Neurological Manifestations of Common Inflammatory Diseases

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NEUROLOGICAL MANIFESTATIONS OF COMMON INFLAMMATORY DISEASES

Author : ALBA CARRERAS, LARA MATIASEK

Categories : Vets

Date : April 27, 2009

ALBA CARRERAS, LARA MATIASEK present a brief review of neurological disorders affecting the UK’s feline population, and explain how a detailed workup is an essential factor, in the first instalment of a two-part article

History and assessment

The first step to approaching neurological disorders is to get a thorough history from the owners. However, it might be difficult to obtain this, as cats can be outdoor animals and clinical signs might not be noticed acutely. While taking the history, let the cat wander around in the consult room and observe its behaviour, posture and gait. Hands-off examination in cats will often provide very valuable information.

A good clinical exam (including ophthalmologic assessment) before focusing on the neurological problem is important, as sometimes it is easy to miss systemic signs that will lead us to the diagnosis.

At the same time, cats tend to cope with stress in a very different way than dogs. Certain deficits might be masked, whereas other abnormal reactions might be stress related — a situation that can occasionally complicate the neurolocalisation. Sometimes, it is easier to perform the neurological examination in a quiet room away from the owners. It is important to proceed systematically and note any findings on a neurology examination form. The paw placement response (“knuckling tests”) is not always consistent in cats. In contrast, hopping response, tactile and visual placing

1 / 17 and withdrawal reflex are usually reliable.

Cranial nerve assessment in cats can be difficult as well, and one should remember that a bilaterally reduced menace response could also be due to a very stressed patient. Clinicians might want to reassess the menace when the cat is calm and acclimatised to the new environment.

Once the history has been taken, the clinical and neurological examination can be performed (and all deficits written down in a logical order). The lesion should then be localised to a particular area of the nervous system and a list of differential diagnoses, going through the “VITAMIN D” scheme, established (Table 1). The most common neurological diseases seen in cats are of neoplastic and inflammatory and/or infectious origin.

The first part of this review will address the neurological manifestations of inflammatory disease in cats; the second part will focus on neurological manifestations of metabolic disorders, intoxications and central nervous system (CNS) neoplasias.

Neurological disturbances

In general, inflammatory diseases have an acute onset and tend to be progressive, with a multifocal or diffuse distribution. A multitude of neurological signs can be present, and these may or may not be associated with systemic signs. Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis are necessary to diagnose inflammatory diseases of the CNS.

Inflammatory diseases of the CNS can be divided into sterile inflammatory disease and infectious disease (see Table 2).

Infectious diseases affecting the CNS include viral (particularly FIP), protozoal (toxoplasmosis), bacterial (such as ascending otitis media and/or interna) and fungal (cryptococcosis) disease.

A large number of cats with infectious CNS diseases have been reported to have histopathologic changes suggestive of a viral infection, but no causal agent could be identified — even following immune staining for the infectious agents known to cause CNS disorders in cats.

FIP

Feline infectious peritonitis (FIP) is a fatal disease caused by a mutation of the feline enteric coronavirus (FCoV).

It is estimated that one in 10 cats infected with the coronavirus will develop FIP. The neurological form manifests as a pyogranulomatous meningoencephalomyelitis, which is often associated with the dry form of FIP.

2 / 17 Neurological signs are a result of a pyogranulomatous inflammatory cell infiltration of the leptomeninges, ependyma and choroid plexuses and, less prominently, the brain parenchyma. FIP virus, therefore, mainly affects the CNS as a surfacerelated disease. However, vasculitis (due to immune complexes) and subsequent necrosis of the parenchyma can be seen, with large amounts of macrophages migrating to the affected areas.

FIP mostly occurs in young cats from multiple-cat households. The affected cats often have concurrent systemic signs, such as persistent pyrexia, weight loss, anaemia and anterior uveitis. Ascites and pleural effusion are common findings in the wet form of FIP. Neurological signs depend on the affected parts of the CNS and often include seizures, cerebellar signs, blindness, hyperaesthesia and ataxia or paresis (see Figure 1).

A presumptive diagnosis is frequently made based on clinical signs and evaluation of abdominal or chest fluid, if available. Comprehensive diagnostic workup results may include the following factors:

• Haematology may reveal neutrophilia, lymphopaenia and non-regenerative anaemia.

• Serum protein electrophoresis typically shows polyclonal gammopathy.

• Commercial ELISA tests are available for feline coronavirus antibodies. However, the authors consider immunofluorescent antibody test offered at the University of Glasgow to be more accurate. Anti-coronavirus antibody titres are often high, but this needs to be interpreted with caution, as feline coronavirus is ubiquitous and cats can be exposed to it — and produce antibodies — without developing FIP.

• Abdominal and chest imaging (ultrasound and radiographs) can be used to look for effusions and rule out other conditions.

• Cytology and biochemical analysis of effusions typically reveals high protein, an albuminto- globulin ratio of less than 0.8, and an increased nucleated cell count with mainly macrophages, mildly degenerated neutrophils, lymphocytes, plasma cells and mesothelial cells.

• Detection of FCoV antigens in macrophages in effusions and biopsy confirmation of affected tissue are the most accurate FIP diagnosis methods, but a negative result will not rule it out.

• If neurological signs are present, CSF often has characteristic findings showing a marked neutrophilic to pyogranulomatous pleocytosis and markedly elevated protein, but mixed pleocytosis can be seen as well (Figure 2 and Table 3), particularly in later stages of the disease. Anti-FCoV antibodies can be detected in the CSF of cats with CNS manifestation. However, a study has shown that CSF antibodies were only detected in strongly seropositive cats, suggesting that CSF antibodies were derived from blood. Therefore, anti-FCoV titres detected in CSF are not a good disease indicator. PCR tests in CSF and EDTA blood are also available, but polymerase chain

3 / 17 reaction (PCR) tests cannot differentiate between the mutated virus that causes the disease, and coronavirus.

• MRI often shows marked dilatation of the ventricles (secondary hydrocephalus) and signs of meningitis and ependymitis (Figure 3), and, occasionally, hydromyelia and parenchymal changes.

• The use of immunosuppressive drugs, since FIP is an immune-mediated disease, may slow down the progression, but there are no effective treatments and the prognosis is very poor, particularly in cats with CNS signs. High prednisolone doses (at 4mg/kg sid) may be administered for two weeks, tapering down to 2mg/kg sid and so on. The use of interferon omega showed very good results in one study, but no benefits were found in subsequent studies.

FIV

Feline immunodeficiency virus (FIV) is an RNA virus from the lentivirus subfamily that causes immunosuppression in cats. It is transmitted via saliva — the most common infection route is through cat fights — and it is more common in males.

The target cells for FIV are the T-lymphocytes, the location from which the virus spreads throughout the lymph nodes of the body. Following that, cats can be infected for years without any obvious signs — sometimes, just a mild pyrexia episode is present at the beginning. During this “quiet period”, there is a progressive reduction of CD4+ T-lymphocytes. Eventually, immunosuppression signs show up as a variety of secondary infections, and these are the signs for which owners will present their cats.

The most common FIVinduced neurological syndrome is FIV encephalitis/encephalopathy. This usually occurs after acquired immunodeficiency syndrome develops — therefore, systemic signs are already present. The way the lentivirus causes encephalopathy is unclear; it is believed that FIV has a tropism for neurons and damages brain parenchyma via its cytolytic effects. Some studies have shown that FIV-associated encephalopathy might be more common than previously thought (one-third of FIV-positive cats can have neurological signs).

Affected animals present with ataxia, reduced motor activity, irritability and disorientation. It is important to remember that neurological signs in FIV-infected, immunosuppressed cats can also be due to opportunistic infectious CNS diseases, such as toxoplasmosis.

Commercial in-house ELISA tests detect antibodies against FIV, but they are not 100 per cent specific. Therefore, it is possible to have false-positive results. In inconclusive cases, immunofluorescence antibody tests are recommended. With ELISA tests, it is also possible to have false-negative results in the early disease stages, when cats have not seroconverted yet. In these cases, repeating the test several weeks later is recommended. PCR assays detect the pro-viral DNA and can be done from EDTA blood or CSF, if neurological signs are present. Discrepant

4 / 17 results are common, as there are different FIV subtypes.

Treatment is based on managing secondary infections (if present) and supportive care. FIV- associated disease recurrence is common, so advising owners about it is important. Anti- inflammatory drugs, such as corticosteroids, are, in some cases, used to treat stomatitis and gingivitis. Careful monitoring is needed when using corticosteroids. Interferon has also been used to treat FIV-associated disease, but it is not effective to eliminate the infection.

FeLV

Feline leukaemia virus (FeLV) is an oncogenic retrovirus that causes a variety of neoplastic, haematologic and immunosuppressive diseases.

A degenerative myelopathy has been reported as a chronic FeLV infection complication. Clinical signs consist of hyperaesthesia and hindlimb paresis, which progress to paralysis. Due to an upper motor neuron dysfunction, bladder disorders can also be present. Microscopic lesions have been found in the spinal cord (especially thoracolumbar) and brainstem, and consisted of diffuse white- matter degeneration in the absence of inflammation. FeLV antigen (FeLV p27) was identified. Degenerative myelopathy is a rare end-stage condition in FeLV-infected cats, so other concomitant infectious diseases and neoplasia (especially lymphoma in FeLV-positive cats) have to be considered as differential diagnoses.

Most of the time, haematology and serum biochemistry are unremarkable. However, in some cases, non-regenerative anaemia is present.

FeLV can be diagnosed inhouse by an ELISA test, which detects a free FeLV protein component in the serum. This test has a high sensitivity and specificity, and is the preferred screening test for FeLV. It is, however, even more accurate to send blood to a laboratory for an immunofluorescence assay, which tests for the FeLV protein component in infected leukocytes. PCR testing allows FeLV DNA detection in EDTA blood and CSF.

Studies have shown that FeLV proviral DNA detection in blood by PCR provides higher predictive values than serology. Routine CSF analysis and MRI do not normally show any abnormalities in cats with degenerative myelopathy associated with chronic FeLV infection. Supportive care is the only treatment, but the prognosis is poor.

Panleukopaenia

Feline panleukopaenia virus (FPV) is closely related to canine parvovirus, and causes similar intestinal and immunosuppressive signs in cats. FPV infects highly dividing cells and destroys them. When queens in the latter stages of pregnancy get infected, the virus spreads transplacentally and can destroy the germinal layers of the cerebellum, causing a congenital

5 / 17 malformation called feline cerebellar hypoplasia. It is probably the most common malformation in cats, and some of them develop concomitant hydrocephalus as well.

The main clinical signs of cerebellar hypoplasia are intention tremors, ataxia and hypermetria. There are no specific diagnostic tests for these kittens. CSF is usually normal and MRI confirms the malformation, but not the cause. Supportive care is needed, but signs are non-progressive and some affected animals might learn to compensate to a degree where they have a decent quality of life.

Toxoplasmosis

Toxoplasma gondii is an intracellular protozoal agent known to occasionally cause CNS infections in cats. Myositis and polyradiculoneuritis can also be seen with toxoplasmosis.

The infection may occur transplacentally or via ingestion of faecally-shed oocysts (cats are the definitive hosts and shed the oocysts), but mostly via ingestion of the intermediate hosts (usually mice) that contain the organism. Many cats will be infected with T gondii and will not develop any signs all their lives. If the cat is not immunocompromised, the infection enters a latent phase, during which only bradyzoites are present. If immunosuppression occurs, those bradyzoites will be reactivated and develop into tachyzoites.

The tachyzoites are responsible for tissue damage, as they divide intracellularly until the cells burst and provoke tissue necrosis. Infection signs are typically seen in young or immunocompromised animals. Early signs can be very subtle and often embrace a progressive rigidity of one or more limbs as a result of myositis, but can also include fever and diarrhoea.

Chorioretinitis may be seen on fundic examination. Neurological signs may include seizures, behavioural changes, paresis, ataxia, cerebellar signs and diffuse neuromuscular disease, depending upon where in the body the protozoa are dividing.

Diagnosis can be confirmed by positive serum and CSF titres, or PCR; however, previously exposed animals can have positive titres without active disease. The most practical test is to compare the IgM and IgG antibodies in different stages of the disease. IgM antibodies appear sooner in infected animals, but they do not persist (IgM titres higher than 1:256 indicate a recent infection). IgG antibodies appear after a month of infection and persist for years.

Titres should be checked when toxoplasmosis is suspected, and rechecked again three to four weeks later — an increase of IgG is expected with active disease. The organisms can be found in histopathology of muscle biopsies if myositis is present.

Routine CSF analysis of protozoal disease typically demonstrates a mononuclear or mixed

Tablepleocytosis 3 (sometimes eosinophils can be seen) with a moderately increased WBC count (see

6 / 17 ). MRI might show single or multiple mass lesions in affected cats’ CNS.

7 / 17 Treatment consists of antibiotics. Clindamycin and/or potentiated sulphonamides, both at 15mg/kg bid for at least four weeks, are the antibiotics of choice. Neurological signs often improve with treatment, but might not resolve due to permanent damage caused by the organisms.

Cryptococcosis

Cryptococcosis is a systemic fungal disease caused by a saprophytic yeast (Cryptococcus neoformans) that is known to affect cats throughout the world. It is mainly found in pigeon droppings, and inhalation of the spores infects cats.

The upper respiratory tract and the lungs are the initial sites of infection in most cases, where the spores get deposited within the cells and the alveoli. The spores are activated and start dividing. The combination of the infection itself and the inflammatory response causes respiratory signs, such as nasal discharge, coughing, sneezing, pyrexia and lethargy. Sometimes, polyp-like masses in the nostrils or nasal cavity can also be seen.

The neurological and ophthalmologic signs are caused by haematogenous spread. In some cases, the infection is transmitted to the CNS through the cribriform plate.

Neurological signs are often forebrain and vestibular-related, but more generalised signs, such as paresis, can be seen. Ophthalmologic examination often reveals anterior uveitis and chorioretinitis.

A commercial latex agglutination test is available for detecting cryptococcal capsular antigen in serum or urine. Chest radiographs are recommended to rule out other respiratory conditions and gain enough information on how advanced the disease is. If rhinoscopy is performed, the diagnosis can be achieved via tissue biopsies and fungal cultures. In animals with neurological disease, Cryptococcus can be diagnosed by cytology and CSF culture or a CSF latex agglutination test. Inflammatory mycotic CNS lesions may be detected using MRI.

Fluconazole (2mg/kg/day to 10mg/kg/day) or itraconazole (10mg/kg/day) are the treatments of choice. FeLV and FIV can be underlying diseases and can worsen the prognosis, and require further supportive therapy for the patient. In general, neurological signs due to Cryptococcus indicate a guarded to poor prognosis.

Otitis media and interna

This is the most common cause of peripheral vestibular disease in cats. Mostly, it is due to an extending otitis externa, and the cultured bacteria are Staphylococcus intermedius and Pseudomonas species.

Alternatively, the infection may ascend from the oral cavity, or even be haematogenously spread. The animal is usually presented with a history of chronic otitis externa, together with vestibular

8 / 17 signs (head tilt, vestibular ataxia, falling, circling and nystagmus) and ipsilateral facial paresis. Horner’s syndrome can also be present. The process is normally unilateral, but can occasionally be bilateral.

Diagnosis can be attempted with a thorough otoscopic examination under general anaesthesia and radiographs of the tympanic bulla. The tympanic membrane should be visualised after a gentle rinse with saline. If it is intact, it can have a bulging appearance due to fluid inside the middle ear. If the tympanic membrane is intact, but otitis media is suspected, a myringotomy should be performed with a 22-gauge spinal needle, and always under general anaesthesia. A sample should be sent for culture and cytology. Radiographs can show the presence of fluid and sclerosis of the bulla, but they are not always diagnostic. MRI or CT can provide more accurate information (see Figure 4). Treatment involves antibiotics based on the culture sensitivity results. Generally, a good choice of antibiotics are cephalosporins at high dosages for six to eight weeks. If medical management is not as effective as expected, drainage via bulla osteotomy is required. Otic cleaners should not be used, as they can pass through the middle ear and worsen the vestibular signs and cause deafness. Some cats will need supportive care until the neurological deficits improve. In subsequent brain abscessation or meningoencephalitis are present.

Other conditions

• Bacterial meningoencephalitis and meningomyelitis, and/or CNS abscessation due to a penetrating injury, are more common than expected within the feline population.

The infection can be limited to the extradural or subarachnoid space, or can spread through the parenchyma. The clinical signs are mainly a result of the inflammatory reaction produced by the bacteria, and the mass effect produced by an abscess. Symptomatic evidence of the abscess can be present long after the causative accident, and can make the diagnosis complicated. Approximately 50 per cent of the cats will present with pyrexia and lethargy. Neurological signs can vary (depending on the affected areas), and head tilt and seizures, or progressive paresis, can frequently be seen.

Routine blood work usually reflects an inflammatory process, and CSF cytology will show neutrophilic pleocytosis with degenerated neutrophils and the presence of intracellular bacteria (see Table 3).

CSF should be cultured; the most commonly identified bacteria are Escherichia coli, Streptococcus and Klebsiella, even though CSF cultures may often remain negative. MRI or CT of the brain or spine is indicated to assess the affected structures and the size of the abscess.Surgical drainage and debridement is the treatment of choice for abscesses. Samples for culture sensitivity should be taken at the time of surgery.

9 / 17 Supportive care and broadspectrum antibiotic therapy (such as amoxicillin clavulanic acid and metronidazole) should be initiated while waiting for the culture results. Prognosis is poor if early diagnosis and surgical treatment are not performed with abscesses.

• Granulomatous meningoencephalomyelitis (GME) is a non-suppurative inflammatory CNS disease with an unknown aetiology, which is suspected to be immunomediated in origin.

GME is very rare in cats and can generally have different clinical presentations due to optic neuritis, focal lesions, or more disseminated forms. Presumptive diagnosis is based on CSF (see Table 3) and MRI findings, where either a single mass lesion or multifocal lesions within the parenchyma (particularly affecting the white matter) are seen. Definitive diagnosis can only be achieved by histology of a representative tissue sample obtained via biopsy.

It is particularly important to rule out infectious and neoplastic disease in cats, as GME is an infrequent finding in this species.

• Feline polioencephalomyelitis (staggering disease) is a condition described as a chronic progressive neurological disorder in which cats show signs such as ataxia, seizures, tremors, decreased pupillary light reflexes and hyperaesthesia. Lesions predominantly affect the spinal cord and show severe degeneration and loss of neurons.

Usually, a definitive diagnosis is made at necropsy. Aetiology and treatment are unknown, and prognosis is poor.

Conclusion

In conclusion, when neurologic signs in cats are present, a thorough neurological examination and diagnostic workup are recommended.

If inflammatory and/or infectious diseases are on top of the differential diagnoses, diagnostic investigations should include blood tests, advanced diagnostic imaging (ideally MRI) and CSF analysis. However, in animals with inflammatory CNS diseases affecting the brain, CSF should be collected after the MRI is performed. This is important to minimise the risk associated with CSF collection in patients with possibly increased intracranial pressure, as it could result in brain herniation and death.

• The authors wish to acknowledge the neurology and neurosurgery unit, neuropathology laboratory and the diagnostic imaging unit at the Animal Health Trust for the images and the help in preparing this manuscript.

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Figure 1. An eight-month-old male Birman that presented with acute-onset ataxia. Neurological examination revealed a depressed mental status, non-ambulatory tetraparesis, ventroflexion of the neck, reduced to absent proprioception on all four limbs, and reduced facial sensation. MRI of the brain and CSF investigations suggested FIP, which was confirmed on postmortem examination.

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Figure 2. Cerebrospinal fluid cytology from a cat with the neurological form of FIP, showing mixed-cell pleocytosis, which is particularly seen in later stages of the disease.

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Figure 3. Transverse post-contrast T1W MRI of the brain of a nine-month-old exotic cat with FIP. The lateral ventricles are enlarged due to obstructive hydrocephalus and there is inflammation of the meninges and of the ependymal lining of the ventricles, shown by contrast enhancement.

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Figure 4. Transverse post-contrast T1W MRI of the head of a five-year-old domestic long- haired cat with right-sided middle-ear disease. Both compartments of the right tympanic bulla (on the left of the image) contain fluid and the bulla lining is thickened and inflamed, shown by contrast enhancement. The left tympanic bulla is normal.

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Table 1. VITAMIN D scheme

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Table 2. Infectious diseases affecting the CNS in cats

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Table 3. CSF characteristics of different feline inflammatory disease

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