32-03: Other Neurotropic Viruses

General Considerations

Rabies is a viral (rhabdovirus) encephalitis transmitted by infected saliva that enters the body by an animal bite or an open wound. Worldwide, over 17 million cases of animal bites are reported every year, and it is estimated that about 59,000 deaths annually are attributable to rabies. Rabies is endemic in over 150 countries; on the basis of interviews, it is estimated that over 40% of the world’s population lives in areas without rabies surveillance. Most cases of rabies occur in rural areas of Africa and Asia. India has the highest incidence, accounting for 36% of global deaths (http://www.who.int/rabies/epidemiology/en/). In developing countries, more than 90% of human cases and 99% of human deaths from rabies are secondary to bites from infected dogs. Rabies among travelers to rabies-endemic areas is usually associated with animal injuries (including dogs in North Africa and India, cats in the Middle East, and nonhuman primates in sub-Saharan Africa and Asia), with most travel-associated cases occurring within 10 days of arrival. Rare but related viruses are the Australian lyssavirus, transmitted by bats including one referred to as the black flying fox, and which has caused three deaths over the last 20 years, and the European lyssavirus, with cases from Germany and the United Kingdom. Rabies-free areas include much of Western Europe, Australia, New Zealand, Japan, and the state of Hawaii in the United States. A map outlining these areas is available with Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Rabies_Free_Countries_and_Territories.svg).

In the United States, domestically acquired rabies cases are rare (approximately 92% of cases are associated with wildlife) but probably underreported. Reports largely from the East Coast show an increase in rabies among cats, with about 1% of tested cats showing rabies seropositivity. The annual caseload in the United States is 1–3 cases (https://www.cdc.gov/rabies/location/usa/surveillance/human_rabies.html). Between 1960 and 2018, a total of 125 human rabies cases were reported in the United States. These included 36 cases (28%) with a history of dog bites during international travel. The remaining 89 cases (72%) were acquired in the United States, most often by bats.

Surveillance for animal rabies in 2017 showed 4454 animal and 2 human cases occurring in 49 states and Puerto Rico. Wild animals accounted for 91% of cases, and among wild animals, bats were the most common animal (31.2%). Wildlife reservoirs, with each species having its own rabies variant(s), follow a unique geographic distribution in the United States: raccoons on the East Coast; skunks in the Midwest, Southwest, and California; and foxes in the Southwest and in Alaska (eFigure 32–2). However, some areas have all three wildlife reservoirs (eg, the hill country of Texas) https://www.cdc.gov/rabies/location/usa/surveillance/wild_animals.html.

Raccoons, bats, and skunks in 2017 accounted for 82% of the rabid animals found in the United States; other rabid animals include foxes, cats, cattle, and dogs. Rodents and lagomorphs (eg, rabbits) are unlikely to spread rabies because they cannot survive the disease long enough to transmit it (woodchucks and groundhogs are exceptions). Wildlife epizootics present a constant public health threat in addition to the danger of reintroducing rabies to domestic animals. Vaccination is the key to controlling rabies in small animals and preventing rabies transmission to human beings.

The virus enters the salivary glands of dogs 5–7 days before their death from rabies, thus limiting their period of infectivity. Less common routes of transmission include contamination of mucous membranes with saliva or brain tissue, aerosol transmission, and corneal transplantation. Recognized mutations in rabies virus proteins can subvert the host immune system. Transmission through solid organ and vascular segment transplantation from donors with unrecognized infection is also reported. A number of transplantation-associated cases are reported, including two clusters in the United States. Postexposure prophylaxis can be administered in these patients and may prevent development of disease.

The incubation period may range from 10 days to many years but is usually 3–7 weeks depending in part on the distance of the wound from the CNS. The virus travels in the nerves to the brain, multiplies there, and then migrates along the efferent nerves to the salivary glands. Rabies virus infection forms cytoplasmic inclusion bodies similar to Negri bodies. These Negri bodies are thought to be the sites of viral transcription and replication.

Clinical Findings

A. Symptoms and Signs

While there is usually a history of animal bite, bat bites may not be recognized. The prodromal syndrome consists of pain at the site of the bite in association with fever, malaise, headache, nausea, and vomiting. The skin is sensitive to changes of temperature, especially air currents (aerophobia). Percussion myoedema (a mounding of muscles after a light pressure stimulus) can be present and persist throughout the disease. Abnormal sexual behavior is also a recognized presenting symptom of rabies and such behavior includes priapism and frequent ejaculation in males and hypersexuality in females.

The CNS stage begins about 10 days after the prodrome and may be either encephalitic (“furious”) or paralytic (“dumb”). The encephalitic form (about 80% of the cases) produces the classic rabies manifestations of delirium alternating with periods of calm, extremely painful laryngeal spasms on attempting drinking (hydrophobia), autonomic stimulation (hypersalivation), and seizures. In the less common paralytic form, an acute ascending paralysis resembling Guillain-Barré syndrome predominates with relative sparing of higher cortical functions initially. Both forms progress relentlessly to coma, autonomic nervous system dysfunction, and death.

B. Laboratory Findings

Biting animals that appear well should be quarantined and observed for 10 days. Sick or dead animals should be tested for rabies. A wild animal, if captured, should be sacrificed and the head shipped on ice to the nearest laboratory qualified to examine the brain for evidence of rabies virus. When the animal cannot be examined, raccoons, skunks, bats, and foxes should be presumed to be rabid.

Direct fluorescent antibody testing of skin biopsy material from the posterior neck of the potentially infected animal (where hair follicles are highly innervated) has a sensitivity of 60–80%.

Quantitative RT-PCR, nucleic acid sequence-based amplification, direct rapid immunohistochemical test, and viral isolation from the patient’s CSF or saliva are advocated as definitive diagnostic assays. Antibodies can be detected in the serum and the CSF. Pathologic specimens often demonstrate round or oval eosinophilic inclusion bodies (Negri bodies) in the cytoplasm of neuronal cells, but the finding is neither sensitive nor specific. MRI signs are diffuse and nonspecific.

Treatment & Prognosis

Management requires intensive care with attention to the airway, maintenance of oxygenation, and control of seizures. Universal precautions are essential. The induction of coma by ketamine, midazolam, and supplemental barbiturates along with the use of amantadine and ribavirin (the Milwaukee protocol) was reportedly helpful in one case but failed to reproduce success in 26 subsequent cases. Corticosteroids are of no use. Survival is rare, and data are insufficient to provide estimate of success.

If postexposure prophylaxis (discussed below) is given expediently, before clinical signs develop, it is nearly 100% successful in prevention of disease. Once the symptoms have appeared, death almost inevitably occurs after 7 days, usually from respiratory failure. Most deaths occur in persons with unrecognized disease who do not seek medical care or in individuals who do not receive postexposure prophylaxis. The very rare cases in which patients recover without intensive care are referred to as “abortive rabies.”

Prevention

Immunization of household dogs and cats and active immunization of persons with significant animal exposure (eg, veterinarians) are important. The most important decisions, however, concern animal bites. Animals that are frequent sources of infection to travelers are dogs, cats, and nonhuman primates.

In the developing world, education, surveillance, and animal (particularly dog) vaccination programs (at recurrent intervals) are preferred over mass destruction of dogs, which is followed typically by invasion of susceptible feral animals into urban areas. In some Western European countries, campaigns of oral vaccination of wild animals led to the elimination of rabies in wildlife.

A. Local Treatment of Animal Bites and Scratches

Thorough cleansing, debridement, and repeated flushing of wounds with soap and water are important. Rabies immune globulin or antiserum should be given as stated below. Wounds caused by animal bites should not be sutured.

B. Postexposure Immunization

The decision to treat should be based on the circumstances of the bite, including the extent and location of the wound, the biting animal, the history of prior vaccination, and the local epidemiology of rabies. Any contact or suspect contact with a bat, skunk, or raccoon is usually deemed a sufficient indication to warrant prophylaxis. Consultation with state and local health departments is recommended. Postexposure treatment including both immune globulin and vaccination should be administered as promptly as possible when indicated.

For patients who had not received rabies vaccination prior to possible exposure, the optimal form of passive immunization is human rabies immune globulin (HRIG; 20 international units/kg), administered once. As much as possible of the full dose should be infiltrated around the wound, with any remaining injected intramuscularly at a site distant from the wound. Finger spaces can be safely injected without development of a compartment syndrome. If HRIG is not available and appropriate tests for horse serum sensitivity are done, equine rabies antiserum (40 international units/kg) can be used.

Two vaccines containing inactivated rabies viruses are licensed for active immunization and available for use in humans in the United States: a human diploid cell vaccine (Immovax) and a purified chick embryo cell vaccine (RabAvert). There are several postexposure prophylaxis strategies. The most commonly used one is the “abbreviated Essen” strategy, where either of the current vaccines is given as four intramuscular injections of 1 mL in the deltoid or, in small children, into the anterolateral thigh muscles on days 0, 3, 7, and 14 after exposure. (The fifth dose at 28 days after exposure is no longer recommended except among immunosuppressed patients.) The vaccine should not be given in the gluteal area due to suboptimal response. An alternative intramuscular vaccination strategy that takes only 1 week, with injections on days 0, 3, and 7 after exposure with a Vero cell vaccine (Verorab) is reportedly successful in achieving adequate neutralizing titers at days 14 and 28 in a study from Thailand; this vaccine is not currently available in the United States. A new rabies vaccine with a similarly short schedule is currently in phase II clinical trials. It is an inactivated rabies vaccine paired with a PIKA adjuvant (synthetic analog of a dsRNA and a refined form of polyinosinic-polycytidylic acid stabilized with kanamycin and calcium) that is given as two doses on days 0 and 3, and then one final dose on day 7. To date, this new vaccine has been well-tolerated with noninferior immunogenicity compared to the classic regimen using the commercially available vaccine in healthy adults.

The WHO supports an intradermal vaccination strategy using Verorab and the inactivated rabies virus vaccine Rabipur (an alternative formulation of the purified chick embryo cell) (0.1 mL per intradermal injection) for regions of the world where vaccine is in short supply; either vaccine can be given at two sites on days 0, 3, 7, and 28.

Rabies vaccines and HRIG should never be given in the same syringe or at the same site. Allergic reactions to the vaccine are rare and include a report of sudden unilateral sensorineural hearing loss and immune thrombocytopenic purpura, although local reactions (pruritus, erythema, tenderness) occur in about 25% and mild systemic reactions (headaches, myalgias, nausea) in about 20% of recipients. Rare cases of post-immunization encephalitis have been reported. Intradermal vaccines appear to be better tolerated than intramuscular vaccines, especially among young children (while titers achieved with intramuscular vaccinations are higher, the titers achieved with intradermal vaccination are deemed sufficient for protection against clinical rabies). The vaccines are commercially available or can be obtained through health departments. Adverse reactions to HRIG seem to be more frequent in women and rare in young children.

In patients with history of past vaccination, the need for HRIG is eliminated (HRIG is in short supply worldwide), but postexposure vaccination is still required. The vaccine should be given 1 mL in the deltoid twice (on days 0 and 3). Neither the passive nor the active form of postexposure prophylaxis is associated with fetal abnormalities and thus pregnancy is not considered a contraindication to vaccination. Peripartum rabies transmission occurs but is rare. Neonates may also receive both forms of postexposure prophylaxis at birth.

The WHO has a program to eliminate dog-transmitted human rabies by 2030.

C. Preexposure Immunization

Preexposure prophylaxis with three injections of human diploid cell (Immovax) vaccine intramuscularly (1 mL on days 0, 7, and 21 or 28) is recommended for persons at high risk for exposure: veterinarians (who should have rabies antibody titers checked every 2 years and be boosted with 1 mL intramuscularly); animal handlers; laboratory workers; Peace Corps workers; and travelers with stays over 1 month to remote areas in endemic countries in Africa, Asia, and Latin America. An intradermal route is also available (0.1 mL on days 0, 7, and 21 over the deltoid) but not in the United States. A prophylactic mRNA-based vaccine encoding rabies virus glycoprotein (CV7201) is currently under development and showed success in a phase I clinical trial given as three doses with a needle-free device. Immunosuppressive illnesses and agents including corticosteroids as well as antimalarials—in particular chloroquine—may diminish the antibody response. A single-dose booster at 10 years after initial immunization increases the level of antibody titers. Unfortunately, data from travel services indicate that only a small proportion of travelers with anticipated lengthy stays in rabies-impacted areas receive the vaccine as recommended.

When to Refer

Suspicion of rabies requires contact with public health personnel to initiate appropriate passive and active prophylaxis and observation of suspect cases.

When to Admit

• Respiratory, neuromuscular, or CNS dysfunction consistent with rabies.

• Patients with suspect rabies require initiation of therapy until the disease is ruled out in suspect animals, and this requires coordination of care based on likelihood of patient compliance, availability of inpatient and outpatient facilities, and response of local public health teams.

General Considerations

The arboviruses are arthropod-borne viral pathogens carried by mosquitoes or ticks that produce clinical manifestations in humans. The mosquito-borne pathogens include togaviruses (Western, Eastern, and Venezuelan equine encephalitis), flaviviruses (West Nile, St. Louis encephalitis, Japanese encephalitis, Murray Valley encephalitis, dengue, Zika, yellow fever, and Rocio viruses), orthobunyaviruses (the California serogroup of viruses, including the Jamestown Canyon [seen largely in Northern states], La Crosse [seen in the upper Midwest and mid-Atlantic primarily], Oropouche, and Keystone viruses), and the alphaviruses (chikungunya, Venezuelan equine encephalitis virus, and Mayaro virus). The tick-borne causes of encephalitis include the flavivirus of the Powassan encephalitis (North American Northeast and Great Lakes), tick-borne encephalitis virus (Europe and Asia), and the Colorado tick fever reovirus. Only those viruses causing primarily encephalitis in the United States are discussed here. The most commonly encountered arboviruses from 2018 in the United States are West Nile virus (2647 cases, 92% of arboviral neuroinvasive disease), Jamestown Canyon virus (41 cases), the La Crosse virus (86 cases), and Powassan virus (21 cases). Rare causes of domestic arboviruses were St. Louis encephalitis virus (8 cases) and eastern equine encephalitis virus disease (6 cases).

West Nile virus is the leading cause of domestically acquired arboviral disease in the United States. West Nile virus disease is a nationally notifiable condition. Among the 2647 cases reported in 2018, cases were reported to the CDC from 48 states and the District of Columbia, 1658 (63%) were classified as neuroinvasive disease. The states reporting the most cases of neuroinvasive disease included California (154 cases), Illinois (126 cases), Nebraska (124 cases), Texas (108 cases), and Pennsylvania (95 cases). Asymptomatic seroconversion is the norm and is not reported.

Outbreaks with West Nile infection tend to occur between mid-July and early September. Climatic factors, including elevated mean temperatures and rainfall, correlate with increased West Nile infection. West Nile virus circulates between mosquitoes (mainly Culex species) and birds. In case of West Nile virus outbreak, infected birds develop high level viremia that leads to substantial avian mortality and a high incidence of mosquito infection. Infected mosquitoes bite and infect people and other mammals. However, humans and other mammals are “dead end” hosts, since they do not transmit the virus on to other biting mosquitoes; only dengue and Venezuelan equine encephalitis viruses produce viremias high enough to allow continued transmission to other mosquitoes and ticks between humans and vectors. Human-to-human transmission is usually related to blood transfusion and organ transplantation. Since 2003, all blood donations in the United States are screened with nucleic acid amplification assays for West Nile virus. Eastern equine encephalitis is now also shown to be transmitted by organ transplantation.

More La Crosse virus disease cases were reported in 2018 than in any year since 2011. La Crosse virus continued to be the most common cause of neuroinvasive arboviral disease in children.

Clinical Findings

A. Symptoms and Signs

West Nile virus infection has an incubation period of 2–14 days. The infection is symptomatic in no more than 10% of the cases; of those, about 10% progress to neuroinvasive disease, including meningitis, encephalitis, and flaccid paralysis. The case fatality rate is 3–15% in symptomatic patients.

Symptoms include acute febrile illness, and a nonpruritic maculopapular rash is variably present. Meningitis is indistinguishable from other viral meningitis. West Nile virus encephalitis presents with fever and altered mental status. Other signs include tremors, seizures, cranial nerve palsies, and pathologic reflexes. Acute flaccid (poliomyelitis-like) paralysis, which is asymmetric and can involve facial and respiratory muscles, is a well-known complication and is less commonly seen with other arboviruses infection. West Nile virus can also present as Guillain-Barré syndrome with radiculopathy. The disease manifestations associated with West Nile virus infection are strongly age-dependent: the acute febrile syndrome and mild neurologic symptoms are more common in the young, aseptic meningitis and poliomyelitis-like syndromes are seen in middle-aged persons, and frank encephalopathy is seen more often in older adults. All forms of disease tend to be severe in immunocompromised persons in whom neuroinvasive manifestations and associated high mortality are more apt to develop. Other risk factors for development of neuroinvasive disease and increased mortality include black race, diabetes, chronic kidney disease, and hepatitis C virus infection.

Host genetic variation in the interferon response pathway is associated with both risk for symptomatic West Nile virus infection and increased likelihood of West Nile virus disease progression.

B. Laboratory Findings

The peripheral white blood cell count is typically normal. Usually a CSF lymphocytic pleocytosis is present, and polymorphonuclear cells predominate early. The diagnosis of arboviral encephalitides depends on serologic tests. For West Nile virus, an IgM capture ELISA in serum or CSF is almost always positive by the time the disease is clinically evident, and the presence of IgM in CSF indicates neuroinvasive disease. Documentation of a fourfold increase in acute/convalescent IgG titers is confirmatory for all arboviruses. Antibodies to arboviruses persist for life, and the presence of IgG in the absence of a rising titer of IgM may indicate past exposure rather than acute infection. Serologic tests are available commercially and through local and state health departments. Cross-reactivity exists among the different flaviviruses, so a plaque reduction assay may be needed to definitively distinguish between West Nile fever, St. Louis encephalitis, and others. PCR assays (available through state laboratories and the CDC) can be used to detect viral RNA in serum, CSF, or tissue early after illness onset and may be particularly useful in immunocompromised patients with abnormal antibody responses. Blood products are best screened using nucleic acid assays. MRI of the brain may reveal leptomeningeal, basal ganglia, thalamic, or periventricular enhancement.

Differential Diagnosis

Mild forms of encephalitis must be differentiated from aseptic meningitis, lymphocytic choriomeningitis, and nonparalytic poliomyelitis.

Severe forms of arbovirus encephalitides are to be differentiated from other causes of viral encephalitis (HSV, mumps virus, poliovirus or other enteroviruses, HIV), encephalitis accompanying exanthematous diseases of childhood (measles, varicella, infectious mononucleosis, rubella), encephalitis following vaccination or infection (a demyelinating type seen after rabies, measles, pertussis vaccination), toxic encephalitis (from drugs, poisons, or bacterial toxins such as Shigella dysenteriae type 1), Reye syndrome, and severe forms of stroke, brain tumors, brain abscess, autoimmune processes such as lupus cerebritis, and intoxications. In the California Encephalitis Project, anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a more common cause of encephalitis than viral diseases, especially in the young, with 65% of cases of encephalitis due to anti-NMDAR occurring among patients 18 or younger.

Complications

Bronchial pneumonia, urinary retention and infection, prolonged weakness, and pressure injuries may occur. Retinopathy occurs in 24% of patients with a history of West Nile virus infection and is associated with increased risk in those with encephalitis. Individuals with chronic symptoms after West Nile virus infection may show persistent kidney infection for up to 6 years with West Nile virus RNA present in urine; kidney infection may lead to progressive renal pathology.

Treatment

Although specific antiviral therapy is not available for most causative entities, vigorous supportive measures can be helpful. Some studies suggest improved outcomes with the use of IVIG enriched with West Nile virus antibody; however, a randomized, controlled trial of IVIG did not show a benefit.

Prognosis

Although most infections are mild or asymptomatic, the prognosis is always guarded, especially at the extremes of age. Most fatalities occur with neuroinvasive disease. The majority of patients with non-neuroinvasive West Nile virus disease or West Nile virus meningitis recover completely, but a syndrome of fatigue, malaise, and weakness can linger for weeks or months. Patients who recover from West Nile virus encephalitis or poliomyelitis often have residual neurologic deficits. The recovery of persons with severe neurologic compromise may take 6 months or longer. The sequelae of West Nile virus infection include a poliomyelitis-like syndrome, cognitive complaints, movement disorders, epilepsy, and depression; and they may become apparent late in the course of what appears to be a successful recovery.

Another entity (nonprimary infection), characterized by elevated serum IgG, absent serum IgM, and occasional detection of West Nile virus RNA in blood or CSF, is associated with underlying psychiatric disorders, hospitalization during times not associated with peak West Nile transmission, fever, and increased in-hospital mortality.

The long-term prognosis is generally better for Western equine than for Eastern equine or St. Louis encephalitis.

Prevention

Mosquito avoidance (repellents, protective clothing, and insecticide spraying) is effective prevention. Laboratory precautions are indicated for handling all these pathogens. No human vaccine is currently available for the arboviruses prevalent in North America. A chimeric live attenuated West Nile virus vaccine is tested in phase I clinical trials and is shown to be safe and immunogenic in healthy adults.

General Considerations

The Japanese encephalitis virus is a flavivirus akin to those causing West Nile infection and St. Louis encephalitis. It is the most common cause of encephalitis in East Asia with over 68,000 estimated annual cases and up to 20,400 annual deaths. It is geographically confined to East Asia. Most cases occur in the summer and late fall, although in tropical and subtropical areas transmission occurs throughout the year. Major outbreaks every 2–15 years often correlate with patterns of agricultural development. The virus is transmitted by mosquitoes, especially Culex species. Areas with high endemicity tend to be warm-temperate, semitropical or tropical areas with high annual rainfalls. Wading birds (such as herons) and pigs more commonly sustain the infection as reservoirs in nature, since the viremia in humans is transient and not usually high enough to sustain transmission. In endemic countries, Japanese encephalitis is primarily a disease of children. Travelers to major urban areas for less than 1 month are at minimal risk for Japanese encephalitis. Transmission by blood transfusion is documented.

Clinical Findings

A. Symptoms and Signs

The median incubation period is 5–15 days. Most persons asymptomatically seroconvert. The 1% of patients in whom disease develops report sudden-onset headaches, nausea, and vomiting, followed by mental status changes, parkinsonian movement disorders, and in a smaller percentage, seizures, typically in children.

Japanese encephalitis most closely resembles St. Louis encephalitis and West Nile encephalitis, although epidemiologic data readily distinguish these infections in most instances. The clinical course is less severe in patients with a history of dengue virus infection.

B. Laboratory Findings and Diagnosis

The disease should be suspected in persons with symptoms of CNS infection who recently visited or who reside in an endemic area.

Common laboratory abnormalities include leukocytosis, mild anemia, and hyponatremia. CSF typically has a mild to moderate pleocytosis with a lymphocytic predominance, slightly elevated protein, and normal glucose.

Diagnosis is confirmed by finding anti-Japanese encephalitis IgM in CSF or serum using ELISA. Definitive diagnosis requires fourfold increase in virus-specific IgG confirmed by plaque reduction neutralization assay. Because of low levels of viremia in humans, RT-PCR is not recommended.

In severe disease, brain imaging reveals thalamic lesions, with the hippocampus, midbrain, basal ganglia, and cerebral cortex affected to varying degrees.

Complications

A variety of cognitive, neurologic, and psychiatric complications, including memory impairment and intellectual impairment in adults and children, are recognized to occur in as many as 50% of survivors and to persist at least 1–2 years after the acute infection. Rare reported complications include the opsoclonus myoclonus syndrome and the Kasabach-Merritt phenomenon of consumptive coagulopathy. The mortality is as high as 30%.

Treatment

Treatment is supportive, including antipyretics, analgesics, bed rest, and fluids. Corticosteroids may be needed for rare complications, such as the opsoclonus myoclonus syndrome.

Prevention

Using mosquito repellents; wearing long sleeves, long pants, and socks; and using air-conditioned facilities and bed nets are essential means of protection.

In the United States, inactivated Vero-cell culture-derived Japanese encephalitis vaccine (IXIARO) is licensed for the prevention of Japanese encephalitis in persons 2 months of age and older. Travelers who plan to spend more than 1 month in rural East Asia during Japanese encephalitis virus transmission season should receive the vaccine. Vaccine should also be considered for travelers who plan to spend less than 1 month in rural East Asia but who are at increased risk for Japanese encephalitis (eg, season, location, activities). Primary vaccination requires two doses administered 28 days apart, to be completed more than 1 week before travel. For adults, a booster dose is recommended in case of potential reexposure or of continued risk for infection if the primary series of the vaccine was administered over a 1 year before.

Four effective types of vaccine against Japanese encephalitis are available worldwide, including live attenuated and inactivated vaccines. The risk of serious reactions, including potential encephalitis with live vaccines, is low and decreases with age. Rare reported neurologic reactions are not definitively associated with vaccination. There are no studies about the safety of IXIARO in pregnant women. Therefore, administration of this vaccine to pregnant women should be deferred, unless the risk of infection outweighs the risk of vaccine complications.

General Considerations

Tick-borne encephalitis (TBE) is a flaviviral infection caused by TBE virus with three subtypes: European, Siberian, and Far Eastern. The principal reservoirs and vectors for TBE virus are ticks with small rodents as the amplifying host; humans are an accidental host. The vectors for most cases are Ixodes ricinus (European subtype) and Ixodes persulcatus (Siberian and Far Eastern subtype). Infection results from tick bites during outdoor activities in forested areas, predominantly in the late spring through fall. Ingestion of unpasteurized milk from viremic livestock (goats, sheep, and cattle) is also a recognized mode of transmission. Transmission by transplantation of solid organs is reported leading to fatal outcomes. TBE is endemic in certain parts of Europe (where its prevalence has been expanding in recent years; eg, in 2018, 377 cases were recorded in Switzerland, 40% more than in 2017) and Asia (principally China but a few cases from Japan as well). The number of cases reported annually fluctuates significantly depending on surveillance, human activities, socioeconomic factors, ecology, and climate. Modeling studies from Prague suggests several superimposed cycles of variable year duration. The incubation period is 7–14 days for tick-borne exposures but only 3–4 days for milk ingestion.

Powassan virus is the only North American member of the tick-borne encephalitides. Its vector is several Ixodes species ticks. Most cases occur in older men (median age, 62; all deaths have occurred in persons over age 50), primarily from Northeast and North Central states (especially Minnesota, New York, and Wisconsin). Most reported cases are neuroinvasive with presentations including acute encephalitis and aseptic meningitis. The incubation period can range from 1 to 5 weeks, although pinpointing the date of actual exposure is often difficult.

Alkhurma hemorrhagic fever is also caused by a flavivirus first uncovered in Jeddah, Saudi Arabia, 1995 and is reemerging in the Middle East with occurrences in tourists to Egypt, Djibouti, and possibly India. Its extent of geographic distribution is currently unknown.

Clinical Findings

A. Symptoms and Signs

Most cases are subclinical, and many resemble an influenza-like syndrome with 2–10 days of fever (usually with malaise, headache, and myalgias). In some cases, the disease is biphasic where the initial flu-like period is followed by a 1- to 21-day symptom-free interval followed by a second phase with fevers and neurologic symptoms (cases from Asia appear not to show this biphasic pattern). The neurologic manifestations range from febrile headache to aseptic meningitis and encephalitis with or without myelitis (preferentially of the cervical anterior horn) and spinal paralysis (usually flaccid). A myeloradiculitic form can also develop but is less common. Peripheral facial palsies, sometimes bilateral, tend to occur infrequently late in the course of infection, usually after encephalitis and generally are associated with a favorable outcome within 30–90 days. The main sequela of disease is paresis. Other causes of long-term morbidity include protracted cognitive dysfunction and persistent spinal nerve paralysis. The post-encephalitic syndrome is characterized by headache, difficulties concentrating, balance disorders, dysphasia, hearing defects, and chronic fatigue. A progressive motor neuron disease and partial continuous epilepsy are complications. Longstanding psychiatric complications are reported and include attention deficits, slowness of thought and learning impairment, depression, lability, and mutism.

Mortality in TBE is usually a consequence of brain edema or bulbar involvement.

B. Laboratory Findings and Diagnosis

Leukocytosis and neutrophilia are common. Abnormal CSF findings include an inconsistent pleocytosis that may persist for up to 4 months. Hyponatremia is more commonly seen than with other viral encephalitides. Neuroimaging might show hyperintense lesions in the thalamus, brainstem, and basal ganglia, and cerebral atrophy.

When neurologic symptoms develop, the TBE virus is typically no longer detectable in blood and CSF samples. Virus detection by RT-PCR in ticks from TBE patients, if available, can help with the diagnosis. TBE virus IgM and IgG are detected by ELISA when neurologic symptoms occur.

Cross-reactivity with other flaviviruses or a vaccinated state may require confirmation by detection of TBE virus–specific antibodies by plaque-reduction neutralization tests.

Differential Diagnosis

The differential diagnosis includes other causes of aseptic meningitis, such as enteroviral infections; poliomyelitis (no longer reported from Eastern Europe); herpes simplex encephalitis; and a variety of tick-borne pathogens, including tularemia, the rickettsial diseases, babesiosis, Lyme disease, and other flaviviral infections. Coinfections are documented with Anaplasma, Babesia, and Borrelia infections.

Treatment

There is no specific antiviral treatment, and therapy is largely supportive.

Prognosis

The three subtypes of TPE have different prognoses. The European subtype is usually milder with up to 2% mortality and 30% neuroinvasive disease. The Siberian subtype is associated with 3% mortality and chronic, progressive disease. The Far Eastern subtype is usually more severe with up to 40% mortality and higher likelihood of neurologic involvement. All three subtypes are more severe among elderly adults compared with children. Coinfection with Borrelia burgdorferi (the agent of Lyme disease; transmitted by the same tick vector) may result in more severe disease.

Prevention

There is no available TBE vaccine in the United States. There are four inactivated TBE virus vaccines for adults and children licensed in Europe (two in Austria and Germany and two in Russia) and one available in China. The vaccine is safe and effective and should provide cross-protection against all three TBE virus subtypes. The initial vaccination schedule requires two to three doses given over 6 or more months with boosters every 1–5 years, the interval dependent on the vaccine and national guidelines. Breakthrough TBE in vaccinated individuals is reported, especially among recipients who are over 50 years of age and among persons who are immunosuppressed, such as those receiving anti-TNF therapy or methotrexate, indicating the need for a modified immunization strategy in such patients. Recent data supports adding an extra booster vaccine dose for individuals aged 50 years and older. Neuritis and neuropathies of peripheral nerves (plexus neuropathy—paresis of lower limb muscles, polyradiculopathy) are recognized complications of TBE vaccination.

The low popular support for the vaccine in endemic countries is responsible for limited abilities to control the disease. Other prevention recommendations include avoidance of tick exposure and pasteurization of cow and goat milk.

General Considerations

The lymphocytic choriomeningitis virus is an arenavirus (related to the pathogen causing Lassa fever, discussed below) that primarily infects the CNS. Its main reservoir is the house mouse (Mus musculus). Other rodents (such as rats, guinea pigs, and even pet hamsters), monkeys, dogs, and swine are also potential reservoirs. The infected animal sheds lymphocytic choriomeningitis virus in nasal secretions, urine, and feces; transmission to humans probably occurs through aerosolized particles and mucosal exposure, percutaneous inoculation, direct contact, or animal bites. The disease in humans is underdiagnosed and occurs most often in autumn. The lymphocytic choriomeningitis virus is typically not spread person to person, although vertical transmission is reported, and it is considered to be an underrecognized teratogen. Rare cases related to solid organ transplantation and autopsies of infected individuals are also reported. All reported cases were donor derived. Outbreaks are uncommon, and usually occur in laboratory settings among those workers with significant rodent exposure.

The ubiquitous nature of its reservoir and the large distribution of the reported cases suggest a widespread geographic risk of lymphocytic choriomeningitis virus infection. Serologic surveys in the southern and eastern United States suggest past infection in approximately 3–5% of those tested, although later data from upstate New York showed less than 1% seroprevalence. Infection risk can be reduced by limiting contact with pet rodents and rodent trappings.

Clinical Findings

A. Symptoms and Signs

The incubation period is 8–13 days to the appearance of systemic manifestations and 15–21 days to the appearance of meningeal symptoms. Symptoms are biphasic, with a prodromal illness characterized by fever, chills, headache, myalgia, cough, and vomiting, occasionally with lymphadenopathy and maculopapular rash. After 3–5 days, the fever subsides only to return after 2–4 days along with the meningeal phase, characterized by headache, nausea and vomiting, lethargy, and variably present meningeal signs. Arthralgias can develop late in the course. Transverse myelitis, deafness, Guillain-Barré syndrome, and transient and permanent hydrocephalus are reported. Lymphocytic choriomeningitis virus is a well-known, albeit underrecognized, cause of congenital infection frequently complicated with obstructive hydrocephalus and chorioretinitis. In fetuses and newborns with ventriculomegaly or other abnormal neuroimaging findings, screening for congenital lymphocytic choriomeningitis may be considered; mothers are asymptomatic half the time. In over one-third of cases, rodent exposure is reported retrospectively. Occasionally, a syndrome resembling the viral hemorrhagic fevers is described in transplant recipients of infected organs and in patients with lymphoma.

B. Laboratory Findings

Leukocytosis or leukopenia and thrombocytopenia may be initially present. During the meningeal phase, CSF analysis frequently shows lymphocytic pleocytosis (total count is often 500–3000/mcL) with a slight increase in protein, while a low to normal glucose is seen in at least 25%. The virus may be recovered from the blood and CSF by mouse inoculation. Complement-fixing antibodies appear during or after the second week. Detection of specific IgM by ELISA is widely used. Detection of lymphocytic choriomeningitis virus by PCR is available in research settings.

Differential Diagnosis

The influenza-like prodrome and latent period may distinguish this from other aseptic meningitides, and bacterial and granulomatous meningitis. A history of exposure to mice or other potential vectors is an important diagnostic clue.

Treatment

Treatment is supportive. In several survivors of transplant-associated outbreaks, ribavirin (which is effective against other arenaviruses) has been used successfully along with decreasing immunosuppression.

Prognosis

Complications and fatalities are rare in the general population. The illness usually lasts 1–2 weeks, though convalescence may be prolonged. Congenital infection is more severe with about 30% mortality rate among infected infants, and more than 90% of survivors suffering long-term neurologic abnormalities. Lymphocytic choriomeningitis in solid organ transplant recipients is associated with a poor prognosis; the mortality rate may exceed 80%.

Prevention

Pregnant women should be advised of the dangers to their unborn children inherent in exposure to rodents. A lymphocytic choriomeningitis virus vaccine using a recombinant rabies virus vector is currently being tested in mice, and early studies show that it seems to generate some protection against both lymphocytic choriomeningitis virus and rabies virus.

General Considerations

The transmissible spongiform encephalopathies are a group of fatal neurodegenerative diseases affecting humans and animals. They are caused by proteinaceous infectious particles or prions. These agents show slow replicative capacity and long latent intervals in the host. They induce the conformational change (“misfolding”) of a normal brain protein (prion protein; PrP[C]) into an abnormal isoform (PrP[Sc]) that accumulates and causes neuronal vacuolation (spongiosis), reactive proliferation of astrocytes and microglia, and, in some cases, the deposition of beta-amyloid oligomeric plaques.

Prion disease can be hereditary, sporadic, or transmissible in humans. Hereditary disorders are caused by germ line mutations in the PrP[C] gene causing familial Creutzfeldt–Jakob disease (fCJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia. Another uncommon hereditary disorder is PrP systemic amyloidosis. Variations at PrP codon sites, in particular codon 129 but also codons 114, 178, 180, and 232, determine host susceptibility to prion disease, the different phenotypes of the disease, and are prognostic for early age of death. Prion concentration does not correlate with cognitive function in Alzheimer disease.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common of the human prion diseases, accounting for approximately 85% of cases; it has no known cause, although a spontaneous misfolding of PrP[C] as well as somatic mutations of PrP[C] or undetectable horizontal transmission are postulated as possible explanations. Transmissible prion disease is described only for kuru and Creutzfeldt-Jakob disease in its iatrogenic (iCJD) and variant (vCJD) form. Iatrogenic transmission of CJD is associated with prion contaminated human corneas, dura mater grafts, pituitary-derived growth hormone, gonadotropins, stereotactic electroencephalography, electrodes, and neurosurgical instruments. Abnormal prion proteins have been detected in the nasal mucosa and urine of patients with Creutzfeldt-Jakob disease, raising health concerns about possibility of transmission. A few patients with iCJD have grey matter pathology similar to that seen in Alzheimer disease, and amyloid beta pathology similar to that seen in cerebral amyloid angiopathy, suggesting that these pathologic findings may be transmissible as well.

Kuru, once prevalent in central New Guinea, is now rare, a decline in prevalence that started after the abandonment of cannibalism in the late 1950s (a protective allele of the PrP gene is now identified at codon 127).

More than 200 cases of vCJD (bovine spongiform encephalopathy [BSE] or “mad cow disease”) were reported in the United Kingdom since the first documented cases there in the mid-1990s. It is far less common in North America, with only four cases reported in the United States (the last one in 2015) and two deaths in Canada from definite or probable vCJD. Of the US-reported cases, none are confirmed to have acquired the disease locally (two of them acquired the infection in the United Kingdom, one in Saudi Arabia, one possibly in a Middle Eastern or Eastern European country). The overall annual incidence of prion disease worldwide is approximately 1–2 persons per million. This disease is characterized by its bovine-to-human transmission through ingestion of meat from cattle infected with BSE. There is no animal-to-animal spread of BSE, and milk and its derived products are not considered infectious. Reports of secondary transmission of vCJD due to blood transfusions from asymptomatic donors are reported in the United Kingdom. Although iCJD and vCJD are not associated with a known PrP gene mutation, a polymorphism in codon 129 is prevalent and seems to determine susceptibility and expression of clinical disease.

A chronic wasting disease also due to a transmissible spongiform encephalopathic agent is increasing; occurs among deer, elk, and moose; and is reported from 26 states including most of Wyoming and parts of Colorado but present in the East and South as well. Although there are no documented cases of transmission to humans, transmission in the laboratory to squirrel monkeys has occurred, and the CDC recommends refraining from killing bizarrely acting animals, not handling or eating roadkill, and wearing gloves when dressing wild game. Testing for the virus in game animals may be useful, but its efficacy is not established.

Prion models as the basis for neurodegenerative disorders such as Parkinson disease and Alzheimer syndrome are currently the subject of considerable discussion in the neurology literature; Parkinson disease may relate to the spreading of misfolded alpha-synuclein.

Clinical Findings

A. Symptoms and Signs

Both sCJD and fCJD usually present in the sixth or seventh decade of life, whereas the iCJD form tends to occur in a much younger population. Clinical features of these three forms of disease usually involve mental deterioration (dementia, behavioral changes, loss of cortical function) that is progressive over several months, as well as myoclonus and extrapyramidal (hypokinesia) and cerebellar manifestations (ataxia, dysarthria). Finally, coma ensues, usually associated with an akinetic state and less commonly decerebrate/decorticate posturing. Like iCJD, vCJD usually affects younger patients (averaging ~28 years), but the duration of disease is longer (about 1 year). The degree of organ involvement is often extensive, and the clinical symptoms are unique, mainly characterized by prominent psychiatric and sensory symptoms. Kuru presents with an early stage of tremors, ataxia, and postural instability followed by a sedentary stage characterized by involuntary movements (myoclonus, fasciculations, and choreoathetosis) and a final stage of dementia. GSS, a rare inherited autosomal dominant (rarely sporadic) disorder that occurs in kindreds is rapidly fatal. It typically causes a disruption of the circadian sleep-activity pattern leading to insomnia, hallucinations, behavioral changes, motor disturbance and, rarely, dementia. Fatal familial insomnia is the only prion disease associated with endocrine disorders and dysautonomia. PrP systemic amyloidosis is characterized by autonomic dysfunction (ie, nausea, diarrhea, incontinence, neuropathy, and postural hypotension).

B. Laboratory Findings

CJD should be diagnosed in the proper clinical scenario, in the absence of alternative diagnoses after routine investigations. Abnormalities in CSF are subtle and rarely helpful. The detection of 14-3-3 protein in the CSF is helpful for the diagnosis of sCJD but not in vCJD and fCJD. Its sensitivity and specificity are widely variable among different studies and may be increased with use of tau protein assays. CSF detection of total PrP can differentiate CJD from atypical Alzheimer disease with 82% sensitivity and 91% specificity.

A blood-based assay and PCR in CSF may help with the diagnosis of vCJD with high specificity but 71% sensitivity. The assay as well as 14-3-3 protein assay and a “quaking induced conversion” assay are all available through the National Prion Disease Surveillance Center at Case Western University in Cleveland. Other referral laboratories with variable availability of assays include state health departments, academic centers, and the National Prion Clinics in the United Kingdom. It is also recognized that the presence of a variant with low titers (“very low peripheral prion colonization”) in peripheral tissue, including frequently biopsied tonsillar tissue, may be responsible for the underrecognition of vCJD.

Probable diagnosis requires the presence of rapidly progressive dementia plus two of four clinical features (myoclonus, visual or cerebellar signs, pyramidal/extrapyramidal signs, and akinetic mutism) as well as a positive laboratory assay (typical EEG, positive 14-3-3 CSF assay with duration under 2 years) and MRI high signal in the caudate and/or putamen on diffusion-weighted imaging (DWI) or fluid-attenuated inversion recovery (FLAIR) imaging. In sCJD, the EEG typically shows a pattern of paroxysms with high voltages and slow waves, while the MRI is characteristic for bilateral areas of increased signal intensity, predominantly in the caudate and putamen. An MRI can improve early diagnosis of sCJD because clinical findings are often missed. When an experienced neuroradiologist or a prion disease expert reviews the MRI, diagnostic sensitivity of MRI for sCJD increases to 91%.

Differential Diagnosis

Autoimmune encephalitis can have a similar clinical picture. The presence of high titer autoantibodies (eg, to the NMDA receptor) in the CSF is consistent with autoimmune encephalitis.

Treatment & Prevention

There is no specific treatment for CJD. Once symptoms appear, the infection invariably leads to death. Flupirtine (an analgesic drug) is sometimes useful in slowing the associated cognitive decline but does not affect survival. Quinacrine (mepacrine) was not shown to improve survival for people with sCJD. Antibodies against PrP are also proposed as a therapeutic strategy. Studies are in progress to identify epitopes for vaccine development, but no promising candidates exist to date.

Iatrogenic CJD can be prevented by limiting patient exposure to potentially infectious sources as mentioned above. Prevention of vCJD relies on monitoring livestock for possible infection. The American Red Cross does not accept blood donations from persons with a family history of CJD or with a history of dural grafts or pituitary-derived growth hormone injections.

An international referral and database for CJD is available at http://www.cjdsurveillance.com.

PML is a rare demyelinating CNS disorder caused by the reactivation of two polyoma viruses, the JC virus (John Cunningham virus or JCV) and, less commonly, the BK virus (associated with nephropathy). The JC virus usually causes its primary infection during childhood with about 80% of adults typically being seropositive. The virus remains latent in the kidneys, lymphoid tissues, epithelial cells, peripheral blood leukocytes, bone marrow, and possibly brain until reactivation occurs and symptoms become evident. This reactivation is usually seen in adults with impaired cell-mediated immunity, especially AIDS patients (5–10% of whom develop PML), as well as those with idiopathic CD4 lymphopenia syndrome. It is also reported among those with lymphoproliferative and myeloproliferative disorders; in those with granulomatous, inflammatory, and rheumatic diseases (systemic lupus erythematosus and rheumatoid arthritis in particular); in those who have undergone solid and hematopoietic cell transplantation; and occasionally in those who have other medical states, including cirrhosis and kidney disease. Diagnostic criteria that use clinical, imaging, pathologic, and virologic manifestations of JCV are available from the American Academy of Neurology.

Medication-associated PML is described with the use of natalizumab, rituximab, infliximab (one case), efalizumab (withdrawn from the market in April 2009), azathioprine with corticosteroids (one case), and mycophenolate mofetil. Natalizumab, a monoclonal antibody used in the treatment of multiple sclerosis, is associated with the risk of PML developing in 4 per 1000 treated patients, with the rate increasing with duration of therapy. The risk of clinical PML appears to increase up to 36 months of therapy and levels off thereafter. The mean interval between use of the drug to the diagnosis of PML is 5.5 months. JCV is detected in the CSF of up to one-half of all patients treated with natalizumab. An immune reconstitution inflammatory state (IRIS) may follow cessation of natalizumab or other monoclonal antibody therapy, although the JCV presence and the residual neurologic deficits may not clear for years after therapy is stopped. The risk of developing PML associated with rituximab is at least 1 in 25,000 exposed patients with cases reported in various autoimmune conditions treated with rituximab (systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis). Although the exact relationship between latent JCV and frank PML remains unclear, higher JC viral loads are detected among patients who are immunosuppressed and among those who have HIV infection with lower CD4 cell counts.

Smoking is reportedly associated with an increased risk of PML.

Clinical Findings

A. Symptoms and Signs

JCV causes lytic infection of oligodendrocytes in the white matter and symptoms presenting subacutely reflect the diverse areas of CNS involvement. Symptoms include altered mental status, aphasia, ataxia, hemiparesis or hemiplegia, and visual field disturbances. Seizures occur in about 18%. Involvement of cranial nerves and the cervical spine is rare.

B. Laboratory Findings

Quantitative PCR for JCV in CSF is used for diagnosis in patients with compatible clinical and radiologic findings. Persistent JC viremia and increasing urinary JCV DNA may be predictive of PML. An anti-JCV IgG was higher 6 months before diagnosis but was not predictive of PML in a cohort of people living with HIV infection.

C. Imaging

MRI of the brain shows multifocal areas of white matter demyelination without mass effect or, usually, contrast enhancement. These findings may not be distinguishable from IRIS. Increased uptake of methionine with concomitant decreased uptake of fluorodeoxyglucose in positron emission tomography may be helpful for diagnosis. In people living with HIV infection, a syndrome of cerebellar degeneration is described. Case reports attest to the variability of MRI findings and one should not rely on them solely for diagnosis. MRI can detect PML-associated lesions before symptom onset in patients taking natalizumab.

Treatment & Prevention

Limiting the immunosuppressed state without inducing an IRIS represents the mainstay of therapy for HIV-associated PML. Treatment of HIV with ART reduces the incidence of PML, improves the clinical symptoms, reverses some of the radiographic abnormalities, and improves the 1-year mortality rate, regardless of baseline CD4 cell count. Immune recovery can induce worsening of the clinical picture in a small number of cases. Immune reconstitution syndromes do not alter mortality but are associated with a form of PML called non-determined leukoencephalopathy associated with a chemokine polymorphism. Significant neurologic sequelae to PML infections are the rule and deficits may persist for years.

Decreasing immunosuppression in non-AIDS patients with PML (eg, multiple sclerosis or transplant patients) is also important. Cidofovir may be beneficial in non–AIDS-related cases, while corticosteroids may be useful with immune reconstitution. Because the JCV infects cells through serotonin receptors, some clinicians recommend the use of risperidone and mirtazapine. Anecdotal reports show that premature stopping of natalizumab in multiple sclerosis may itself lead to IRIS states. Mefloquine alone is ineffective, but combination therapy with mefloquine and mirtazapine was reportedly effective in one patient without AIDS. Two patients responded positively to treatment with interleukin-7 and adjuvanted exposure to JCV capsid protein VP1. Plasma exchange, which theoretically reduces the plasma level of agents associated with PML, may be useful in natalizumab-associated PML but is associated with a high risk of IRIS. A variety of lymphocyte markers studied have not been shown to predict which patients with multiple sclerosis will develop PML. In kidney transplant patients, a preinduction regimen with IVIG and rituximab and transplantation with lymphocyte- depleted cells appears to reduce the risk of PML. Similarly, titers of JC antibody are not shown to significantly increase prior to clinical onset of PML.

A new therapy for PML entails inhibition of the programmed cell death protein (PD-1), a negative regulator of immune clearance. A down-regulator of PD-1, pembrolizumab reduces JC viral load and increases CD4+ and CD8+ activity against the virus in a preliminary set of eight patients with PML with different predisposing conditions. In addition, allogeneic BK virus-specific T cells are useful in lowering JC viral load.

Two centers are currently recruiting patients for a clinical trial evaluating the ability of virus-specific cytotoxic T lymphocytes to control JC virus infection (NCT02479698 and NCT02694783). The course of post-PML in multiple sclerosis–related PML can be followed by magnetic resonance spectroscopy, tracking chemical ratios such as choline/creatine and the JV viral load. Studies are currently underway to identify patients with multiple sclerosis who have an increased risk of developing PML in the setting of natalizumab therapy.

HTLV-1 and -2 are retroviruses that infect CD4 and CD8 T cells, respectively, where they persist as a lifelong latent infection. HTLV-1 currently infects approximately 20 million individuals worldwide. It is endemic to many regions in the world including southern Japan, the Caribbean, much of sub-Saharan Africa, South America, Eastern Europe, and Oceania. The Caribbean basin and southwestern Japan show the highest prevalence of infection (4–37%). Conversely, HTLV-2 is mainly found in native populations of South (1–58%), Central (8–10%), and North America (2–13%) as well as African pygmy tribes. In some areas of Africa (eg, Malawi), HTLV-2 seroprevalence is higher than HTLV-1 seroprevalence.

In the United States, studies done in blood donors show a seroprevalence of HTLV-1 of 0.005% and HTLV-2 of 0.014%, a decline since the early 1990s. The virus is transmitted horizontally (sex), vertically (intrauterine, peripartum, and prolonged breastfeeding), and parenterally (injection drug use and blood transfusion). Hence, a higher prevalence is seen among injection drug users. Coinfection with HIV-1 occurs (in less than 5% in a series from Spain) but is often underrecognized. Transmission via organ transplant has been reported. Disease may flare when biologic agents are used for rheumatoid conditions. HTLV-1 infection is associated with HTLV-1 adult T-cell lymphoma/leukemia (ATL) and HTLV-1 associated–myelopathy/tropical spastic paraparesis (HAM/TSP). In contrast, HTLV-2 is significantly less pathogenic, with few reported cases of HAM/TSP as well as other neurologic manifestations. The causative association of HTLV-1 with ATL, attributed to the virally encoded oncoprotein tax, is well established.

Clinical Findings

A. Symptoms and Signs

The lifetime risk of developing ATL among HTLV-1 seropositive persons is estimated to be 3% in women and 7% in men, with an incubation period of at least 15 years. The mean age at diagnosis of ATL is 40–50 years in Central and South America and 60 years in Japan.

ATL clinical syndromes may be classified as chronic, acute (leukemic), smoldering, or lymphomatous. A primary cutaneous tumor is also described (with appearance ranging from popular lesions to exfoliative erythroderma) and shows a worse prognosis compared with the smoldering type. Clinical features of ATL include diffuse lymphadenopathy, maculopapular skin lesions that may evolve into erythroderma, periodontitis, a bronchoalveolar disorder, organomegaly, lytic bone lesions, and hypercalcemia. Opportunistic infections, such as P jirovecii pneumonia and cryptococcal meningitis, are common.

HAM/TSP, associated with both HTLV-1 and HTLV-2, develops in 0.3–4% of seropositive individuals and is more common in women and in older individuals. A chronic inflammation of the CNS and spinal cord leads to intense and progressive motor weakness and symmetric spastic paraparesis, bilateral facial palsies, cognitive impairment, falls, nociceptive low back pain, and paraplegia with hyperreflexia. Bladder and sexual disorders (eg, dyspareunia, erectile dysfunction), sensory disturbances, and constipation are also common. Both viruses can also induce motor abnormalities, such as leg weakness, impaired tandem walk, and vibration sense, without overt HTLV-associated myelopathy.

Current studies from Brazil show that a subset of chronically inflamed patients with HTLV-1 infections may be asymptomatic and are recognized as having an “intermediate syndrome” that may progress to full blown myelopathy.

HTLV-1 seropositivity is associated with an increased risk of tuberculosis, Strongyloides stercoralis hyperinfection, crusted scabies, and infective dermatitis. Inflammatory states associated with HTLV-1 infection include arthropathy, recurrent facial palsies, polymyositis, uveitis, and sicca, but inconsistently Sjögren syndrome, vasculitis, cryoglobulinemia, infiltrative pneumonitis, and ichthyosis. Bronchioloalveolar carcinoma is increased in frequency in the presence of HTLV-1.

HTLV-2 appears to cause a myelopathy that is milder and slower to progress than HAM. All-cause and cancer mortality are higher among HTLV-2 seropositive patients. Seropositivity to both viruses (HTLV-1 and HTLV-2) is associated with increases in depression and anxiety.

HTLV-1/HIV coinfection is associated both with higher CD4 cell counts and a higher risk of HAM.

B. Laboratory Findings

The peripheral smear can show atypical lymphoid cells with basophilic cytoplasm and convoluted nuclei (flower cells) but the diagnostic standard is evidence of clonal integration of the proviral DNA genome into tumor cell. The identification of HTLV-1 antibodies supports the diagnosis. Serum neopterin levels may indicate disease activity. An HTLV-1 provirus load in peripheral blood mononuclear cells and CSF cells and an HTLV-1 mRNA load are proposed as markers of HAM risk and progression. HTLV positivity is associated with erythrocytosis, lymphocytosis (HTLV-2), and thrombocytosis (HTLV-1).

Treatment, Prevention, & Prognosis

No vaccine or antiviral therapy currently exists for the prevention and treatment of HTLV infections, although considerable research in Japan on the use of the viral product tax in immunotherapy remains underway.

Management of ATL consists mainly of chemotherapy, with allogeneic stem cell transplantation and the use of monoclonal antibodies (the anti-CCR4 inhibitor mogamulizumab, anti-CD25 agents), and the dual SYK/JAK (spleen tyrosine kinase/Janus kinase) inhibitor cerdulatinib. A chemotherapy regimen in Japan using eight different agents shows a higher response rate than traditional biweekly CHOP (40% vs 25%). Combination therapy with interferon-alpha is used with success. Prophylaxis against infections is needed in ATL because patients show a profound immunodeficiency. Patients who are coinfected with HIV-1 and HTLV reportedly do respond to ART.

HAM is treated with a variety of immune-modulating agents (including corticosteroids) without consistent results. Currently studied modalities of therapy, none of which are uniformly accepted as a mainstay, include combination therapy with the antiretroviral raltegravir alone or in combination with zidovudine; interferon-alpha; and a combination of prednisolone, pegylated interferon, and sodium valproate; pentoxifylline, cyclosporine, and the retinoid tamibarotene. Small, uncontrolled studies suggest plasmapheresis results in improvement in gait and sensory disturbance among some patients and improvement in muscle pain with pulsed methylprednisolone.

Screening of the blood supply for HTLV-1 is required in the United States. There is significant cross-reactivity between HTLV-1 and HTLV-2 by serologic studies, but PCR can distinguish the two. Improved assays to screen organ donors for HTLV-1 and -2 infections are needed, although such screening is not currently required. Antenatal screening and avoiding breastfeeding (where the virus can be transmitted) are also important preventive measures.