West Nile Virus in the Elderly: Transmission, Diagnosis and Treatment
by Lara E. Jeha, M.D.
| Geriatric Times |
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September/October 2004 |
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Vol. V |
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Issue 5 |
West Nile virus (WNV) is a flavivirus that produces damage of varying severity and anatomical predilection, causing a wide spectrum of manifestations ranging from mild aseptic meningitis to fulminant meningoencephalitis and flaccid poliomyelitis-like paralysis (Gea-Banacloche et al., 2004). Since its first description in the United States in New York state five years ago, the virus has spread westward, causing an exponential increase in the number of cases from 62 in 1999 to 4,156 in 2002, according to the Centers for Disease Control and Prevention, with an up to 13.6% case-fatality rate (Sampathkumar, 2003).
Older age seems to be the main risk factor for severe meningoencephalitis and death: People older than 50 have a 10-fold higher risk of developing neurologic symptoms, and the risk is 43 times higher in patients older than 80 (Sampathkumar, 2003). It is therefore particularly imperative to be familiar with aspects of disease transmission, diagnosis and treatment while caring for this vulnerable patient population.
Epidemiology of WNV
The virus is amplified in birds and is transmitted to humans most commonly through infected Culex mosquito bites. People, horses and other mammals do not develop high-level viremia. The implication is that humans are considered "dead-end hosts" and therefore WNV can not be transmitted from person to person by mosquitoes (Gea-Banacloche et al., 2004). Patients seldom recall a specific mosquito bite, but are often self-reported active individuals with significant outdoor--and therefore mosquito--exposure (Pepperell et al., 2003). Transmission through blood transfusion, organ transplantation, breast-feeding, transplacental route and via laboratory acquisition have also been reported (Biggerstaff and Petersen, 2002; CDC, 2002; Iwamoto et al., 2003; Sampathkumar, 2003).
Fortunately, most of the WNV seroconversions are subclinical, with one in five infected patients developing only mild fever and overt clinical neurological illness affecting 1:100 to 1:150 cases (Nash et al., 2001). This low incidence of symptoms with infection appears to be related to the strength of the host's immune system, but could partly be due to the difference in severity of neurovirulence among different WNV strains (Beasley et al., 2002). Risk factors for increased mortality include host characteristics such as old age (older than 75), diabetes mellitus and level of immunosuppression, as well as measures of disease severity such as decreased level of consciousness, neuroimaging abnormalities and the development of limb weakness (Nash et al., 2001). The peak incidence of WNV infection is in August and September. Elderly men are most susceptible to severe disease, with the median age of hospitalized patients in the seventh or eighth decade and a male:female ratio of 3:1 (Jeha et al., 2003; Marfin and Gubler, 2001; Nash et al., 2001; Pepperell et al., 2003; Sejvar et al., 2003).
Clinical Features
Like most viral illnesses, common systemic complaints from patients with WNV include fever, fatigue, myalgias and gastrointestinal symptoms (e.g., nausea and vomiting, abdominal pain, and diarrhea). More characteristic features include back or limb pain in around one-third of the cases (Jeha et al., 2003). One-fourth of cases have a nonpurulent, maculopapular erythematous rash, usually antedating any neurological manifestations by several days (Jeha et al., 2003; Pepperell et al., 2003; Sejvar et al., 2003).
The most common neurological signs and symptoms include headache, altered level of consciousness and focal weakness, observed in various combinations. West Nile fever usually presents as headache and fever following back pain, myalgias, and, in 20% to 50% of infected individuals, rash (Hirsch and Werner, 2003). Meningeal signs are often absent on physical examination, with neck stiffness and photophobia observed in less than one-third of patients (Pepperell et al., 2003). This aseptic meningitis tends to occur more in younger cases and usually resolves without major sequelae (Jeha et al., 2003). Meningoencephalitis manifests as behavioral or personality changes, such as irritability, confusion or disorientation that can evolve into stupor and even coma, with mental status changes persisting for up to several weeks (Pepperell et al., 2003). Reduced level of consciousness--a general symptom of encephalitis--is frequently associated with other more localizing signs such as tremor, bulbar dysfunction, ataxia or focal weakness reflecting more specific areas of central nervous system involvement. Physical examination usually reveals hyperreflexia as would be expected with upper motor neuron injury, unless there is associated myelitis where areflexia becomes the rule. Focal weakness develops in around half of patients with WNV CNS infection, with progression to frank paralysis in 10% to 35% of patients (Jeha et al., 2003; Nash et al., 2001; Pepperell et al., 2003).
Earlier studies suggested that older age and medical comorbid conditions could predispose to weakness. Those factors have not been uniformly confirmed. In contrast to headache and mental status alterations that are the usual presenting symptoms, weakness frequently develops in the subacute phase of the illness. The limb weakness is typically asymmetric and rapidly progressive, reaching its nadir within two to eight days of symptom onset (Jeha et al., 2003). It typically involves proximal musculature, and the upper lumbar segments can be affected in isolation mimicking an upper lumbar radiculopathy or plexopathy. Although weakness usually happens in the context of encephalitis, it can occur as the sole manifestation of WNV infection (Jeha et al., 2003; Nash et al., 2001; Sejvar et al., 2003).
Laboratory Findings
Routine laboratory abnormalities include hyponatremia in up to one-third of the cases: either a mild leukocytosis or a mild leukopenia. Most commonly, however, routine blood count and basic metabolic panels are normal. Cerebrospinal fluid (CSF) studies reveal a significant pleocytosis usually 30 cells/µL to 170 cells/µL, with a neutrophilic predominance in the first week followed by a lymphocytic preponderance thereafter (Jeha et al., 2003; Sampathkumar, 2003). This CSF pleocytosis is helpful in differentiating WNV from Guillain-Barre syndrome, which can cause a rapidly progressive flaccid weakness but in which white blood cells are classically absent in the spinal fluid. In Guillain-Barre syndrome, CSF protein might be elevated, but glucose concentration is usually normal, as expected in viral CNS infections.
Viremia has usually resolved by the time symptoms begin, except in immunocompromised patients where it may be prolonged up to 11 days. Viral culture and serum viral polymerase chain reaction (PCR) studies are therefore of very low sensitivity and not typically useful. Within the first one or two days of symptoms, viral PCR may still be positive in the CSF and thus might be helpful. More commonly, diagnosis of acute WNV infection is based on serologic studies (Gea-Banacloche et al., 2004). The most sensitive test is immunoglobulin M (IgM) capture enzyme-linked immunosorbent assay (ELISA) in the CSF (>90%): it detects antibodies in the spinal fluid three to five days into the clinical illness and three or more days earlier than in the serum (Tardei et al., 2000). Since IgM does not cross the blood-brain barrier, its presence in the CSF is considered diagnostic of an acute infection. However, a positive IgM in the serum should be interpreted with caution. After an acute infection, IgM antibodies may persist in the blood for up to 500 days (Tardei et al., 2000). Therefore, a positive serum IgM is significant only if it is associated with a positive CSF IgM or if it represents a documented seroconversion from a known baseline. Serum IgG appears around one week after symptom onset and can be detected in most cases three weeks after infection. It can cross-react with antibodies against other flaviviruses and with Saint-Louis encephalitis virus (Gea-Banacloche et al., 2004; Sampathkumar, 2003; Tardei et al., 2000).
Radiological Findings
Computer tomography is usually normal and is therefore of limited significance. In the setting of WNV encephalitis, magnetic resonance imaging of the brain is abnormal in 8% to 33% of cases, with hyperintense signal abnormalities affecting either the cerebral cortex, the underlying subcortical white matter or both on the T2 and fluid attenuated inversion recovery sequences (FLAIR) (Jeha et al., 2003; Nash et al., 2001). Similar changes were described in the thalami, cerebellum and brain stem in patients with prominent cerebellar, parkinsonian or brain stem symptoms (Pepperell et al., 2003; Sejvar et al., 2003).
In up to 75% of patients with WNV-associated flaccid paralysis, MRI of the spine can be abnormal, with T2 and FLAIR hyperintensities involving the cord parenchyma at the level of the cervical or lumbar cord, and gadolinium enhancement in the cauda equina compatible with myeloradiculitis (Jeha et al., 2003; Pepperell et al., 2003).
Treatment and Prevention
The treatment for WNV infection remains largely supportive, focusing on prevention of secondary medical complications such as aspiration and bacteremia and on early institution of mechanical ventilation for respiratory failure (Sampathkumar, 2003). The common presence of significant medical comorbidities such as heart failure, diabetes and hypertension in the elderly population increases their vulnerability to such problems and thereby complicates their management. This becomes particularly problematic since some studies suggested a more severe disease in WNV-infected elderly people, probably related to their comorbidities and generalized nonspecific age-related immunosuppression (Nash et al., 2001). Such a clear correlation between disease severity and age has not been established, however, in other studies.
There is still no available standardized and proven targeted effective therapy. Both ribavirin (Copegus, Rebetol, Virazole) and interferon-α2b (Intron A, Rebetron) were effective against WNV in vitro, but animal and/or human studies have not been encouraging until now (Gea-Banacloche et al., 2004). Currently, there is an ongoing open-label interferon-α2b trial and a multicenter trial using high-titer intravenous immunoglobulin (Omr-IgG-am). Immunoglobulin has shown some benefit in anecdotal reports and offers the advantage of a pathophysiologically plausible mechanism of benefit since it contains high titers of WNV-specific immunoglobulins (Hamdan et al., 2002).
Prevention becomes crucial in the absence of specific therapy. Approaches to prevention include reduction of the mosquito population by draining water from mosquito breeding sites and using mosquito larvicides and maturation inhibitors to reduce the numbers of mosquitoes (Petersen et al., 2003). Lifestyle modifications include avoiding outdoor activities during the hours around dawn and dusk--when mosquitoes are most active--and wearing protective, light-colored clothing to limit insect bites. Insect repellants containing 10% to 50% N,N-diethyl-3-methylbenzamide (DEET) have also been recommended as an alternative to the organophosphate insecticides that have significant side effects (Hirsch and Werner, 2003). Concentrations of DEET >50% have no additional benefit. It can be safely used in infants older than 2 months and in pregnant women (Fradin and Day, 2002). Several human vaccines are being developed but none has been accepted in clinical practice yet.
Conclusions
West Nile virus causes significant morbidity and mortality. Our knowledge about its modes of transmission and clinical manifestations has expanded tremendously over the past few years. Much remains to be discovered in the aspects of treatment and prevention, where most research is currently focused.
Dr. Jeha is training in epilepsy at the Cleveland Clinic. At last year's American Academy of Neurology plenary session, she gave a presentation on West Nile virus.
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