In July 2003, when Lyle Petersen, MD, MPH, was 48, he learned first-hand that West Nile virus (WNV) can knock you to your knees. A long-distance runner who serves, ironically, as director of the Division of Vector-Borne Diseases at the Centers for Disease Control and Prevention, Dr. Petersen failed to apply insect repellent before walking to his mailbox at dusk near his home in Fort Collins, CO. (Vector-borne diseases are transmitted by insects such as mosquitoes.)
“Three days later, about half way into my run, I felt like I had no energy at all. My head and body began to hurt. Within minutes, I felt so bad I had to walk home,” Dr. Petersen recalls. He stayed in bed for a week with severe headaches, a stiff neck, and sensitivity to light—all, it turned out, due to WNV.
Dr. Petersen's experience isn't unique. Since WNV surfaced in New York in 1999, thousands of Americans have become infected from a simple mosquito bite. Summer 2012 marked the biggest national outbreak of WNV since 2002: more than 5,600 Americans contracted the virus and nearly 300 died from West Nile-related complications.
Around 80 percent of people infected with WNV have no symptoms. However, 20 percent develop fever, headaches, body aches, joint pains, fatigue—called West Nile fever (WNF). Another 1 percent of those infected with WNV develop the neuroinvasive form of the disease, which enters and infects the central nervous system (brain and spinal cord). Neuroinvasive WNV causes serious symptoms such as disorientation, confusion, tremors, muscle weakness or incoordination, and convulsions.
“WNV may be the most common viral cause of acute encephalitis in the United States,” says Ken Tyler, MD, Reuler-Lewin professor and chair of neurology at the University of Colorado School of Medicine, and Fellow of the American Academy of Neurology (FAAN). Yet, scientists still don't understand exactly how WNV attacks the brain—or how to treat it. While treatments are available for WNV-related complications, experts agree they act mostly as Band-Aids. Where we have the most control, says Dr. Petersen, is in prevention.
WNV IN THE BRAIN
When WNV crosses the blood-brain barrier, which keeps out foreign substances, it can kill nerve cells (neurons) in the brain and spinal cord. Patients may develop encephalitis (inflammation of the brain), meningitis (infection of the coating around the brain and spinal cord), or polio-like limb weakness due to infection of the spinal cord.
The risk of developing encephalitis after WNV infection increases with age as well as other medical conditions and use of certain medications. “People whose immune systems are compromised because of an underlying medical condition, or because of medications they're taking, may be at increased risk of developing serious illness after WNV,” explains Dr. Tyler. Medications that can increase risk include immunosuppressive drugs for organ transplantation and drugs for treating diseases that affect the immune system, such as HIV, lymphoma, leukemia, or multiple sclerosis.
Several studies have also suggested a genetic link, meaning some people may be more genetically susceptible to contracting the neuroinvasive form of the disease.
The virus replicates in the skin near the site of the infecting bite, travels to lymph nodes (oval-shaped organs that act as filters for foreign particles), and eventually circulates in the blood. In severe cases, the infection can cause swelling of the brain, bleeding within the brain, and nerve damage. Depending on which areas of the brain are affected, some people may develop long-term physical or cognitive problems.
“WNV seems to target the brain's deep gray matter, including structures like the thalamus, the basal ganglia, the upper part of the brainstem (called the mid-brain), and the cerebellum,” explains Dr. Tyler.
Injury to the basal ganglia and substantia nigra in the midbrain can result in symptoms similar to Parkinson's disease, including tremors, slow movement, and stiffness or rigidity. Damage to the cerebellum produces coordination problems. Death of the motor neurons in the spinal cord can cause weakness and paralysis that resembles polio. And injuries to the thalamus can range from visual field defects, to memory impairment, to disorders of language, to motor and sensory deficits.
“WNV involves an acute injury followed by a period of recovery,” explains John Morrey, PhD, director of the Institute for Antiviral Research and research professor at Utah State University. In some cases, brain cells recover when the swelling and inflammation resolve. In other cases, parts of the brain take over function for damaged areas.
Quick Facts: West Nile Virus
West Nile virus (WNV) was first detected in New York in 1999. By 2004, all 50 states reported WNV activity in either humans or animals.
* Humans get infected with WNV when bitten by a mosquito carrying WNV.
* Human-to-human transmission only occurs through rare events like blood transfusions and organ donations. No amount of hand washing can protect you against this virus.
* People who develop West Nile fever (WNF) typically test negative for antibodies within the first several days of infection.
* WNF is a misnomer. “About half of people infected will not report a fever,” says Lyle Petersen, MD, MPH, director of the Division of Vector-Borne Diseases at the Centers for Disease Control and Prevention. Among those who do develop a fever, it tends to be very low grade.
“When parts of the brain are irreversibly injured, the question becomes, ‘How well can other parts of the brain balance out the injury?’” Dr. Morrey says. In the polio-like form of the disease, for example, about a third of patients are left with significant weakness. In the encephalitis cases, one in 10 die; the others may be left with residual deficits, including fatigue, muscle weakness, headaches, and cognitive problems at 8 to 18 months of follow up. The recovery from WNV meningitis is typically better: 95 percent of patients recover normal function at 8 months of follow up. For the vast majority of patients with WNV meningitis, recovery tends to occur within the first three to six months.
Even people who don't have the neuroinvasive form of the disease may have long-term neurologic symptoms. “I had a stiff neck, a headache, sensitivity to light—the sorts of things you think about with a mild case of meningitis—for months,” says Dr. Petersen.
The silver lining: You only get WNV once. “If you're infected, you develop antibodies against the virus so you're protected for life,” says Dr. Tyler.
Quick Facts: West Nile Virus
While identifying safe and effective treatments for West Nile virus (WNV) is proving to be a challenge, scientists have already developed safe and effective vaccines for several similar viruses (called flaviviruses), including yellow fever and Japanese encephalitis. At least four vaccines are currently used in horses and birds. And early human trials found that healthy individuals over age 50 produced protective antibodies 28 days after receiving a WNV vaccine.
“Development of a well-tolerated and effective human WNV vaccine is feasible,” says Ken Tyler, MD, of the University of Colorado Denver, “but it's an economic challenge. Either a company has to make a reasonable profit from commercializing a vaccine, or the government has to subsidize the cost.”
A WNV vaccine might be useful for at-risk populations, such as people over 60 or those who live in mosquito-ridden areas, but vaccinating such groups would be challenging. “For a variety of reasons—such as cost and the age when it's administered—only a modest number of people get the shingles vaccine, for example, compared to childhood immunizations such as for polio,” explains Dr. Tyler.
Sure, vaccination will protect people from contracting the disease, but it won't halt the spread of WNV (the disease already can't be transmitted from person-to-person), and that may make it low priority—at least for now.
Fight the Bite
Once the weather warms up to the mid-60s, mosquitoes are out, about, and ready to bite. The good news: keeping mosquitoes at bay is often a matter of choosing—and wearing—the right repellent.
But people are often confused by repellent. “There are many repellents in the marketplace, and people may have difficulty choosing,” says Lyle Petersen, MD, MPH, director of the Division of Vector-Borne Diseases at the Centers for Disease Control and Prevention, who claims the situation is likely to improve soon. “We're working with the Environmental Protection Agency (EPA) to develop a mark that companies can put on the repellent to indicate how long it offers protection.”
In the meantime, experts recommend scouring labels for one of the four following ingredients proven to help combat mosquitoes:
DEET is the most common mosquito repellent on the market, but some consumers are understandably concerned about potential side effects. Excessive use has been linked to memory loss, headache, weakness, and shortness of breath. Research shows that products containing more than 30 percent DEET don't offer additional protection and could cause serious side effects. However, when used as directed, experts agree DEET is a safe and effective way to avoid becoming a mosquito's next meal. In fact, according to the EPA, the risk of adverse reactions from DEET is on the order of 1 per 100 million people.
IR3535 is a synthetic amino acid that, like other repellents, interferes with mosquitoes' ability to sniff you out as a hearty meal. The health risks of IR3535 are minimal to nonexistent, according to the EPA, though there have been reports of eye irritation. A bonus: IR3535 doesn't have the same stench as other ingredients.
Picaridin repels and deters insects, keeping them from feeding on a tasty human host. Studies show picaridin evaporates from the skin more slowly than DEET or IR3535, repelling insects for longer periods of time. It doesn't seem to irritate the eyes or skin, and there are no concerns of neurotoxicity as there are with DEET.
Oil of Lemon Eucalyptus
Oil of Lemon Eucalyptus is the only botanical (a.k.a., plant-derived) ingredient registered by the EPA (meaning it meets stringent efficacy standards) and approved by the CDC. The repellent originated as an extract of an Australian eucalyptus tree. Studies suggest that products with 30 percent Oil of Lemon Eucalyptus repel as well as those with 15 to 20 percent DEET. It hasn't been studied in children, so it's not for use in children under three.
Other Preventive Measures
Stay indoors when mosquitoes are at their peak (usually at dusk). If you must go outdoors, wear long sleeve shirts and pants. And remove standing water (including Fido's water bowl), which is where female mosquitoes lay their eggs.
“WNV is not easily recognizable, because it involves a huge range of illness. Most (but not all) people with the neuroinvasive form of the disease have a positive antibody test for WNV when they show up in the doctor's office or emergency room,” says Dr. Petersen. But that's not the case for people who have WNF. Many of those patients haven't yet developed antibodies when they first seek medical care.
“For routine cases of WNF, we don't recommend diagnostic tests. Not only will most people test negative for antibodies in the early days after infection, but there's also no available therapy that can alter the course of the disease. Treatment is strictly for managing symptoms,” says Dr. Petersen, who regularly took non-steroidal anti-inflammatory drugs such as Advil (ibuprofen) when he was bedridden. While scientists have explored many medications, from intravenous immunoglobulins to steroids, nothing seems to alter or shorten the course of WNV.
“The drugs that work for herpes or HIV target very specific steps in the life cycle of those viruses. In WNV, those steps either don't exist or they aren't similar to those in herpes or HIV,” says Dr. Tyler. Most antiviral drugs are targeted treatments that work only for a particular virus or a particular class of related viruses. “Antiviral drugs are not like a broad-spectrum of antibiotics,” he notes.
Still, according to Dr. Morrey, some drugs are being studied to see if they improve the neurologic effects of the disease, such as lesions in the central nervous system caused by the virus. “Our approach is to study WNV as a neurologic disease, not just a virus, and take advantage of the neurologic research for other diseases similar to WNV.”
To that end, Dr. Morrey and his colleagues are looking closely at drugs that treat motor neuron diseases like spinal cord injury and amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease).
But for now, treatments for symptoms of the neuroinvasive form of the disease seem to be the only option. “We use some of the same medications we use in Parkinson's disease. If patients have depression or other mood-related symptoms, we treat those symptoms the same way we would in any neurologic disease, such as with antidepressants. Physical therapy, occupational therapy, and other forms of rehabilitation can also be helpful,” says Dr. Tyler.
THE RESEARCH CONUNDRUM
Every year, Americans experience serious neurologic symptoms as a result of WNV. In 2012, for example, the United States saw nearly 3,000 cases of the neuroinvasive form of the disease—a condition that carries a 10-percent mortality rate.
“That's not a good situation,” says Dr. Petersen. “We have an urgent need for effective therapies.” Not only are cases of WNV spread randomly across the country, they also occur seasonally and in relatively small numbers. In order to conduct clinical trials, researchers have to identify institutions that can house them. That's nearly impossible with WNV, since scientists can't predict where an outbreak will occur from year to year.
Since WNV belongs to the flavivirus family (which includes Japanese encephalitis, dengue fever, and hepatitis C), one of the more promising approaches may be to test drugs known to be effective against other members of this family of viruses.
“Once you have a safety profile for a drug, it's a lot easier to test it in another setting,” says Dr. Tyler. “With a disease like hepatitis C, for example, the number of people affected is much greater, the disease is more widespread, and it isn't seasonal. So, if a drug is safe and effective for hepatitis C, it makes sense to test it against WNV.”
The ideal therapeutic approach, say experts, is one that will also treat other related viral infections and forms of viral encephalitis. That way, scientists can garner funding, attract more interest from drug companies, and push potential therapies further along in the development process.
“We estimate that about a million people have developed WNF since it first appeared in the United States in 1999. Many of these people were unable to fulfill family and work responsibilities during their acute illness. WNV has a fairly large societal impact that is largely unrecognized,” says Dr. Petersen, who recalled that he could barely walk up the stairs in his house for two months after he was infected.
Now Dr. Petersen is back to running 5 miles every day. WNV is a distant memory. Unfortunately, that's not the case for many others, including Dr. Petersen's mailman, who was forced to retire due to persistent symptoms. “This is not a benign illness,” says Dr. Petersen. It deserves to be recognized.