About Encephalitozoon (Ez)

Written by: Miyuki Matsuda and Daisuke Fukui, DVM

Changes are periodically made to the information herein; any such changes will be reported in subsequent revisions.
Latest revision: April 21, 2002

1. Summary of Encephalitozoon

1.1 Pathogen causing Encephalitozoonosis
Formally called Nosematosis, Encephalitozoonosis is broken out by the infection with Encephalitozoon cuniculi, an obligate intracellular protozoa that belongs to the phylum Microspora. A protozoa is a unicellular parasite. "Encephalitozoon cuniculi" means "of Nerves, Rabbit" in Latin.

1.2 E. cuniculi infecting numerous mammals
The infections with E. cuniculi are widely observed in numerous mammals including mice, rats, guinea pigs, goats, monkeys, people, etc., and the rabbits are infected with it most frequently among them. According to some recent researches, many E. cuniculi isolates from different mammals were identified to fall into several strains. Many reports say that immunocompromised people with the acquired immune deficiency syndrome (AIDS) were opportunistically infected with E. cuniculi and had headaches or high fever accordingly. Healthy humans who have proper immune system against it don't need to worry catching Encephalitozoon.

1.3 Encephalitozoonosis causing mainly central nervous disorders
The clinical signs of Encephalitozoonosis include various symptoms, such as torticollis (head tilts), circling, convulsions, partial paresis, opening limbs, urinary incontinence, ataxia, nystagmus, cataract, granulomatous uveitis, eye lesions, depressions, poor appetites, stunted growth, emaciation and nephritis. You will see most of them are caused by central nervous disorders. Knowing the lifecycle of E. cuniculi will let you understand it easily. As we mention it in detail in the next section, E. cuniculi are propagated in the brain or kidney. As a result of immunoreaction against E. cuniculi by the host, the parasites are broken out and the nervous tissues are damaged. According to a report on the research of Encephalitozoonosis in a rabbit colony of Asahiyama Zoo in Asahikawa City, Hokkaido, the infection was investigated in the kittens showing weight loss or stunted growth at the age of one month in which they were losing their maternal immunity effects, as well as in the adults showing poor appetites or depression (Fukui and others, 1999). Therefore, you should pay attention to such clinical signs as commonly observed. Encephalitozoonosis is often considered as an incurable disease leading to a sudden death, but it is not a correct understanding. The rabbits suffering from torticollis or circling for a long period are also reported.

1.4 Horizontal infection of Encephalitozoon
When a spore, a form of E. cuniculi, comes into a rabbit body and starts propagating, it is considered " infected ". There seem to be several ways of how spores are taken into the body and some examples are (No. 1 is considered as the main route of the infection):
1. Ingested spores are absorbed from intestines.
2. Spores are taken into the body with respiration and are absorbed from mucous membrane like lungs.
3. Spores enter directly from a wound on a skin, and so on.
Once in the body, E. cuniculi affect the inside of macrophage, in which they metamorphose into trophozoites. They, then, repeat agamogenesis by dual segmentation and fill macrophage (Schizogony). Macrophage filled with E. cuniculi are carried in the blood circulation to target the organs with affinity such as the brain, liver, lung and kidney. The infection in the kidney terminates in 40 to 70 days, and a pathological change in the brain has been established until then. When the propagation in the kidney reaches to a certain stage, a large amount of spores newly move to the urinary tubules and are excreted in the urine. Spores are most excreted in the urine on the 30th to 40th day after the infection, and then excreted intermittently afterwards. The excreted spores are very tough and transmitted to a new body, keeping infectious capability for 1 to 2 months. The infection from one body to another explained here is called a "horizontal infection".

1.5 Vertical infection of Encephalitozoon
Some fetus infected with E. cuniculi in the uteri have proved that there also exist intrauterine infections from mothers' bodies through their placentas. However, they say that the infections due to the contacts of mothers and kittens after birth are more frequent than placental infections (the latter is included in the vertical infection in a wide sense, but the route is the same as that of the horizontal infection). The results of the research in Asahiyama Zoo supported it (Fukui and others, 1999). E. cuniculi are often infected inapparently (infections persist without clinical signs), so infected kittens can be born from mothers observed normally or all the same litters can be infected. When breeding rabbits, you may notice that all the same litters sometimes show opening of the limbs at a few weeks after birth. Most of such cases used to be considered as a genetic neurological disorder. However, some of them might be E. cuniculi infections between mothers and kittens, actually. If so, both prevention and treatment can be applied as described below.


2. Diagnosis and Treatment of Encephalitozoonosis

2.1 Outbreaks of Encephalitozoonosis in Japan
The prevalence of infected rabbits with E. cuniculi in Japan is unknown, as research on it is not performed widely yet. However, there is no wonder even if half of the rabbits in Japan are infected because 70% of the rabbits in Europe and America are said to be infected according to the sero-epidemiological researches. Today a large number of rabbits are imported from these countries to Japan without being quarantined for E. cuniculi and are distributed as companion animals. This means that E. cuniculi may be also imported with their rabbit hosts in a probability of 70%. The only sero-epidemiological research in Japan was performed to the 42 rabbits in the Rabbit Colony of Asahiyama Zoo in Hokkaido. According to the results of this research, 71% of them were seropositive to antibodies to Ez, 67% were infected inapparently, and the outbreaks were observed in 11 rabbits of the 32 infected ones (34%) (Fukui and others, 2000; see reference, only in Japanese). They suppose that E. cuniculi infection is widespread in Japan, as individual reports cover its sporadic outbreaks in the whole country from Hokkaido to Kyushu. Considering these backgrounds, we assume approx. 70% of the rabbits brought to animal clinics might be infected with E. cuniculi.

2.2 Diagnosis of Encephalitozoonosis
To differentiate the cause of the disorder and identify Encephalitozoonosis, you need to do the following clinical procedures:
- Ask an owner about his/her pet's breed, age, history, and specific information.
- Perform a general physical check-up including otoscopy and neurological tests.
- Check the physical condition completely by each clinical test (blood test, urine test, etc) as needed.
- Check a skull and Bulla tympanica by an X-ray examination of the head.
If a disorder is observed in a central nervous system, E. cuniculi infection should be suspected as one of the causes regardless of sex and age of the animal. The clinical signs of Encephalitozoonosis are not extraordinary, so you should NOT omit it unless causes can be clearly specified. For example, in some cases of torticollis causing from pasteurellosis, changes of the skull and Bulla tympanica can be recognized using Imaging techniques (X-ray, MRI or CT tests), but are not in the case of Encephalitozoonosis. It is difficult to diagnose Encephalitozoonosis definitely during the lifetime. It used to be confirmed only at postmortem examinations. When specific pathological changes, such as granulomatous meningoencephalitis and parasites in the central nervous system or interstitial nephritis in kidney, are observed, you can diagnose it as Encephalitozoonosis (see reference). If parasites are isolated from brain or kidney tissue, this case can be also diagnosed as Encephalitozoonosis, but it can be nothing but a material for a postmortem examination. Some serological tests may be effective as aids to a clinical diagnosis during the lifetime, but from a clinical viewpoint, we think they should be utilized for preventing the outbreak of the disease, as described below. To prevent the aftereffects, it is important to start treating neurological signs caused by Encephalitozoon as soon as possible. The fastest and easiest diagnostic way for this may be the treatment with "fenbendazole", which will be explained in detail later.

2.3 Considerations on serological tests in diagnosis
By utilizing the host's immunoreaction caused by E. cuniculi to detect the antibodies to Ez in a serum, it is possible to know indirectly if this animal is infected with E. cuniculi. However, serological tests cannot always define E. cuniculi as a cause of clinical signs. These tests show a positive immunoreaction with a high interrelation with an animal whose infection can be determined histopathologically, but it is impossible to define that the infection, the production of the antibody and the breakout of the disease are mutually related. For example, similar to other infections, it takes a certain time from the first establishment of infection with E. cuniculi until the antibodies to it are produced. Even if a sudden propagation of pathogens or a form of pathological change occurs during this period, they are out of the range of a detectable area in serological tests. When the host's immunoreaction is exceptionally weak, it is not detected either. On the other hand, even if a case rabbit is seropositive, this may be caused by a different disease, so you should be careful before making a final decision. The antibodies to Ez found in a serum are not always "on-going"; they may be the "wreck" of E. cuniculi formally infected but driven off by the host's own immunity, or may be the inapparent infection.

2.4 A search on effective drugs for Encephalitozoonosis
Because E. cuniculi are not bacteria, general antibacterial drugs are not effective for them. By researches on drugs suppressing the propagation of E. cuniculi, the benzimidazole derivatives, such as albendazole or fenbendazole, should be proved effective for them. Albendazole has been proved effective for human patients. In a case report describing a rabbit with phacoclastic uveitis, treatment with oral albendazole for eight weeks resulted in the resolution of the intraocular granuloma. However, albendazole is reported to be experimentally embryotoxic and teratogenic in rats and rabbits, so its use to a pregnant animal is not recommended.

2.5.1 Fenbendazole eliminating E. cuniculi from the brain and kidney
The oral administration of fenbendazole (20 mg/kg bodyweight daily) was proved effective for the prevention and treatment of Encephalitozoonosis in a report in published in 2001 (see reference). According to the report, when rabbits were experimentally infected with the spores of E. cuniculi orally, the infections were established in the untreated rabbits, while the ones medicated with fenbendazole beforehand were not infected. Also, the oral treatment with fenbendazole (20 mg/kg bodyweight daily) to the animals already infected with E. cuniculi (i.e., seroposive) for four weeks resulted in the failure to isolate the parasites from the brains and kidneys.
According to the prophylactic study, the same treatment was administered to 16 rabbits with neurological signs, and eight rabbits were free of them (three showed some residual signs, and five responded poorly to the medication). This means that the administration of fenbendazole is effective in eliminating the E. cuniculi spores from the brains and kidneys of the rabbit hosts and shows the efficacy even after the infections have been established.

2.5.2 An old but new drug, Fenbendazole
Fenbendazole, which has been used as an anthelmintic of rabbit pinworms for a long time, is experimentally known as safe, and costs less expensive than albendazole. Taking advantage of the following merits:
- no side effects; it can be administered to the rabbits without any concern
- presentation of an appropriate administration amount to the rabbits
- moderate price
fenbendazole will be the primary choice for the treatment of Encephalitozoonosis.

2.5.3 Combination of fenbendazole and glucocorticoids is effective for Encephalitozoonosis
In addition to fengendazole, glucocorticoids are also reported to be effective for Encephalitozoonosis. As glucocorticoids may alleviate the neurological signs thorough the suppression of the granulomatous inflammation, they can be effective in an acute case. However, they may possibly activate the parasite activities or cause a secondary lesion as side effects, so you should pay attention when using them. Combination of fenbendazole and glucocorticoids should be administered first, glucocorticoids should be then reduced by degrees after a neurological sign is alleviated, and finally the progress should be examined by keeping medication with fenbendazole.


3. Prevention of Encephalitozoonosis and future prospects

3.1 Shutdown of the infection routes
As described earlier, Encephalitozoon is in general infected horizontally via spores excreted in the urine. Therefore, it is important to disinfect the living areas of rabbits to prevent infection; you should remove straws or bowls with urine immediately. You can sterilize them by using hot water, formalin 1% or NaOH 1%. After the urine is dried up, spores may be scattered with dusts and the infection will be possibly spread. The infected rabbits should be apart from healthy rabbits until E. cuniculi is completely exterminated. Infected rabbits excrete spores intermittently, which will raise a risk that healthy rabbits can be infected as well if they are kept in the same place. To avoid the infection between mothers and kittens, do not use female rabbits inapprently infected for breeding or treat them with fenbendazole before breeding. Younger rabbits at the age of 1 to 4 months excrete spores actively, so you should pay an extra attention not to spread the infection. Various serological tests are valid to know the inapparent infection.

3.2 Finding rabbits inapparently infected with E. cuniculi by serological tests to treat them before outbreaks of Encephalitozoonosis
Serological tests can recognize the host's immunoreaction by detection of the Ez antibodies, which result from the host's immunoreaction to E. cuniculi in the body If the antibodies to Ez are seropositive, the following cases can be considered:
- It was once exposed with E. cuniculi or a pathological change is formed in the body, while showing no clinical signs (inapparent or chronic infection).
- Due to a pathological change established in the body, it shows serious clinical signs, such as torticollis, etc.
The latter case becomes naturally the target of the treatment. The advantage of serological tests is that they can find the rabbits with no apparent clinical signs actually that may possibly fall into a severe disease (i.e., the rabbits inapparently infected with E. cuniculi. Logically, to avoid the outbreak or prevalence of the infection, you can take appropriate actions at the time when the infection is observed, such as medicating the infected rabbit with fenbendazole, isolating it from the healthy ones, and so on. However, the possibility of the outbreak of Encephalitozoonosis is considered lower than the possibility of its inapparent progress, so some of you may not agree with treating such rabbits. Our goal is to perform sero-epidemiological researches in more colonies and follow-up studies of seropositive rabbits to propose the best possible protocol to control Encephalitozoonosis.

3.3 Where is a serological diagnosis available?
In the United States, several test facilities provide a service to assay the antibodies to Ez in rabbits' sera using an ELISA or IFAT, but no institution supplies commercially similar services in Japan (as of June 2002). From a technical viewpoint only, it is possible to perform a test that detects the antibodies to Ez from a rabbit at any regular test institution. 0.2 ml (about two drops) of serum is required for this test. 0.2 ml of serum can be made from 0.4 to 0.5 ml of blood drawn from the vein of an anterior or posterior limb or an ear. Supposing that a consigned test to test facilities should be available in Japan, you could have your vet collect blood from your rabbit, isolate the serum and send it in a cold or frozen state to the test facilities. The test facilities would test all the sera gathered from various animal hospitals. The test results would be then reported to each animal hospital, and the veterinarians would examine them (i.e., the diagnosis). Finally, a rabbit owner would be reported his/her pet's test results and diagnosis from his/her vet. We will appeal for the importance of serological tests for Encephalitozoonosis to make the consigned test available in Japan as well.

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