The Neurological Form of Feline Infectious Peritonitis and GS-441524 treatment

1.6.2021
Niels C. Pedersen, DVM PhD
Original article: The Neurological Form of Feline Infectious Peritonitis and GS-441524 treatment

Introduction

Neurological impairment occurs in about 5–10% cases of FIP. This may vary from region to region, as the author's experience suggests that Turkish street cats are more prevalent. The age of onset is similar to other forms of FIP, with most cases occurring within 3 years.

Neurological FIP is considered a form of dry FIP, and typical dry FIP lesions in the abdomen, chest, or eyes occur in about half of the neurological cases of FIP. Neurological symptoms are only visible in about 5% cats with manifestations of wet FIP.1 However, in cats, there was a significant increase in the incidence of neurological FIP either during treatment with GS-441524 or in the form of post-treatment relapse periods in cats that were originally treated for non-neurological FIP.

Clinical signs

Neurological FIP occurs in two forms, primary and secondary. Abnormal neurological symptoms are present in cats with primary disease. However, general symptoms of ill health are also common, such as failure to thrive, weight loss, lethargy and anorexia. The fever may be overt or covert. About half of cats with primary neurological FIP will also have identifiable lesions outside the CNS and typical blood test results. However, cats with no obvious signs of CNS damage will often have normal or near-normal levels on the CBC and in their serum.

Early neurological symptoms, recognizable prospectively or retrospectively, include licking the floor or walls, sporadic muscle twitching, and indeterminate behavior and cognitive abnormalities. Anisocoria is another early sign. Suspicion of neurological FIP increases as clinical symptoms become more functional. The earliest sign is usually a gradual loss of coordination and balance (ataxia). The reluctance to jump up or down from high places is one of the first signs of incoordination. Incoordination is initially most noticeable on the hind legs, but quickly becomes general. In some cases, seizures of the grand mal type or psychomotor type may also occur. Grand mal seizures are manifested by a brief loss of consciousness, strong rhythmic muscle cramps affecting the whole body. Psychomotor epilepsy is associated with varying degrees of consciousness and uncontrolled or partially controlled body movements.

Cats with secondary neurological FIP show signs of extra-intestinal disease and CNS involvement occurs at a later stage of the disease. It often occurs during antiviral treatment of other forms of FIP and is a common cause of relapse in cats treated with other forms of FIP. These relapses usually occur within the first 1-4 weeks after successful treatment.

Spinal cord involvement is often overlooked in neurological FIP, although more than 50% cats with inflammatory spinal cord disease have FIP.2 Spinal cord involvement leads to fecal and / or urinary incontinence of varying severity. Paralysis of the tail or hind limbs are also symptoms of spinal cord disease. Spinal cord involvement is likely to lead to permanent neurological deficits and then to brain disease.

Diagnosis

The sudden onset of neurological abnormalities in cats less than 5-7 years of age is strong evidence of FIP on the basis of probability alone, as few other diseases will have similar symptoms in this age group. However, there is a tendency among veterinarians to include systemic toxoplasmosis on their diagnostic list above, especially when ocular or CNS symptoms are observed. Systemic toxoplasmosis in cats is a rare disease compared to FIP and often occurs in immunocompromised hosts, including hosts with FIP. 15-17 This is understandable because cats are the definitive host of Toxoplasma gondii in nature and have developed a state of facultative symbiosis. In addition, the main clinical manifestation of systemic toxoplasmosis is characteristic pneumonia, sometimes associated with hepatitis, pancreatic necrosis, myositis, myocarditis, and dermatitis.3-8 FIP-like uvitis occurs in approximately 10% cats with systemic toxoplasmosis, 4 and encephalitis is even less common.7,17 The diagnostic test for systemic toxoplasmosis is based on a comparison of IgG and IgM antibody titers using the indirect fluorescent antibody (IFA) procedure. 3 High IgG titers in the absence of IgM antibodies indicate previous toxoplasma exposure, which can reach up to 50% in feral cat populations.4 The presence of high titers of IgM antibodies is an indication of the systemic spread of the organism from the intestine to other tissues and is one of the requirements for the diagnosis of systemic disease. However, many cats with ocular and neurological signs are inappropriately treated for systemic toxoplasmosis only on the basis of high IgG titers.

The diagnosis of typical forms of FIP is usually made by combining information on the age and origin of the cat, historical and physical signs (eg ill health, fever, abdominal or thoracic effusions, palpable abdominal mass) with certain laboratory abnormalities in the complete blood count (anemia; high white blood cell count, low lymphocyte count and high neutrophil count), serum biochemical panel (high total protein, high globulin, low albumin and low A: G ratio), effusion tests, if present (exudate or modified exudate, yellow tint) and determining the likelihood that these findings can best be explained by the FIP. A definitive diagnosis can be obtained by identifying coronavirus proteins or RNA in effusions or tissue samples by PCR or immunohistochemistry. However, it is possible that cats that develop neurological FIP during or after treatment with a non-neurological form will lack many or all of these clinical signs.

Diagnosis of neurological FIP, especially in the primary form, is usually made in three ways: 1) consider all historical, clinical, and laboratory findings and estimate the likelihood of FIP, 2) examine the brain for FIP by magnetic resonance imaging (MRI), and / or cerebrospinal fluid (CSF) analysis, 8,9 and 3) treat on the assumption that it is a neurological FIP, and hope for a positive response to antiviral therapy.

Contrast-enhanced magnetic resonance imaging is increasingly being used in the diagnosis of neurological FIP. Dilation (hydrocephalus) of one or more ventricles is a common lesion in the brain.8,9 Similar dilatations in the form of syringomyelia can be observed in the spinal cord. Dilatations are secondary to inflammation of the surrounding ependyma. The ependyma ensures the excretion, circulation and maintenance of CSF homeostasis. Therefore, the severity of FIP secondary obstructive hydrocephalus is proportional to the degree of ependymal inflammation and the associated increase in contrast. Discrete lesions of the parenchyma are not identified. MRI significantly increases the cost of diagnosis, anesthesia increases the risk of death in seriously ill cats, and expertise and equipment are not always available. Therefore, the final diagnosis often falls in response to a specific antiviral treatment. The drug of choice for FIP neurological cases is GS-441524.9,12

CSF analysis is an alternative way to quantify the nature and severity of inflammation in the ependymus and meninges. CSF protein levels and cell numbers are elevated in cats with FIP, and it is often possible to obtain suitable samples for the detection of infected macrophages by IHC or PCR.10,11 CSF analysis is associated with a low risk of anesthesia and needle puncture into the magna tank.

Treatment

Neurological FIP can be cured if a sufficient amount of antiviral drug crosses the blood-brain barrier and the virus does not acquire drug resistance.9,12 Field tests with the GS376 viral protease inhibitor were the first to show that neurological symptoms could be significantly suppressed, but the infection could not be cured. The reason was considered the inability to reach sufficiently high levels of GC376 in the CNS. Greater success in treating cats with neurological FIP has been achieved with the nucleoside analog and viral RNA transcription inhibitor GS-441524.9,12 GS-441524 was shown to enter cerebrospinal fluid (CSF) at concentrations from 7-21% blood, depending on the cat tested. 13 These differences in the blood-brain barrier between cats are likely to explain the variable doses of GS-441524 from 4 to 10 mg / kg per day required for the treatment of naturally occurring cases of neurological FIP.9,12

The current starting dose for GS-441524 was based on recent findings7 set at 10 mg / kg daily by the subcutaneous route. Although it is possible to treat some cats at lower doses, 9,12 There is no easy way to measure the strength of the blood-brain barrier, so use the lowest dosage that will have a healing effect for most cats. Treatment success is measured by both improvement in clinical symptoms and improvement in critical blood test abnormalities. Weight gain and coat quality are also important quality traits that need to be observed. Sequence analyzes of MRI and CSF will provide more direct evidence of response to treatment,9 but in most cases they are impractical.

Improvement in general health and neurological symptoms usually appear within 24-48 hours, and most cats destined for complete recovery will return to normal within 4-6 weeks. However, a significant proportion of cats will respond more slowly and require a reassessment of their clinical condition and blood test status every 4 weeks. Slowing down the course of treatment, either clinically or in the form of a reversal in the initial abnormalities of the blood test, will require an increase in the dose from +2 to +5 mg / kg per day.9,12

Discontinuation of treatment, which is usually after 84 days, is not always easy to confirm. Typical blood test abnormalities used in most other forms of FIP either do not occur at the time of diagnosis or return to normal before treatment is stopped. Persistent neurological abnormalities may persist after the infection has healed, making clinical evaluation difficult. Without magnetic resonance and / or cerebrospinal fluid analysis to confirm that the disease has passed, the only option left is to stop treatment and hope that there will be no relapse.

Complications of neurological FIP

Relapses in cats treated for neurological FIP usually occur within a few days of stopping treatment and are caused by either inappropriate dosing and / or the acquisition of drug resistance. The incidence of relapses appears to be slightly higher than after treatment of forms of FIP without CNS involvement. Underdosing may be the result of a stronger blood-brain barrier in some cats compared to others, a poor quality antiviral drug, or incorrect dose calculation. However, it is common for cats to recover from re-treatment until drug resistance has occurred.

The acquisition of drug resistance is well known in antiviral drugs used in humans for diseases such as HIV / AIDS. It has also been reported with GC37611,14 also GS-441524 in cats.12 Drug resistance can occur by mutations in either the native FECV or its wild-type FIP biotype14, and manifested by an insufficient initial response to treatment, but this is not a common phenomenon.12 Resistance is more likely to occur during treatment and is due to both chronic drug exposure and lower sub-inhibitory drug levels. Drug resistance is usually partial and can often be overcome by increasing the dose. Drug resistance may worsen over time, and further dose increases will have no effect.

Cats with neurological FIP may show residual brain and / or spinal cord damage and permanent consequences after cessation of treatment. Disabilities include varying degrees of incoordination, behavioral changes, and dementia. The most problematic consequences are associated with spinal cord injury. The spinal cord is enclosed in a bone tube that does not allow for large expansion in the event of inflammation or some form of syringomyelia. Spinal cord involvement in FIP is often manifested by varying degrees of fecal and / or urinary incontinence. Paralysis of the hind limbs and tail is also observed, but is less common. Unfortunately, these clinical abnormalities are often permanent, especially if the neurological disease is not treated for a long time.

One of the most common negative antiviral treatment outcomes in cats with neurological FIP is failure to cure, although continuing high-dose treatment still allows for a sustainable quality of life (ie, management of disease symptoms without cure). This situation suggests that inhibition of virus replication by antiviral drugs may not be sufficient to cure the infection, and that an effective immune response is also required. This phenomenon of "treatment without cure" has in many cases led many owners to continue treatment at all costs for more than a year. It has also led to many experiments with ultra-high doses of GS441524 (> 15 mg / kg daily), divided doses, switching from injections to oral therapy, concomitant oral and injectable therapy, combination antiviral therapy (eg GS-441424 plus GC376) and antiviral support. treatment with high doses of corticosteroids and other immunosuppressants. Treatment with such treatments is occasionally required, but the result has been unfavorable for most of these cats.

There is circumstantial evidence that the host's immunity to FIP is shared between the CNS and other parts of the body. The incidence of CNS involvement appears to be increased when GS-441524 inhibits infection outside the CNS. Therefore, active disease outside the CNS appears to have an inhibitory effect on CNS disease. Cats with pure neurological disease often do not show abnormal blood test values on the CBC panel or in the serum, even with significant inflammatory changes in the cerebrospinal fluid.8 Compared to other forms of FIP, cats with neurological FIP often have the highest serum, ie the highest CSF antibody titers.8 These are all evidence of "compartmentalization" of the infection on either side of the blood-brain barrier.

References

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