Herpesviruses

Most infections caused by the human herpesviruses HSV-1 and -2, EBV, CMV, and VZV are self-limited. Unfortunately, however, because of the neurotropism of herpesviruses, severe infections of the CNS are not uncommon, particularly in immuno-compromised patients.

Herpes simplex virus. HSV accounts for 2 to 5% of encephalitis cases in the United States.9 The case-fatality rate associated with untreated disease is as high as 70%, and survivors are almost always neurologically impaired. Both HSV-1 and HSV-2 cause encephalitis, but beyond the newborn period, most cases are caused by HSV-1. Although HSV is known to replicate in all areas of the brain, the infection has a predilection for the temporal lobes and the orbital regions of the frontal lobes ( Fig. 5.1 ). HSV encephalitis must be differentiated from HSV meningitis, which is usually caused by HSV-2 and is a complication of primary genital herpes infection. In HSV meningitis, headache, photophobia, and meningismus appear before or shortly after the genital lesions are noticed. Unlike in HSV encephalitis, recovery is almost always complete, even without antiviral therapy, although acyclovir is recommended to accelerate recovery. Therefore, HSV meningitis mimics other causes of viral “aseptic” meningitis and carries the same excellent prognosis. HSV encephalitis, on the other hand, is a highly lethal infection caused by HSV-1 in more than 90% of cases.10 Infection can be either a result of primary HSV infection or associated with HSV reactivation.11 Unlike most of the other, more common causes of viral meningoencephalitis, such as enterovirus and arbovirus infection, HSV disease is not seasonal. From a diagnostic standpoint, the cerebrospinal (CSF) reveals pleocytosis with a mononuclear cell predominance. The majority of cases are associated with hemorrhagic necrosis, so erythrocytes are found on CSF examination. As many as 25% of patients will have hypoglycorrhachia with an elevated CSF protein concentration (mean levels of approximately 80 mg/dL are seen in nearly all patients).12 HSV is only rarely cultured from CSF, so historically, brain biopsy was required to confirm a suspected diagnosis. With the development of sensitive and specific DNA amplification assays over the past 15 years, the gold standard for diagnosis from CSF is now polymerase chain reaction (PCR).13 Among available neurodiagnostic tests, only electroencephalography has proved somewhat useful. A typical pattern of uni- or bilateral periodic focal spikes against a background of slow activity, referred to as paroxysmal lateral epileptiform discharges (PLEDs), is suggestive of HSV encephalitis. For neuroimaging, magnetic resonance (MR) imaging is generally preferred over computed tomography (CT) during the initial evaluation because MR imaging findings are more likely to be abnormal.14 Imaging studies performed later during the illness may reveal low-density, contrast-enhancing lesions, particularly in the temporal lobe. Patients with abnormalities like these, or who have already developed edema and/or hemorrhage, have a poor prognosis.15

Epstein-Barr virus. Acute neurologic symp toms complicate between 1 and 5% of infectious mononucleosis cases. EBV encephalitis may present in the absence of infectious mononucleosis syndrome and should be considered as a cause of acute neurologic symptoms, particularly in teenagers. Typical CSF findings in cases of EBV encephalitis include a mild to moderate pleocytosis with mononuclear cells predominating, a slight elevation in CSF protein, and a normal glucose.16 Serologic proof of acute EBV infection is strongly diagnostic, whereas CSF PCR specific for EBV provides a definitive diagnosis. The prognosis is generally favorable, but long-term sequelae are well described. EBV-associated cerebellitis is a rare occurrence that develops primarily in children.17 Full recovery is expected but may require several weeks. Cranial nerve palsies, single or in combination, have also been described. Other manifestations of cranial nerve involvement with EBV infection include optic neuritis, deafness, and ophthalmoplegia. Some cases of brainstem encephalitis have also been reported.18

Cytomegalovirus. CNS involvement is common in infants with symptomatic congenital CMV infection, but in postnatal life, CMV meningoencephalitis is quite rare.19 When it does occur, it may appear as a complication of CMV mononucleosis, as an isolated manifestation of primary CMV infection, or more likely as a primary or recurrent (reactivation) infection in an immunocompromised host.20 Patients with solid-organ transplants may develop CMV encephalitis as a complication of their immunosuppression, and the recognition that patients with acquired immunodeficiency syndrome (AIDS) develop meningoencephalitis secondary to CMV infection is well established.21

Varicella-zoster virus. CNS complications of varicella, which may precede or follow the chickenpox, include transient cerebellar ataxia, encephalitis, aseptic meningitis, and transverse myelitis.22 Encephalopathy as a sequela of Reye syndrome has become a rare complication because of the nearly complete elimination of aspirin use in pediatric patients. Patients who present with dermatologic findings consistent with varicella or zoster and who experience CNS symptoms should be evaluated and treated for the possibility that the infection has involved the CNS.

Herpes B virus. Herpes B virus, a pathogen indigenous in macaques, is a nonhuman herpesvirus that can cause encephalitis in humans. Transmission occurs by direct contact with the virus, usually from a monkey bite. The high prevalence of excretion of herpes B virus in the saliva of macaques has important implications for zoo handlers, veterinarians, and laboratory researchers. A vesicular rash may occur at the inoculation site, signaling a herpes-type infection. The virus has robust neurovirulence, causing rapidly progressive, often fatal hemorrhagic encephalitis. Guidelines for the prevention of herpes B viral infection emphasize proper and expert animal handling and assume that all macaques are shedding herpes B virus unless proven otherwise. For cases of macaque bites, post-exposure recommendations are available from the U.S. Centers for Disease Control and Prevention (Viral Exanthems and Herpesvirus Branch, Division of Viral Diseases [1-404-639-3595 or 1-888-232-6348]), including the use of acyclovir pending culture results.23

Enteroviruses and Parechoviruses

Enteroviruses and parechoviruses comprise two genera of the family Picornaviridae and include more than 100 distinct human viruses. These small RNA viruses are responsible for frequent and often significant infections, including neurologic illness. By far, the most common neurologic manifestation of enterovirus infection is aseptic meningitis, which can occur either sporadically or in epidemics. In general, infection is more common in children, but during large outbreaks, substantial numbers of adults develop aseptic meningitis as well. Virtually all patients have fever and pharyngitis. Adolescents and adults often experience retrobulbar pain and photo-phobia, whereas young infants present with fever and irritability. Examination of the CSF will reveal a pleocytosis. Depending on the timing of the lumbar puncture, a neutrophil predominance may be observed, but neutrophils rarely account for more than 60% of the total number of cells (as is seen in bacterial meningitis). CSF protein levels are usually normal or slightly elevated, and CSF glucose concentrations, characteristically normal, may be slightly depressed. CSF PCR specific for enterovirus is available and should be used to confirm the etiology. The duration of illness is typically less than a week, although headaches may persist longer. The prognosis for enterovirus aseptic meningitis is excellent. Enteroviruses can also cause encephalitis, with echovirus 9 the most frequent cause of this more serious CNS infection. In general, patients with enteroviral encephalitis have a good prognosis, although fatalities do occur. Enterovirus 71 tends to infect the brainstem and since the 1980s has caused severe outbreaks in Asia. During some of those epidemics, mortality from enterovirus 71 encephalitis was as high as 30%.24 Enteroviruses may also cause acute flaccid paralysis. The tropism of enteroviruses for the anterior horn cells is well appreciated in paralytic polio, but it should be mentioned that other enteroviuses, including coxsackievirus A7 and enteroviruses 70 and 71, have been linked to polio-like outbreaks.25,26

Adenovirus. Adenoviruses only rarely cause meningitis and meningoencephalitis, but when they do, the illness is generally more severe than infection caused by enteroviruses.27

Arboviruses

Arboviruses are RNA viruses that are transmitted to humans through the bite of infected arthropods, such as mosquitoes, ticks, sand flies, and midges. Among the more than 400 distinct arthopod-borne viruses, at least 150 are known to cause human disease. The medically important viruses that cause human CNS infections are listed in Table 5.1 , along with their arthropod vectors and geographic distribution. Although most arbovirus infections are subclinical, symptomatic illness manifests in one of three ways: systemic febrile illness, hemorrhagic fever, or neuroinvasive disease. When neuroinvasion occurs, it may manifest as aseptic meningitis, encephalitis, or acute flaccid paralysis. Following a prodrome of fever, the neurologic symptoms begin, sometimes progressing rapidly. The severity and long-term outcome depend on the etiologic agent and several host factors, such as age, immune function, and underlying medical conditions.

In the United States, eight specific arbo-viruses that cause encephalitis have been isolated: the eastern equine encephalitis (EEE), western equine encephalitis (WEE), Venezuelan equine encephalitis (VEE), St. Louis encephalitis, Powassan, West Nile, California encephalitis, and Colorado tick fever viruses. EEE occurs throughout the eastern part of the United States. Most cases are sporadic and occur in the summer or fall in Florida and Georgia, although swampy areas as far north as New York State also harbor the virus, leading to rare human infections. The mosquito vector thrives only in swampy environments, limiting the spread of the infection much beyond these specific environs. Subclinical cases of EEE in humans are not common. Illness is abrupt, with high fever, headache, vomiting, seizures, and coma. The case-fatality rate is approximately 30%. WEE in the United States is slightly more common than EEE but geographically shifted west of the Mississippi River. Colorado leads the United States in the number of reported cases. The case-fatality rate is approximately 25%.28 The VEE virus, named such because it was isolated first in that country, causes encephalitis, although infection is typically less severe, and with supportive care, fatalities are rare. Adults typically develop only an influenza-like illness, while encephalitis is confined to children. Outbreaks of VEE with epizootic spread to humans can be extensive. One such outbreak in 1971, extending from Central America into Texas, killed 200,000 horses and infected thousands of people.29 St. Louis encephalitis virus is the most important mosquito-borne viral cause of epidemic encephalitis in the United States. The last major outbreak occurred in the late 1970s, when thousands of individuals in the Midwest were infected. Cases are concentrated in the states of Indiana, Illinois, Ohio, Mississippi, Florida, and Texas, but nearly all states in the United States have reported some disease activity over the past 50 years. On average, approximately 200 cases are reported in a given year, with the vast majority occurring in the elderly population; however, only 10 cases were reported in 2010.30 The overall case-fatality rate is between 5 and 15%. Powassan virus is a rare cause of meningoencephalitis in the northeastern United States and Canada that, unlike the other arthropod-borne infectious agents found in the United States, is transmitted by ticks, not by mosquitoes. There were no fatalities among the eight cases reported in 2010. Since WNV was first detected in the western hemisphere in 1999, it has become the leading cause of neuroinvasive arboviral illness in the United States. Among 629 cases reported in 2010, half of the patients had encephalitis, 38% had meningitis, and 8% had acute flaccid paralysis. Mortality was 9%. California serogroup viruses that cause encephalitis in the United States include the endemic La Crosse virus and the less commonly appreciated California encephalitis and Jamestown Canyon viruses. Most infections with La Crosse virus are subclinical. Typically, when clinical disease is seen, it occurs in young children. Infection can progress to fulminant encephalitis, but La Crosse virus encephalitis is only rarely fatal. Colorado tick fever virus is prevalent in the western mountainous region of the United States, where the tick vector resides. The typical infection caused by this virus is an influenza-like illness with fever, myalgia, and malaise. Neuroinvasive disease, although rare, can occur in young children. Like other viral infections of the CNS, illness can be self-limited to meningeal irritation or progress to encephalitis with coma. Fatalities from CNS complications are reported.31

Rabies Virus

Rabies is an acute, progressive, and almost uniformly lethal viral infection of the CNS that is transmitted to humans from animals. Rabies is transmitted from an infected animal to a human through a bite, scratch, or aerosol. Domestic animals, especially dogs, account for nearly all rabies cases outside developed countries. In the United States and Canada, the raccoon has replaced the skunk as the most important potential source of rabies exposure. Humans who are scratched or bitten by wild mammals should be evaluated for post-exposure prophylaxis, which, when carried out properly, prevents rabies very effectively. Unlike bites from potentially rabid raccoons, skunks, foxes, and other medium-size wild mammals, the bite from a bat, especially during sleep, can go completely unnoticed. For this reason, bat bites can go unrecognized, resulting in a patient who does not seek post-exposure prophylaxis. Perhaps this explains why nearly all nonimported human cases of rabies in developed countries are caused by bat strain viruses.

The incubation period between the bite and the onset of symptoms is usually 20 to 90 days; however, well-documented cases have occurred 6 years following exposure.32 Occasionally, symptoms occur sooner, with the shortest incubation periods being 7 to 10 days, usually when the animal has bitten or scratched the victim′s face. The earliest symptoms are rather vague and insidious, but the most striking clinical clue may be pain, itching, burning, or tingling at the inoculation site. Together with fever and nausea, this prodrome lasts several days, after which time the more obvious neurologic symptoms result. Two broad presentations are seen. The more common presentation is referred to as furious rabies. Such patients exhibit extreme agitation, hyperactivity, fluctuating levels of consciousness, hypersalivation, and hydrophobia. Paralytic rabies is not associated with hydrophobia; instead, the patient develops acute flaccid paralysis, usually beginning in the limb that was bitten. The cranial nerves are involved, and rather than expressing agitation and fright, the patient appears expressionless. Paralytic rabies can be confused with Guillain-Barré syndrome. Distinguishing features supporting a diagnosis of rabies include fever, intact sensation, and urinary incontinence.33 The majority of patients with rabies will have meningismus, with the CSF findings abnormal in a minority. When abnormal, the CSF shows a mild mononuclear cell pleocytosis. Rabies-specific diagnostic testing includes direct fluorescent antibody staining of corneal epithelial cells, which are easily obtained from corneal impressions on a glass slide, and of skin from a punch biopsy at the nape of the neck. These results are positive early because the virus migrates from the brain along the richly innervated cornea and hair follicles.34 Additional testing to consider as the diagnosis is being established or confirmed includes CSF and saliva for rabies PCR and culture. The diagnosis can be confirmed post mortem by identifying the pathognomonic Negri bodies (cytoplasmic inclusions) in brain tissue.

The acute neurologic phase of infection continues for approximately a week until the patient develops coma. Before death, some patients are described as having acute, brief periods of lucidity fluctuating with periods of agitation and hopelessness. During the comatose period, complications to be expected include cerebral edema, syndrome of inappropriate antidiuretic hormone secretion, diabetes insipidus, and other manifestations of hypothalamic dysfunction. Cardiac arrhythmias are common. Survival after rabies infection has been documented in a very small number of patients, most of whom were previously vaccinated.35 The first unvaccinated patient to survive rabies was a 15-year-old girl, who was treated with coma induction, midazolam, ribavirin, ketamine, and amantadine.36 Multiple subsequent attempts at using this original Milwaukee protocol for rabies treatment have been discouraging, and two children who survived the initial phase died of complications during rehabilitation.37 Details regarding the outcomes of 43 patients treated with evolving versions of the Milwaukee protocol can be found at http://www.mcw.edu/Pediatrics/InfectiousDiseases/PatientCare/Rabies.htm. Detailed metabolomics performed serially on CSF obtained from patients with rabies will likely allow further advances in treatment protocols. All human rabies cases should be managed with assistance from the U.S. Centers for Disease Control and Prevention so that the most current protocols can be implemented.