Canine Meningoencephalitis of Unknown Origin—The Search for Infectious Agents in the Cerebrospinal Fluid via Deep Sequencing

Abstract

Meningoencephalitis of unknown origin (MUO) describes a group of meningoencephalitides in dogs with a hitherto unknown trigger. An infectious agent has been suggested as one possible trigger of MUO but has not been proven so far. A relatively new method to screen for viral RNA or DNA is next-generation sequencing (NGS) or deep sequencing. In this study, a metagenomics analysis of the virome in a sample is analyzed and scanned for known or unknown viruses. We examined fresh-frozen CSF of 6 dogs with MUO via NGS using a modified sequence-independent, single-primer amplification protocol to detect a possible infectious trigger. Analysis of sequencing reads obtained from the six CSF samples showed no evidence of a virus infection. The inability to detect a viral trigger which could be implicated in the development of MUO in the examined population of European dogs, suggests that the current techniques are not sufficiently sensitive to identify a possible virus infection, that the virus is already eliminated at the time-point of disease outbreak, the trigger might be non-infectious or that there is no external trigger responsible for initiating MUO in dogs.

Editorial: Neuroinflammatory diseases of domestic animals

“…In the continuing quest to elucidate autoimmune triggers of MUO, Barber et al demonstrate that viral genomic material could not be recovered from the cerebrospinal fluid (CSF) from 98% (168/172) of North American dogs with neurological dysfunction and inflammatory CSF. These data add to existing literature supporting that occult viral infections are either not a common cause of MUO in dogs or that the genomic screening techniques used to date are sufficiently insensitive to detect these pathogens ( 4 ). Another study contributed by Barber and Koos did not demonstrate a functional or survival benefit when cytosine arabinoside treatment was added at the time of diagnosis of MUO to dogs chronically treated with cyclosporine and prednisone.…”

Mystery of fatal ‘staggering disease’ unravelled: novel rustrela virus causes severe meningoencephalomyelitis in domestic cats

“…The latter holds true particularly for the large histopathologically convergent group of non-suppurative, lymphohistiocytic encephalitides. A substantial proportion of these cases remains unsolved using conventional diagnostic methods, such as immunohistochemistry (IHC), in situ hybridization (ISH), and polymerase chain reaction (PCR) techniques for regional neurotropic pathogens [2][3][4][5][6][7][8][9] .One of those controversial encephalitides of possibly infectious origin is the so-called 'staggering disease' of domestic cats (Felis catus). It has been described first in the 1970s in the Swedish Lake Mälaren region between Stockholm and Uppsala 10 , which remains a hotspot of 'staggering disease' to the present.…”

“…The latter holds true particularly for the large histopathologically convergent group of non-suppurative, lymphohistiocytic encephalitides. A substantial proportion of these cases remains unsolved using conventional diagnostic methods, such as immunohistochemistry (IHC), in situ hybridization (ISH), and polymerase chain reaction (PCR) techniques for regional neurotropic pathogens [2][3][4][5][6][7][8][9] .…”

Concomitant necrotizing encephalitis and granulomatous meningoencephalitis in four toy breed dogs

“…Attempts by several working groups to identify an infectious agent in any subtype of MUO failed ( 4 – 9 , 27 ). As in this case series, no further in-depth search for infectious agents was performed, e.g., next generation sequencing ( 4 ), it cannot be completely ruled out that these dogs might have suffered from a so far unidentified infection, which causes this specific mixed pattern of granulomatous and necrotizing meningoencephalitis. However, immunohistochemistry and special staining for known infectious agents were negative, supporting the classification of MUO.…”

“…Typically, patients display progressive clinical signs of focal or multifocal central nervous system (CNS) dysfunction, with focal to multifocal CNS lesions in advanced imaging and often non-suppurative cerebrospinal fluid (CSF) pleocytosis, indicating CNS inflammation. An infectious agent can be found neither in the CSF nor in the neuronal parenchyma ( 4 – 9 ), and immunomodulatory therapy often improves clinical signs ( 2 , 10 , 11 ).…”