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Central nervous system manifestations of West Nile virus (WNV) infection include meningitis, encephalitis, and poliomyelitis-like syndrome. We describe a 44-year-old man with no past medical history who presented with a meningoencephalitic syndrome and spastic paralysis bilaterally in the upper and lower extremities, hyperreflexia, and myoclonus and was ultimately diagnosed as being infected with HIV and WNV.
A 44-year-old African American male with no significant past medical history presented to the emergency department (ED) with altered mental status for 1 day prior to presentation. The patient had a history of fevers, chills, headaches with neck pain, and photophobia for a duration of 1 week. During this time, the patient was seen at two other hospitals and was discharged from both with a diagnosis of sinusitis. However, the patient's symptoms did not resolve and his wife brought him to our facility's ED after a sudden alteration of the patient's mental status. The patient had no recent travel history, sick contacts, or use of medications.
On examination, it was noted that the patient was febrile with a temperature of 101.2°F. His lungs were clear upon auscultation. Neuromuscular examination was remarkable for neck stiffness, spasticity, hyperreflexia, and myoclonic jerks. Plantar reflexes were flexor. A computed tomography (CT) scan showed no gross intracranial abnormalities. A lumbar puncture demonstrated a clear fluid with a cerebrospinal fluid (CSF) protein concentration of 73 mg/dl, a white blood cell (WBC) concentration of 3/mm3, a red blood cell concentration of 4/mm3, and a glucose concentration of 55 mg/dl. No organisms were grown on CSF or blood cultures, and the Gram stain was negative. Urine toxicology was negative. A complete blood count demonstrated a depressed white cell count of 3.34 × 103 with a neutrophilic predominance. The patient was admitted to the hospital with a presumptive diagnosis of aseptic meningitis and/or encephalitis.
Empirical therapies for viral and bacterial meningitis/encephalitis (acyclovir, ceftriaxone, and vancomycin) were initiated. Laboratory tests for HIV infection, herpes simplex virus infection, syphilis, toxoplasmosis, cryptococcal antigen, Epstein-Barr virus infection, and West Nile virus (WNV) infection were performed. Cultures were also performed to rule out fungal and bacterial infections. A CD4 cell count was also performed because of a strong suspicion of HIV infection and HIV-associated encephalitis. A magnetic resonance imaging (MRI) scan demonstrated extensive patchy enhancement in the thalami bilaterally with extension to cerebral peduncles, consistent with a viral encephalitic illness (Fig. 1).
A rapid HIV test was positive and confirmed by Western blotting. The CD4 cell count was determined to be 10/mm3. All other tests were negative, including WNV serologic analyses of both CSF and serum. However, a CSF reverse transcription (RT)-PCR assay for WNV was positive. A follow-up CT scan demonstrated a mild hydrocephalus, which prompted a neurosurgery consult and subsequent extraventricular drain (EVD) placement. Despite the EVD and improving hydrocephalus, the patient continued to deteriorate. The patient became minimally responsive on neurological examination but had intact cranial nerve reflexes and hyperreflexia in the upper and lower extremities bilaterally. An electroencephalogram was remarkable for severe cerebral dysfunction. Currently, the patient remains intubated and febrile with minimal changes in neurological examination results. Cranial nerve reflexes are weak but intact. He is likely to have permanent neurological deficits.
WNV is an acute, self-limited, influenza-like illness that occurs 2 to 14 days after exposure to the virus (1, 2). It is a mosquito-borne disease endemic to Africa, the Middle East, western and central Asia, and the Mediterranean (1, 2). The virus first appeared in North America during an outbreak in New York City during the summer and fall of 1999. Texas was the epicenter of a 2012 WNV outbreak (3). Thus far, 551 cases of WNV have been reported, with 21 deaths (3). Since a majority of WNV infections are asymptomatic, outbreaks of disease are difficult to track (1–3). Less than 1% of infected patients develop central nervous system disease, i.e., WNV neuroinvasive disease, which includes a spectrum of meningitis, encephalitis, and acute flaccid paralysis (AFP)/poliomyelitis (1, 2).
The Centers of Disease Control and Prevention (CDC) defines WNV neuroinvasive disease as showing at least one of the following (1): (i) an altered mental status, (ii) central or peripheral neurological dysfunction, or (iii) cerebrospinal fluid (CSF) pleocytosis associated with an illness that is clinically compatible with meningitis. Tremor and myoclonus are also common findings (1, 2). In WNV meningoencephalitis, neuromuscular weakness is seen, which can manifest itself as an AFP/poliomyelitis-like syndrome, a Guillain-Barre-like syndrome, or a generalized myeloradiculitis (1, 2). AFP is the most common form of neuromuscular weakness and the best characterized. Patients often present with acute monoplegia, asymmetric upper or lower extremity weakness, or generalized asymmetric tetraplegia or quadriplegia (1, 2).
WNV neuroinvasive disease in a background of HIV infection is uncommon (1, 2). To our knowledge, there are five reported cases of WNV neuroinvasive disease in HIV-positive patients (4–8) (Table 1). In one case, a 38-year-old HIV-positive woman (CD4 cell count, 351/mm3) presented with meningitis-like symptoms and was diagnosed with WNV meningitis on the basis of the presence of WNV-specific IgM in her CSF (6). The patient had complete resolution of her symptoms and fever 7 days after the initial onset (6). Another report presented the case of a 69-year-old HIV-positive man who presented with acute confusion and was diagnosed as being WNV infected, also on the basis of positive serology (4). However, this case was complicated by aspiration pneumonia that eventually progressed to respiratory failure and death (4). Torno et al. presented the case of a 47-year-old HIV-positive male (CD4 cell count, 324/mm3) with a 3-day history of progressive weakness of the right upper extremity (7). The patient was diagnosed with WNV infection on the basis of WNV-specific IgM and was discharged within 13 days with complete resolution of his symptoms (7). Similarly, Jamison et al. reported the case of a 41-year-old HIV-positive man (CD4 cell count, 93/mm3) with acute-onset fever, bilateral upper and lower extremity weakness, and hyporeflexia (5). The diagnosis of WNV neuroinvasive disease was made on the basis of positive serology (5). Finally, Unzek et al. reported a case of a 45-year-old HIV-positive male (CD4 cell count, 128/mm3) with meningitis-like symptoms, hyperreflexia, CSF pleocytosis, and hypoglycorrhachia (8). The patient was diagnosed with WNV on the basis of positive serology (8).
AFP or poliomyelitis-like neuromuscular weakness is the most often described manifestation of neuroinvasive WNV. Of the five cases of WNV infection associated with HIV infection in the literature, two case reports described AFP, one described encephalitis, and two described an aseptic meningitis-like illness, one of which included hyperreflexia (Table 1). In this case report, we describe an atypical presentation of neuroinvasive WNV infection that falls within the spectrum of neurological manifestations associated with WNV infection but has yet to be described in an HIV-positive patient. The patient in this report presented with a meningoencephalitic syndrome with bilateral thalamic and cerebral peduncle involvement, spastic paralysis, myoclonus, and hyperreflexia.
The diagnoses in all of the aforementioned studies were based on enzyme-linked immunosorbent assays (ELISAs) positive for WNV-specific IgM in either the CSF or serum. WNV-specific IgM becomes elevated in the CSF at the onset of symptoms, and it can take up to 8 days for serum to become positive (1). A CSF or serum ELISA for WNV-specific IgM is often used to make a diagnosis of WNV infection and is the most sensitive test available; however, the ELISA has the potential to cross-react with other flaviviruses and therefore a positive result is often verified by other tests, such as an indirect immunofluorescence assay, a virus neutralization assay, or an RT-PCR assay (1). Despite negative test results for WNV-specific IgM in CSF and serum in this case, the diagnosis was made on the basis of a positive CSF RT-PCR assay result for WNV and the exclusion of other possible causes of meningoencephalitis. Since the patient presented more than 8 days after the initial onset of symptoms, the negative WNV-specific IgM and IgG finding is peculiar but may be explained by his HIV status. During his hospitalization, the patient's CD4 cell count was as low as 10/mm3, indicating severe immunodeficiency in both cell-mediated and humoral immunity. Similarly, Penn et al. described a 57-year-old male treated with chemotherapy for a follicular B cell lymphoma who was diagnosed with WNV infection on the basis of negative serology, CSF negative for WNV-specific IgM, and a positive CSF WNV RT-PCR assay result (9). Similarly, Huang et al. described a 70-year-old female with non-Hodgkin B cell lymphoma who was also diagnosed on the basis of negative serology and positive CSF WNV RT-PCR and nucleic acid amplification tests (10). The lack of an antibody response in these patients was ascribed to their underlying humoral immunity dysfunction (9, 10). Thus, the severely immunocompromised state of this HIV-positive male likely contributed to his inability to produce WNV-specific IgM.
The purpose of this case report is to raise awareness of possible atypical presentations of WNV infection. First, upper motor neuron manifestations such as spastic paralysis are in the realm of WNV neurological manifestations and therefore should not be dismissed, given the predominance of an AFP/poliomyelitis-like syndrome associated with WNV in the literature. Second, despite negative WNV serology, strong clinical suspicion and a positive WNV RT-PCR result were used for the diagnosis. Although WNV serology is commonly used as the diagnostic test of choice, the RT-PCR test is fairly accurate in diagnosis and has a very low false-positivity rate (11, 12). A positive RT-PCR test for WNV is diagnostic, whereas a negative result does not exclude infection (12). Therefore, the absence of WNV-specific IgM in CSF and/or serum should not exclude WNV from the differential diagnosis, especially in immunocompromised patients from regions where WNV is endemic.
Special thanks to John Quale for case discussions/consultation and critical analysis of this case report.
Published ahead of print 16 January 2013