Neurological and ocular FIP
Niels C. Pedersen, DVM PhD
Distinguished Professor Emeritus
UC Davis, Center for Companion Animal Health

April 29, 2019

Background- Many owners of cats with FIP have turned to the Chinese black market to obtain
GS-441524. This black market is not entirely profit motivated as the FIP problem in China ishorrendous. Pets are the in-thing in China, and expensive pedigreed Western breeds of catsproduced locally are imported from abroad are especially valued. As a result of the associated
FIP problem, Chinese were producing, selling, and applying drugs like GC376 and GS-441524
months before we were even able to publish our results. The reality is that the immediate needfor drugs like GS-441524 has outpaced the official approval and commercialization process, whichtakes years. The result is a wild-west with new producers and suppliers entering the market
weekly. Ultimately the black market will disappear as official suppliers come forward and patents
are finally enforced. In the meantime, it is not beneficial for FIP anti-viral drug therapy to begiven a bad name. Therefore, the purpose of this article of this communique is to discuss one of
the main problems that has arisen, i.e., what to do with cats that have the neurological and/orocular forms of FIP. This group of cats is increasingly a focus of my communications and also thetype of cat that is most difficult to treat and requires a lot more clinical research.
The blood-to-brain and blood-to-eye barriers-The eye and nervous system are protected fromharmful substances/agents by what is called the blood-to-eye and blood-to-brain barriers. Thesebarriers have great evolutionary significance because they protect both brain and ocularfunctions from the effects of systemic toxins and infectious agents. Such barriers evolved overmillions of years by positive selection for the fittest. The blood-to-brain barrier in cats will exclude
around 80% of most drugs, while the blood-to-eye barrier excludes about 70%. Therefore, if agiven dose of drug such as GS-441524 achieves an effective blood (plasma) level of 10 uM, thelevels in the brain (cerebrospinal fluid) will be only 2 uM and the level in the eye (aqueous humor)only 3 uM.
There are several other aspects of these barriers that need to be considered. First, their efficiency
at excluding unwanted substances and agents varies between individuals. Second, the efficiencyof this barrier will decrease in inflamed tissues and increase as inflammation subsides. This isgood for treatment in the early stages of disease but bad for treatment in the final stages when
the inflammation is gone and only the virus is left. Thirdly, there is no simple, safe or effectivemeans to decrease these barriers and the only way to increase drug levels in brain or eyes is toincrease their levels in blood plasma with higher dosages.
How these barriers cause disease- Paradoxically, the ocular and neurological forms of FIP are
also a result of these same barriers, but in this case of neurological and/o ocular FIP, theimpediment is to the entry of antibodies and immune lymphocytes. The phenomenon ofneurological disease following a common systemic virus infection is well known in humans andanimals. The prime example is polio-encephalomyelitis in people and canine distemper in dogs.
The polio virus is a common enteric pathogen and usually causes an inapparent or mild intestinal
infection. However, in some people the virus also escapes to the brain and spinal cord. People
mount a vigorous systemic immune response to the polio virus, which is highly effective ineliminating the virus in parts of the body except for the nervous system, where the blood-tobrain barrier limits is an impediment to immunity. These unfortunate people will develop theclassical neurologic form of the infection. A similar phenomenon occurs with canine distemper.
The canine distemper virus, which is closely related to the human measles virus, causes an acuterespiratory infection in young dogs that manifests 7-14 days after exposure and lasts for a weekor two. Most of these dogs will completely recover, but a proportion will develop neurologicaldisease three or more weeks later. This highly fatal secondary form of canine distemper is causedby virus that escaped into the brain and spinal cord during the respiratory phase of infection andis shielded from the host's immune system by the blood-to-brain barrier.
What is FIP? - FIP is ultimately caused by a common and a largely innocuous enteric coronavirus,
similar to coronaviruses causing diarrhea in humans, foals, calves and poultry. In about 10% ofcats, mainly kittens, the enteric coronavirus will undergo specific mutations that allow it toescape the cells lining the lower intestine and infect the most basic cell of the immune system,
the macrophage. This macrophage infection is eliminated in all but 0.3-1.4% of cats, which forunknown reasons are unable to develop the required protective immunity. The disease that
occurs in this unfortunate small group of cats can clinically manifest within days, several weeks,sometimes months, and rarely a year or more. The form of disease that is manifested is referred
to simply as wet (effusive) or dry (non-effusive). These two forms are easily distinguishable,
although there may also be transition forms between the two. Some cats may present with signsof dry FIP but later develop wet FIP, or vice versa. Overall, about 75% of cats will present withwet FIP and 25% will present with dry FIP. Less than 5% of cats, usually those with milder formsof dry FIP to start, will survive longer than one year with the best symptomatic care.
Clinical manifestations of FIP- The clinical manifestations of wet (Table 1) and dry (Table 2) FIP
vary according to the main site(s) of disease in the body. Wet FIP is characterized by theaccumulation of large amounts of inflammatory fluid either in the abdominal cavity and/or chestcavity. Involvement of the central nervous system (CNS) and eyes is relatively uncommon in thewet form of FIP. The dry form of FIP is characterized, not by diffuse inflammation and fluid
effusion, but rather by less numerous and larger tumor-like lesions (i.e., granulomas) in organs(e. g., kidney, cecum, colon, liver, lung, lymph nodes) within the abdominal or thoracic cavities,
or in the eyes and brain. Whereas the brain and/or eyes are only involved in 9% of the cases,
neurological and-or ocular disease is seen as the main presenting clinical sign in 70% of cats with
dry FIP.
Table 1. Variability in clinical signs of effusive (wet) FIP from cats necropsied at UC DavisSigns referable to:
Peritoneal cavity
Peritoneal & pleural cavity% affected
58.022.0

Pleural cavity
Peritoneal cavity, eyes
Peritoneal cavity, CNS*
Peritoneal and pleural cavity, CNS
Peritoneal and pleural cavity, eyes
Pleural cavity, CNS, eyes
Peritoneal cavity, CNS, eyes________________*Central nervous system (brain, spine)

11.0
2.8
1.9
0.9
0.9
0.9
0.9

Table 2. Variability in clinical signs of non-effusive (dry) FIP from cats necropsied at UC Davis

Signs referable to:
Peritoneal cavity
CNS
Eyes
CNS & eyes
Peritoneal cavity, eyes
Peritoneal & pleural cavities
Peritoneal & pleural cavities, CNS
Peritoneal & pleural cavities, eyes
Peritoneal cavity, CNS, eyes
Pleural cavity% affected
3022148743221

The FIP virus spreads to sites outside of the body cavities through infected macrophages thathave gained entry to the bloodstream. The main clinical signs of neurological FIP are fever,inappetence, weight loss, and incoordination (most intense in posterior). Some cats may also
develop seizures and varying degrees of dementia. Ocular disease often accompaniesneurological FIP due to the intimate relationship of eyes and brain. Ocular disease is most often
manifested by inflammation of the anterior uveal tract (iris and ciliary body) with discolorationof one or both irises, precipitates on the back side of the cornea, and cloudiness of the aqueoushumor. Ophthalmoscopic examination may also demonstrate inflammation in the retina andoptic nerve.

Diagnosis of neurological and/or ocular FIP- The neurological and/or ocular forms of FIP can be confusedwith feline systemic toxoplasmosis, which is why so many cats with these forms of FIP are tested fortoxoplasmosis and treated with Clindamycin or other antibiotics. However, systemic toxoplasmosis is anexceedingly rare disease of cats, especially when compared to FIP. FIP can be easily differentiated origin(cattery, foster/rescue, shelter), signalment (age, gender, breed), and basic blood test results. Deep fungal
infections (coccidioidomycosis, blastomycosis, histoplasmosis) can cause similar clinical signs to dry FIP
but are still uncommon even in their endemic regions. Lymphoma may also be a differential diagnosis fordry FIP, but this disease is usually sporadic and in older cats. The diagnosis of neurological and/or oculardisease is ultimately based on where a cat comes from the clinical signs, age, common changes incomplete blood count (anemia, lymphopenia), serum protein changes (high total protein, high globulin,
low albumin, low A:G ratio). The diagnosis may be confirmed if there is still doubt, by characteristicchanges in cerebrospinal fluid (CSF) and aqueous humor (high protein, high cells, neutrophils,
lymphocytes, macrophages), suggestive lesions on MRI, PCR or immunohistochemistry on CSF, or highserum coronavirus antibody titer by IFA (>1:3200). One must be careful, however, to follow the 70% rule,i.e., no single typical laboratory abnormality will occur 100% of the time. The rapid response of FIP to GS441524 is in itself a diagnostic indicator.
Treatment of neurological and/or ocular FIP- The only effective treatment for neurological and/or ocular
FIP is an antiviral drug such as GS-441524. The minimum dosage regimen for this form of FIP should be 5
mg/kg, SC, q24 h for at least 12 weeks. We have found this treatment to cause a rapid reversal of clinicalsigns within days, a return to near normal within two weeks, and a return to full normalcy within 8 weeks
or so. The best gauges of normalcy are weight gain, growth if retarded by the disease, and the ability toonce again jump to previous heights without hesitation. Although GS-441524 is highly effective inreversing abnormal clinical signs in cats with neurological disease, it is not always curative. Relapses ofdisease following cessation of treatment have occurred within days to several weeks after stopping
treatment and the relapse rate appears to be much higher than for cats suffering other forms of FIP. We
have treated only six cats with neurological disease (four also with ocular disease). One cat relapsed withneurological disease after completing treatment at a dosage of 2 mg/kg, SC, q24h and was cured at adosage of 4 mg/kg, SC, q24 h, while a second cat was treated twice at 2 mg/kg and relapsed each time. A
third and fourth cat was treated at a dosage of 5 mg/kg and cured, while a fifth cat relapsed after twoidentical treatments at the same dosage. A sixth cat relapsed at 5 and 8 mg/kg and is now being treatedat a dosage of 10 mg/kg. Cats that cannot be cured of FIP can be kept in a state of normalcy with indefinite
treatment, but this can be a costly endeavor and with unknown long term side effects and the spectrumof drug resistance.
Can most cats with neurological FIP be cured? - The bottom line is that we do not know whether all catswith neurological FIP can be cured and in this regard, people treating cats with neurological FIP aredefinitely in a research mode. We feel that increasing the blood levels may be part of the solution basedon very few cases. It is also interesting that ocular lesions in cats with neurological involvement are moreamenable to treatment. We found that ocular disease signs can be eliminated at a dosage that is not
sufficient to cure brain disease. This may reflect the greater permeability of the blood-to-eye barriercompared to the blood-to-brain barrier in cats.
The ability of drugs like GS-441524 to inhibit inflammation caused by FIPV infected macrophages may also
be a two-edged sword. Increased vascular permeability in lesions may allow more drug to pass into tissues
in the initial stages of treatment, while resolution of the inflammation may re-instate the barrier andprevent sufficient drug levels later in treatment.
Finally, the problem of drug resistance of FIP virus in brain has to be considered. We know from our fieldtrial experience, and from the published research of others, that drug resistance occurs in a very smallproportion of naturally infected cats and can be also induced by repeated passage in cell culture. There isadditional evidence from the literature that different forms of the infecting virus can evolve in different
tissues, so that virus in the brain may respond different to GS-441524 than virus in other parts of the body.
The long-term exposure of variant viruses in the brain to low levels of drug could be conducive to theevolution of drug resistance. If drug resistance is present naturally or occurs after long term treatment,
increasing drug dosage will not succeed.