Encephalitozoonosis in Pet Rabbits

Introduction

Neurologic diseases are relatively common in companion rabbits (Oryctolagus cuniculus), and recognition of these conditions by the exotic animal clinician is very important (Fig 1). Encephalitozoonosis is endemic in the pet rabbit population worldwide, and is an important cause of neurologic disease in this species.

 

Pathogenesis of disease

Encephalitozoon cuniculi is an obligate, intracellular, microsporidian parasite. The primary mode of transmission is ingestion of infective spores shed in the urine, although transplacental transmission may also occur. Spores may also become trapped within the anterior lens capsule during intrauterine transmission. During horizontal transmission, spores infect intestinal epithelium then spread to gut-associated lymphoid tissue. From here, spores enter the bloodstream and travel to various organs including the liver, lungs, heart, and kidneys. Spores are excreted in urine between Day 38 to 63 and then intermittently. Non-suppurative, chronic granulomatous interstitial nephritis develops in some individuals. Approximately 3 months post-infection the brain is reached, and granulomatous meningoencephalitis may develop in affected rabbits.

 

Clinical picture

Although many rabbits with E. cuniculi infection are asymptomatic, clinical disease is caused by lesions within the central nervous system, kidney, and/or eye. Neurologic, renal, and ocular disease can occur separately or in combination.

Neurologic disease often includes vestibular signs such as head tilt, torticollis or wry neck, nystagmus, ataxia, circling, and rolling. Other neurologic signs may include seizures, urinary incontinence, a stiff rear gait, posterior paresis, and head tremors. Occasionally rabbits will exhibit behavioral changes or cranial nerve deficits.

Most cases of nephritis are subclinical, however signs of chronic renal failure may include non-specific signs of illness such as anorexia, lethargy, and dehydration, and possibly polyuria and polydypsia. In rare instances, renal hyperparathyroidism may lead to osteodystrophy causing pathologic long bone fractures.

Ocular encephalitozoonosis is usually seen in young rabbits. Inflammatory cells such as granulocytes, macrophages, and giant cells infiltrate the lens. The lens capsule may eventually rupture causing phacoclastic uveitis, which appears as a white mass within the eye. Cataracts and/or uveitis are typically unilateral, although disease can be bilateral.

 

Differential diagnoses

The most important differential diagnosis for vestibular disease in pet rabbits is bacterial otitis media/interna. Other less common causes of vestibular disease include:

• Extension of ear mite infection
• Suppurative meningoencephalitis, which occasionally develops in rabbits with bacterial rhinitis due to ascending infection along the cranial nerves
• Neoplasia of the central nervous system, especially lymphosarcoma
• Toxoplasmosis
• Cerebrospinal nematodiasis or cerebral larval migrans caused by Baylisascaris procyonis
• Cranial trauma, or
• Listeriosis

Potential causes of paresis include spinal vertebral fracture or luxation, splay leg, lead poisoning, hypovitaminosis D, and spondylosis.

 

Diagnosis

Antemortem diagnosis of encephalitozoonosis is difficult. Stressed or immunocompromised animals appear to be more susceptible to clinical disease. There may also be a breed predisposition, since head tilt in dwarf breeds may be more frequently caused by encephalitozoonosis, while standard breeds are more commonly affected by otitis media/interna.

 

Minimum database

Complete blood count, serum chemistry profile, and urinalysis results are frequently unremarkable. Patients with nephritis may develop changes consistent with chronic renal failure including azotemia and anemia

Bacterial culture and antimicrobial sensitivity testing as well as skull radiographs may be performed to rule-out otitis media/interna. Alternate imaging such as computed tomography, magnetic resonance imaging, and/or myelography may also be indicated.

 

Serology

Serology is the most important diagnostic tool for diagnosis of E. cuniculi infection in the living animal, and there are several methods for detecting antibodies against E. cuniculi are available from commercial laboratories in the US. Enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence (IIF) assays, and carbon immunoassays (CIA) are all suitable for detecting antibodies (see Sound Diagnostics, Inc. or the University of Miami). There is no difference in the ability of any of these assays to detect antibodies in serum, although a comparison of techniques showed that IIF, rather than ELISA, may be best for quantitative measurements of antibodies. In laboratory rabbits, serum antibodies against E. cuniculi develop within 3 weeks post-infection. Urine spores are first detected 3 to 5 weeks after seroconversion. Titers remain high for several months after exposure, then decrease slightly and can persist for years with fluctuating levels.

However, a positive antibody titer also does not necessarily indicate active or recent infection, and many seropositive rabbits are asymptomatic. Presumptive diagnosis of encephalitozoonosis may be based on the presence of neurologic disease and high serum antibody levels. Paired, rising titers increase the index of suspicion. Seronegativity for E. cuniculi suggests that other differential diagnoses should be strongly considered in sick rabbits.

 

Cerebrospinal fluid evaluation

A recent study by Jass et al (2008) found that cerebrospinal fluid in rabbits with presumptive encephalitozoonosis was characterized by lymphocytic-monocytic pleocytosis. The number of white blood cells observed ranged from 1-87/uL (median 15/uL) and protein ranged from 0.31-1.54 g/L (median 0.79 g/L).

 

Pathology

A common, and frequently incidental, gross finding in rabbits with chronic infection are multifocal, pinpoint, white pitted lesions on the serosal surface of the kidneys. Definitive diagnosis of encephalitozoonosis requires histologic identification of the organism in tissues associated with lymphocytic-plasmacytic inflammation. This non-suppurative inflammation is often granulomatous, with granulomas found in 77.5% of rabbits with encephalitis and in 12.5% with nephritis.

 

Considerations for the future

Immunoglobulin G (IgG) antibodies to E. cuniculi have been documented in urine samples from seropositive rabbits using ELISA. This test may have important potential as a future screening test since uropositivity was only found in strongly seroreactive rabbits.

 

Treatment

In the absence of controlled studies, it is difficult to assess the efficacy of therapeutic agents against E. cuniculi because latent infections occur and some clinical cases improve spontaneously without treatment, presumably as a result of the host’s immune response. Treatment for encephalitozoonosis is not always successful but can result in improvement in some cases. Lack of response to treatment generally leads to euthanasia.

 

Neurologic disease

Neurologic signs may not always be associated with the presence of E. cuniculi, but with the inflammatory response that persists after the organism has been eliminated. Most treatment regimes include medication to attack the causative agent, anti-inflammatory agents, and drugs to control signs of vestibular disease.

1. Causative therapy: Encephalitozoon cuniculi is reportedly susceptible to the following anthelmintics:
   • Albendazole (30 mg/kg PO q24h x 30 days); However, albendazole is embryotoxic and teratogenic in rabbits and has been associated with anecdotal reports of pancytopenia, fever, and death in rabbits, and so should be used with caution. If using this drug, evaluation of an intra-treatment complete blood count is recommended.
   • Fenbendazole (20 mg/kg PO q24h x 28 days); A small study by Suter et al. (2001) has described the eradication of E. cuniculi organisms in rabbits treated with this dose.
   • Oxibendazole (30 mg/kg PO q24h x 7-14 days); If neurologic signs abate, reduce the dose to 15 mg/kg PO q24h q30-60 days. If clinical signs recur, give oxibendazole 15-30 mg/kg PO q24h indefinitely.
   • Thiabendazole
2. Anti-inflammatory therapy:

The use of corticosteroids in rabbits with E. cuniculi is controversial because of their immunosuppressive effects. Encephalitozoon cuniculi infection is controlled by the regulatory function of T-lymphocytes, and immunosuppressive doses of corticosteroids may affect T-cell populations. Although rabbits are a corticosteroid-sensitive species, a single dose of a short-acting corticosteroid such as dexamethasone (1-2 mg/kg SC) has been recommended for rabbits with encephalitozoonosis. If further treatment is required, anti-inflammatory rather that immunosuppression doses of dexamethasone are indicated (0.2 mg/kg). An alternative regime that has been described is dexamethasone 0.1-0.2 mg/kg SC on Days 1, 3, and 5. Non-steroidal anti-inflammatory agents, such as meloxicam, have also been tried in affected rabbits.

1. Ancillary therapy:
   • Some clinicians have reported a favorable response with the concurrent use of motion sickness medication such as  meclizine (Antivert, Pfizer).
   • Episodes of circling or rolling may also be precipitated by stressors, so maintain affected rabbits in a quiet, stress-free environment.
   • Rabbits may initially require supportive care such as fluids and nutritional support.
   • Control seizures with the use of a benzodiazepine.
2. Treatment of potential concurrent disease: The primary differential diagnosis for rabbits with vestibular disease is bacterial otitis media/interna. If otitis is suspected or cannot be immediately ruled out, begin antibiotic therapy immediately until E. cuniculi serology results are available.

 

Ocular disease

Medical management of phacoclastic uveitis including systemic and topical dexamethasone and oxytetracycline has been described, however results are equivocal at best. The treatment of choice for phacoclastic uveitis is surgical removal of the lens by phacoemulsification. Recommend enucleation for chronic cases with endophthalmitis.

 

Prognosis

The severity of clinical signs is the best prognostic indicator for encephalitozoonosis. As a general rule, rabbits that continue to eat voluntarily have a good chance of survival.

 

Prevention and control

Until microsporidian-negative rabbit colonies were established, encephalitozoonosis was an important confounding variable in rabbit biomedical research. Encephalitozoon cuniculi is now controlled in a laboratory setting with the use of serologic screening and careful hygiene.

Encephalitozoon cuniculi is eradicated by boiling for 5 minutes or by autoclaving. Spores are inactivated when exposed to the following disinfectants for 30 minutes at recommended concentrations:  ethanol 70%, formaldehyde 0.3%, hydrogen peroxide 1%, and sodium hydroxide 1%.

 

Zoonotic potential

Encephalitozoon cuniculi has a wide host range among mammals including rodents, horses, carnivores, non-human primates, and humans. Cases have been reported in individuals with human immunodeficiency virus (HIV) as well as organ transplant or idiopathic CD4 T-lymphocytopenia patients. Enteritis, nephritis, and keratoconjunctivitis are among the conditions associated with encephalitozoonosis in humans.

Guinea pigs (Cavia porcellus) housed with infected rabbits can contract encephalitozoonosis, but develop nephritis rather than cerebral granulomas and neurologic signs.

 

Summary

Encephalitozoon cuniculi is a microsporidian parasite commonly found in pet rabbits. Rabbits are most commonly infected by ingestion of E. cuniculi spores. Chronic latent infection can persist asymptomatically for years, however clinical disease may be more common in dwarf rabbit breeds. Clinically affected rabbits most commonly suffer from granulomatous meningoencephalitis, although a small percentage of rabbits may have ocular or renal disease. Antemortem diagnosis of encephalitozoonosis can be challenging, however a high antibody titer paired with clinical signs support a presumptive diagnosis of encephalitozoonosis. Treatment often involves causative therapy using a benzimidazole anthelmintic, an anti-inflammatory agent, and possibly an agent to control ancillary neurologic signs, such as meclizine.

 

References