West Nile Virus: Researchers Make Inroads Into Diagnosis and Treatments

April 10, 2005
Cary Groner

Since its 1999 appearance in New York, West Nile virus (WNV) has spread relentlessly westward each year, opening up new fronts in the Midwest and the mountain states until pummeling California in the summer of 2004. The flavivirus, which is spread primarily by mosquitos, affects a variety of animals, including humans, horses, and nearly 300 bird species. As of October 15, 2004, about 940,000 Americans had been infected, of whom 190,000 became ill and 6790 developed WNV's most feared complications: neuroinvasive disease, including meningitis, encephalitis, and acute flaccid paralysis.1

Since its 1999 appearance in New York, West Nile virus (WNV) has spread relentlessly westward each year, opening up new fronts in the Midwest and the mountain states until pummeling California in the summer of 2004. The flavivirus, which is spread primarily by mosquitos, affects a variety of animals, including humans, horses, and nearly 300 bird species. As of October 15, 2004, about 940,000 Americans had been infected, of whom 190,000 became ill and 6790 developed WNV's most feared complications: neuroinvasive disease, including meningitis, encephalitis, and acute flaccid paralysis.1Fortunately, WNV produces symptoms of illness in only 20% of infected humans, and neuroinvasive disease occurs in just 1 of 140.1 Nevertheless, the severity of WNV's neurologic manifestations-including death and long-term disability-has spurred researchers to develop faster and more sophisticated diagnostic tools so that neurologists and primary care physicians can distinguish the disease from similar conditions. This is crucial because WNV infection has been misdiagnosed as anything from Guillain-Barre syndrome (GBS) to stroke, myopathy, and even myocardial infarction. Such misdiagnoses may prompt misguided treatments that prove injurious.2Although effective treatment of WNV infection remains elusive, patients may ultimately benefit from a variety of therapeutic approaches now under investigation. In addition, the NIH, through the National Institute of Allergy and Infectious Diseases (NIAID), is conducting research into aspects of WNV that include virus structure and replication, immune response, vectors, and geographic spread. The agency also sponsors vaccine research.3CDC: "GET USED TO IT""West Nile is now endemic and should be part of neurologists' differential diagnosis for anyone with apparent viral meningitis, encephalitis, or acute flaccid paralysis," said James Sejvar, MD, a medical epidemiologist at the CDC and one of the country's leading West Nile experts. Researchers and clinicians are still evaluating the disease's long-term outcomes, Sejvar said, and there is both good news and bad news."Some people with even severe encephalitis-those who are comatose-can go on to do very well, because initial severity of illness doesn't necessarily portend ultimate outcome," he explained. "With flaccid paralysis, however, persistent physical and functional difficulties are the norm even up to 12 months later. In that regard, physical and occupational rehabilitation is going to be critical."In a 2003 article in the Journal of the American Medical Association, Sejvar and his colleagues4 described the disease's most prominent neurologic manifestations and provided much-needed diagnostic criteria (Table).OUTCOMES VARYAccording to the CDC, severe WNV infection typically presents with symptoms that may include fever, altered mental status, headache, GI complaints, ataxia, optic neuritis, seizures, weakness, myelitis, polyradiculitis, or rash.5 In Sejvar's article, which documents a 2002 outbreak of West Nile disease in St Tammany Parish, La, researchers reported these and other symptoms in patients with all 3 neuroinvasive conditions. Outcomes varied: for example, of 8 encephalitis patients, 1 died; and although 5 reported normal functioning at 8-month follow-up, 2 required the use of walkers. All 5 patients with meningitis survived, and 4 of those reported normal functioning at follow-up.The most serious condition, WNV-associated paralysis, is a poliomyelitislike syndrome that affects the anterior horn cells of the spinal cord, which are responsible for movement. This flaccid paralysis may occur alone or with meningitis or encephalitis, and it causes acute respiratory failure in roughly a third of patients, according to Sejvar. In the Louisiana study, he and his colleagues found that the 3 patients who developed paralysis fared comparatively poorly, still requiring wheelchairs at 8-month follow-up.Others have recounted similar outcomes, and not only in paralysis patients. A 2004 paper in Emerging Infectious Diseases reported that only 37% of New York patients with WNV infection who were surveyed had fully recovered after a year.6 And Christina Marciniak, MD,7 inpatient medical director of the Rehabilitation Institute of Chicago, reported in the Archives of Physical Medicine and Rehabilitation last December that of 4 patients recovering from WNV paralysis, none had fully recovered or become ambulatory by 6-month follow-up."With rehab, we were trying to maximize the muscles that were less affected by the West Nile virus, but patients weren't able to gain much strength," Marciniak said by phone from her clinic. "Most patients will probably have persistent weakness." Marciniak added that one of her patients-surprisingly, the oldest, at age 72-subsequently improved enough to become ambulatory again. She also said that many of her patients are relatively young (in their late 20s or early 30s) but that this more likely reflects referral bias (physicians wanting the best rehabilitation for those most likely to benefit) than any shift in the characteristics of the disease.Another report indicates that elderly patients with WNV infection are at the highest risk for encephalitis and death, and the immunocompromised (eg, transplant recipients or those with AIDS) face elevated risks of all conditions, including flaccid paralysis.8 Such increased risks are likely due to delayed virus-specific IgM response.DIAGNOSIS REMAINS DIFFICULTRapid and accurate diagnosis is critical to effective treatment of WNV's neurologic complications, but physicians often fail to detect the disease in time to affect their therapeutic strategies. "I know for a fact that a lot of patients go undiagnosed during their initial hospitalization," said Arturo Leis, MD, senior scientist for neuroscience and neurologic recovery at the Methodist Rehabilitation Center in Jackson, Miss. "One major limitation is that, depending on where you are in the US, it can still take over 10 days to document that the patient is indeed suffering from West Nile infection."Part of the problem is that by the time IgM or IgG antibodies can be detected in patients' blood or cerebrospinal fluid-a week or two after infection-via a typical enzyme-linked immunosorbent assay, those with neuroinvasive disease may already be critically ill. Immunocompromised patients may experience even longer delays. The tests may also cross-react with antibodies to closely related flaviviruses, such as those that cause yellow fever, St Louis encephalitis, or dengue fever, complicating the diagnostic picture.5New methods, such as microsphere immunoassays and immunofluorescence assays, better discriminate among such viruses and may improve diagnoses but aren't yet in wide use.9 CT scans have proved relatively ineffective, and although MRI reveals abnormalities about a third of the time, they aren't specific to WNV.6Nucleic acid amplification (polymerase chain reaction [PCR]) tests, now used to screen donated blood for WNV, are highly sensitive and specific, but they aren't generally available for diagnosis in ill patients yet. Moreover, because they detect viral RNA, such tests will be helpful only if clinicians suspect WNV infection relatively early in the course of illness, according to Leis."The viremic phase, in which the virus is recoverable from the bloodstream, is extremely short," he said, because after a week or two the patient's immune response has largely eliminated it. "Your clinical index of suspicion would have to be high very early in the illness to order PCR testing, even if it were available." In Mississippi, where Leis practices, it is not.TREATMENTS ON THE HORIZONAs Leis noted in his article, misdiagnosis can have serious consequences, because treatments for the conditions for which WNV disease is mistaken may be deleterious to patients with actual WNV infection. Patients thought to have stroke have been given anticoagulants, for example, and those with a misdiagnosis of GBS have received plasma exchange or intravenous immune globulin (IVIg) targeted to GBS.In addition, one aspect of WNV neuroinvasive disease-that the most serious illness often arises relatively late-raises a number of questions about proposed treatments. A clinical trial comparing an Israeli anti-WNV IVIg preparation with a US IVIg without WNV antibodies has had trouble enrolling enough participants for data analysis, but it may not matter.8 Some researchers suspect that this approach is unlikely to work because patients' own antibodies have largely eliminated the virus from the body by the time serious neurologic complications develop. They question why additional antibodies would make any difference in most patients."You'd have to obtain the immune globulin and give it at a very early stage," Leis commented. "But for patients with HIV or other immunosuppressive disorders, if it were readily available, it might have some benefit." Leis believes that other approaches now on the horizon are more promising. Several target the biochemical cascade resulting from infection that may contribute more to neuronal death than does viral invasion itself-an approach that addresses why such severe symptoms may develop after the virus is largely gone from the body.For example, clinicians at the University of Nebraska Medical Center used interferon alpha in 2 patients with WNV encephalitis and reported substantial improvement by the second day of therapy (larger clinical trials are under way).10 And although corticosteroid use in viral encephalitis has been controversial, recent studies have found that high doses modulate immune response and hasten recovery in West Nile meningitis, encephalitis, and flaccid paralysis.9,11 Further, because a natural amino acid called glutamate appears strongly related to neuronal cell death, Johns Hopkins researchers recently tested b-lactam antibiotics, which stimulate GLT1, a chemical that inactivates glutamate. The scientists found that in mice with amyotrophic lateral sclerosis, the drug delayed loss of neurons and muscle strength and increased survival.12"The same mechanism is likely contributing to the cell loss in West Nile spinal cord involvement," Leis said. "Agents like these all...are directed at this biochemical cascade that ultimately destroys motor neurons."AN OUNCE OF PREVENTIONOf course, with even such promising therapeutic approaches still not validated in large studies, the proverbial ounce of prevention starts to figure more heavily. To this end, several vaccines are under development. Patricia Repik, MD, program officer for emerging viral diseases at NIAID, evaluates proposals from pharmaceutical, biotech, and university researchers and provides funds to those the agency deems most likely to succeed. She also helps guide NIAID's intramural vaccine development efforts."We're trying to do vaccines using both replicating and nonreplicating viruses," she said. "We're also working on chimeric and DNA vaccines." Examples of NIAID-supported private efforts include one which is based on an existing yellow fever vaccine. It was created by Acambis, a Cambridge, Mass, biotech company, and has already entered clinical trials.3For now, however, the best prevention is the same one that has worked for decades in related illnesses: don't get bitten by mosquitos. For people who live in rural areas or work outdoors, this is easier said than done, of course, but clinicians stress its importance regardless. "Neurologists should encourage their patients to practice mosquito avoidance, to use DEET, and to avoid times of high mosquito activity-dusk to dawn," said Sejvar. The NIAID's Web site notes that DEET is considered safe if used as directed.3 "It's important to remember that this disease is entirely preventable."Cary Groner is a freelance writer in Northern California.REFERENCES1. Petersen LR, Hayes EB. Westward ho?-the spread of West Nile virus. N Engl J Med. 2004;351:2257-2259.2. Leis A, Stokic DS. Neuromuscular manifestations of human West Nile virus infection. Curr Treat Options Neurol. 2005;7:15-22.3. National Institute of Allergy and Infectious Diseases. NIAID fact sheet: West Nile virus. Available at: www.niaid.nih.gov/factsheets/westnile.htm. Accessed February 12, 2005.4. Sejvar JJ, Haddad MB, Tierney BC, et al. Neurologic manifestations and outcome of West Nile virus infection. JAMA. 2003;290:511-515.5. Centers for Disease Control and Prevention. West Nile virus: clinical description. Available at: www.cdc.gov/ ncidod/dvbid/ westnile/clinicians/ background.htm. Accessed February 12, 2005.6. Klee AL, Maldin B, Edwin B, et al. Long-term prognosis for clinical West Nile virus infection. Emerg Infect Dis. 2004;10:1405-1411.7. Marciniak C, Sorosky S, Hynes C. Acute flaccid paralysis associated with West Nile virus: motor and functional improvement in 4 patients. Arch Phys Med Rehabil. 2004;85:1933-1938.8. Granwehr B, Lillibridge KM, Higgs S, et al. West Nile virus: where are we now? Lancet Infect Dis. 2004;4:547-556.9. Narayanaswami P, Edwards LL, Hyde, CJ, et al. West Nile meningitis/encephalitis: experience with corticosteroid therapy. Poster presented at: the 56th American Academy of Neurology Annual Meeting; April 24-May 1, 2004; San Francisco.10. Kalil AC, Devetten MP, Singh S, et al. Use of interferon-alpha in patients with West Nile encephalitis: report of 2 cases. Clin Infect Dis. 2005;40:764-766.11. Pyrgos V, Younus F. High-dose steroids in the management of acute flaccid paralysis due to West Nile virus infection. Scand J Infect Dis. 2004;36:509-512.12. Darman J, Backovic S, Dike S, et al. Viral-induced spinal motor neuron death is non-cell-autonomous and involves glutamate excitotoxicity. J Neurosci. 2004;24:7566-7575.---Table - Diagnostic criteria for WNV neurologic manifestationsWest Nile meningitisA. Clinical signs of meningeal inflammation, including nuchal rigidity, Kernig or Brudzinski sign, or photophobia or phonophobiaB. Additional evidence of acute infection, including one or more of the following: fever (temperature > 38 degrees C [ > 100.4 degrees F]) or hypothermia (temperature 10,000/microL; neuroimaging findings consistent with acute meningeal inflammationWest Nile encephalitisA. Encephalopathy (depressed or altered level of consciousness, lethargy, or personality change lasting greater than or equal to 24 hours)B. Additional evidence of CNS inflammation, including 2 or more of the following: fever (temperature greater than or equal to 38 degrees C [greater than or equal to 100.4 degrees F]) or hypothermia (temperature lesser than or equal to 35 degrees C [lesser than or equal to 95 degrees F]); cerebrospinal fluid pleocytosis (greater than or equal to 5 leukocytes/microL); peripheral leukocyte count > 10,000/microL; neuroimaging findings consistent with acute inflammation (with or without involvement of the meninges) or acute demyelination; presence of focal neurologic deficit; meningismus (as defined in A); electroencephalography findings consistent with encephalitis; seizures, either new-onset or exacerbation of previously controlledAcute flaccid paralysisA. Acute onset of limb weakness with marked progression over 48 hoursB. At least 2 of the following: asymmetry to weakness; areflexia/hyporeflexia of affected limb(s); absence of pain, paresthesia, or numbness in affected limb(s); cerebrospinal fluid pleocytosis (greater than or equal to 5 leukocytes/microL) and elevated protein levels (greater than or equal to 45 mg/dL); electrodiagnostic studies consistent with an anterior horn cell process; spinal cord MRI documenting abnormal increased signal in the anterior gray matterReprinted with permission from Sejvar J et al. JAMA. 2003.4