GUIDELINE for Staggering Disease

These Guidelines were first published as Bornavirus Disease Guidelines by Hans Lutz et al. in Journal of Feline Medicine and Surgery 17 (7), 2015, 614-616, and updated by Hans Lutz in 2017. This recent update (2024) has been compiled by Uwe Truyen with valuable input from Kaspar Matiasek, Institut für Tierpathologie, Ludwig-Maximilians-Universität, Munich, Germany.

Key points

• Staggering disease is a rare central nervous syndrome in cats.
• It is characterized by abnormal gait, ataxia progressing to paralysis, lower back pain and behavioural changes.
• Pathological evidence of a disseminated lymphohistiocytic meningoencephalomyelitis with neuronotropism, in conjunction with clinical signs, are considered the most reliable diagnostic methods.
• Formerly Borna disease virus 1 (BoDV-1) was believed to be the cause of staggering disease, with shrews (Crocidura leucodon) as the reservoir host.
• However, evidence now suggests that the recently described Rustrela virus (RusV) is the aetiological agent. Mice (Apodemus sylvaticus, Apodemus flavicollis) likely act as reservoir hosts for Rustrela virus.
• The mode of transmission is unknown, but might be through direct contact, or indirectly via the secretions of an infected animal.
• Rustrela-like virus infections have also been described in various rodents, bats, large cats, a donkey, an otter, a coati, and a wallaby (Bennet et al., 2020; Pfaff et al., 2022; de la Roi et al., 2023).

Introduction

In the mid-1970s, staggering disease – a non-suppurative meningoencephalomyelitis – was described in cats in Western Sweden (cited in Cubitt and de la Torre, 1994 and Lundgren et al., 1995). Later, it was found that antibodies recognising Borna disease virus 1 (BoDV-1) were common to these cases (Lundgren and Ludwig, 1993). Finally, in 1995, BoDV-1 was considered “confirmed” as the aetiological agent of staggering disease (Lundgren et al., 1995). According to current understanding these data most likely resemble laboratory artefacts.

The detection of cases of fatal encephalitis in humans in Bavaria caused by BoDV-1 and a closely related Bornavirus of squirrels indicated that these viruses are zoonotic (Schlottau et al., 2017; Niller et al., 2020).

Just recently, another virus, Rustrela virus (RusV), has been identified in historical and actual case material from 27 of 29 cats affected with staggering disease, and also in wood mice of matching areas. In this investigation, the agent has not been identified in control cats and other types of encephalitis. These findings strongly suggest an aetiological role for RusV in staggering disease of cats.

It is not known whether RusV can infect, or cause disease, in humans.

Aetiology of staggering disease

Although the aetiologic agent of staggering disease was long thought to be BoDV-1 because either the virus or antibodies against BoDV-1 could be detected in many clinical cases, there was no clear correlation between their detection and disease.

Later studies employing metagenomic analyses determined that another virus, namely RusV, was associated with feline staggering disease; RusV was identified in archival samples from 27 of 29 cats displaying staggering disease (i.e. non-suppurative meningoencephalomyelitis). RusV was detected in these cases and confirmed using various techniques that demonstrated the presence of either the viral genome or viral antigen. RusV was also detected frequently in wood mice (Apodemus sylvaticus), which is consistent with the epidemiology of staggering disease, which is strongly associated with forest regions.

Agent properties of Rustrela virus (RusV)

RusV is an enveloped RNA virus (Rubivirus strelense), which has been classified as a member of the Matonaviridae family. It is named for its rubella virus-like genome and the Strelasund of the Baltic Sea in Germany (Bennet et al., 2020). It is closely related to rubella virus (RuV; Rubivirus rubella). RusV was first described in cases of lymphohistiocytic encephalitis in a free-ranging otter and a coati kept at a zoological garden in northern Germany (Pfaff et al., 2022). Interestingly, subclinically infected yellow-necked field mice (Apodemus flavicollis), without apparent encephalitis, were also detected and considered possible reservoir hosts of the virus.

Epidemiology and Transmission

In the comprehensive study published by Matiasek et al. (2023), RusV was detected in archival samples from 27 of 29 cats (93%) from Germany, Sweden and Austria with a history of clinical signs and histopathological findings indicative of staggering disease. All of the sampled cats were adults with outdoor access. The onset of disease occurred more often in winter and spring than in summer or autumn. Clinical signs included gait abnormalities, fever, behavioural changes, and depression. Most cats had to be euthanised within weeks after clinical presentation. Histological examination of brain and spinal cord revealed widespread, polio-predominant angiocentric lymphocytic and/or lymphohistiocytic infiltrates. Notably, RusV RNA or antigen was found in the tissues around the lesions.

RusV RNA was also detected in archival samples from rodents collected from regions in Southern Sweden, close to the regions in which RusV-positive cats were detected. PanRusV reverse transcription quantitative PCR (RT-qPCR) detected RusV RNA in eight of 106 (7.5%) wood mice (synonym ‘long-tailed field mice’; Apodemus sylvaticus), but not in 10 yellow-necked field mice from the same location (Matiasek et al., 2023). It was striking that none of the positive wood mice showed inflammatory central nervous system lesions.

Predisposing factors

Access to forested areas was reported to be an important risk factor for staggering disease, since 68% of all clinical cases occurred in cats with access to forests. The frequency of staggering disease shows a clear peak in the spring and winter months (Lundgren, 1992; Matiasek et al., 2023). So far, no association between staggering disease and gender has been described. Affected animals reported by Matiasek et al. (2023) had a median age of 3.2 years (when reported) and all had outdoor access.

Pathogenesis and Immunity

Not much is known about the pathogenesis and a possible immunity of RusV in cats. In humans, the closely related rubella virus induces a lifelong immunity.

Clinical signs

Affected cats develop gait disturbances, ataxia, pain in the lower back region and behavioural changes (Fig. 1).

Fig. 1. One-year old female domestic shorthair with typical clinical signs of staggering disease. Courtesy A.L. Lundgren, PhD thesis 1995

In some cases, the affected cats lose the capacity to retract their claws. Clinical signs will usually progress and affected cats will eventually die after developing severe paralysis of the hind legs. However, some cats partially, or even completely, recover. Subclinical infections can also occur. For a further review on clinical signs, please see Tizard et al. (2016).

Diagnosis

In the study by Matiasek et al. (2023), RusV RNA or antigen were detected by RT-PCR or immunohistochemistry respectively in the tissues of infected cats and mice, confirming RusV infection. the authors generated monoclonal antibodies directed against recombinant capsid proteins of RusV and developed various RT-PCR protocols. Therefore, appropriate tools for the detection of both virus and antibody are available. Some commercial laboratories offer PCR testing on frozen tissue or cerebrospinal fluid.

Prevention of RusV infection

Currently, no vaccines have been developed for the prevention of staggering disease. As the exact modes of transmission are still unclear, it is difficult to make specific recommendations for the prevention of infection. Cats without access to a rural environment are probably at a low risk of the disease compared to those with unlimited access to forested areas. In areas where staggering disease has been reported, it might therefore be recommended that cats are kept indoors. However, the adverse behavioural and welfare effects of limiting outdoor access for some cats should be carefully considered and compared against the risk of RusV infection when making such decisions as, for many cats, outdoor access is important for their well-being.

Only symptomatic treatment is recommended, there are no antivirals known to be effective available at present.

Zoonotic risk

There is no evidence of RusV infection, or disease caused by RusV, in humans.

Acknowledgement

ABCD Europe gratefully acknowledges the support of Boehringer Ingelheim (the founding sponsor of the ABCD), Virbac and MSD Animal Health.

References

Bennett AJ, Paskey AC, Ebinger A, Pfaff F, Priemer G, Höper D, et al (2020): Relatives of rubella virus in diverse mammals. Nature 586, 424–428. 10.1038/s41586-020-2812-9

Cubitt B, de la Torre JC (1994): Borna disease virus (BDV), a nonsegmented RNA virus, replicates in the nuclei of infected cells where infectious BDV ribonucleoproteins are present. J Virol 68, 1371-1381.

de le Roi M, Puff C, Wohlsein P, Pfaff F, Beer M, Baumgärtner W, Rubbenstroth D (2023): Rustrela Virus as Putative Cause of Nonsuppurative Meningoencephalitis in Lions. Emerg Infect Dis 29(5), 1042-1045.Formularende

Lundgren AL (1992): Feline non-suppurative meningoencephalomyelitis. A clinical and pathological study. J Comp Pathol 107, 411-425.

Lundgren AL, Johannisson A, Zimmermann W, Bode L, Rozell B, Muluneh A, et al (1997): Neurological disease and encephalitis in cats experimentally infected with Borna disease virus. Acta Neuropathol 93, 391-401.

Lundgren AL, Ludwig H (1993): Clinically diseased cats with non-suppurative meningoencephalomyelitis have Borna disease virus-specific antibodies. Acta Vet Scand 34, 101-103.

Lundgren AL, Zimmermann W, Bode L, Czech G, Gosztonyi G, Lindberg R, et al (1995): Staggering disease in cats: isolation and characterization of the feline Borna disease virus. J Gen Virol 76, 2215-2222.

Matiasek K, Pfaff F, Weissenböck H, Wylezich C, Kolodziejek J, Tengstrand S, et al. (2023): Mystery of fatal ‘staggering disease’ unravelled: novel rustrela virus causes severe meningoencephalomyelitis in domestic cats. Nat Commun 4;14(1), 624. doi: 10.1038/s41467-023-36204-w. PMID: 36739288; PMCID: PMC9899117.

Niller HH, Angstwurm K, Rubbenstroth D, Schlottau K, Ebinger A, Giese S, et al  (2020): Zoonotic spillover infections with Borna disease virus 1 leading to fatal human encephalitis, 1999–2019: an epidemiological investigation. Lancet Infect Dis 20, 467–477.

Pfaff F, Breithaupt A, Rubbenstroth D, Nippert S, Baumbach C, Gerst S, et al (2022): Revisiting Rustrela Virus: New Cases of Encephalitis and a Solution to the Capsid Enigma. Microbiol Spectr 10(2), e0010322. doi: 10.1128/spectrum.00103-22. Epub 2022 Apr 6. PMID: 35384712; PMCID: PMC9045237.

Schlottau K, Jenckel M, van den Brand J, Fast C, Herden C, Hoper D, et al (2017): Variegated Squirrel Bornavirus 1 in Squirrels, Germany and the Netherlands. Emerg infect dis 23, 477-481.

Tizard I, Ball J, Stoica G, Payne S (2016): Review: The pathogenesis of bornaviral diseases in mammals. Animal Health Research Reviews 17(2), 92–109, ISSN 1466-2523 doi:10.1017/S1466252316000062