Despite the widespread use of vaccines, distemper has not been eliminated and is a difficult disease to diagnose in domestic and wild dogs. Distemper is a multisystem infection caused by an RNA virus belonging to the family Paramyxoviridae, genus Morbillivirus. It mainly affects dogs, but can also be caught by ferrets, badgers and lions. The transmission is usually direct from one animal to another and although the virus is air-borne, in particular, it is present in most of the body’s secretions (faeces, urine, etc.). The virus starts to spread from the initial site of infection after 7 days and remains in the body for several weeks, but rarely beyond 60-90 days.
After exposure, the virus first replicates in lymphoid tissue of the upper respiratory tract, such as the tonsils, and lymphoid tissue associated with the bronchi. The virus replicates in macrophages and lymphocytes (B and T) and then spreads in the lymph system throughout the whole body (lymph nodes, spleen, gastrointestinal-associated lymphoid tissue, Küppfer cells in the liver, thymus, bone marrow).
The degree of immunocompetence of the infected animal determines the appearance and evolution of the clinical signs of the distemper infection. If the immune response is weak, viral replication occurs within epithelial cells and the nervous system and clinical signs start to appear from the 14th day after infection. A severe, systemic disease develops, which often leads to the death of the infected animal within 1-2 weeks of the onset of the clinical signs (2-4 weeks post-infection). If the immune response is intermediate (slow humoral response, weak cell-mediated response), the disease can evolve in a subacute or chronic manner, with apparent healing or subclinical infection. The virus is eliminated progressively from most of the organs with the exception of the nervous system, eyes, lungs and some areas of epidermis (foot pads). The persistence of the virus in some sites leads to the delayed development of lesions related to immunopathological phenomena.
THE STAGES OF DAMAGE TO THE CENTRAL NERVOUS SYSTEM
There are essentially two routes through which distemper virus can enter the central nervous system (CNS): in the cerebrospinal fluid and across the blood-brain barrier. Once the virus has reached the CNS it can infect all the cellular components of the nervous tissue.
The infection of oligodendrocytes, cells dedicated to the synthesis of myelin, appears to be fairly rare compared to the infection of macrophages, ependymal cells, neurones and astrocytes. These last seem to the main target of the virus, also in the white matter.
The CNS signs of distemper are mainly due to demyelination, which is the distinguishing feature of the acute lesions.
- In the acute stage, in the absence of an adequate immune response, the virus enters the CNS across the blood-brain barrier 10-14 days after the initial infection. The virus is first found in the perivascular astrocytes and then in the neurones; it infects and then replicates within the epithelium of the choroid plexus and enters the cerebrospinal fluid, causing multifocal lesions, localised predominantly in the white matter but also in the grey matter. These lesions develop 3 weeks after the initial infection, during the first period of immunodepression, and are not inflammatory. It is currently thought that the initial lesions of the white matter are related to replication of the virus and are probably a result of degeneration of oligodendrocytes, even though ultrastructural and immunohistochemical investigations have not yet been able to demonstrate the presence of complete virus particles in these cells. The demyelination, which derives from altered production of myelin as a result of an effect on cell metabolism, can potentially be worsened by the action of microglial cells (local macrophages in the CNS which are hyperactivated in all stages of distemper infection) which produce substances that are toxic to myelin.
- In subjects that survive the acute demyelinating encephalitis, the distemper evolves into a chronic form which coincides with the recovery of immune system function. This form is characterized by inflammatory events which add to the pre-existing lesions induced by the virus. The inflammatory process that is established in the CNS is much more intense than that found in the very earliest period of the infection: 6-7 weeks after the infection, lymphocytes, plasma cells, monocytes and macrophages are collected around the vessels, forming typical “perivascular sheaths”, and subsequently invade the parenchyma. The consequent demyelination is the result of immunopathological phenomena which cause collateral damage to the oligodendrocytes. The destruction of infected astrocytes by microglial cells leads to the release of pro-inflammatory cytokines and free radicals, these latter being responsible for the destruction of the nearby oligodendrocytes. In this stage of the disease the lesions could, therefore, be the result of a combined effect of humoral cytotoxicity and an immune reaction against the cells infected by the virus. The finding of antimyelin antibodies contemporaneously with the development of the lesions suggests that these antibodies also play an important role in the destruction of the oligodendrocytes.
- Delayed demyelinating lesions can also occur in animals apparently healed years earlier and cause an encephalitis called “encephalitis in the mature dog” (“old-dog encephalitis”). This disorder is still considered a rare manifestation of nervous system distemper separate from the above described forms. These cases of encephalitis are equivalent to the cases of leucoencephalitis or subacute sclerosing panencephalitis (SSPE) which have been recognized in humans following infection be the measles virus. A possible explanation is that, in some circumstances, the virus develops strategies enabling it to escape the immune system, remaining inactive within the neurones and oligodendrocytes. When viral replication recommences, new demyelinating lesions appear.
Suggested readings
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10. Vandevelde M., Zurbriggen A., Higgins R.J., Palmer D.: Spread and distribution of viral antigen in Nervous Canine Distemper. Acta Neuropathologica, 67, 211-218, 1985.
11. Blakemore W.F., Summers B.A., Appel M.J.G.: Evidence of oligodendrocyte infection and degeneration in canine distemper encephalomyelitis. Acta Neuropathologica, 77, 550-553, 1989.
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13. Cammer W., Bloom B.R., Norton W.T., Gordon S.: Degradation of basic protein in myelin by neutral proteases secreted by stimulated macrophages. A possible mechanism of inflammatory demyelination.Proc. Natl. Acad. Sci. USA, 75, 1554-1558, 1978.
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16. Axthelm M.K. and Krakowka S.: Experimental Old Dog Encephalitis (ODE) in a Gnotobiotic Dog. Vet. Pathol. 35, 527-534, 1998.
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