Louping ill virus is a flavivirus that causes an acute, tick-transmitted viral disease of the CNS that primarily affects sheep and red grouse. The disease occurs throughout the British Isles wherever the vector tick, Ixodes ricinus, is prevalent, but louping ill is especially common in rough hill grazing.
Diseases of sheep and goats indistinguishable from louping ill have been reported in Norway, Spain, Turkey, and Greece, whereas disease caused by tickborne encephalitis viruses that are similar to louping ill have been reported across Europe (1, 2). Tickborne encephalitis virus has been reported in humans in the UK but has not been shown to cause disease in sheep (2). Both louping ill and tickborne encephalitis have been reported in other species, including cattle, goats, horses, dogs, pigs, South American camelids, and wild boars (1).
Louping ill is also considered zoonotic. Humans can be infected by tick bites or exposure to tissues or instruments contaminated with virus. Risk of this disease is increasing as climate change causes changes in tick habitats (2).
Etiology and Transmission of Louping Ill in Animals
Louping ill virus belongs to the Flaviviridae family and is part of an antigenically closely related complex of viruses known as the tickborne encephalitides, which are primarily associated with disease in humans and distributed throughout the northern temperate regions. Infection is transmitted transstadially (from one developmental stage to another) by the tick vector; transovarial transmission of louping ill virus does not appear to occur. The whole tick life cycle takes 3 years, and louping ill cases typically occur in the autumn and spring, which coincides with seasons when ticks feed.
Although different strains of louping ill virus have been identified by genome sequencing, none appear specific to susceptible species.
In sheep flocks, mortality rates range from 5% to 10% in sheep acclimatized to pasture to 60% in newly introduced stock. On farms where louping ill virus is endemic, losses are mainly confined to animals < 2 years old; adults tend to be immune as a result of previous infection, and lambs are protected in their first season by colostral antibody. However, when the disease appears for the first time, or after a lapse of several years, all ages of sheep are susceptible.
Mortality rates are variable in other species but tend to be high in red grouse. All species of vertebrates that come in contact with questing ticks may become parasitized and infected with louping ill virus; however, only sheep and red grouse develop titers of viremia sufficient to pass the infection to the vector tick. Infection also can be spread through contact with contaminated instruments or tissues.
Infected lactating goats can excrete virus in their milk, which may cause fatal infection of their kids and be a potential human health hazard.
Pathogenesis, Clinical Findings, and Lesions of Louping Ill in Animals
The course of louping ill virus infection in all species is similar, varying only in the intensity of viremia and frequency with which clinical signs develop. After inoculation by an infected tick, the virus initially replicates in lymphoid tissues, which gives rise to viremia that lasts 1–5 days. Only animals that develop high titers can transfer the virus to ticks.
During viremia, a febrile reaction may be present, but overt clinical signs are generally absent until the virus enters the CNS and begins replication, even though the immune response has eliminated the virus from the extraneuronal tissues. The extent of neuronal damage consequent to viral replication determines the severity of clinical signs, from none (subclinical) through varying degrees of neurological dysfunction to sudden death.
Histological lesions may be present whether or not clinical signs develop. Clinical signs include fine muscular tremors, nervous nibbling, ataxia (particularly of the hindlimbs) progressing to posterior paralysis, weakness, and collapse; death may occur 1–3 days after onset of clinical signs. The name louping ill is thought to come from the old Scots word to “loup” or leap, demonstrating the common clinical sign (3).
Peracute deaths may also occur with few histological lesions present. In some recovered animals, residual paresis or torticollis may persist. All recovered animals are solidly immune for life.
The severity of disease in animals recently infected with Anaplasma phagocytophilum (the cause of tickborne fever) is markedly increased, presumably because of the immunosuppressive effect of this organism. Weaned lambs are at highest risk when naive animals, after colostral antibodies have waned, are turned out onto hill pastures where the I ricinus tick is present. The accompanying pathology can be complex and associated with secondary bacterial and mycotic infection, accounting for the high mortality rates experienced when naive flocks are introduced to tick-infested pasture.
No specific gross lesions are present, although secondary pneumonia may develop. Histological examination of the CNS usually shows nonsuppurative (lymphocytic) polioencephalomyelitis characterized by perivascular cuffing, neuronophagia, vacuolation of the cytoplasm, and gliosis, with lesions throughout the brain, but predominantly in the medulla, pons, cerebellum, midbrain, and thalamus. Lesions in the spinal cord have also been reported (3).
Diagnosis of Louping Ill in Animals
Neurological signs with tick exposure followed by confirmatory testing
Louping ill virus infection typically occurs only in animals that have had access to tick-infested pasture; however, the variable clinical picture necessitates differentiation from other conditions that cause locomotor or neurological dysfunction. Differential diagnoses include the following:
caprine arthritis encephalitis virus, ovine progressive pneumonia (maedi-visna), or suppurative meningitis
polioencephalomalacia (cerebral cortical necrosis)
toxins
scrapie (if older animals are affected)
rabies (where present)
Postmortem confirmation of infection is by histological examination of the brain and immunohistochemical analysis using a specific monoclonal antibody, virus detection in CNS tissue by PCR assay, and serological testing.
The whole brain should be fixed in formaldehyde solution (10% in saline), and sections should be examined for the characteristic lesions, which can provide a presumptive diagnosis that is confirmed by immunohistochemical analysis. For routine diagnosis, virus isolation is seldom undertaken and has been replaced by RT-PCR assay. This requires a piece of brainstem or proximal spinal cord to be collected into virus transport medium and dispatched to a suitable diagnostic laboratory.
Measurement of serum neutralizing and hemagglutination inhibition antibodies also can help in diagnosis and for surveys. The presence of IgM antibody in cattle and sheep serum, detected by the hemagglutination inhibition test by comparison with a heat-inactivated aliquot of serum or plasma, provides good evidence that the animal was infected within the preceding 10 days.
Treatment and Control of Louping Ill in Animals
No specific treatments or vaccines
No specific treatment for louping ill is available; however, nursing, hand-feeding, minimizing external stimuli, and sedation may be helpful.
An inactivated, tissue culture–propagated vaccine has successfully protected sheep, cattle, and goats but is no longer available, and development of a recombinant vaccine is only in the early experimental phase.
Areas are considered high-risk where the tick burden on a sheep is > 20 ticks and prevalence of louping ill virus in the flock is > 10%. In these high-risk areas, lambs should be grazed on tick-infested pasture only while they are protected by maternal antibodies from colostrum. Handling of sheep, which causes stress, should primarily occur when tick activity is low, avoiding peak times of spring and autumn and when temperatures are > 7°C (44.6°F).
Acaricides can be delivered via plunge dip using organophosphate products or topical application of synthetic pyrethroids. While plunge dips will cause immediate tick kill, they carry substantial operator and environmental risks. Using both methods of acaricide delivery will prevent development of tick chemical resistance. The use of acaricides will also prevent disease in red grouse, which are frequently raised in the same environment as upland sheep and are also highly susceptible.
Management of the moorland habitat, including bracken fern control and fencing for deer and sheep, can control the tick population (4). No vaccines are available, although experimental vaccines are under development.
Zoonotic Risk of Louping Ill in Animals
Louping ill virus infection in humans can cause severe encephalomyelitis. Symptoms are biphasic; the initial, flulike symptoms are replaced 4–5 days later with clinical signs of encephalitis. Humans become infected through the bite of infected ticks or through contact with infected carcasses, contaminated sharp instruments, or aerosolized virus particles.
Cases in humans are rare, with those in direct contact with infected sheep and those working with the virus at highest risk. Only a few cases of natural transmission have been reported, most occurring in laboratory workers. Those engaged in the diagnosis or research of this virus should be vaccinated with a human vaccine against tickborne encephalitis virus.
Because goats can excrete high titers of virus in their milk, there is a high risk of transmission to humans.
Key Points
Louping ill is a viral infection that often causes fatal encephalitis.
The disease primarily affects sheep and red grouse, but cattle, goats, horses, dogs, pigs, South American camelids, and humans also can be affected.
No specific treatments or vaccines are currently available.
References
Adjadj NR, Veraeke M, Sohier C, Cargnel M, De Regge N. Tick-borne encephalitis virus prevalence in sheep, wild boar and ticks in Belgium. Viruses. 2022;14(11):2362. doi:10.3390/v14112362
Clark JJ, Gilray J, Orton RJ, et al. Population genomics of louping ill virus provide new insights into evolution of tick borne flaviviruses. PLoS Negl Trop Dis. 2020;14(9):e0008133. doi:10.1371/journal.pntd.0008133
Jeffries CL, Masfield KL, Phipps LP, et al. Louping ill virus: an endemic tick-borne disease of Great Britain. J Gen Virol. 2014;95(Pt 5):1005-1014. doi:10.1099/vir.0.062356-0
