*From the Northwestern University Feinberg School of Medicine (Drs. Mutlu and Kuzniar), Chicago, IL; and Columbia University College of Physicians and Surgeons (Dr. Factor), New York, NY.
Correspondence to: Gökhan M Mutlu, MD, Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, 303 E Chicago Ave, Tarry 14–707, Chicago, IL 60611; e-mail: firstname.lastname@example.org
A 41-year-old man with a history of thymoma resection was admitted to the hospital with a 3-week history of generalized body aches and fever during late summer. He also reported severe headache for 1 week and photophobia for 3 weeks. He denied any recent travel, sick contacts, insect bites, rash, muscle weakness, or neck stiffness. He reported dizziness and blurred and double vision, and was noted to have an unsteady gait 1 day prior to hospital admission.
Physical examination on hospital admission revealed a well-built man with a temperature of 39.2°C, BP of 110/68 mm Hg, pulse rate of 98 beats/min, and respiratory rate of 16 breaths/min. His neck was supple but slightly tender when fully flexed. Examination of eyes, ears, and throat was normal. There were no palpable lymph nodes. Examination of the lungs, heart, and abdomen were normal. Inspection of the skin revealed no rash. The neurologic examination was normal, and there were no Brudzinski and Kernig signs.
Initial workup showed a WBC count of 7,500/μL with 85% neutrophils, hemoglobin of 15 g/dL, and a platelet count of 121,000/μL. Basic metabolic panel was within normal limits. Creatine kinase was 632 U/L (normal, 25 to 90 U/L), and lactate dehydrogenase was 447 U/L (normal, 100 to 190 U/L). The creatine kinase normalized on the second hospital day. Serum anti-acetycholine receptor antibodies were negative. Neuroimaging studies including CT and MRI of the brain were normal. Cerebrospinal fluid revealed a glucose level of 54 mg/dL, protein of 140 mg/dL, WBC count of 1,450 cells/μL (neutrophils 78%), and RBC count of 40 cells/μL. The Gram stain was negative for organisms.
The patient was empirically started on vancomycin and ceftriaxone for possible bacterial meningitis. On day 1, fever resolved but he continued to have headache and myalgia and also had confusion and generalized muscle weakness with a muscle strength of 3/5 bilaterally. Acyclovir was added for possible herpes simplex virus infection. On day 2, he had a low-grade fever (37.6°C); muscle weakness progressed (muscle strength 1 to 2/5) such that he was unable to sit or stand up independently. Fasciculations were also noted in lower extremities. There was no loss of fine/crude sensation. Bedside spirometry showed a FVC of 500 mL (approximately 5.5 mL/kg). Arterial blood gas analysis results on room air were pH 7.43; Paco2, 38 mm Hg; and Pao2, 69 mm Hg. The patient was transferred to the medical ICU for respiratory monitoring.
Within 3 h of admission to the medical ICU, the patient was quadriplegic with only a weak hand squeeze (strength 2/5). Concomitantly, his respiratory status worsened requiring intubation and mechanical ventilation for hypercapnic/hypoxemic respiratory failure (arterial blood gas analysis on a nonrebreather mask showed pH 7.37; Paco2, 50 mm Hg; and Pao2, 73 mm Hg). Chest radiograph showed silhouetting of the left hemidiaphragm, which was attributed to possible nosocomial pneumonia. Electrodiagnostic tests including electromyography and nerve conduction studies showed a marked loss in motor amplitudes and widespread denervation but preservation of sensory responses.
West Nile virus infection is predominantly an infection of wild and domestic birds and mosquitoes (Culex species), with humans being the secondary or incidental hosts. The incubation period ranges from 3 to 15 days. Spread of the virus begins with the emergence of adult mosquitoes in early spring and continues until fall, which corresponds to the peak in clinical infections in late summer and early fall. In addition to mosquito-borne spread, the virus can also be transmitted via transplanted organs.
Given that clinically evident disease occurs in approximately 1% of infected individuals, most West Nile virus infections are subclinical. Clinical presentations range from a mild febrile illness in 20% of cases to CNS involvement presenting as meningoencephalitis. Symptoms generally last for 3 to 6 days and include malaise, headache, eye pain, GI complaints (ie, diarrhea, nausea, vomiting), and petechial rash. Meningoencephalitis develops in approximately 1 in 150 infected persons and is generally seen in persons > 50 years of age and in immunocompromised patients.
Neuromuscular weakness is a common finding and an important predictor of death in West Nile virus infection. Among the first cases of West Nile virus reported in 1999, muscle weakness was documented in 27% of patients, 10% of whom had complete flaccid paralysis (Table 1
). The etiology of muscle weakness in West Nile virus infection is not clear at this time. Although in earlier cases muscle weakness was attributed to Guillain-Barré syndrome, cerebrospinal fluid pleocytosis and electrodiagnostic studies showing both demyelinating and axonal changes (the latter being most prominent) did not support the diagnosis. More recent data suggest poliomyelitis-like syndrome (anterior horn cell involvement) as the cause of muscle weakness in majority of patients.
While both poliomyelitis-like syndrome and Guillain-Barré syndrome are considered in the differential diagnosis of acute flaccid paralysis, they differ in many aspects and thus can be readily distinguished based on clinical and electromyographic findings (Table 2
). Poliomyelitis is a clinical syndrome that is characterized by fever, meningitis, and flaccid paralysis. The syndrome was historically associated with poliovirus but is now more commonly seen with other enteroviruses. Like West Nile virus, other flaviviruses can also cause poliomyelitis-like picture in humans presenting with acute flaccid paralysis (Table 3
Demonstration of West Nile virus or its RNA in serum, cerebrospinal fluid, or other tissues confirms the diagnosis. The RNA of West Nile virus can be identified either by qualitative reverse-transcriptase polymerase chain reaction or quantitative real-time reverse-transcriptase polymerase chain reaction but has limited sensitivity. Isolation of the virus in culture is also insensitive, especially if specimens have not been frozen. Moreover, virus growth may take 3 to 7 days, depending on the amount of virus in the specimen.
Because of the limitations of virus-detection assays, West Nile virus is most frequently diagnosed by assessment of the antibody response using an IgM antibody-capture enzyme-linked immunosorbent assay, which can be performed in state public health laboratories within 24 h. Serum or cerebrospinal fluid IgM is detected in most patients (75%) with flavivirus encephalitis during the first 4 days of illness and nearly in all patients by 7 to 8 days. These antibodies generally persist for approximately 1 year. While identification of West Nile virus-specific IgM in cerebrospinal fluid confirms the presence of a current infection, its presence in serum indicates only a probable infection and necessitates further testing, (ie, a fourfold rise in serum antibody titers from acute to convalescent phases). Due to serologic cross-reactivity with other closely related flaviviruses, virus neutralization tests are used to confirm the diagnosis when only serum specimens are available.
At this time, there is no proven specific therapy for West Nile virus infection. Israeli IV Ig has been successfully used in one case of West Nile virus encephalitis. It is noteworthy that Israeli IV Ig, unlike the one in the United States, contains the specific antibody against West Nile virus. Both interferon α-2b and ribavirin are active against hepatitis C virus, which like West Nile virus is a flavivirus. Similarly, both ribavirin (at high concentrations) and interferon α-2b inhibit West Nile virus in vitro.
Based on these in vitro studies, the US Food and Drug Administration has approved the use of interferon α-2b to be tested in the treatment of West Nile virus meningoencephalitis. Systemic administration of interferon α-2b does not achieve high levels in cerebrospinal fluid but may be beneficial against West Nile virus encephalitis through suppression of viremia and/or enhancement of cell mediated immunity systemically and in CNS. The dose of interferon α-2b used in the ongoing clinical trial is 3 million units administered IV followed by another 3 million units administered subcutaneously 12 h later, and then 3 million units administered subcutaneously every 24 h for 14 days.
The diagnosis of West Nile virus infection in our patient was made based on the enzyme-linked immunosorbent assay that showed positive cerebrospinal fluid West Nile virus IgM and the ratio of IgM antibodies against West Nile virus (the ratio of reactivity of the patient’s serum to the same antigen) of 3.57:1 (reference ratio, <2.00:1). Bacterial culture results and polymerase chain reaction for Herpes simplex virus 1 and 2 DNA in cerebrospinal fluid were negative, and acyclovir was discontinued. Serology for Eastern Equine, St. Louis, and Western Equine encephalitis were negative. Blood, urine, and tracheal aspirate culture results and fecal leukocytes remained negative.
Results of electromyography were consistent with anterior horn disease suggesting a polio-like picture. The patient underwent tracheostomy on hospital day 9. Although mental status gradually improved, he continued to have some degree of somnolence. His muscle strength was limited to a weak hand squeeze (muscle strength 2/5) bilaterally with no appreciable lower-extremity strength. The rest of his hospital stay was complicated by ventilator-associated pneumonia, left lung collapse due to mucus plugging requiring therapeutic bronchoscopic intervention, deep venous thrombosis, and central venous catheter infection with Gram-positive bacteremia. On day 28, he was transferred to a long-term acute care facility for further management. He remained bedridden with no significant improvement in neurologic findings, and he died of pneumonia 8 months after the initial diagnosis of West Nile virus infection.
Most patients with West Nile virus infection are asymptomatic with clinically evident disease in approximately 1% of infected individuals.
CNS involvement (meningoencephalitis develops in approximately 1 in 150 infected persons, and is generally seen in persons > 50 years of age and immunocompromised patients).
Muscle weakness is a common finding (up to 40% of patients) and an important predictor of death.
The cause of muscle weakness appears to be poliomyelitis-like syndrome in majority of cases and also Guillain-Barré syndrome in others.
Diagnosis is made by assessment of the antibody response using an IgM antibody-capture enzyme-linked immunosorbent assay in cerebrospinal fluid specimens.
Treatment is supportive, as there is no specific therapy proven for West Nile virus infection. Israeli IV Ig and interferon α-2b may be beneficial.
West Nile virus infection should be considered in the differential diagnosis of acute flaccid paralysis (Table 3) and neuromuscular ventilatory failure that develops particularly during summer and early fall.
This work was supported by the American Heart Association and NIH HL-66211.
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