Antiseizure Medications

Emergency control of acute seizures is usually achieved with diazepam (0.02 to 0.5 mg/kg, IV, usually 5 to 10 mg for juvenile or adult camelids, as needed). For controlling persistent, recurrent seizures, phenobarbital (15–20 mg/kg diluted, IV over 30 minutes for loading dose, followed by approximately 1 to 4 mg/kg, IV or orally [PO], q12h) is superior. If cerebral edema is suspected, mannitol (0.5 to 2.0 g/kg in a 20% solution) may be used, and dextrose (0.5 g/kg, IV) is effective against hypoglycemic seizures.

Hydrocephalus and Hydranencephaly

Developmental brain abnormalities are present in a small percentage of crias and account for less than 2% of all congenital malformations.⁵ Some of these also have overt cranial malformation, but many have a grossly normal appearance from the outside. The severity of the signs depends on the degree of compromise of brain tissue. Signs are usually present at birth, although in rare cases of hydrocephalus, they may develop and worsen over the first 2 weeks of life or so. Affected crias are generally hypoactive and hyporeflexive. They appear weak and do not suckle readily. Thus, most suffer some degree of failure of passive transfer. Breathing may be normal or weak. Hydrocephalus has also been identified in an adult, and a cria with meningitis, but appears to be extremely rare.^4,6

In the absence of overt cranial abnormalities, this disorder is difficult to differentiate from more common conditions such as sepsis and hypoxemia. It may also contribute to those two disorders. Without another condition, blood work and CSF are usually normal. Clinical examination reveals anything from a slightly underperforming cria to one with no muscle tone or reactions to stimuli. Cross-sectional imaging techniques offer the most direct means of diagnosis. No treatment exists beyond supportive care. No specific etiologies have been identified.

Polioencephalomalacia and Other Causes of Cerebral Necrosis

Polioencephalomalacia (cerebrocortical necrosis) in camelids is similar in some ways to the condition in ruminants but also appears to have some unique features.⁷ In all species, polioencephalomalacia is a histologic abnormality, which may be the common end point of a diverse set of conditions. In all cases, increased intracranial pressure (ICP) leading to pressure necrosis of the deep cerebral laminae, particularly those of the occipital lobe and parietal cortex, appears to be the final mechanism. The individual causes for that increase in pressure may vary, and they may occur at different frequencies in camelids and ruminants.

ICP usually increases with water accumulation. In ruminants, this is often the result of failure of the adenosine triphosphate (ATP)–dependent sodium–potassium pump. This pump exports three intracellular sodium molecules in exchange for two extracellular potassium molecules, thus promoting the outflow of intracellular water. Free water eventually passes from the cranial vault. Although some compounds may interfere with this pump directly, most cases of polioencephalomalacia in ruminants affect the pump indirectly by impairing ATP production. This has rapid consequences. The grey matter of the brain is metabolically very active and has a high energy demand (2% of body weight, but 20% to 30% of body glucose use). It is able to take up glucose in an insulin-independent fashion but must metabolize it aerobically (Krebs cycle) to obtain sufficient ATP.⁸ The brain stores very little glycogen and no oxygen and therefore relies on constant delivery of both compounds.

Much has been made of the role of the glycolytic pentose–phosphate shunt, which may augment other glycolytic pathways. Thiamine diphosphate is a rate-limiting co-factor in this shunt. Thiamine is made by microbes in the forestomach, and thus its production may be disturbed by illness, feed changes, or oral medications. Very little is stored, so constant production is required. In young crias or ruminants, ingestion of preformed thiamine is required and may be insufficient with some feeds. In juvenile and mature ruminants, outbreaks of polioencephalomalacia are often linked to changes to high-carbohydrate feeds or administration of oral antiparasitic agents. High-energy feeds lead to acidification of the rumen fluid, die-off of thiamine producers, and propagation of type II thiaminase-producing bacteria. Some deworming agents act as co-factors to other bacterial (type I) thiaminases, and some plants such as bracken fern, horsetail, and Nardoo fern contain thiaminases as well. Amprolium is an inactive thiamine analog, which blocks thiamine’s activity by competitive inhibition. Amprolium-induced polioencephalomalacia has been experimentally produced in camels, but only when the animals were fed a barley diet.⁹ A number of other minor and unlikely conditions may also decrease thiamine production or affect its function. Although some camelids with polioencephalomalacia, particularly those in scientific reports, have been exposed to some of these risk factors, namely, high-energy feeds, feed changes within 3 to 5 days, dewormers, or amprolium, many have not.^9–13 Most reported cases involve adults, but preruminant crias account for half or more of our cases; whether this suggests dietary thiamine inadequacy or another mechanism is unknown.

Although thiamine may play a role in the development of polioencephalomalacia, other factors are known to be important as well. Most neuronal glucose is not broken down by the pentose–phosphate pathway anyway, which suggests that its role as a bottleneck may be small. Factors that inhibit the electron transport chain also have the potential to dramatically reduce ATP production. In ruminants, sulfur and lead intoxication have both been identified as electron transport chain inhibitors linked to polioencephalomalacia. These have not been identified in camelid cases, but since camelids are often housed under similar conditions as ruminants, exposure is plausible. Lead exposure usually comes from car batteries or lead-based chemicals. Sulfur may come from a variety of sources. Water is considered toxic at greater than 1000 parts per billion (ppb) of sulfur and feeds at greater than 4000 ppb. Occasionally, it is the summation of dietary and water sulfur that leads to intoxication. Dietary sulfur is usually oxidized and nonodoriferous, but it is then reduced to hydrogen sulfide gas in the rumen and probably inhaled during eructation. Other unusual syndromes that have been reported anecdotally are focal symmetric polioencephalomalacia in camelids with selenium toxicosis or recent heat stress.

Insufficient oxygen delivery is another possible cause. The brain normally has at least 20 times more glucose than it has oxygen to metabolize it, so oxygen is more limiting. This is especially true in camelids, which tend to have high blood glucose concentrations. The ability of camelids to thrive in low oxygen environments may play a role as well. Young crias often appear far more active than their degree of hypoxemia would suggest. The same is occasionally seen in adults with cardiac or respiratory disease. It is possible that the greater functionality of camelids while hypoxic allows CNS disease to develop unexpectedly, instead of against a backdrop of obtundation and lethargy. Acute carotid spasms, which may occur after errant venipuncture attempts, may also acutely decrease oxygen delivery. Stressors such as being chased by dogs have been implicated, but the mechanism is not known.

A last putative cause, and one that may be common in camelids, is the abrupt shift of body water into the intracranial space. Hypoproteinemia is common in sick camelids, and although it alone should not promote cerebral edema, it makes camelids very susceptible to overhydration with fluid therapy. Camelids are also prone to rapid and dramatic fluctuations in blood glucose. Increases in blood glucose may lead to initial dehydration of the brain, but too rapid correction may reverse the flow of fluid. These conditions are covered separately, but it is important to recognize that they cause signs and lesions compatible with polioencephalomalacia, are common in camelids, and are also uncommon in ruminants.

Clinical signs are also more varied in camelids than is typical in ruminants. Central blindness is common but not universal. Obtundation, lethargy, anorexia, weakness, salivary loss, and recumbency are common but nonspecific. Head and body tremors, head pressing, opisthotonus, aimless wandering, hyperreflexia or hyporeflexia to external stimuli, ataxia, seizures, and coma are more specific to the neurologic system. Clinical pathology abnormalities are normally mild or reflect the primary disease such as hypoxemia or enteritis in neonates and forestomach acidosis in adults. Spinal fluid may contain a high number of vacuolated mononuclear cells and a mild increase in protein concentration. Diagnosis is mainly presumptive, based on signs, history, and CSF analysis. Postmortem identification of flattening and widening of gyri, necrosis of grey matter, and edema is confirmatory. In severe cases, the occipital lobes may have herniated under the tentorum cerebelli, and the hindbrain may have herniated into the foramen magnum. Fluorescence of brain sections under ultraviolet (UV) light was detected in one case but not another.11,13 Histologic lesions resemble those seen in ruminants.¹¹

Treatment for polioencephalomalacia is mainly through thiamine administration. This appears to help, even when thiamine deficiency is not the direct cause. In severe cases, 10 mg/kg IV once, followed by the same dose IM or SQ, q6h for at least 2 days, often leads to improvement within 24 hours. In milder cases or for prophylaxis, half the dose and frequency or dilution of the thiamine in any IV fluids being administered may be beneficial. Because of the diversity of signalments and presentations, using some form of prophylactic treatment in any camelid showing neurologic signs is considered appropriate. Seizing camelids should be treated appropriately.

Although amprolium-related polioencephalomalacia appears to be rare, prophylaxis may also be useful with extended treatment (>5 days at the 10 mg/kg dose). Prophylactic thiamine administration with any use of amprolium is not recommended because it may decrease the efficacy of the antiparasitic.

Cerebral Edema

Cerebral edema is a relatively common complication of IV fluid therapy in camelids because they are generally prone to hypoproteinemia and also hyperosmolar disorder. In addition, fluid requirements of camelids have not been worked out clearly, and aggressive regimens used successfully in other species may be too rapid for camelids. Signs are similar to those of hyperosmolar disorder and include lethargy, weakness, obtundation, fine head tremor that worsens to a coarse, whole-body tremor, base-wide stance, ataxia, seizures, coma, and death. Eyes and mucous membranes may also appear excessively moist. Because the signs are so similar to hyperosmolar disorder, history and clinical pathology data may be necessary to differentiate the disorder; camelids with cerebral edema would not specifically be expected to have high blood or CSF sodium concentrations. Increased CSF pressure may be indicative, but reference values have not been determined, and fluid from normal camelids often appears under pressure at the lumbosacral tap site. Cerebral edema is rare in camelids not being administered IV fluids. Pulmonary edema and respiratory signs may be present concurrently.

In addition to decreasing the rate of any fluid therapy and halting the administration of hypotonic fluids, mannitol (0.5–2 g/kg in a 20% solution) is effective at reducing edema. Other diuretics are not as effective but may be used if mannitol is not available. Administration of plasma or a synthetic colloid should also be considered. Prognosis is good if the animal is treated early.

Toxic Neuropathies and Neurohepatopathies

Toxic neuropathies appear to be rare in camelids as are hepatoencephalopathies. We could find no reports of lead poisoning in Old or New World camelids, but it is likely that this would lead to similar signs as those seen in ruminants. Renal encephalopathy may occur with severe azotemia, but diagnostic and treatment efforts are usually directed toward improving renal function.

The most widely suspected toxic neuropathy was the outbreak of suspected salinomycin-related feed contamination.¹⁴ Affected camelids eating a specific feed developed signs that included dyspnea, ataxia, recumbency, and seizures before dying. Blood evaluation demonstrated increases in muscle enzymes. On postmortem evaluation, heart and brain tissues appeared to be affected.

Overdosing lidocaine hydrochloride may lead to depression, behavior changes, ataxia, muscle tremors, opisthotonus, blindness, apnea, hypotensive shock, and seizures. The toxic threshold for camelids is not known but is likely to be similar to what is seen in ruminants (<5 mg/kg or <4 mL/kg of 2% solution). Tolazoline reversal of xylazine has also been associated with the development of neurologic signs, including evidence of anxiousness, hyperesthesia, and convulsions. Other possible signs include profuse salivation, diarrhea, gastrointestinal (GI) hypermotility, tachypnea, and hypotension.¹⁵ This toxicosis was associated with giving too much tolazoline too quickly and potentially after much of the xylazine had been metabolized. Giving smaller doses gradually is generally considered safe. Intracarotid injection of a variety of agents has also been associated with the acute development of central neurologic signs, including seizures, obtundation, and central blindness.¹⁶ For all these acute reactions to pharmaceuticals, general care is the rule: antiseizure medications as needed, cardiopulmonary support, and a low stress environment where self-trauma is unlikely. Some toxicoses are rapidly fatal, but if the animal maintains or regains cognizance within around 4 hours, the prognosis for general recovery is good; some neurologic deficits may remain and be considered permanent.

Idiopathic Epilepsy

Epilepsy is rare is camelids and usually attributable to a metabolic or infectious condition. In rare cases, otherwise healthy camelids will develop short, recurrent seizures. Blood and CSF are usually normal, although muscle enzymes may climb after seizure activity. Now that cross-sectional imaging modalities have become widespread, they may reveal etiologies for some of these cases. We have seen this is a dam and cria, which suggests the potential for heritability.

Treatment depends on frequency, duration, and severity. Ultrashort (<3 second), infrequent seizures may not require treatment. Phenobarbital may be used to suppress longer, more frequent ones. If long-term treatment is anticipated, periodic monitoring of blood phenobarbital is recommended to ascertain that it is being kept within the therapeutic range.

Cranial Trauma and Intracranial Hemorrhage

Head trauma is an unusual condition in camelids. Intracranial hemorrhage (ICH) is slightly more common and may occur independent of evidence of trauma (Figure 38-5). No real risk factors have been identified, but trauma from conflicts, encounters with other animals, projectiles, or motorized vehicles, or any other process leading to violent activity could potentially lead to concussive injury. Hemorrhage without trauma could be associated with a vascular accident or coagulopathy. Severe trauma may focally damage the brain directly through penetrating injuries or depression fractures. More commonly, it leads to ICH without fracturing the skull. Hemorrhage acts as a space-occupying lesion, and as it usually disseminates throughout the subdural space, it may lead to diffuse pressure on the cerebral cortex or the brainstem. Cerebral signs include anorexia, weakness, or obtundation in mildly affected animals, and ataxia, central blindness, head pressing, opisthotonus, or coma in more seriously affected animals.

Diagnosis may be based on history, especially if the event is witnessed, evidence of external trauma, CSF analysis, or imaging studies. CSF may contain numerous erythrocytes and often have high protein and neutrophil counts. Evidence of erythrophagocytosis helps differentiate pathologic hemorrhage from iatrogenic bleeding during the procedure but may not develop for the first 24 hours or so. Atlanto-occipital fluid may be revealing when lumbosacral fluid is not. Conventional radiography is helpful if the skull is fractured, if penetrating foreign bodies are present, or if gas has entered the cranial cavity. Cross-sectional studies, particularly MRI, may be used to identify abnormalities of brain tissue or the presence of subdural hemorrhage.

With milder cases, conservative management, including stall confinement and shelter, may be beneficial. If hemorrhage is suspected, nonsteroidal antiinflammatory drugs (NSAIDs) or other anticoagulants may be contraindicated. δ-aminocaproic acid and other procoagulants have seen little use in camelids but may have some value if hemorrhage persists. Mannitol should be avoided because it may cross the damaged blood–brain barrier and draw water into the cranial vault.

With more severe cases or with obvious fractures, surgical repair to release ICH, remove debris or foreign bodies, and prevent subsequent infection may be helpful. Antibiotics are also indicated if the cranial vault has been penetrated.

Bacterial Meningitis, Encephalitis, and Myelitis

Bacterial infections of the CNS are relatively common but are usually the result of systemic infection or of infection with opportunistic organisms, as opposed to infection with any particular neurotropic organism. The most commonly reported infection, and the most common cause of sepsis in general, is Escherichia coli. Salmonella, Enterococcus, Pasteurella, Streptococcus, Listeria, and a variety of other organisms have been recovered from the CNS.17–23 Most may also be recovered simultaneously from other sites, including blood, the liver, or the lungs. While neonatal sepsis accounts for many of these cases, adult sepsis is also an important disorder. Neonatal sepsis is often a complication of failure of passive transfer, an otherwise compromised neonate, or housing in a dirty environment. Adult sepsis is often the result of chemical, infectious, or parasitic GI damage. Immunodeficiencies may also play a role. Most of the organisms are opportunists. Salmonella and Streptococcus equi ssp. zooepidemicus are known primary pathogens. Listeria monocytogenes is another primary pathogen, and does appear to show some degree of neurotropism. It is also a cause of sepsis.

Most of these organisms cause diffuse meningoencephalitis. Clinical signs, which may overlap with signs of sepsis, may include fever, obtundation sometimes progressing to somnolence, anorexia, recumbency, mucous membrane abnormalities, and weakness. More specific signs include ataxia, dysmetria, seizures, dysphagia, abnormal head carriage, circling, head tilting, dysphagia, facial paresis, miosis, spastic or flaccid paresis, and blindness. Listeria may also cause focal myelitis with signs resembling a spinal lesion. However, it has not yet been identified with unilateral cranial nerve lesions in camelids as it has in cattle and other ruminants.

Blood work may be normal or reflect the septic state. Spinal fluid is usually abnormal. With most bacteria, neutrophilic pleocytosis and an increase in protein concentration are characteristic. Bacteria may also be present, especially in neonates or immuncompromised patients. With listeriosis, mononuclear pleocytosis predominates. Culture of CSF, blood, or infected organs may yield the specific organism. Imaging studies are rarely helpful, unless hydrocephalus, gas, or an abscess is present, although MRI may detect more subtle inflammatory lesions.

Treatment consists of supportive care, treatment of underlying disorders, preventing or controlling seizures, decreasing inflammation, and eliminating the infection. Treatment of underlying disorders may include GI protectants, antiparasitics, and plasma transfusion. Seizure control may involve diazepam (0.02–0.5 mg/kg, IV) or phenobarbital (15–20 mg/kg diluted, IV over 30 minutes for loading dose, followed by approximately 1 to 4 mg/kg, IV or PO, q12h). Flunixin meglumine (0.5–1.0 mg/kg. IV, q12-24h) is the most common antiinflammatory agent. Glucocorticoids, dimethyl sulfoxide (DMSO), and a variety of antimicrobials have been used. Given the variety of organisms isolated from camelids with meningoencephalitis, empirical choices should be broad-spectrum agents. With early or less inflammatory disease, selection of a lipid-soluble agent that penetrates the blood–brain barrier may be beneficial. With later or more inflammatory disease, blood–brain permeability increases, and most antimicrobials will reach the brain and spinal cord. Because of the general lack of efficient antimicrobial defense mechanisms in the brain, high concentrations of bactericidal antibiotics are preferred. Agents reported to be useful in other species when the blood–brain barrier is reasonably intact include penicillin, erythromycin, trimethoprim sulfas, and florfenicol.24,25 The choices broaden with meningeal inflammation and include ceftiofur.²⁶

Prognosis is guarded, even if the disease is caught early and treated appropriately. Moribund camelids that do not respond well to the initial round of treatment have a grave prognosis.

Viral Encephalitis

Herpesviral encephalitis has been described after natural infection and experimentally reproduced using a virus originally described as neurotropic equine herpesvirus 1 (EHV-1).27–29 The largest outbreak of natural disease occurred in a group of llamas and alpacas imported together from South America and housed for 6 months in proximity with zebra, gnus, and antelope. Signs developed in a number of the camelids in the herd over a 30-day period, and a separate alpaca developed signs simultaneously 31 days after leaving the herd and less than 2 months after the arrival of a new group of zebras. This suggests that an incubation period of at least 1 month is possible before signs develop. In experimentally infected llamas, signs developed 5 to 8 days after intranasal inoculation.²⁸

The major clinical sign is blindness with dilated pupils and absent papillary light reflexes. This is associated with chorioretinitis, vitritis, and optic neuritis. In some cases, only the retrobulbar optic nerve is affected, resulting in a normal funduscopic examination. Fever occurs during the acute phase, up to 4 weeks before the onset of blindness. The minority of affected camelids also develop tremors, dysphagia, ataxia, head pressing, obtundation, head tilting, paralysis, or vestibular signs, including nystagmus and head tilting. Blood changes are mild. CSF was judged to be normal in the one outbreak.²⁷ If present, abnormalities would presumably consist of mononuclear pleocytosis and an increase in protein.

Diagnosis in live camelids may be supported by identification of a high or rising serum or CSF antibody titer. Clinically normal herdmates may also have increasing titers. In dead camelids, eosinophilic intranuclear inclusion bodies, cerebral edema, nonsuppurative meningoencephalitis, and lymphocytic perivascular cuffing may be found in the brain. Virus isolation, electron microscopy, immunohistochemistry, and fluorescent antibody testing may all be used to confirm the role of herpesvirus.

Camelids with widespread neurologic signs are likely to die within 1 week of onset of signs. Those with blindness alone may remain otherwise healthy, but the blindness is likely to be permanent. Treatment is mainly supportive. Specific antiviral treatments and the use of agents to decrease CNS inflammation have not been reported. These modalities may be beneficial.

Although the connection between EHV-1 infection and clinical signs is strong in this case, the incidence of clinical infection in camelids appears to be very low in spite of frequent contact between camelids and horses. We have seen this in a single llama with a previously diagnosed immunodeficiency. Considering that the virus in the experimental trial was derived from a dead alpaca from the original outbreak, it is likely that that particular strain of herpesvirus, potentially originally from a zebra, was particularly pathogenic in camelids. Recent evidence suggests that zebras may be the reservoir host for the newly described EHV-9, which is closely related to EHV-1 and has also been linked to fatal encephalitis in artiodactylids and other species.²⁹ Because herpesvirus infection was one of the first specific diseases described in New World camelids in the United States, many early references recommend vaccination with killed equine vaccine. The infrequency of this disease should be considered when making vaccine recommendations.

West Nile virus infection in New World camelids was first noted in 2002 in the United States, soon after its introduction into the Western hemisphere and has since been reported in several areas.30–32 More recently, the disease has also been identified in camels in the Middle East. Currently, the disease may be found in most of the world except in South America and eastern Asia. It is chiefly a disease of birds and spread by mosquitoes. Waterfowl and corvid birds appear to be some of the most sensitive hosts, and mass deaths among birds during mosquito season are harbingers of an outbreak. When West Nile virus, a flavivirus, first moves into an area or when large populations of naïve birds migrate into an infected area during mosquito season, the amount of virus in birds and mosquitoes increases. Mosquitoes then carry the virus to other hosts, including camelids, horses, and humans. The majority of mammals seroconvert over a very short period. They are considered dead-end hosts, though blood transfusion, organ transplantation, and breast feeding have been linked to spread in humans. The likelihood of disease in mammalian hosts relates to their degree of immunity, genetic susceptibility, and the amount of challenge.

In susceptible or overwhelmed hosts, clinical signs are thought to develop within 7 days of infection. Signs include torticollis or opisthotonus, ataxia, obtundation, lethargy, weakness, inappetence, hyperesthesia, tremors, facial twitching, sternal or lateral recumbency, seizures, coma, and death. Fever may be present in the acute stages. “Swan neck,” which is dorsal cervical convexity while trying the lift the head, is a nonspecific sign of weakness that is present in many cases. The course of the disease is usually less than 4 days, and case mortality is high. Multiple cases may appear within the same herd over a few days to weeks.

Blood evaluation is likely to reveal only secondary changes caused by stress, dehydration, exposure, and possibly seizures. CSF analysis reveals mononuclear pleocytosis and a high protein concentration. Antemortem diagnosis is usually presumptive on the basis of clinical signs, the presence of the disease in the area, and the appropriate season for mosquitoes. July through October represent the height of danger in most of the United States. Serologic evidence, from either the plaque reduction neutralization test or the microtitration neutralization test, is supportive but may be difficult to interpret in vaccinated camelids. Progress is being made on an immunoglobulin M (IgM) capture enzyme-linked immunosorbent assay (ELISA).

Postmortem evaluation is more definitive. Brain sections show the nonsuppurative inflammation, perivascular cuffing, and astrocytosis characteristic of viral infection. Lesions are most pronounced in the caudal medulla and in the adjacent spinal cord. Immunohistochemistry or polymerase chain reaction (PCR) may be used to specifically identify the virus in tissues. Immunohistochemistry staining localizes it to the cytoplasm of neurons and axons of the brain stem and midbrain.

Treatment is mainly supportive. In addition to fluids, NSAIDs, steroids, DMSO, and mannitol have all been used to decrease brain inflammation. Plasma from camelids hyperimmunized against West Nile virus may provide specific immunotherapy, but experiences in other species suggest this must be administered very early in the course of disease for the highest efficacy.³²

Vaccination may lower susceptibility. Trials using killed vaccines produced for horses have produced minimal side effects.³³ However, up to 10% of inoculated camelids still have inadequate virus-neutralizing titers after the second shot, leading some to suggest a third dose during the initial series. Annual boosters at least 2 weeks before mosquito season are recommended. Fly control and housing camelids from before dusk until after dark may also decrease exposure.

Louping ill is a tick-borne flaviviral encephalitis.34,35 It mainly affects lambs but occasionally also affects grouse, cattle, and goats. Less commonly, pigs, deer, rodents, camelids, and humans may also be infected. Currently, it is thought to occur only in and near Scotland and in Dartmoor, although a third focus in Eastern Europe is surmised. Transmission is most common during tick season, and Ixodes ricinus is thought to be the most important infective host. In sheep, most infected animals clear the infection after a few days of fever and viremia, but others develop severe, fatal viral encephalitis. In camelids, most reports are from younger adults and adolescents, and immunologic naïveté to the virus may contribute to more severe signs. In other species, the virus is shed in many body secretions, including milk, and may spread through contact, but this has not been reported in camelids.

Clinical signs include anorexia, lethargy, head and neck tremors, ataxia, and posterior weakness progressing over a few days to recumbency or death. A hind-limb “goose-stepping” gait may be seen. Progression is fairly rapid over a few days. Difficulty swallowing was reported in one case.³⁵ Ixodes ticks may be found on affected camelids or herdmates. Herd outbreaks, or sporadic occurrence on farms have been reported. Severity of disease may depend on immunity: in sheep, previous exposure gives long-lasting immunity and colostrum is protective. Naïve flocks may have fatality rates as high as 60%.

Diagnosis is achieved initially by clinical signs in a camelid in an endemic area during tick season. No blood or physical abnormalities except neurologic signs have been reported. High acute and convalescent antibody titers determined by hemagglutination inhibition may be used to detect infection in sick or recovering animals or their herdmates. Virus isolation or immunohistochemistry may be performed on postmortem tissues. Viremia may be detected by PCR in the preclinical phase of herdmates. Histologic lesions are worst in the brainstem but also may be found in the cerebrum and the cerebellum. The lesions are characterized by nonsuppurative meningoencephalitis with necrosis, lymphocytic perivascular cuffing, and focal microgliosis.

Treatment is entirely supportive. Antiinflammatory agents, as well as treating affected animals and herdmates for ticks, may be beneficial. Two out of five animals in two reports survived.34,35 For prevention, effective tick control and limiting animal exposure to tick habitats during active times of the year are recommended. Additionally, vaccines are available in endemic areas.

Eastern equine encephalitis virus is an alphavirus with a similar natural cycle to West Nile virus. Birds are the reservoir population, and spread occurs through mosquito bites. Aberrant infection has been reported in a variety of mammals, including horses and humans, and involves different species of mosquitoes. Mammals are considered dead-end hosts. Eastern equine encephalitis virus is found along the coasts of the Atlantic, the Great Lakes, and the Gulf of North America; the Caribbean; and the Atlantic coasts and adjacent riparian regions of Central and South America. Infection is sporadic in mammalian hosts and tends to occur in the middle of the optimal season for mosquitoes and bird infection (August through October on the East Coast of the United States). Camelids less than 1 year of age appear to be more susceptible than adults, potentially because of lower immunity but also potentially before their immature fleece leaves them more open to mosquito bites.³⁶

Clinical signs include lethargy, ataxia, recumbency, torticollis or opisthotonus, behavior changes, head twitching, seizures, fever, and possibly other cranial nerve signs (specifically involving CNV, VII, and VIII). Blindness and outbreaks involving multiple camelids are uncommon. Mild neutropenia may be present. Other blood changes are minor and usually secondary. Cerebrospinal abnormalities have been difficult to interpret in reported cases because of iatrogenic hemorrhage. Some degree of pleocytosis and increase in protein concentration would be expected. In horses, eastern equine encephalitis virus infection causes more neutrophilic pleocytosis rather than the increase in lymphocytes typically seen with West Nile virus or herpesvirus infection.

Antemortem diagnosis is usually presumptive and is based on clinical signs, the presence of the disease in the area, and the appropriate season for mosquitoes. The presence of fever in the acute stages is helpful in distinguishing herpesviral or flaviviral encephalitis from many other causes of CNS signs. Serologic evidence is supportive but requires survival of the patient. Postmortem diagnosis may be accomplished by immunohistochemistry or PCR of brain tissue or isolation of virus from this tissue. Histopathologic changes include lymphocytic perivascular cuffing, gliosis, and sporadic neuronal necrosis. Encephalitis may be mild and multifocal and also tends to be more neutrophilic compared with other viral encephalitides. The white matter is largely spared. Some camelids also have spinal cord inflammation, but viral antigen has not been identified in the cord. Immunohistochemistry staining localizes the virus to the cytoplasm of neurons, astrocytes, oligodendrocytes, and occasionally neutrophils.³⁶

The course of the disease is usually less than 3 days, and case mortality is high. Reported treatments were mainly supportive and reflective of the uncertainty of diagnosis. In other species, treatment is also supportive. Specific effective antiviral agents have not been found.

Prevention of infection follows similar principles to prevention of West Nile virus infection. Risk is seasonal and relates to the mosquito cycles. Fly control and housing camelids from before dusk to well after dark reduces the risk of exposure. Use of the killed equine vaccine appears to be safe in nonpregnant adult camelids. Similar to vaccination against West Nile virus, three vaccinations at 2- to 4-week intervals appears to be necessary to achieve serum titers comparable with those seen in horses. Peak titers are reached 10 weeks after the initial vaccination; that is, the initial series and the annual boosters should be administered 2 to 3 months before the period of highest risk.

Rabies in camelids is much like this disorder in other mammalian species.37–43 It occurs worldwide except for a number of pockets of exclusion, namely, the British Isles, Australia, New Zealand, Scandinavia, the Iberian peninsula, Italy, Greece and the southern Balkans, and Hawaii. Virus is present in the saliva of infected animals, and transmission most commonly occurs through animal bites causing skin breaks. Most of the cases in the United States have been reported in the southeastern states, where raccoons are the major wildlife reservoir. Raccoons act as the major wildlife reservoir along the Atlantic coast of North America, foxes are the major reservoir in Asia, Europe, coastal Alaska, southern Arizona, central Texas, and parts of northern New England. Skunks are the major reservoir throughout the central United States, and coyotes are important in southern Texas. Rabid bats are found in many areas but are a rare source of exposure for domestic animals except where vampire bats are found. In areas where domestic animal vaccination is common, camelid exposure usually occurs through a bite from an infected wild animal. In areas where vaccination is sporadic, domestic dogs represent an important source of exposure for camelids.^38–40 Dog attacks are also commonly associated with multiple infected camelids, whereas other wild animal encounters rarely result in more than one case. Infected alpacas biting other herd members, contaminating the fleece with saliva, and causing skin breaks on the ear has been reported, and alpaca-to-alpaca transmission has been suspected.³⁹ Attempts to experimentally infect alpacas through conjunctival inoculation did not result in rabies.

Clinical signs have been documented 15 to 90 days after a known exposure in alpacas and up to 6 months later in camels.38,39,41 In other species, incubation periods of over a year have been postulated. Hindlimb bites may first lead to signs of rear-end weakness and ataxia, frequently interpreted as lameness, and progress to ascending paralysis and central signs. Forelimb bites may also lead to lameness signs, but these are rapidly overshadowed by central signs. Bites on the face lead to the most rapid development of cerebral and brainstem signs, potentially within a few days. Central signs include behavior changes and functional changes. Behavior changes may be toward aggressiveness (furious form) or, more rarely, toward lethargy (dumb form). Aggressive signs include aimless charges, head shaking, head, neck, and body tremors, pruritus, attacks on penmates, handlers, and inanimate objects, self-mutilation, obsessive biting and chewing, rejection of offspring, falling, aggressive breeding behavior in males, repetitive alarm vocalization, and intolerance of the environment. Dumb signs include generalized weakness, lethargy, flaccid paresis of various muscles, and hyporeactivity. With either form, pharyngeal and GI function may be impaired, leading to ptyalism and pseudoptyalism, cud loss, inappropriate regurgitation, dysphagia, tenesmus, colic, and bloating. In camelids, incessant yawning has been described, which may represent compromised attempts to vocalize.⁴¹ Progression from first signs to coma and death appears to take approximately 6 to 8 days.^38,44

Premortem diagnosis is based on suspicion of exposure and compatible clinical signs. Blood CK activity may increase with struggling or recumbency but is a nonspecific change. No effective treatment is available, and the disease is ultimately fatal. Camelids with suspected rabies should be handled as little as possible and with extreme caution to prevent transmission. Isolation of suspected cases is strongly advised. Postmortem confirmation is encouraged, especially in cases of possible human or other animal exposure. The most common method of diagnosis is a direct fluorescent antibody test on fresh or chilled brain. False-negative tests have been reported, and the spinal cord was positive in one camel with a negative brain test. Specimens should not be frozen prior to testing, and the brain should not be removed from the skull outside of the laboratory. Histologic examination reveals mononuclear perivascular cuffing and the presence of intraneuronal, intranuclear, 3- to 8-micrometer (µm) eosinophilic inclusion bodies (Negri bodies). Monoclonal antibody and deoxyribonucleic acid (DNA) testing may be performed on tissues to identify the strain of the virus and the likely animal source. Rabies is reportable in many places.

Vaccination with killed vaccines devised for livestock produces titers and possibly protects camelids against clinical rabies.⁴⁵ Although these products are not approved for camelids, their apparent efficacy and safety support their use in rabies-endemic areas. In camels, boosters every 6 to 8 months may be necessary.⁴¹ Some modified vaccines may be problematic; postvaccination complications were reported in over 10% of the vaccinates in one herd.³⁹ These complications included unilateral or bilateral hindlimb paralysis 14 to 30 days after vaccination in adults, with possible quadriparesis and difficulty urinating and defecating. In 6- to 10-month-old crias, eating, urination, and defecation ceased, but paralytic signs were not observed. This incident occurred over 50 years ago, and the vaccine used was a Flury low-egg passage strain. These have been shown to retain residual virulence in some species, and alpacas may have been affected for that reason.⁴⁶ Modified live vaccines generated by other methods may present less risk, but this outbreak emphasizes the need for safety testing before using products in large numbers of animals.

Rabies is zoonotic. Secondary potential human exposure has been documented, so prophylactic immunization is required, although no clinical disease has been reported.38,42 Concerns about transmission through spitting appear to be overblown, considering pharyngeal function is usually impaired in animals with salivary infection.

Bornavirus was originally detected in Germany and was long thought to be confined to central Europe. Recent evidence suggests that it may be found worldwide. It was also originally thought to cause disease mainly in sheep and horses, but it is now thought to infect a wide variety of mammals, including humans and birds. The possibility of natural infection throughout this broader host range and the importance of infection in individual species have yet to be defined. Some infected individuals develop clinical T-cell–mediated, nonsuppurative meningoencephalomyelitis, but others develop subtle to no signs. Clinical infections in camelids have been reported only in Germany: an outbreak in zoo llamas and alpacas, a single adult alpaca in a private herd of four, and another single adult alpaca that moved between regions for breeding purposes.47–49 Asymptomatic horses were long thought to be the reservoir hosts, but recent data implicate shrews, and other mammals or birds may prove to be important as well.

Transmission is thought to occur through direct contact or through contact with infective nasal or salivary secretions. Clinical signs are thought to develop approximately 1 month to several months after exposure. The virus is predominately neurotropic and ascends to peripheral and cranial nerve axons in a similar fashion to rabies, but Bornavirus also infects a variety of nonneurologic tissues. Viremia is maintained through infected monocytes.

Clinical signs include lethargy, anorexia, weight loss, progressive hindlimb lameness, weakness, ataxia, recumbency, and seizures. Specific neurologic signs may be obscured by the general weakness and malaise. In one male, chronic lack of libido was noted. Progression occurs over several weeks, although the disease may progress quickly once overt neurologic signs are noted. Survival appears to be rare. A furious form has also been seen in other species, confounding differentiation from rabies, but this has not yet been identified in camelids. Possible premortem tests include blood or cerebrospinal serology and PCR for virus within peripheral blood monocytes. Postmortem examination of the brain reveals lymphocytic inflammation and perivascular cuffing. Intranuclear inclusion bodies (Joest-Degen bodies) may be seen in neurons, especially of the hippocampus, but often throughout the brain. Occasionally, diffuse, homogenous intracytoplasmic staining exists. The presence of Bornavirus antigen may be confirmed by immunohistochemistry of tissue sections or cell cultures inoculated with homogenates of the brain or CSF, or the virus may be detected by PCR or isolated from infected cell cultures.48,50 Testing for Bornavirus is not available everywhere, especially in nontraditional areas, so samples from suspect animals may have to be sent to laboratories that offer testing. Because Bornavirus may infect humans and because rabies is the most important differential diagnosis, appropriate precautions should be taken when handling suspect animals or samples. Bornavirus infection is reportable in many areas. Vaccination is practiced as a preventive measure in endemic regions.