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The Disease
Encephalomyelopathy
Rhinopneumonitis
Reproductive


Encephalomyelopathy:
 
Equine Herpesvirus 1 (EHV-1) encephalomyelopathy may affect horses of any age or breed (3).  The disease is characterized by immune-mediated vasculitis leading to infarction and hemorrhage within the brain and spinal cord (4).  The encephalomyelopathy has an acute onset, typically less than 24 hours, and may or may not be preceded by respiratory disease or abortion.  Once horses are infected with EHV-1 they do not ever fully clear the virus, but instead they become latent carriers.  This means that they will not show clinical signs and that they do not normally shed the virus, however, in periods of high stress viral shedding may reoccur (5).  An increased incidence in the neurological form of EHV-1 has been noted in the fall, winter and early spring (19).  Encephalomyelopathies are more common in females above 3 years of age,  particularly in Hispanic, Standardbred and Draught breeds.

Previously, EHV-1 encephalomyelopathy was rare and sporadic however, the incidence of this disease appears to have greatly increased and has lead to tremendous losses in the equine industry. Recently, a mutation in EHV-1 has been found, and appears to be linked to the neurological form of the disease.  It is thought that this mutation allows for enhanced viral replication and infectivity of the central nervous system.  Researchers are unsure whether the mutation is arising with each outbreak or whether there are latent horses carrying and shedding the mutated form of EHV-1 (7). 

Pathogenesis: The natural reservoir for EHV-1 is the horse, and it is ubiquitous in horse populations worldwide.  Transmission is most commonly aerosol by inhalation of infected droplets, and animals typically shed for 7-10 days following resolution of clinical signs (17).  The virus can also be indirectly spread by contact by nasal secretions, aborted fetuses, placentas or placental fluids (4) as well as by fomites.  The virus is able to survive for several weeks in the environment once shed by infected horses, however it likely does not survive beyond 7 days outside of the host (17). 
The following diagram illustrates the epithelial invasion by EHV-1 and development of viremia.  Following infection of epithelial cells, EHV-1 infects endothelial cells in the lamina propria.  Virus-infected mononuclear cells and T lymphocytes subsequently appear in the drainage lymph nodes and are released into the circulation producing viremia.

  ehv pic 1
Diagram: Epithelial invasion of EHV-1 (33)

Incubation may range from 24 hours to many days, but is typically 4-6 days.  (17)  Further, it is possible for latency or carrier states to develop in animals whereby the virus particles will establish in the neurologic tissue (in the case of EHV-1) and may be reactivated and cause disease if the animal is stressed (17).  The following diagram illustrates the establishment of latency by EHV-1.  Following infection of respiratory epithelium latent infections are established in circulating T lymphocytes and trigeminal ganglionic neurons (white arrows).  Reactivation results in shedding of virus from nasal epithelium and probably uterine infection (yellow arrows).

ehv pic2
Diagram: Establishment of latency by EHV-1 (33)

Once the animal has been infected the disease is characterized by an initial period of respiratory symptoms including rhinopneumonitis and tracheobronchitis.  Rarely with EHV-1 an encephalomyopathy may develop following respiratory disease.  The neurological symptoms are caused by vascular damage to the endothelium of the blood-brain barrier resulting in vasculitis and thrombosis (17).    Until recently, it was thought that animals showing neurological symptoms were no longer able to shed the virus, however a case report from Ohio State University Veterinary Hospital in 2003 reported that EHV-1 was likely transmitted to five horses in the teaching hospital and a sixth horse at a distant site after being shed by animals with neurological symptoms (16). 

Clinical Signs: The severity of clinical signs will vary from hindlimb incoordination to quadriplegia (determined by the extent of damage to the brain and spinal cord) and the horse may be recumbent.  This is usually accompanied by urinary dribbling or retention, fecal retention and loss of sensation to the perineum and the tail.  Occasionally other neurological signs such as opisthotonus, circling and head pressing may be seen (6). 

Diagnosis: A nasal swab and blood sample (within a EDTA tube) should be collected by the veterinarian and sent to a lab for PCR (2).  PCR will demonstrate the presence or absence of EHV –1.  Presence in the nasal sample will be indicative of nasal shedding and presence in the blood is indicative of a viremia.  Some labs are offering molecular assays to differentiate between the neurogenic and non-neurogenic strains of EHV-1, while others are still conducting more research on these detection methods before providing this service to clients.  The problem with PCR testing for EHV in the horse population is that it will not only detect those animals which are clinically ill and shedding but also those who carry latent infections, dead virus or low levels that would not be a significant risk for transmission.  It is important therefore that the results of PCR and the clinical signs are taken into account when making a diagnosis of EHV.  Diagnosis should be based on histological evidence, clinical signs and on cerebrospinal fluid (CSF) analysis (4).  CSF indicative of EHV may be xanthochromic with increased levels of protein (4).  Also, 2 serum samples may be taken, one acute and one convalescent, and used in a virus neutralization test to look for an increase in antibody’s for EHV-1 (15).  An increase in serum antibodies would indicate the presence an active EHV infection and thus enhances the liklihood that the neurological signs are caused by EHV-1.

Pathology: On gross examination there may be absent to moderate amounts of hemorrhage within the meninges, brain and spinal cord.  Histology will show vasculitis, perivascular cuffing, and hemorrhage.

Treatment: While there is no specific treatment for EHV-1 encephalomyelopathy, recovery may occur with proper supportive care.  This includes using a sling for horses that can’t stand, catheterization, fluids and anti-inflammatory drugs (4, 5).  The use of antiviral treatment is debatable as some researchers say that by the time clinical neurological disease is seen the virus will have stopped replicating and thus the antiviral medication is of little use (14).  However, in a recent outbreak of EHV-1 in Ohio, acyclovir was used in treatment and the results seemed promising (12).

 

Acyclovir Treatment for EHV:  Is it efficacious?

Acyclovir has been used in both clinical cases and in research studies, however its efficacy is still debated.  In the 2003 outbreak of EHV at the University of Findlay, acyclovir was used in both the clinically ill patients and prophylactically in those animals which were not yet showing either neurological signs or a fever (15).  After the outbreak was contained an analysis was conducted looking at the efficacy of acyclovir in the treatment and prevention of encephalomyelopathy.  It appeared that there was a lower incidence of mortality in those who received acyclovir as either a treatment or prophylactically, and thus that acyclovir was efficacious in the treatment and prevention of EHV.  It is difficult however to determine the accuracy of this data because the treatment was not set up in a research situation and thus there are many confounding factors that could be responsible for the decrease in mortality.  A 200 study conducted by, Bradford et al, looked at the pharmokinetics of oral and IV acyclovir in horses (13).  Their study showed that oral bioavailibility and serum concentrations of acyclovir after oral administration were low.  These results indicated that acyclovir would not be efficacious in the treatment of EHV-1 infections as the serum concentrations would not reach the necessary threshold for antiviral activity against even the most sensitive strains of EHV.  Also, it was thought that increasing the oral dosage would not create an increase in serum concentrations that would be both safe and efficacious.  Intravenous use of acyclovir is thought to be of little use against EHV due to the high costs and lengthy duration that would be required for treatment.

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Image:  A. A horse with encepalomyelopathy is being held up in a sling. B.  HIstological hemorrhagic lesions in the spinal cord. C. Swollen axons and hemorrhage within the spinal cord. D. Thrombo-occlusive hemorrhage in the spinal cord. (11).

Prognosis:  Chances of recovery vary based on the severity of the disease.  Recumbent horses may recover, however, if they have not stood for more than 24 hours then prognosis is poor (3, 4). 

Prevention and Management:  While vaccines for EHV-1 exist, they are not believed to provide protection from neurological disease (4).  Thus proper management and minimization of outbreaks is critical. If EHV-1 is suspected then diagnostics should commence immediately.  Any EHV-1 positive horses should be isolated, and the farm quarantined for 3 weeks after the recovery of the last actively infected animal.  All horses should be monitored closely for neurological signs so that supportive care can be given immediately to those individuals that require it.  After a farm is infected all organic material (manure, dirt, bedding) should be removed, and all surfaces should be disinfected with a solution of 1 part bleach and 10 parts water (5).

 

Rhinopneumonitis:

Equine viral rhinopneumonitis is a disease of the upper respiratory tract of horses caused by infection with EHV-1 or EHV-4 (4).  Respiratory disease occurs most commonly in foals, living within concentrated equine geographical areas, particularly after infection with EHV-4. Disease onset is acute, with initial rhinopharyngitis followed by tracheobronchitis.  Secondary bacterial infections of the respiratory system are common because the virus leads to decreased macrophage function and to deciliation of the respiratory mucosal surfaces (4).     

Pathogenesis: The pathogenesis for rhinopneumonitis is the same as for encephalomyelopathy without the establishment in nervous tissue.  The natural reservoir for EHV-1 and EHV-4 is the horse, and it is ubiquitous in horse populations worldwide.  Transmission is most commonly aerosol by inhalation of infected droplets, and animals typically shed for 7-10 days following resolution of clinical signs (17).  The virus can also be indirectly spread by contact by nasal secretions as well as by fomites.  Once the animal has been infected the disease is characterized by an initial period of respiratory symptoms including rhinopneumonitis and tracheobronchitis.  The virus is able to survive for several weeks in the environment once shed by infected horses, however it likely does not survive beyond 7 days outside of the host (17).  See above diagram for details of epithelial infection.   Incubation may range from 24 hours to many days, but is typically 4-6 days.  (17)  Further, it is possible for latency or carrier states to develop in animals whereby the virus particles will establish in the lymphatic or neurologic tissue and may be reactivated and cause disease if the animal is stressed (17).  

Clinical signs:
  Fever (38.9-41.7 °c), bilateral nasal discharge, coughing, inappetance and depression are the most common manifestations of the disease (4,8).  However, submandibular and retropharyngeal lymphadenopathy are often seen as well.  Bloodwork will show decreased neutrophils, and lymphocytes. 

Diagnosis:  A nasal swab and blood sample (within a EDTA tube) should be collected by the veterinarian and sent to a lab for PCR (2).  PCR will demonstrate the presence or absence of EHV –1 or EHV-4.  Presence in the nasal sample will be indicative of nasal shedding and presence in the blood is indicative of a viremia (note: negative blood PCR does not indicate that the horse is EHV negative because viremia may be sporadic) (12).  The problem with PCR testing for EHV in the horse population is that it will not only detect those animals which are clinically ill and shedding but also those who carry latent infections, dead virus or low levels that would not be at a significant risk for transmission.  It is important therefore that the results of PCR and the clinical signs are taken into account when making a diagnosis of EHV.  If serum is being tested for antibodies against EHV then two samples must be submitted.  If there is an increase in the serum antibody levels then the animal is undergoing an active infection of rhinotracheitis.   

Pathology:
On gross examination the respiratory epithelium appears hyperemic and ulcerated and histology shows inflammation and necrosis of the respiratory epithelium and alveoli (4).






Image (11) :  Top Left:  Herpetic vesicular lesions on the nasal mucosa.  Bottom left:  Destruction of respiratory ciliated epithelium. Right: the brown stain indicates viral antigen in the nasal epithelium.

Treatment:
  There is no specific treatment of EHV, however, it is important that supportive care is given to the patient.  Prophylactic antibiotics may be given to minimize the risk of secondary bacterial infections and antibiotics should be given if purulent nasal discharge or pulmonary disease is noted (4).  Antipyretics may be indicated for fevers greater than 40°c and non steroidal anti-inflammatory drugs may be used to decrease inflammation within the respiratory tract (10).

Prognosis:  In the majority of infections prognosis is very good and spontaneous resolution of clinical signs usually occurs within a couple of weeks.  However, if severe secondary bacterial infection occurs then prognosis is more grave and increase in mortality may be noted (11).

Prevention and Management:  New horses brought onto the farm should be isolated for 3-4 weeks before being allowed to interact with the resident horses (4).  Stress should be minimized to decrease the risk of disease recrudescence and viral shedding.  Vaccinations should begin at 4-6 months of age and repeated at 5-7months and 6-8 months.  Then boosters should be given every 3 months to a year depending on the risk (10, 11).  The vaccine should include both EHV-1 and EHV-4.  While the vaccination will not prevent the horse from acquiring an infection it can reduce amount and duration of viral shedding from the nasopharynx (14).  If an outbreak of respiratory diseases or abortions occurs then horses should be isolated and the premises disinfected with a bleach solution.  The farm should be quarantined for at least 3 weeks after the recovery of the last clinically ill horse.

 

REPRODUCTIVE:

Pregnant mares who are infected with EHV-1, or occasionally with EHV-4, may abort their fetus 2-12 weeks after infection (4).  Mares who abort are typically 7-11 months through gestation, however, infection may occur later in gestation resulting in sick foals. 

Pathogenesis: The pathogenesis for abortive disease begins with respiratory infection.  Typically abortion occurs late in pregnancy, after eight months gestation, but may occur as early as four months.  Abortion may occur from two weeks to several months following infection, particularly if previously infected animals are stressed.  Once the animal has been infected the disease is characterized by an initial period of respiratory symptoms including rhinopneumonitis and tracheobronchitis.  See above diagram for details of epithelial infection.  

Clinical Signs:  There are rarely any preliminary signs prior to abortion.  Abortion consists of expulsion of fetus, with minimal autolysis, followed by placental expulsion.  This does not affect future conception or parturition of the mare.  Sick foals usually present with severe viral pneumonitis and are highly susceptible to secondary bacterial infections, death usually follows within hours to days. 

Diagnosis:  This is based on the gross findings in the fetus, on virus isolation and detection of viral antigen in the fetal tissues (4).  Also the placenta should be examined as viral antigens can sometimes be detected in the endothelium of the chorionic villi (18).  Looking at the dam’s serum antibody levels is of little to no use because the fetus may be infected when the dam’s antibodies are low (ie: she has a latent infection) and because the dam could have high antibody levels but the fetus remain uninfected (12).

Pathology: On gross the aborted fetus usually demonstrates pulmonary edema, hepatic necrosis, thymic necrosis, as well as petechial hemorrhages of the adrenal glands, myocardium and spleen (4).

Image (11):   A. aborted fetus from a mare infected with EHV. B. Pleural effusion within the thoracic cavity of the aborted fetusl.  C. Meconium staining on the perineal region of the aborted fetus.  D.  Multifocal Hepatic Necrosis.

Treatment:  No specific treatment can be given for aborting mares, however, rest and good management will help the mare to recover more rapidly.  Sometimes antibiotics may be indicated to aid in the prevention of secondary infections.  The mare should not be bred for at least 30 days after aborting to avoid infecting the stallion with her nasal shedding (9).

Prognosis:  The mare usually recovers from the disease with no significance to her future reproductive capabilities (4).  For foals that are born with the EHV infection, prognosis is very poor and they usually die within hours to days.

Prevention and Management:  New horses brought onto the farm should be isolated for 3-4 weeks before being allowed to interact with the resident horses (4).  Stress should be minimized to decrease the risk of disease recrudescence and viral shedding.  Also, keep the pregnant mares housed in small groups (with other pregnant mares, not with young or transient horses) to minimize the risk of abortion storms. Pregnant mares should be vaccinated against EHV-1 at 5, 7 and 9 months of gestation (9).  The vaccine should contain EHV-1 strains 1P and 1B. If an outbreak of respiratory diseases or abortions occurs then horses should be isolated and the premises disinfected with a bleach solution.  The farm should be quarantined for at least 3 weeks after the recovery of the last clinically ill horse. 







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