Abstract
Case summary
Meningoencephalitis of unknown origin (MUO) is a term encompassing non-infectious inflammatory brain diseases with no identifiable underlying cause, widely studied in dogs but rarely in cats. This case describes a 9-year-old male castrated domestic shorthair cat diagnosed with feline MUO (FMUO). The cat presented with progressive vestibulocerebellar signs refractory to immunosuppressive treatment. MRI revealed multifocal, symmetrical intra-axial cerebellar lesions that were isointense to mildly hyperintense on T2-weighted and fluid-attenuated inversion recovery images, mildly hyperintense on T1-weighted images and enhanced with contrast. Cerebrospinal fluid analysis showed elevated protein concentration and lymphocytic pleocytosis. A post-mortem examination revealed widespread inflammatory infiltration affecting the frontal cortex, thalamus, parietal cortex and cerebellum in a bilateral and random distribution. Immunohistochemistry for common viral and protozoal pathogens was negative.
Relevance and novel information
This case illustrates the heterogeneity of FMUO, highlighting MRI and histo-pathological features that deviate from previously reported patterns. The findings highlight the need to include FMUO in the differential diagnosis for progressive vestibulocerebellar signs in cats, despite its rarity. Further research is necessary to better characterise FMUO and refine diagnostic and therapeutic approaches.
Keywords
Case description
A 9-year-old male castrated indoor domestic shorthair cat presented with a 3.5-week history of progressive vestibulocerebellar ataxia and tremors. Initial evaluation noted weakness, loss of balance and pelvic limb muscle atrophy. Frunevetmab (Solensia) was administered for presumptive osteoarthritic pain. The clinical signs deteriorated despite this treatment. Pre-referral haematology revealed neutropenia (1.2 × 109/l, reference interval [RI] 2.3–10.29), eosinopenia (0.14 × 109/l, RI 0.17–1.57) and lymphopenia (0.65 × 109/l, RI 0.92–6.88). Results for feline leukaemia virus (FeLV), feline immunodeficiency virus and Toxoplasma gondii were unremarkable except for a titre level reflecting previous exposure to Toxoplasma species (IgG by immunofluorescence assay 400, IgM <20).
On presentation, the cat was alert and responsive but mildly disoriented. Intermittent generalised intention tremors, moderate vestibulocerebellar ataxia and thoracic limb hypermetria were observed, along with a wide-based stance in the pelvic limbs. All limbs exhibited hypertonus. During the hopping test, a delayed protraction followed by hypermetric placement was observed in all limbs. Menace response was reduced bilaterally, though the cat’s vision appeared to be intact. A lesion affecting the vestibulocerebellar system was suspected. At this stage, differential diagnoses included neoplasia and inflammatory/infectious encephalopathy. Metabolic and toxic encephalopathy, although possible, were considered less likely.
MRI of the head was performed using a 1.5 T MRI scanner (Magnetom Essenza 1.5T; Siemens). The brain protocol included sagittal, transverse and dorsal plane sequences in T2-weighted (T2W) imaging, transverse planes in T1-weighted (T1W) imaging, fluid-attenuated inversion recovery (FLAIR) and T2*W gradient echo (GRE). After intravenous administration of gadobutrol (GADOVIST 1.0 mmol/ml solution for injection; Bayer), T1-weighted images were acquired in the transverse and dorsal planes. Multiple, symmetrical, ill-defined lesions within the cerebellar medulla that demonstrated irregular contrast enhancement were observed (Figure 1). The lesions were suspected to be centred on the bilateral cerebellar medullar nuclei (dentate, interposital and fastigial), with possible extension into the medullary white matter. On T2W and FLAIR images, the lesions appeared iso- to mildly hyperintense in comparison with grey matter. On T1W imaging, they were mildly hyperintense (Figure 1), and no signal voids were observed on GRE images. The remaining brain parenchyma appeared unremarkable; however, cerebrocortical sulci were noted to be prominent.
Transverse MRI scans of the brain at the level of the medulla in T1-weighted (T1W) (a) pre- and (b) post-contrast images. (c) A T1W post-contrast image of the brain at the level of the caudal colliculi in the dorsal view. Ill-defined, irregular, bilateral, intraparenchymal contrast-enhancing lesions are seen centred on the cerebellar medulla. Mildly hyperintense cerebellar medulla lesions are noted on the (d) transverse T2-weighted (T2W) and (e) fluid-attenuated inversion recovery sequences (red arrows). (f) The dorsal T2W sequence demonstrated a normal medulla.
Cerebrospinal fluid (CSF) obtained from the cerebellomedullary cistern revealed an elevated protein concentration (50.5 mg/dl, RI <45) and a nucleated cell count of 8 cells/µl (RI <5). CSF cytology showed a predominance of morphologically normal small lymphocytes. No infectious agents or neoplastic cells were detected. These findings were consistent with an inflammatory encephalopathy; however, given the symmetry of the cerebellar lesions, a metabolic or nutritional disease was reconsidered. To investigate further, blood samples were submitted for repeat haematology, venous blood gas analysis, total thyroxine, serum ammonia, bile acid stimulation testing and measurement of folate, cobalamin and thiamine concentrations. Results were unremarkable except for a mild non-regenerative anaemia and a low folate concentration (6.8 µg/l, RI 9.5–20.2). Abdominal ultrasound, urinalysis, urine culture and organic acid analysis from a cystocentesis sample were all unremarkable.
The cat was initially discharged without medication while awaiting results; however, a marked deterioration occurred within 48 h, with the patient becoming unable to get up without assistance. Considering the high suspicion of immune-mediated encephalitis, prednisolone was initiated at an immunosuppressive dose (0.75 mg/kg PO q12h). Clinical stabilisation was reported 4 days later. To enhance immune suppression, a constant rate infusion (CRI) of cytosine arabinoside (CA) was administered (200 mg/m2 IV over 24 h) 10 days after initial presentation, alongside prednisolone at the previously stated dose. Marginal clinical improvement was observed within 72 h, including improved ambulation; however, vestibulocerebellar ataxia and tremors persisted. Two weeks later, the ataxia and tremors worsened, prompting a second CRI of CA at the same dosage, administered 1 month after the initial infusion.
Rapid deterioration continued despite treatment and the cat became non-ambulatory. Euthanasia was elected on welfare grounds 2 weeks after the second CRI of CA. The owners consented to a post-mortem examination (PME) and the brain was submitted for analysis.
Although gross examination of the brain did not reveal relevant alterations, histopathology demonstrated widespread inflammatory lesions affecting the frontal cortex, thalamus, parietal cortex and cerebellum, with a bilateral and random distribution. A caudorostral gradient of ascending severity was observed, with 3–5-cell thick lymphoplasmacytic perivascular cuffs identified in both the leptomeninges and the neuroparenchyma, showing a relative preference for the grey matter (Figure 2). Accompanying findings included Mott cells, rod cell activation with occasional glial nodules, astrogliosis and neuronal degeneration with loss. There was no morphological evidence of specific aetiological agents, while immunohistochemistry against feline herpesvirus 1, parvovirus, T gondii, H1N1 and FeLV was negative. Widening the space between adjacent folia and expansion of the subarachnoid space were interpreted as indirect signs of cortical atrophy.
Representative histopathological appearance of meningoencephalitis of unknown origin in a cat. (a) Subgross magnification view of the cerebellum and brainstem. (b) Large discrete focus of lymphoplasmacytic infiltration among arachnoid vessels over the cerebellar folia (white asterisk); bar: 200 µm. (c) Multiple lymphocyte-rich thick perivascular cuffs disseminated throughout the cerebellar nuclei (arrows); bar: 500 µm. (d) Three to five cell-thick perivascular cuff (black asterisk) accompanied by spongiosis and gliosis within the context of a cerebellar nucleus; bar: 200 µm
Discussion
MUO is a diagnosis of exclusion that requires a combination of clinical and histopathological evaluation, along with the exclusion of infectious causes. Although this condition has been extensively studied in dogs, it remains rarely reported in cats. Most available literature describes either the clinical or histopathological feature of feline MUO (FMUO), but seldom both. In 2017, Negrin et al 1 were the first to report on the clinical investigation, treatment and outcomes of 16 suspected FMUO cases; however, definitive histopathological diagnosis was not possible as all cats survived. In 2020, Nessler et al 2 described four FMUO cases, with a comprehensive overview that included signalment, clinical signs, diagnostic findings and histopathology. By summarising the clinical presentation, diagnostic results and histopathology, this case report contributes valuable information to the limited body of evidence on FMUO.
Most findings in this case were consistent with previous FMUO studies, though some deviations were noted. The patient – a 9-year-old domestic shorthair cat – fitted within the predisposed population identified in earlier reports,1,2 although FMUO can also affect both younger and older cats. Clinical signs of FMUO can vary greatly, with focal or multifocal involvement of the brain and spinal cord. This patient exhibited common signs, including ataxia, paresis and altered postural reactions. 1 As reported in other suspected FMUO cases, cerebellar involvement was evident.1,3
Extensive investigations were conducted to rule out other potential causes of encephalopathy. CSF analysis revealed elevated protein concentration and a mild lymphocytic pleocytosis, findings consistent with typical central nervous system (CNS) inflammation and typical of FMUO. However, these findings are not pathognomonic and can also be seen in conditions such as feline infectious peritonitis, Cryptococcus species, T gondii or lymphoma. 4 These differentials were ruled out or deemed unlikely based on other test results. Other infectious agents that could have been considered include viruses such as rustrela, Borna and rabies or prion diseases.5 –8 Nonetheless, the clinical history, vaccination and parasitic prophylaxis status, lifestyle, geographical location and diagnostic findings (including histopathological features) rendered these viral encephalitides unlikely, both ante and post mortem. Mild non-regenerative anaemia and low folate concentration, although non-specific, were also observed. Although folate deficiency has been linked to neurodegenerative diseases in humans, 9 no previous FMUO cases have reported such abnormalities.
Consistent with existing literature, the cerebellar lesions observed on MRI were intra-parenchymal, ill-defined and irregularly contrast-enhancing. However, the intensity of these lesions differed from that reported in FMUO findings, where lesions are generally T1W hypo- to isointense and T2W hyperintense. 1 In contrast, this case revealed T2W isointense lesions that were mildly hyperintense on T1W images. Apart from mild cerebrocortical atrophy, the MRI findings corresponded with the neurolocalisation, consistent with other previous reports.1,2 Although FMUO lesions can vary widely in location (intra-axial, extra-axial, cervical or thoracolumbar), cerebellar involvement is commonly described.1,2 Neurons within the cerebellar nuclei project to multiple regions’ locations in the mesencephalon and metencephalon. Dysfunction in these areas typically result in clinical signs such as ataxia, nystagmus and an absent menace response, all of which were present and progressed over time in this case. This is supported by the most severe histopathological changes localised to the cerebellum, including marked spongiosis and perivascular cuffing observed within the nuclei (Figure 2). The cerebrocortical atrophy was considered incidental in a geriatric patient and was confirmed by histopathology.
Our histopathological findings aligned with established features of FMUO. Multifocal lymphohistiocytic inflammation was identified in the frontal cerebral cortex, hippocampus, thalamus, brainstem and, most severely, the cerebellum. Despite the prominent cerebellar lesions seen on MRI, the imaging significantly underestimated the extent of pathology affecting the rest of the brain parenchyma. Perivascular infiltrations were observed within both the neuroparenchyma and meninges. A caudorostral gradient of increasing severity was noted, suggesting a progressive disease process originating in the cerebellum and extending rostrally, with only mild involvement on the frontal cortex. The widespread inflammation was accompanied by parenchymal gliosis, neuronal degeneration and neuronal loss. In addition, the widening of spaces between adjacent cerebellar folia supported the MRI interpretation of cortical atrophy. Immunohistochemistry for common infectious agents yielded negative results, further supporting the FMUO diagnosis; however, the presence of an unknown pathogen could not be entirely ruled out.
Idiopathic generalised tremor syndrome (IGTS) was initially considered based on the clinical presentation. Two young domestic shorthair cats with IGTS have previously been reported, both exhibiting whole-body intention tremors and ataxia that progressed over several weeks before presentation. 10 However, significant differences distinguished those cases from the present one. The IGTS cats were aged under 2 years, had unremarkable MRI and CSF findings, and showed complete resolution of their clinical signs after immunosuppressive corticosteroid treatment. These factors made IGTS a less likely diagnosis in this instance, although the use of low-field (0.2 T) MRI in the IGTS cases may have missed subtle changes.
This FMUO case illustrated both similarities and differences with existing literature, further demonstrating the heterogeneity of FMUO and the importance of including it in the differential diagnosis for cats presenting with CNS signs. This case report has some limitations. Toxoplasma species serology was not repeated after referral, possibly missing an increasing IgM titre; however, immunohistochemistry for T gondii and morphological examination for tissue cysts or tachyzoites in brain tissue were negative. The PME was confined to the brain, despite previous reports describing extraneural FMUO lesions.1,2,4 Other systemic findings may have provided further insight into the disease aetiology. Fewer infectious agents were screened compared with other studies. Although no overt signs of viral infection (eg, inclusion bodies) were present, viral agents do not always induce significant histopathological changes in the brain. 11
Conclusions
Although rare, FMUO should be considered in cats presenting with progressive vestibulocerebellar signs, particularly when supported by MRI and CSF findings indicative of CNS inflammation. FMUO might have a multifactorial nature, similar to that observed in the dogs.12,13 Given its apparent heterogeneity and rarity, future studies of FMUO should aim to undertake comprehensive diagnostic investigations, including extensive diagnostic, post-mortem and pathogen screening. This would ultimately be beneficial in accumulating primary data necessary for a systematic review in a larger population to further the understanding of FMUO, similar to the approach taken by Jeffery and Granger in 2023. 14
Footnotes
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The publication of this article was funded by the College of Veterinary Medicine, North Carolina State University.
Ethical approval
The work described in this manuscript involved the use of non-experimental (owned or unowned) animals. Established internationally recognised high standards (‘best practice’) of veterinary clinical care for the individual patient were always followed and/or this work involved the use of cadavers. Ethical approval from a committee was therefore not specifically required for publication in JFMS Open Reports. Although not required, where ethical approval was still obtained, it is stated in the manuscript.
Informed consent
Informed consent (verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (experimental or non-experimental animals, including cadavers, tissues and samples) for all procedure(s) undertaken (prospective or retrospective studies). No animals or people are identifiable within this publication, and therefore additional informed consent for publication was not required.
