sections include: herpes simplex virus encephalitis, anthropod-borne viruses, postmeasles encephalomyelitis, neurosyphilis
Encephalitis means simply “inflammation of the brain,” and encephalomyelitis translates as “inflammation of the brain and spinal cord.” The two terms are often used interchangeably. Inflammation can result from infections or from immune (allergic) reactions. Infectious encephalitis is most commonly caused by viruses, and more than 100 different viruses have been related to acute encephalitis; acute disseminated encephalomyelitis, or postinfectious encephalomyelitis, is an autoimmune disease that follows infections or, occasionally, immunizations with vaccines containing brain tissue.
The varied viruses that can cause encephalitis can be spread by people (some through saliva or respiratory droplets, and others through breast milk, fecal contamination, sexual contact, blood transfusion, or organ transplantation), by domestic or wild animals (through bites or urine), or by female mosquitoes and ticks when they inject saliva while taking blood meals from humans. Many viruses that can cause encephalitis are common infections that only rarely affect the brain; encephalitis is therefore usually a rare complication of a common systemic infection.
Fever, headache, stiffness of the neck, and depression of consciousness are the hallmarks of encephalitis. Paralysis, changes in sensation or vision, and seizures may also occur. To make a positive diagnosis, a doctor will examine the spinal fluid for inflammatory cells, a leakage of serum proteins, and sometimes an increase in pressure, which can indicate inflammation and swelling of the brain. Modern imaging studies (computed tomography, or CT, and magnetic resonance imaging, or MRI) may also be helpful.
To discuss the varied features of encephalitis, we focus on three diseases: herpes simplex virus encephalitis, the most common form of fatal nonepidemic viral encephalitis; arthropod-borne virus encephalitis, the most common form of fatal epidemic encephalitis; and postmeasles encephalitis, a major cause of serious autoimmune encephalomyelitis before the worldwide immunization program. Neurosyphilis, a fourth disease, will then be discussed as an example of chronic brain infection and inflammation and as an example of infection by a bacterium rather than a virus.
Herpes Simplex Virus Encephalitis
This is the most common fatal, nonepidemic form of encephalitis worldwide. Herpes simplex virus is ubiquitous: half of all people show evidence of a prior infection by adolescence, and 90 percent of adults have antibodies. Infection is spread by saliva and respiratory droplets, commonly by family contacts. The primary infection is either asymptomatic or a mild respiratory disease. The virus is then moved along peripheral nerves from the mucous membranes of the mouth and throat to sensory nerve cells in ganglia near the base of the brain, and it is in these nerve cells that the virus remains latent for life. Periodically the virus is activated, spreads down the nerves, and may, in some individuals, cause cold sores (herpes labialis). In other individuals the virus is shed in the throat without symptoms; this happens particularly at times of stress. We are all commonly infected with this virus, and most are unaware of it except for the 25 percent who are inconvenienced or embarrassed by cold sores. On very rare occasions, however, with new infections, the virus may spread from the mucous membranes of the nose into the brain along the neurons related to smell, or, with activation, the virus may spread to the underside of the brain rather than to the lip. In either case this life-threatening brain infection localizes in the lateral lower, or so-called temporal, part of the brain, and it is thought that infection remains localized because the individual’s immune status prevents generalized spread of the virus.
Because of the localization of the infection, in addition to signs of headache, fever, stiff neck, and depression of consciousness, there are often signs of temporal lobe abnormalities, such as bizarre behavior, hallucinations, strange smells, a feeling of unfamiliarity—signs that have also been recognized with temporal lobe tumors and other abnormalities. The disease may run an acute course over a few days or a rather protracted course over several weeks. It may be localized to one temporal lobe or involve both lobes. The infected person progresses from confusion, to stupor, to deep coma, and to death in the majority of untreated patients.
Diagnosis and Treatment
‘The diagnosis of herpes simplex encephalitis is suspected because of the localization of signs and symptoms; this localization is often confirmed by an electroencephalogram that shows characteristic patterns over one or both temporal lobes, or by imaging with computed tomography or magnetic resonance that shows evidence of tissue destruction and inflammation in one or both temporal lobes. In the past, definite diagnosis required a biopsy of the brain to isolate the virus or identify the viral proteins. In recent years, however, a highly sensitive and specific method has become available that uses polymerase chain reactions to detect tiny fragments of the viral DNA in spinal fluid.
Before the advent of modern antiviral drugs, the fatality rate of herpes simplex virus encephalitis was approximately 70 percent. With antiherpes drugs such as acyclovir, given intravenously for 10 to 14 days, this mortality rate has been reduced to 20 percent. Many patients now survive with few if any long-term effects, although one of the most distressing is an inability to form new memories because of the involvement of the more central parts of the temporal lobe on both sides.
Two factors strongly influence the outcome of treatment. First, younger patients survive at a higher rate with fewer problems than older patients. Second, treatment early in the course of the disease, when the patient is still alert and oriented, results in a far better outcome than if treatment is delayed until the patient is in a coma. Thus, in patients thought to have viral encephalitis the two most important factors the physician must deal with are 1) whether this may be herpes simplex virus encephalitis requiring specific treatment, and 2) whether it is something other than a virus for which other treatments are available.
Unlike herpes simplex virus encephalitis, which is a worldwide disease with no seasonal variation, the arthropod-borne viruses, or arboviruses, are localized geographically and occur only in seasons when the arthropods (usually mosquitoes or ticks) are feeding. These viruses undergo a biological cycle in the arthropods; thus these viruses are not transferred like an enteric virus that may contaminate the feet or mouthparts of flies or cockroaches and then be passively spread to our food. Arboviruses go through an incubation period in the mosquito or tick and eventually infect the creature’s salivary glands, from which they can be injected into a warm-blooded host. The viruses cause little if any disease in the arthropod, and the arthropod may remain active and infected for life—in some cases the viruses are passed on to their offspring by infection of the eggs. The warm-blooded hosts are usually birds or small mammals that may or may not become ill but do circulate virus in their blood, so that further arthropods can be infected and complete the cycle.
There are over 400 different arboviruses. Some cause hepatitis, such as yellow fever virus. Others cause tropical fevers, such as dengue. More than 20 are known to cause human encephalitis, and 8 of these occur in various regions of the United States. Eastern equine encephalitis virus occurs mainly along the Atlantic Coast. Western encephalitis occurs west of the Mississippi. The LaCrosse strain of California virus occurs in the midwestern United States, Venezuelan virus in Florida and along the Texas border. A tick-borne virus exists along the Canadian border, and in 1999 an African virus, West Nile virus, was transported to New York City. St. Louis virus causes the largest epidemics, with several thousand cases in the summer of 1975, and it has the widest distribution, from coast to coast. The LaCrosse strain of California virus is the most consistent from year to year, causing several hundred cases of childhood encephalitis each year. These epidemics are often preceded by warnings—for example, increasing mosquito populations in particular areas due to rainfall and temperature. Some outbreaks are heralded by the death of other animals, such as the sudden death of horses on the East Coast prior to a human case of Eastern equine encephalitis, or the death of crows and exotic birds in some zoos before the human cases of West Nile virus.
Most infections with arboviruses are either asymptomatic or cause general muscle aches or rash. Only on rare occasions do they enter the central nervous system from the blood and cause severe encephalitis. Worldwide, the most important of these viruses is Japanese encephalitis, which causes from 30,000 to 50,000 cases of encephalitis each year over a very large area of Asia and is spread by mosquitoes that breed in rice fields.
Encephalitis due to arboviruses is usually characterized, like other forms of encephalitis, by headache, fever, stiff neck, confusion, or coma and often seizures. These tend to lack the localizing signs of herpes simplex virus encephalitis. The severity of the encephalitis varies with each particular virus. Less than 1 percent of LaCrosse virus encephalitis cases are fatal, and very few of the children infected with this virus sustain permanent damage. At the other extreme, about 50 percent of persons, adults or children, with encephalitis due to Eastern equine encephalitis virus die, and many survivors are left with permanent disabilities. Japanese encephalitis virus, which accounts for the majority of arbovirus encephalitis, causes about 20 percent to 30 percent fatality, and about 30 percent of survivors are left with permanent brain damage.
Diagnosis, Prevention, and Treatment
The diagnosis of an arbovirus infection is suspected because of the season, an increase in mosquitoes, and, usually, public health warnings. Arboviruses must also be suspected in people who have traveled in areas where other arboviruses are spread, such as travelers in Asia during the summer months, or to the woodlands in southern Germany or Austria, where tick-borne viruses cause encephalitis in the spring and summer.
There is no specific antiviral drug that is effective against arboviruses. Once encephalitis has developed, treatment is limited to supportive intensive care. Some of the more severe infections can be prevented by vaccines. These are available for Japanese encephalitis virus in Asia and for tick-borne encephalitis virus in Europe. Some of these vaccines, however, are made in mouse brain, and on rare occasions they can cause an autoimmune encephalomyelitis resembling postinfectious encephalomyelitis.
The measles virus is a highly infectious virus with no known host other than humans. Before there were immunization programs, measles was usually acquired when children first gathered for schooling. Although measles is often thought of as a mild childhood rash, it has been one of the three most common infectious causes of death in the world, second only to malaria and dysentery. Indeed, 3 million children used to die every year from measles, and in areas where immunization has not been universal, over a million children still die every year from pneumonia, gastroenteritis, and secondary bacterial infections related to measles. Acute encephalomyelitis occurs in 1 in 1,000 cases of measles and is not associated with infection of the brain but is a complication of the systemic infection, which disrupts normal immune responses. In the course of the immunosuppression and deregulation that accompanies measles virus infection, an autoimmune disease against brain myelin can occur. It occurs most commonly in children over age 2 and adults, and, unlike pneumonia and gastroenteritis, it is unrelated to malnutrition.
Encephalitis usually follows uncomplicated measles and occurs five to eight days after the rash, when the child has gone back to school or is resuming normal activities. There is suddenly a recurrence of fever, depression of consciousness, and a variety of neurological abnormalities, such as paralyses, unsteadiness, abnormal movements, and loss of sensation. This may proceed to coma and death in about 25 percent of those who develop this complication.
Diagnosis, Prevention, and Treatment
The diagnosis is not difficult, because measles is a readily diagnosed disease and this autoimmune form of encephalitis follows directly thereafter. A similar encephalitis can follow chicken pox or rubella, where again, the diagnosis of the antecedent disease is straightforward. When an autoimmune encephalomyelitis occurs after nonspecific upper respiratory or gastrointestinal infections, it is very difficult to differentiate from cases of direct infectious encephalitis. Often the spinal fluid shows less of an inflammatory response than is seen in acute viral encephalitis. Imaging studies, either computed tomography or magnetic resonance imaging, may show multiple areas of inflammation specifically in the white matter of the brain.
Although steroids are commonly given to patients with this disease, there is no evidence that they alter the course or outcome. Fortunately, the disease is almost totally preventable with immunization, and postmeasles encephalomyelitis has essentially disappeared in the western hemisphere, where persistence of the virus in the population has been eliminated by vaccine programs.
In contrast to the acute diseases of the brain caused by viruses described earlier, syphilis is caused by a spiral mobile bacterium (Treponema pallidum), which causes a chronic inflammation of the brain that can remain symptomatic or cause a variety of diseases years after the primary infection. After the introduction of penicillin in the mid-1940s the frequency of neurosyphilis fell more than tenfold, but in recent years there has been a modest increase in the frequency of this disease.
Syphilis is spread through sexual contact, blood transfusions, or across the placenta to the fetus. After sexual spread, a painless genital sore called a chancre usually develops. Several weeks later the bacteria spread via the blood, when a rash is often seen and other organs are seeded. In approximately a quarter of persons the brain and spinal cord are involved, and this involvement usually occurs within 3 to 18 months after the primary infection. Some patients at the time of bacterial spread suffer a mild meningitis, with headache, fever, and stiff neck, but this clears within a few days. The infection, however, remains in the nervous system, with a chronic mild inflammatory response. Years later some patients may develop vasculitis with strokes, chronic involvement of the gray matter of the brain resulting in dementia, or inflammation and thickening of the thin covering of the brain, causing sensory loss and pain in the legs or blindness.
Meningovascular neurosyphilis is primarily an involvement in and around blood vessels, with a marked inflammatory response and strokes. This commonly occurs within 5 to 10 years after the primary infection. Paretic neurosyphilis is a syndrome of slowly progressive dementia and typically occurs 10 to 15 years after the primary infection. Tabetic neurosyphilis, or tabes dorsalis, is an indolent fibrosis (slow growth of the fibrous tissue) of the meninges (delicate coverings of the brain) around the nerve roots coming into the spinal cord, and leads to a loss of sensation and reflex in the legs, often accompanied by pain referred to as lightning pains. This usually occurs 15 to 20 years after the initial infection.
Diagnosis and Treatment
The diagnosis of neurosyphilis may be suspected when a positive reaction to syphilis is found in blood tests, but the critical factor in diagnosis is examination of the cerebrospinal fluid, which during asymptomatic neurosyphilis will show a positive reaction to the spirochete. But during the active phases of meningovascular syphilis, paresis, or tabes dorsalis, the spinal fluid also shows an increase in cells and an elevation of spinal fluid protein.
The treatment is penicillin, but there has long been a controversy as to how much penicillin should be given and for how long. Because of the difficulty with which penicillin enters the cerebrospinal fluid in the absence of marked inflammation, it is probably better to use daily large intravenous doses of penicillin for a period of 14 days. Subsequently, the patient’s spinal fluid should be reexamined at six-month intervals to ensure that the spinal fluid abnormality has reversed, with a disappearance of cells, a reduction of protein, and a decrease in the amount of reactivity to the organism.
bacl to top