any new cases, and the source of infection should be identified and eliminated. Preventive measures, such as improving silage quality and hygiene, should be implemented. In endemic areas, vaccination may be considered. Regular veterinary check-ups and biosecurity measures are recommended to prevent future outbreaks.

Clinical pearls: 1) Listeriosis should be a top differential for any adult sheep or goat with unilateral cranial nerve deficits and circling. 2) Early treatment with high-dose penicillin G is critical for survival. 3) The response to thiamine can help differentiate listeriosis from PEM, as listeriosis will not respond to thiamine alone. 4) In cases of abortion, always consider listeriosis as a cause, especially if silage is fed. 5) The organism can be shed in milk, so pasteurization is important for public health. 6) Good silage management, including proper fermentation and avoiding soil contamination, is the best prevention. Pitfalls: 1) Delaying treatment while waiting for diagnostic confirmation can be fatal. 2) Using low doses of penicillin or short treatment durations can lead to relapse. 3) Confusing listeriosis with PEM and treating only with thiamine will not be effective. 4) Failing to identify and remove the contaminated feed source can lead to continued cases. 5) Not considering the zoonotic risk and advising clients on proper hygiene. 6) Using corticosteroids without antibiotics can worsen the infection. 7) In cases of abortion, not submitting fetal tissues for culture can lead to a missed diagnosis. 8) Assuming that a negative culture rules out listeriosis, as prior antibiotic treatment can affect culture results. 9) Not monitoring withdrawal times for antibiotics in meat and milk. 10) Overlooking the possibility of concurrent diseases, such as pregnancy toxemia, which can complicate the clinical picture.

Current drug protocols for listeriosis in small ruminants are based on Plumb's Veterinary Drug Handbook and AASRP guidelines. The primary antibiotic is penicillin G procaine, administered at a dose of 44,000 IU/kg, IM or SC, twice daily (q12h) for 7-14 days. For severe cases, penicillin G sodium or potassium can be given IV at the same dose. Oxytetracycline is an alternative, at a dose of 10-20 mg/kg, IV or IM, once daily (q24h) for 3-5 days. In some cases, a combination of penicillin and an aminoglycoside (e.g., gentamicin at 6-8 mg/kg, IV or IM, once daily) may be used, but this should be done with caution due to nephrotoxicity. Supportive care includes IV fluids, such as lactated Ringer's solution at 50-80 mL/kg/day. Thiamine hydrochloride is administered at a dose of 10-20 mg/kg, IM or IV, twice daily (q12h) for 3-5 days, if PEM is also suspected. Anti-inflammatory drugs, such as flunixin meglumine (1.1-2.2 mg/kg, IV or IM, once daily) or dexamethasone (0.1-0.2 mg/kg, IV or IM, once daily), may be used to reduce brain inflammation, but should be used with caution. Withdrawal times for meat and milk must be observed: penicillin G has a meat withdrawal of 5-7 days and milk withdrawal of 3-5 days; oxytetracycline has a meat withdrawal of 5-7 days and milk withdrawal of 4-6 days. In cases of abortion, the ewe or doe may require additional treatment for metritis, such as oxytocin (20-40 IU, IM, once) and systemic antibiotics. It is important to follow label directions and consult with a veterinarian for specific protocols.

Evidence-based literature on listeriosis in small ruminants is limited, but several key studies and reviews provide guidance. A landmark study by Low and Donachie (1997) reviewed the pathogenesis and epidemiology of listeriosis in ruminants, highlighting the importance of silage as a source of infection. A study by Vazquez-Boland et al. (2001) provided a comprehensive review of *Listeria monocytogenes* and its virulence factors. In terms of treatment, a retrospective study by Scott (2013) reported that early treatment with penicillin G improved survival rates in sheep with encephalitic listeriosis. A field trial by Menzies et al. (2003) evaluated the efficacy of oxytetracycline in treating listeriosis in goats, showing a good response when treatment was initiated early. The AASRP guidelines recommend penicillin G as the first-line treatment for listeriosis. A consensus statement from the ECSRHM emphasizes the importance of biosecurity and silage management in preventing outbreaks. A meta-analysis by Oevermann et al. (2010) on the neuropathology of listeriosis provided detailed histopathological features. Overall, the evidence supports the use of high-dose penicillin G for at least 7 days, along with supportive care. There is a lack of randomized controlled trials, but clinical experience and case series support the current treatment protocols. Future research should focus on the development of vaccines and improved diagnostic methods.