Encephalitis

Encephalitis, an inflammation of the brain parenchyma, presents as diffuse and/or focal neuropsychological dysfunction. Although it primarily involves the brain, the meninges are frequently involved (meningoencephalitis).
From an epidemiologic and pathophysiologic perspective, encephalitis is distinct from meningitis, though on clinical evaluation both can be present, with signs and symptoms of meningeal inflammation, such as photophobia, headache, or stiff neck. It is also distinct from cerebritis. Cerebritis describes the stage preceding abscess formation and implies a highly destructive bacterial infection of brain tissue, whereas acute encephalitis is most commonly a viral infection with parenchymal damage varying from mild to profound.
Although bacterial, fungal, and autoimmune disorders can produce encephalitis, most cases are viral in origin. The incidence of encephalitis is 1 case per 200,000 population in the United States, with herpes simplex virus (HSV) being the most common cause. Considering the subacute and chronic encephalopathies, the emergency department (ED) physician is most likely to encounter toxoplasmosis in an immune-compromised host.
The relatively common acute arboviral encephalitides vary widely in epidemiology, mortality, morbidity, and clinical presentation, and no satisfactory treatment exists for these infections. However, attempts to distinguish these acute arboviral encephalitides from the treatable acute viral encephalitides due to herpes simplex or varicella are important.
Herpes simplex encephalitis (HSE), which occurs sporadically in healthy and immune-compromised adults is also encountered in neonates infected at birth during vaginal delivery and is potentially lethal if not treated. Varicella-zoster virus encephalitis (VZVE) is life threatening in immune-compromised patients. Swift identification and immediate treatment of HSE or VZVE can be lifesaving. From a risk-benefit standpoint, most authorities recommend initiating ED treatment with acyclovir in any patient whose central nervous system (CNS) presentation is suggestive of viral encephalitis, especially in the presence of fever, encephalopathy, or focal findings, and in all neonates who appear ill for whom a CNS infection is being considered.

Encephalitis Causes

• Herpes simplex (HSV): This type of virus causes cold sores and lesions of the genitals. HSV is transmitted directly through human contact. Newborns can also get the virus by passing through an infected birth canal. Once inside the body, the virus travels through nerve fibers and can cause an infection of the brain. The virus may also undergo a period of latency in which it is inactive. At a later time, emotional or physical stress can reactivate the virus to cause an infection of the brain. It causes the most subacute (between acute and chronic) and chronic (lasting three or more months) encephalitis infections in humans.
• Arbovirus: Hosts are animals such as birds, pigs, chipmunks, and squirrels that carry the virus. Mosquitoes (known as vectors or ways of transmitting the virus) feed on these animals and become infected. The virus grows and cycles between the hosts and the vectors. Humans become infected through mosquito bites. Once inside the body, the virus replicates and travels in the bloodstream. If there is a large enough amount of the virus, the brain can become infected. The majority of cases occur between June and September when the mosquitoes are most active. In warmer climates, the disease can occur year-round.

Figure 2: Picture of arbovirus transmission cycle and worldwide distribution; SOURCE: CDC.

• West Nile virus (WNV): This virus was first isolated from an adult woman with a fever in the West Nile District of Uganda in 1937. The nature of the virus was studied in Egypt in the 1950s. In 1957, as a result of an outbreak in Israel in the elderly, the WNV became recognized as a cause for severe inflammation of the spinal cord and brain in humans. In the early 1960s, it was first noted that horses were becoming ill in Egypt and France. This virus then emerged in North America in 1999, with encephalitis reported in humans and horses.
• The virus cycles between the Culex mosquito and hosts such as birds, horses, cats, bats, chipmunks, skunks, squirrels, and domestic rabbits. The mosquito feeds on the infected hosts, carries the virus in its salivary glands, and then passes it on to humans or other animals during a blood meal. It usually takes three to 15 days from the time of infection to the onset of disease symptoms. In the U.S., crows became a major host, but the disease would kill the crows; as a result, the number of infections dropped dramatically as the crow population died off.
• West Nile encephalitis is not transmitted from person to person (such as through touching or kissing or from a health care worker caring for a sick person) nor can it be passed from animal to human. Blood transfusions are the exception; the virus may be passed among people with blood transfusions.
• The chance that people will become severely ill from a mosquito bite is extremely small. According to the Centers for Disease Control and Prevention (CDC), even in areas where mosquitoes are reported to carry the virus, much fewer than 1% are infected. Furthermore, less than 1% of the people who get bitten and become infected will become severely ill. Therefore, the majority of cases are mild, and people can fully recover. The CDC reported 690 people infected in 2011,with a total of 43 deaths.
• Prognosis is usually guarded in the extremes of age (infants, young children, and the elderly). Death rates as a result of West Nile encephalitis range from 3%-15% and are highest among the elderly. At the present time, there is no documented evidence to suggest that a pregnancy is at risk due to WNV infection. It is assumed that if a person contracts WNV, he or she will develop a natural immunity that is lifelong. However, it may wane in later years. Currently, as of 2012, there is no commercially available vaccine for humans.
• La Crosse encephalitis: The first case occurred in La Crosse, Wisconsin, in 1963. Since then, the largest number of cases has been identified in woodland areas of the Midwestern and Mid-Atlantic United States. This virus is the most common cause of mosquito-borne encephalitis in children younger than 16 years of age. Each year, about 75 cases are reported to the Centers for Disease Control and Prevention (CDC). The virus cycles between the daytime-biting treehole mosquito (Aedes triseriatus) and hosts such as chipmunks and squirrels. Some investigators consider the cause of California encephalitis to be the La Crosse virus. The La Crosse encephalitis virus can cause adverse effects on IQ and school performance. About 80-100 people are diagnosed each year in the U.S., and 1% of people with this infection may die.
• St. Louis encephalitis: Since 1964, an average of about 102 people are reported infected per year. Outbreaks can occur throughout most of the United States, although large urban epidemics have occurred in the Midwestern and Southeastern regions. The last major epidemic of St. Louis encephalitis occurred in the Midwest from 1974-1977. There were 2,500 cases in 35 states reported to the CDC. Most recently, there were 20 reported cases in New Orleans in 1999. The virus cycles between birds and the Culex mosquitoes breeding in stagnant water. It grows in both the mosquito and the bird but does not make either one sick. Only the infected mosquito can transmit the disease to humans during the blood meal. The virus cannot be transmitted from person to person through kissing or touching nor can it be transmitted from the infected bird. The disease tends to affect mostly adults and is generally milder in children.
• Eastern equine encephalitis (EEE): According to the CDC, there have been confirmed cases in the United States since 1964 with a rate of about 0-21 diagnosed infections per year (average about six per year). This virus is found along the East and Gulf Coasts. The virus causes severe disease in horses, puppies, and birds such as pheasants, quails, and ostriches. In humans, flulike symptoms develop four to 10 days after the bite of an infected mosquito. Usually, human illnesses are preceded by those in horses. EEE can cause death in 50%-75% of all human infections; 90% of infected people have mild to severe impairments. Those who recover may suffer severe permanent brain damage such as mental retardation, seizures, paralysis, and behavior abnormalities.
• Western equine encephalitis (WEE): This virus was isolated from the brain of a horse with encephalitis in California in 1930. The worst epidemic was in Canada and the western U.S. when over 300,000 horses and mules were diagnosed along with over 3,300 humans in 1941. Since 1964, there have been at least 639 confirmed cases, but currently only a few per year are reported. However, it remains a cause of encephalitis in the western part of the United States and Canada. In 1994, there were two confirmed and several suspected cases of WEE reported in Wyoming. In 1997, 35 strains of WEE virus were isolated from mosquitoes collected in Scotts Bluff County, Nebraska. The WEE virus cycles between certain types of birds (small, mostly songbirds) and the Culex tarsalis mosquitoes, a species associated with irrigated agriculture and stream drainage. The virus has also been found in several other mammals. Horses and humans become sick through mosquito bites by infected mosquitoes. Infants are particularly affected and can have permanent problems such as seizure disorders and developmental delay as a result of the infection. A vaccine is not available for humans.
• Venezuelan equine encephalitis (VEE): This virus is found in Central and South America and is a rare cause of encephalitis in the southwestern part of the United States. It is an important cause of encephalitis in horses and humans in South America. From 1969-1971, an outbreak from South America to Texas killed over 200,000 horses. In 1995, there were an estimated 90,000 human infections with VEE in Columbia and Venezuela. The virus cycles between forest-dwelling rodents and mosquito vectors, especially the species Culex. VEE infection in humans is much less severe than that of WEE and EEE. While adults tend to develop a flulike illness, children tend to develop overt encephalitis. Deaths are rare in humans but are common in horses. There is an effective vaccine for horses but none for humans.
• Japanese encephalitis: This virus is responsible for 50,000 cases and 15,000 deaths per year. Most of China, Southeast Asia, and the Indian subcontinent are affected. The geographic distribution is expanding. Rarely, cases may appear in United States civilians and military personnel traveling to and living in Asia. Children and young adults are mostly affected. Older adults are affected when there are epidemics in new locations. The virus cycles between domestic pigs, wild birds, and the Culex tritaeniorhynchus mosquitoes, which breed in rice fields. The disease is not transmitted through human contact, pigs, or birds. Only the mosquitoes can transmit the disease during feedings.
• The following is a short summary of the viruses that cause the majority of encephalitis infections, although they may also cause other diseases.

Disease	Geographic Location	Vector/ Hosts	Comment
Herpes encephalitis	United States/the world	Human-to-human contact	Prompt treatment with acyclovir increases survival to 90%
West Nile encephalitis	Africa, West Asia, Middle East, United States	Mosquito/mostly birds	Majority are mild cases. Less than 1% of those infected will become severely ill. Full recovery is expected. A vaccine for humans is not commercially available.
Eastern equine encephalitis	East Coast (from Massachusetts to Florida), Gulf Coast	Mosquito/birds	Often occurs in horses. High mortality rate (50%-75%); frequent outcomes (seizures, slight paralysis), especially in children
Western equine encephalitis	Western United States and Canada	Mosquito/birds	Often occurs in horses. Particularly affects infants
Venezuelan equine encephalitis	Western Hemisphere	Mosquito/rodents	Rare in United States; low mortality rate, rare after-effects
La Crosse encephalitis	Throughout the United States, especially in midwestern & southeastern regions	Mosquito/ chipmunks, squirrels	Most common cause of encephalitis in children younger than 16 years of age
St. Louis encephalitis	Midwestern & mid-Atlantic United States	Mosquito/birds	Mostly affects adults
Japanese encephalitis	Temperate Asia, southern and southeastern Asia	Mosquito/birds and pigs	Vaccine available for ages 17 and older. See Prevention section. High morbidity/mortality rates

Other causes of encephalitis are as follows but will not be further discussed in this article; the reader is referred to the links provided:

• Bacteria, such as N. meningitidis, and those that cause Lyme disease, syphilis, tuberculosis, and occasionally other bacteria
• Fungi such as Candida, Mucor, Cryptococcus, and others
• Parasites such as Toxoplasma (often seen in HIV-infected patients) or the parasite Naegleria
• Allergies to vaccinations
• Autoimmune disease such as Rasmussen's encephalitis
• Cancers involving the brain tissue

Signs & Symptoms

Initially, the signs and symptoms of encephalitis are similar to that of flu or any other viral infection symptoms. Encephalitis can affect any brain function and the common symptoms are:

• Severe headache
• Fever
• Nausea
• Vomiting
• Drowsiness or confusion
• Sensitivity to bright lights
• Loss of memory
• Unable to speak
• Unable to control movement
• Weakness of one or more parts of the body
• Behavior that is not characteristic
• Change to any of the senses, e.g. touch
• Taste
• Smell
• Sight
• Hearing
• Stiff neck and back
• Muscle weakness
• Seizures (fits)
• Sleepiness that may lead to coma. (8)

Neurological complications may be permanent or improve as the infection runs its course with following signs and symptoms:

• Altered mental state (e.g., disorientation, personality changes)
• Convulsions
• Drooping eyelids (ptosis), double vision (diplopia), crossed eyes (strabismus)
• Hyperactive deep tendon reflexes
• Increased intracranial pressure
• Loss of consciousness
• Motor dysfunction
• Partial paralysis (paresis) of the extremities
• Projectile vomiting
• Pupil irregularities
• Restlessness
• Seizures
• Tremors (1)
• 
  

• Medical Tests & Diagnosis Methods/Tools

  Diagnosis of encephalitis is done with the help of the following:
  Medical History: Recent exposure to insects, travel, personality changes and contact with unusual animals or illnesses (9).
  Neurological Examination: Neurological examination consists of several components with each focusing on different parts of the nervous system such as:
  
  • Mental status
  • Cranial nerves
  • Motor system
  • Sensory system
  • The deep tendon reflexes
  • Coordination and the cerebellum
  • Gait
  Therefore, a neurological exam helps evaluate mental status, detect neurological problems such as motor dysfunction and seizures and help determine the area of brain that is affected (9) & (10). Other tests include:
  

  Blood and Urine Tests: These tests help isolate and identify the viruses. Enzyme-linked immunosorbent assays (ELISA), including IgM-capture ELISA (MAC-ELISA) and IgG ELISA can help identify the virus causing encephalitis. Polymerase chain reaction (PCR) helps in identification of small amounts of viral DNA. Imaging Tests: Imaging tests consist of Computed Tomography (CT scan) and Magnetic Resonance Imaging (MRI scan) producing computer images of the brain which help in detecting abnormalities like swelling (edema) and bleeding (hemorrhage). In Electroencephalogram (EEG), electrodes placed on the scalp are used to record and analyze the electrical activity in the brain. Wave patterns thus recorded suggest seizure disorder or specific viral infection.

  Spinal tap: In this procedure, cerebrospinal fluid is collected by inserting a needle between two vertebrae in the lower spine. The fluid is analyzed for an elevated count of White Blood Cells (WBC), blood and presence of virus (9). 
•  

Treatment for mild cases mainly consists of:

• Bed rest
• Plenty of fluids
• Anti-inflammatory drugs — such as acetaminophen (Tylenol, others), ibuprofen (Advil, Motrin, others) and naproxen (Aleve, others) — to relieve headaches and fever.

Antiviral drugsMore-serious cases of encephalitis usually require aggressive antiviral treatments. Antiviral drugs commonly used to treat encephalitis include:

• Acyclovir (Zovirax)
• Ganciclovir (Cytovene)

Some viruses, such as insect-borne viruses, don't respond to these treatments. However, because the specific virus causing the infection may not be identified immediately or at all, treatment with acyclovir is often begun immediately. This drug can be effective against the herpes simplex virus, which can result in significant complications or death when not treated promptly.
Side effects of the antiviral drugs may include nausea, vomiting, diarrhea, loss of appetite, and muscle or joint soreness or pain. Rare serious problems may include abnormalities in kidney or liver function or suppression of bone marrow activity. Appropriate tests are used to monitor for serious adverse effects.
Supportive careAdditional supportive care also is needed in the hospital for people with severe encephalitis. The care may include:

• Breathing assistance, as well as careful monitoring of breathing and heart function
• Intravenous fluids to ensure proper hydration and appropriate levels of essential minerals
• Anti-inflammatory drugs, such as corticosteroids, to help reduce swelling and pressure within the skull
• Anticonvulsant medications, such as phenytoin (Dilantin), to stop or prevent seizures.

Follow-up therapyAfter the initial illness, it may be necessary to receive additional therapy depending on the type and severity of complications. This therapy may include:

• Physical therapy to improve strength, flexibility, balance, motor coordination and mobility
• Occupational therapy to develop everyday skills and to use adaptive products that help with everyday activities
• Speech therapy to relearn muscle control and coordination to produce speech
• Psychotherapy to learn coping strategies and new behavioral skills to improve mood disorders or address personality changes — with medication management if necessary