Diagnosing and treating common neurologic diseases in rabbits

Neurologic diseases are relatively common in companion rabbits and are being identified more frequently because of owners' greater interest in providing better healthcare to their pets, better-trained veterinarians, and improved diagnostic aids. In addition, many rabbits are living longer. Also, more has been discovered about the causes and treatment of neurologic diseases in rabbits in recent years, increasing our confidence in diagnosis and possible treatment.

Signs of neurologic disease in rabbits may include behavioral changes, torticollis (head tilt or wry neck) (Figure 1), nystagmus, tremors, paresis, paralysis (generally of the hindlimbs), and seizures. Other signs include loss of skin sensation (which is not always reliable in rabbits because of their stoic nature), loss of motor control of the urinary bladder and anal sphincter, development of decubitus ulcers (possibly as a result of paresis or paralysis), and a perineum stained with feces.

1. A rabbit with torticollis and nystagmus.

An understanding of the nervous system is, of course, necessary for diagnosing and treating neurologic problems in rabbits. Neurologic conditions in rabbits can be caused by a number of factors, although most cases are a result of infection or trauma (Table 1). For example, in a study in pet rabbits in the United Kingdom, head tilt in dwarf breeds appeared to be most frequently caused by Encephalitozoon cuniculi infection, whereas in standard breeds it was more likely caused by Pasteurella multocida infection.1 Fortunately, the diagnostic procedures used in rabbits with neurologic signs are similar to those used in other companion animals:

• History

• Physical examination

• Neurologic examination

• A complete blood count and serum chemistry profile

• Bacterial culture and antimicrobial sensitivity testing

• Radiography, computed tomography, magnetic resonance imaging, and myelography

• Serology

• Cerebrospinal fluid evaluation

Table 1. Common Causes of Neurologic Signs in Rabbits

PASTEURELLOSIS

Torticollis in rabbits may be caused by the extension of P. multocida infection from the nasal cavity to the middle or inner ear through the eustachian tube, or it may arise centrally in the medulla or cerebellum.2 Rule-outs include encephalitozoonosis, and, less commonly, otitis externa, cranial trauma, listeriosis, ascarid migration, or extension of an ear mite infection.

Diagnosis

Although you can reliably diagnose Pasteurella species infections in young rabbits with serologic testing, serology is of limited use in older rabbits because they develop antibodies to gram-negative core antigens shared by P. multocida and Enterobacteriaceae, and false positive results may occur.3 Serology in older rabbits is more useful to rule out the absence of infection than to identify infection.3 The best method for diagnosing P. multocida infection is a combination of polymerase chain reaction (PCR) on nasal swabs and serology.3

Differentiating pasteurellosis from encephalitozoonosis as a cause of vestibular disease is challenging and is most often determined by using the diagnostic techniques outlined in Table 2. Rabbits with suppurative otitis media caused by P. multocida often show no clinical evidence of infection. The otitis may extend into the inner ear, resulting in torticollis. If the infection is unilateral, the rabbit's head will tilt down on the affected side. Occasionally, nystagmus may be present. Affected middle ears are characterized by tympanic bullae filled with thick, yellow pus. Tympanic membrane rupture is possible. Radiographic or computed tomographic examination of the skull may show soft tissue density in the bullae, indicating pus-filled bullae.

Table 2. Differentiating Pasteurellosis from Encephalitozoonosis

Treatment

The head tilt in these rabbits is generally irreversible, but its worsening can be prevented with appropriate antibiotic therapy. Some clinicians report a lower incidence of residual head tilt after successful therapy. Chloramphenicol, enrofloxacin, ciprofloxacin, and trimethoprim-sulfa have been reported to be successful antibiotic therapy.4 The prognosis is favorable if a positive response is exhibited within the first week after therapy; therapy is continued for one week after clinical signs resolve.

Treatment of otitis media and externa should be long-term (four weeks or longer). Antimicrobials commonly used as initial therapy while waiting for results of culture and sensitivity include chloramphenicol (50 mg/kg subcutaneously or orally every 12 hours) or enrofloxacin (5 to 10 mg/kg orally every 12 hours). Also for otitis externa, clean and flush the ear canals, and apply topical 0.5% enrofloxacin–1% silver sulfadiazine otic solution (Baytril Otic—Bayer).5 In cases of severe, painful otitis externa, medical treatment may need to precede ear cleaning. Another treatment option when tympanic bullae are involved is tympanic bulla osteotomy, although complications—including facial nerve palsy, fistula formation, vestibular disease, and hypoglossal nerve dysfunction—have been associated with this surgery.

ENCEPHALITOZOONOSIS

Encephalitozoon cuniculi, an obligate, intracellular, microsporidian parasite, is often associated with neurologic disease in pet rabbits. Although many rabbits infected with E. cuniculi are asymptomatic, signs of neurologic disease caused by E. cuniculi include behavioral changes, torticollis, nystagmus, ataxia, rolling, or seizures and often follow a stressful event in the rabbit's life. Encephalitozoonosis in pet rabbits is more likely to be the cause of vestibular signs than is pasteurellosis.6 Other neurologic signs may include urinary incontinence, a stiff rear gait, and posterior paresis. Stressed or immunocompromised animals appear to be more susceptible. Transmission is generally by ingestion or by oral inoculation of infective spores shed in the urine, although transplacental transmission may also occur.

Diagnosis

Although it has been reported that encephalitozoonosis can be presumptively diagnosed based on signs of neurologic disease together with demonstration of high concentrations of serum antibodies (paired titers are preferable),5 this diagnostic approach is not always reliable. While rabbits with encephalitozoonosis are seropositive, many seropositive rabbits are apparently healthy and do not show signs of disease.3 In addition, a high antibody titer in a rabbit does not necessarily indicate it has an active or recent infection. However, the absence of antibodies (seronegativity) for E. cuniculi indicates that other differential diagnoses must be considered in sick rabbits.3 Enzyme-linked immunosorbent assays (ELISAs), indirect immunofluorescence assays, and carbon immunoassays are all suitable for detecting antibodies.5 So although a serologic evaluation can be helpful, it is far from diagnostic, and a definitive diagnosis of E. cuniculi as the cause of disease in a live rabbit is difficult6 and requires histologic identification of the organism.7,8 Table 2 shows how to differentiate between encephalitozoonosis and pasteurellosis as the cause of neurologic disease.

Treatment

A highly effective treatment for encephalitozoonosis has not been determined,5 and, in fact, some rabbits improve with no treatment at all. There are many studies of both in vitro and in vivo treatment of encephalitozoonosis, but one recommended treatment protocol includes dexamethasone (0.1 mg/kg subcutaneously once, then again 48 and 96 hours later), chloramphenicol (50 mg/kg subcutaneously every 12 hours for seven days), and oxibendazole (30 mg/kg orally every 24 hours for seven to 14 days).5 Dexamethasone is intended to reduce the inflammation associated with E. cuniculi and presumably increase plasma concentrations of albendazole (and possibly other benzimidazoles). Although corticosteroids should be used with caution in rabbits because they are a corticosteroid-sensitive species,9 a single dose of a short-acting corticosteroid (e.g. 1 to 2 mg/kg dexamethasone) has recently been recommended. If further treatment is required, anti-inflammatory rather than immunosuppressive doses of dexamethasone are indicated (0.2 mg/kg).6 If the neurologic signs abate, reduce the oxibendazole dose to 15 mg/kg every 24 hours for 30 to 60 days. If clinical signs recur, these patients should receive indefinite oxibendazole therapy (15 to 30 mg/kg orally every 24 hours).5

Another antiparasitical, albendazole, is also often used to treat encephalitozoonosis. This drug is only parasitostatic, so rabbits require long-term treatment. A dosage of 25 mg/kg/day given orally for 30 days has been suggested.6 Also, a small study has described the eradication of E. cuniculi organisms in rabbits treated with fenbendazole (20 mg/kg/day orally for 28 days).10 In addition, some clinicians have reported a favorable response with the concurrent use of medication used to treat motion sickness in people (i.e. meclizine).11

Treatment for encephalitozoonosis is not always successful but has resulted in improvement in some cases; a lack of treatment generally leads to euthanasia.

VERTEBRAL FRACTURE OR LUXATION

The most common cause of acute-onset posterior paralysis is vertebral fracture or luxation. Fractures are more common than dislocations, and the most common fracture site is L7 (Figure 2).5 This injury often results from improper handling but can also occur in caged rabbits that are startled or frightened. Injury occurs when the heavily muscled hindquarters are allowed to twist about the lumbosacral junction, which acts as a fulcrum and applies leverage to the vertebral column. Struggling rabbits, therefore, may kick and twist to exert abnormal stresses on these vertebrae, which may lead to fractures or luxations of the vertebral column. Rabbits are predisposed to vertebral fractures because their skeletal system is only 7% to 8% of their body weight (in contrast to a cat in which it is 13%) and because they have powerful hindlimbs that can kick violently.12 In addition, pet rabbits generally have minimal opportunity to exercise, which further contributes to poor bone density.

2. A rabbit with posterior paralysis resulting from a traumatically induced fracture at L7.

In addition to paraplegia, neurologic signs of fracture or dislocation may include the loss of skin sensation and motor control of the urinary bladder and anal sphincter, depending on the amount of spinal cord compromise. Decubitus ulcers often develop, and the perineum may become stained with feces. The extrusion of intervertebral disk material into the vertebral canal can also cause spinal cord compression and paresis. Posterior paresis or paralysis and other neurologic and locomotor disorders can also result from spondylosis, kyphosis, or lordosis of the vertebral column.

Diagnosis

The clinical diagnosis of posterior paresis or paralysis due to vertebral column disorders is confirmed radiographically, including myelography if indicated.13 An absence of deep pain sensation on neurologic evaluation generally indicates a poor prognosis. However, this test is not always reliable in rabbits because of their ability to hide clinical signs of pain and disease. Likewise, a withdrawal reflex restricted to the hindlimbs might be a purely local reflex and may not confirm a functionally intact spinal cord.

Treatment

If treatment is delayed, rabbits with broken backs can become azotemic or uremic because of urine retention in the bladder. Occasionally, mildly affected rabbits respond to conservative medical management if the spinal cord is not transected. In cases of urine retention, supportive therapy must include manual expression of the bladder. Although spinal surgery is a possibility, it is still in its infancy in rabbits compared with in dogs and cats13 and is seldom performed. Thus, euthanasia is often indicated in rabbits that do not respond to medical management. Alternatively, some house rabbits have been fitted with a trolley or cart to support the hindquarters (Figure 3). If the owners are attentive enough to prevent such complications as urinary retention and pressure sores, some of these rabbits can lead a life of reasonable quality.

3. A rabbit with posterior paralysis resulting from luxation of the spine. The patient was fitted with a cart, permitting daily exercise periods.

SPLAY LEG

Splay leg is a nonspecific term used to describe any condition affecting the limbs that prevents standing.13 This condition is generally a developmental musculoskeletal condition and is commonly seen in pet rabbits ranging in age from a few days to a few months. These rabbits are unable to adduct from one to all four limbs, so they cannot ambulate effectively (Figure 4). Hindlimbs are more commonly affected, with femoral neck anteversions, femoral shaft torsion, and subluxations of the coxofemoral joint.

4. Splay leg in a rabbit unable to adduct three of its legs.

Because splay leg is considered to be inherited in a simple autosomal recessive pattern,5 breeding of the affected animal and its parents should be discouraged. Although a few animals recover some limb functions, euthanasia is advisable for most.14 Occasionally, older rabbits are presented for evaluation of similar clinical signs, often resulting from a traumatic insult.

PREGNANCY TOXEMIA

Pregnancy toxemia can manifest neurologic signs in rabbits. Although primarily a problem of late gestation, toxemia also occurs in postpartum and pseudopregnant does. Neurologic signs may occur as a result of ketosis or other metabolic derangements and include weakness, depression, incoordination, and convulsions; coma may also occur. Death may occur within a few hours after the signs are first noted. Obesity and fasting are predisposing factors.

Treating the associated ketosis includes intravenously administering lactated Ringer's and 5% glucose solutions. Owners can prevent toxemia by avoiding fasting and preventing obesity in pregnant does and by providing a high-energy diet during late gestation.5

HEAT STROKE

Rabbits are tolerant of low temperatures but are particularly susceptible to heat stroke or heat stress, in part because of their dense fur and the fact that they do not sweat and cannot pant effectively.13 Signs of heat stroke include anorexia, increased respiratory rate, prostration, pulmonary edema, cyanosis, shock, and seizures. Signs are accompanied by an elevation in rectal temperature to greater than 105 F (40.5 C) (normal temperature = 101.3 to 104 F [38.5 to 40 C]).7

Treatment includes slowly reducing the body temperature by spraying the rabbit with or immersing it in tepid water or wrapping the patient in cool wet towels and administering intravenous fluids.5 Treatment may also involve the control of seizures, mannitol to reduce cerebral edema, and, if necessary, tracheal intubation and artificial ventilation.

Closely monitor rabbits that recover from heat stroke for several days for metabolic abnormalities or renal failure. Rabbits with heat stroke usually do not respond well, and the prognosis is poor. Pet rabbits housed outdoors during the summer when the ambient temperature can exceed 85 F (29.4 C) require shade, good ventilation, and an adequate supply of cool drinking water.

CEREBROSPINAL NEMATODIASIS

Cerebrospinal nematodiasis (cerebral larval migrans), caused by Baylisascaris procyonis (the common roundworm in raccoons) or possibly Baylisascaris columnaris (the common roundworm in skunks), has been reported in rabbits and may produce severe or fatal neurologic disease.5,15 Severe encephalopathy can be caused by just a few B. procyonis larvae. Neurologic signs include ataxia, circling, opisthotonos, tremors, and torticollis.

Rabbits most commonly acquire these parasites from hay, bedding, or edible vegetation that has been contaminated by raccoon feces.5,15 Eggs remain infective for at least one year.16 After embryonated eggs (generally in hay or bedding) are ingested, larvae are released in the intestine where they begin an aggressive somatic and pulmonary migration. Central nervous system signs can be profound because of the parasites' ability to migrate to the brain, grow rapidly, and produce metabolic wastes and enzymes resulting in a severe inflammatory response.

Cerebral larva migrans should be considered in rabbits with neurologic signs that are housed outdoors and that have potentially been exposed to Baylisascaris species eggs. However, diagnosis is by postmortem histologic evaluation of the brain. Evidence of larval migration can be found in the cerebrum, cerebellum, midbrain, and medulla and includes multifocal areas of necrosis with aggregations of inflammatory cells (eosinophils, lymphocytes, plasma cells, and macrophages). The Baermann technique can be used to recover larvae from brain tissue.

Once in the brain, B. procyonis larvae cause destruction of nervous tissue that is basically nonresponsive to medical therapy. Although euthanasia is generally indicated in affected rabbits, some veterinarians have had success slowing the progression of presumptive cerebrospinal nematodiasis with oxibendazole (60 mg/kg orally every 24 hours indefinitely).5 To prevent this disease, owners should guard against fecal contamination of rabbit housing, feed, and bedding by raccoons.

TOXOPLASMOSIS

Toxoplasmosis is an uncommon cause of central nervous system disease in domestic rabbits. Neurologic signs associated with this disease include ataxia, muscle tremors, posterior paralysis, and tetraplegia. The immunoperoxidase technique used on neural tissue is probably the best test available for diagnosing toxoplasmosis.

Histologically, Toxoplasma gondii can be differentiated from E. cuniculi by its strongly positive uptake of hematoxylin stain. Toxoplasma gondii is transmitted primarily by the ingestion of oocysts in infected cat feces. Rabbits with toxoplasmosis can be treated with pyrimethamine in combination with a sulfonamide such as trimethoprim-sulfa.5 To prevent toxoplasmosis, do not expose pet rabbits to an environment that may have been contaminated with cat feces.

NUTRITIONAL DEFICIENCIES

Some neurologic diseases in rabbits have a nutritional basis. For example, nutritional muscular dystrophy in rabbits is caused by hypovitaminosis e and is characterized by degeneration and necrosis of skeletal muscle fibers.5,7,13 Because prolonged storage of feed adversely affects the vitamin e content, rabbits should only be fed fresh feed, or rabbits' diets should be supplemented with an alternative vitamin e source, such as wheat germ or leafy green vegetables. Hypovitaminosis a has also been reported to cause a neurologic disturbance in rabbits characterized by circling, convulsions, opisthotonos, and paralysis.5 Hydrocephalus has been observed in young born to vitamin a-deficient does. In addition, convulsions can occur in rabbits maintained on a diet deficient in magnesium. Prevent these nutritional disorders by making sure owners feed pet rabbits only a fresh, high-quality diet.

LEAD POISONING

Lead poisoning in rabbits may be characterized by subtle neurologic signs, depression, reduced appetite, and lethargy.5,13 In later stages, more severe neurologic signs (ataxia, seizures) may be noted. Rabbits can be exposed to this poisoning because of their tendency to gnaw on almost anything they can find, including walls with old paint, toys, drapery weights, linoleum, and golf balls, some of which contain lead. This exposure most commonly occurs in rabbits that are free-roaming in the house, garage, or garden.

Diagnosis includes evaluating abdominal radiographs for gastrointestinal metallic densities and obtaining blood lead concentrations. Blood lead concentrations > 10 µg/dl and clinical signs of plumbism are diagnostic for lead toxicosis.5 The treatment of choice is chelation with edetate calcium disodium (Ca EDTA) (Calcium Disodium Versenate—3M) at a dosage of 25 mg/kg given subcutaneously every six hours for five days.5,11 Two courses of treatment one week apart may be required.

OTHER NEUROLOGIC CONDITIONS

Although less commonly observed, general neurologic signs in rabbits have also been associated with listeriosis and other infectious causes and trauma.5 In addition to the aforementioned causes in this article, seizures in rabbits may also be caused by hypoxia secondary to empyema, pneumonia, hepatic lipidosis (terminal stages), or metastatic tumors or may result from the azotemia and electrolyte imbalances associated with renal disease. Bacterial encephalitis can also cause seizures in rabbits.5 Primary epilepsy has been described, but most of these cases are thought to be associated with encephalitozoonosis or other forms of meningitis.14

Although rare, cases of rabies have been reported in pet rabbits. Rabbits usually develop the paralytic form of this disease. Early signs of rabies in rabbits may be nonspecific and include anorexia, fever, and lethargy.17 Thirty cases of rabies in pet rabbits were reported from 1971 to 1997, and most of these cases occurred in rabbits housed outdoors that were exposed to raccoons.17 One case resulted from an encounter with a skunk. Another report reviewed seven cases of rabies in pet rabbits in New York state between 1992 and 2001.18 In one of these cases, neurologic signs, which developed about one month after exposure to a raccoon, included blindness and forelimb paralysis. Because no rabies vaccine is approved for use in rabbits in the United States, pet rabbits housed outdoors should be protected from contact with wildlife, especially in areas where rabies is endemic or a rabies epizootic is under way.5

James W. Carpenter, MS, DVM, DACZM

Zoological Medicine

College of Veterinary Medicine

Kansas State University

Manhattan, KS 66506

Dr. Carpenter lectured on this topic at the 2006 CVC Central, and this article is adapted from the conference proceedings. Parts of this article are also adapted from Deeb BJ, Carpenter JW. Neurologic and musculoskeletal diseases. In: Quesenberry KE, Carpenter JW, eds. Ferrets, rabbits, and rodents: clinical medicine and surgery. 2nd ed. St. Louis, Mo: WB Saunders Co, 2004;203-210.

James W. Carpenter, MS, DVM, DACZM

REFERENCES

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3. Donnelly TM. Applications of laboratory animal immunoassays to exotic pet practice. Exotic DVM 2006;8:19-26.

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5. Deeb BJ, Carpenter JW. Neurologic and musculoskeletal diseases. In: Quesenberry KE, Carpenter JW, eds. Ferrets, rabbits, and rodents: clinical medicine and surgery. 2nd ed. St. Louis, Mo: WB Saunders Co, 2004;203-210.

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18. Eidson M, Matthews SD, Willsey AL, et al. Rabies virus infection in a pet guinea pig and seven pet rabbits. J Am Vet Med Assoc 2005;227:932-935.