West Nile VIrus

Chills
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Diagnosis and reasoning

One could say that a hallmark of an astute clinician is the ability to accurately and comprehensively elicit signs and symptoms, both subtle and pronounced. It is also reasonable to say that another hallmark is the ability to see patterns in the clinical findings elicited, and thus weave them into a skein of probable diagnoses. Consider this elderly patient. He initially developed a fever with chills, rigors and myalgia, with subsequent development of neurological symptoms including tremors, lower limb weakness and difficulty in walking. Most alarmingly, the presence of behavioral changes suggests at involvement of the brain. The general examination objectively quantifies the fever, while additionally demonstrating the presence of altered mentation; this is strongly suggestive of an encephalopathy. Examination of the central nervous system reveals unilateral hypotonia, with reduced power and diminished reflexes, i.e. an asymmetrical acute flaccid paralysis with predominant proximal involvement; note that sensation is unaffected. When considered together, the above are most suggestive of a focal encephalitis; Herpes Simplex Virus (HSV) encephalitis is the commonest cause of this presentation, while other key possibilities include flavivirus infections such as St. Louis Encephalitis, tick borne encephalitis or West Nile Virus, or a cerebral abscess. Note also that very rarely, acute anterior poliomyelitis and atypical presentations of Guillain Barre Syndrome (GBS) and Japanese Encephalitis (JE) can also give rise to a similar clinical picture. Magnetic resonance imaging (MRI) of the brain is the ideal study in this setting, but is contraindicated in this patient due to the presence of a pacemaker. Computerized Tomography (CT) of the brain can be performed in lieu of an MRI, but is less sensitive for detection of features of encephalitis (such as focal inflammation); however, this is still useful in excluding space occupying lesions such as brain abscesses. A cerebrospinal fluid (CSF) analysis may also be of diagnostic utility. The pleocytosis with neutrophil predominance and a mildly elevated protein level seen here is further suggestive of an infectious etiology. The presence of neutrophilia in the CSF does not necessarily imply a bacterial pathology; flavivirus infections can also give rise to similar results. Note that CSF analysis is usually normal in HSV encephalitis. While the likelihood of acute anterior poliomyelitis is low, stool cultures are a must in all patients with compatible clinical presentations, for notification and eradication purposes. Thus, following investigations, the tentative diagnoses are HSV encephalitis or a flavivirus infection; further serological studies are essential to determine which of these viruses is the culprit. Note that serologic test results may take several days to arrive; this patient's treatment should not be delayed pending this. The Infectious Diseases Society of America (IDSA) recommends that all patients with encephalitis receive empirical treatment with intravenous (IV) Acyclovir, due to the high prevalence of HSV. Acetaminophen is of value as an antipyretic and analgesic. While certain authorities recommend the use of IV Dexamethasone in individuals with potential HSV encephalitis, this is still a matter of controversy; little data is available on its efficacy. IV Gamma Globulins are used in the management of GBS, and are not indicated in this patient. Considering the patient in this case, serological studies eventually revealed the presence of IgM antibodies for West Nile Virus, establishing the diagnosis to be West Nile neuroinvasive disease.


Discussion

West Nile Virus (WNV) is a mosquito-borne arbovirus belonging to the genus Flavivirus; it is encountered in both temperate and tropical regions of the world. While WNV was first discovered in Africa and in the Middle East, it is now considered endemic to Africa, Asia, Australia, the Middle East, Europe and the United States. Note that in 2012, the US experienced an epidemic of WNV, with 286 fatalities. The virus is maintained in an enzootic cycle between ornithophilic mosquito vectors and avian hosts; however, it can also infect mammals as an incidental host. WNV shows a predilection for neural tissue; subsequent infection results in induction of cytokines and chemokines, promoting leukocyte invasion into the central nervous system (CNS) and neuroinflammation. Note that the inflammatory contribution to the pathology of disease remains unclear. A potent and rapid type I interferon (IFN) response is considered essential for successful control of the WNV infection; this further emphasises the importance of the innate immune response in reducing WNV replication. It has also been noted that individuals at the extremities of age, and/or with immunosuppression due to drugs or pre-existing medical conditions, are more susceptible for a serious outcome. The incubation period of WNV typically ranges between 2 to 15 days. In the majority of cases, infected individuals remain asymptomatic; however, between 20% to 30% of patients experience a mild flu like illness. Symptoms of West Nile fever include fever, malaise, fatigue, headaches, anorexia, nausea, vomiting, myalgia and rash. Note that the last is observed in less than 30% of the patients and though nonspecific, may suggest at a viral exanthem. Less than 1% of the cases are severe, resulting in neurological disease such as West Nile encephalitis, West Nile meningitis, West Nile meningoencephalitis and West Nile poliomyelitis. Non-neurologic complications are even rarer; these include pancreatitis, fulminant hepatitis, nephritis, myocarditis, cardiac dysrhythmias, rhabdomyolysis, optic neuritis, orchitis and coagulopathy. Note that multifocal chorioretinitis is a relatively frequent ophthalmologic complication in patients with West Nile encephalitis; fundal examination is mandatory in such patients. Dyskinesias including static and kinetic tremors, myoclonus, and parkinsonism, are neurologic manifestations associated with the disease. The preliminary diagnosis of WNV is based on clinical symptoms, the epidemiological history, and exposure to vectors. The laboratory diagnosis relies on isolation of the virus, detection of virus specific IgM antibodies or detection of viral antigens or RNA in blood or tissue. Detection of IgM antibodies in cerebrospinal fluid (CSF) using the IgM antibody-capture enzyme-linked immunosorbent assay (MAC-ELISA) forms the cornerstone for diagnosis of West Nile neuroinvasive disease, as IgM does not cross the blood brain barrier except with severe CNS inflammation. Viral RNA can also be detected through reverse transcription polymerase chain reaction (RT-PCR) assays, with a high degree of sensitivity and specificity; this is another method used for confirmation of the disease. There are no specific treatments for WNV; supportive therapy forms the mainstay of management, with key elements including hospitalization, fluid management, respiratory support and prevention of secondary infections. Personal protective measures including use of repellents containing DEET (N,N-diethyltoluamide) and picaridin, sleeping under an insecticide treated bed net, wearing protective clothes to cover exposed skin and application of permethrin-containing (e.g., Permanone) or other insect repellents to clothing, shoes, tents etc. are helpful for prevention of the disease. The general prognosis of WNF is favourable, however some patients experience multiple somatic complaints such as fatigue, tremors and motor dysfunction, which may last for several years.


Take home messages

  1. WNV is a mosquito borne virus with a global footprint.
  2. In the majority of patients, WNV is asymptomatic or self limiting; rarely, it may cause neuroinvasive disease resulting in meningitis, encephalitis, meningoencephalitis and/or West Nile poliomyelitis.
  3. Laboratory diagnosis relies on isolation of the virus, detection of viral antigens, or detection of virus specific IgM antibodies.
  4. There is no specific therapy for WNV; supportive measures remain the mainstay of treatment.

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