HONOLULU—A wet spring and a higher than usual mosquito population are causing experts to predict an increase in the incidence of West Nile virus this mosquito season, which spans from July to October. With this possibility, physicians are advised to keep in mind that focal neurologic deficits, polio-like symptoms, gastrointestinal distress, and muscle weakness have been identified as major—and sometimes unexpected —presenting symptoms among patients with West Nile virus infection. Findings from a number of studies were presented at the 55th Annual Meeting of the American Academy of Neurology.

FOCAL NEUROLOGIC DEFICITS

During the 2002 summer epidemic of West Nile virus infection, researchers from three Chicago-area medical centers examined presenting symptoms in cases of West Nile virus infection. They found that 54% of cases in their series had a spectrum of neurologic complications such as paralysis, trouble with vision, slurred speech, and tremors. These complications can mimic those of other common neurologic diseases such as stroke, Parkinson’s disease, Bell’s Palsy, Guillain-Barré syndrome, and polio.

“As West Nile virus cases continue to be seen across the United States, we hope physicians benefit from the findings of our study by being aware of the varied presentations of the West Nile virus,” said study author Nidhi K. Watson, MD, of the Department of Neurological Sciences of Rush-Presbyterian–St. Luke’s Medical Center, Chicago.

Her team’s particular interest in focal neurologic deficits stems from the fact that Illinois experienced a higher number of West Nile virus cases than did any other state: 884, or 20% of all US cases reported by January 2003.

The team’s series included 43 patients, representing 6% of those seen in Illinois; detailed data were available for 28 cases. Neurologic deficits in these patients manifested three to 21 days (mean of 10 days) following onset of a febrile illness. “We further divided these groups based on the nature of the preceding illness—whether it was simply an acute febrile episode or if was more of a meningitis or encephalitis syndrome,” Dr. Watson explained. “Of the 15 patients with focal deficits, 47% did not have a meningitis or encephalitis syndrome; they simply had a high fever.” There were two deaths (both in patients who had had focal deficits on presentation).

“For the 15 cases [with focal deficits] the median length of time to deficit was seven days. For the group with an acute febrile illness the median time to onset of neurologic deficit was 14 days, which is significantly different from the meningitis and encephalitis group, which had a median of only five days,” she commented.

“Focal deficits seen in our series included visual loss, flaccid monoplegia, hemiparesis, bradykinesia, parkinsonian-type tremor with rigidity, bilateral abducens palsies, bilateral facial nerve palsies, focal polyradiculopathy, ataxia or dysmetria, acute motor polyneuropathies, acute sensory polyneuropathies, or acute motor-sensory polyneuropathies,” the researchers reported. Only one case had specific MRI abnormalities (enhancement of intradural root). All surviving patients, at the time of Dr. Watson’s presentation, had made a reasonable recovery.

Dr. Watson concluded that “neurologic complications can be frequent in patients who have symptoms of West Nile virus infection and that neurologists need to be actively involved in the evaluation of patients with suspected West Nile virus infection.” As the West Nile virus remains a fixture in US ecology, neurologists also need to be aware that neurologic complications can occur in the absence of meningitis or encephalitis, the researchers advised.

 

First Test for West Nile Virus Approved by the FDA

In July, the FDA cleared the first diagnostic test for West Nile virus infection. The West Nile Virus IgM Capture ELISA is intended for use in patients with clinical symptoms consistent with viral encephalitis/ meningitis. The new test takes only hours, and the results are available the same day, unlike the current test, which takes about two days and up to two weeks for results to be available. The new test will cost about $25. The West Nile IgM assay—manufactured by PanBio Limited in Windsor, Australia—was evaluated using more than 1,000 patient sera, which were tested at four different clinical sites. The test correctly identified antibody in 90% to 99% of West Nile virus disease cases. Because detection of antibody is not always specific in patients with acute viral infections, this test is considered presumptive and should be confirmed by more specific testing. The disease is most prevalent during the peak mosquito season, which is typically July through the end of October. Over the past several years, the geographic range of the virus as well as the number of new infections has expanded, and it now covers most of the continental United States.

WEST NILE VIRUS CAN CAUSE POLIO-LIKE SYMPTOMS

Research has provided further evidence that West Nile virus can cause the polio-like symptoms of muscle weakness, acute paralysis, and impaired breathing, according to investigators who sought to provide pathologic confirmation of poliomyelitis in patients with confirmed West Nile virus infection.

“As we head into another season with this virus, it’s very important for doctors to recognize that people with symptoms of sudden muscle weakness or paralysis could have West Nile virus,” said the study’s lead author, Jonathan D. Fratkin, MD, of the Department of Pathology, University of Mississippi Medical Center in Jackson.

Dr. Fratkin and his colleagues have seen eight cases of polio-like paralysis due to West Nile virus, and several other cases have been reported around the country. Their current research reported on four of the Mississippi patients who died within weeks or months of developing the virus.

“These were difficult cases, because West Nile virus had not previously caused these types of symptoms, and the symptoms were similar to those of another neurologic disorder, Guillain-Barré syndrome,” Dr. Fratkin explained. Clinical presentations were similar in all four cases, including fever, chills, muscle weakness, and acute respiratory distress requiring endotracheal intubation or tracheostomy; none suffered prolonged hypoxemia.

At autopsy, inflammation of the spinal cord gray matter was the major central nervous system finding in each case. The lesions varied from patchy gliosis and neuronal dropout in the ventral gray matter to extensive perivascular cuffs of chronic inflammatory cells, including abundant histiocytes and microglial cells, they noted. Inflammatory cells were also clustered around dying anterior horn cells (neuronophagia). The investigators reported that the autopsies also ruled out other causes of the symptoms, such as a lack of blood flow or oxygen to the brain. However, the tests to see whether the West Nile virus was present at the time of death were negative.

“Enough time had elapsed between when these people became sick and when they died—and they had been showing improvement before they died—so it’s possible that the virus was gone from their bodies,” Dr. Fratkin hypothesized. “Another possibility is that our tests are not sensitive enough to detect the virus.”

INFECTION IN THE ABSENCE OF SYMPTOMS

The researchers emphasized that most people who become infected with West Nile virus do not get sick, or they experience relatively mild, flu-like symptoms. According to the Centers for Disease Control and Prevention (CDC), less than 1% of those infected with West Nile virus will develop a severe illness.

The pathologic process in all of the patients was characteristic of viral infection involving gray matter neurons and identifies acute poliomyelitis as a possible etiology for the muscle weakness and acute flaccid paralysis seen in patients with West Nile virus infection. “Although different viruses, including other flaviviruses, can produce the same histopathologic change, the poliomyelitis in our patients occurred in the setting of an acute West Nile virus infection.

“Neuronal degeneration produced by nonviral etiologies, including hypoxia and ischemia, would not produce the perivascular chronic inflammation and microglial nodules with neuronophagia. Moreover, we did not observe changes in the hippocampus, cerebral cortex, and cerebellar cortex suggesting a hypoxic/ischemic event,” Dr. Fratkin’s team stated.

Physicians and other health care workers in areas with active West Nile virus transmission should be aware that muscle weakness and acute flaccid paralysis could be a manifestation of West Nile virus poliomyelitis, the investigators cautioned. They also noted that since the virus can survive in some blood products, West Nile virus poliomyelitis should also be considered in recent organ transplantation or blood transfusion recipients who develop muscle weakness or acute flaccid paralysis. It is their hope that this awareness will help to avoid the morbidity associated with unnecessary diagnostic procedures and inappropriate treatment.

CLINICAL AND LABORATORY FEATURES OF WEST NILE MENINGOENCEPHALITIS

A research team led by Jenice Robinson, MD, of the University Hospitals of Cleveland and Case Western Reserve University, sought to evaluate the clinical, cerebrospinal fluid, radiologic, and neurophysiologic features of all patients treated for West Nile virus infection at an academic tertiary care hospital. Inpatient and outpatient records were screened for those treated for West Nile virus infection, and laboratory records were screened to identify all inpatients with serologically proven West Nile virus. Patient charts were reviewed for clinical features, date of symptom onset, cerebrospinal fluid results, neuroradiologic findings, and results of neurophysiologic studies, if available.

“Our goals were to identify commonalities in cerebrospinal fluid findings and predictors of poor clinical outcomes and to identify any previously unrecognized manifestations of West Nile,” Dr. Robinson said.

In all, 15 patients (average age, 65.8; age range, 11 to 88) were identified. Initial symptoms included fever (80%); gastrointestinal distress (73%); confusion (60%); fatigue (53%); somnolence (53%); headache (40%); stiff neck (27%); tremulousness (20%); myalgias/arthralgias (13%); and seizure, ataxia, photophobia, and rash in one patient (7%) each. Cerebrospinal fluid was obtained in 13 patients (five patients had two separate samples taken at different time points), spanning days 2 to 28 of illness; cell count trends were strongly consistent with an initial high neutrophilic pleocytosis followed by a prolonged lymphocytic pleocytosis. No sample had a low glucose level; elevated protein levels were highly common. The investigators reported that 10 patients underwent MRI; only four patients had abnormalities that were attributable to West Nile virus infection, including high T2 signal in the subcortical white matter, thalami, substantia nigra, and spinal cord in the region of the anterior horns. Seven patients underwent electromyography; results were suggestive of disease of the lower motor neurons. “In four of these patients, electromyogram clearly showed there was no evidence of demyelination and supported a diagnosis of poliomyelitis,” Dr. Robinson related.

Six patients underwent EEG; all showed generalized slowing without epileptiform abnormalities. Five patients were discharged to home in good functional status; five went to rehabilitation with the expectation of returning home; two went to rehabilitation with significant deficits likely precluding eventual independence; three were bedridden and cognitively devastated; none died. “On average, our patients with the decline in Glasgow Outcomes Scale scores had more comorbid conditions than those patients without a decline, but we were not able to demonstrate significance,” she acknowledged. Older age, presence of medical comorbidities, and positive findings on neuroimaging were associated with a worse outcome. “However, four of our six patients with decline in Glasgow Outcomes Scale [scores] at discharge had abnormal MRI findings that were directly attributable to West Nile, compared with none of the remaining nine patients—and this is significant,” observed Dr. Robinson.

Initial manifestations of West Nile virus infection vary in some respects from those an evaluating neurologist might expect. Gastrointestinal distress was highly prevalent in this series, while neck stiffness was not. “We present the most complete data we have yet seen regarding the course of cerebrospinal fluid findings in West Nile virus infection, substantiating that the expected evolution from neutrophilic to lymphocytic predominance does take place,” Dr. Robinson reported.

WEST NILE VIRUS: A SPECTRUM OF PRESENTATION

To demonstrate the increasing relevance of West Nile virus diagnosis to the clinical neurologist, Montu Sumra led a team of investigators from the Department of Neurology at Henry Ford Hospital, who implemented a surveillance program at the tertiary care center. From August through October 2002, patients presenting with aseptic meningitis, meningoencephalitis, and/or flaccid pareses were evaluated by clinical examination, pertinent laboratory studies including cerebrospinal fluid analysis, and electrodiagnostic studies.

Fifteen patients (eight female; age range, 37 to 91; median age, 57) were identified as having positive IgM titers in cerebrospinal fluid for West Nile virus and negative St. Louis encephalitis IgM cerebrospinal fluid titers. The spectrum of clinical presentation included flaccid paresis in six patients, facial mononeuropathy in one, paresis in four, bibrachial weakness in two, and paraparesis in one.

Thirteen of the 15 patients had electrodiagnostic studies, which revealed diffuse/segmental motor neuronopathy in eight, bilateral lumbosacral polyradiculopathy in one, a mixed picture of demyelination with conduction blocks and axonal injury in one, carpal tunnel syndrome in two, and C7 radiculopathy in one.

“I think the importance here is that the nature of the neurologic manifestations of West Nile virus is protean,” said Dr. Sumra. “The take-home message is that the diagnosis is very pertinent in any patient presenting with a combination of weakness with or without clinical encephalitis. It should be considered in the differential of any patient presenting with any combination of weakness with or without meningoencephalitis during the summer months.”

CEREBELLAR SYNDROME IS A PROMINENT FEATURE

During the 2000 West Nile virus epidemic in Israel, “We were struck by the high number of patients with cerebellar syndrome admitted to our institution,” said Yaron River, MD, of Haifa, Israel. To follow this trend, his team conducted a retrospective study to determine the characteristics, incidence, and prognosis of cerebellar syndrome in patients with West Nile virus infection. A secondary goal was to determine the relationship of the patients’ discharge prognoses to cerebellar syndrome, he related.

The evaluation included 19 patients (10 female) with West Nile fever who were admitted to the hospital from January through October 2002. The diagnosis of West Nile fever was based on elevated ELISA-IgM titers in the cerebrospinal fluid and/or serum. The severity of the cerebellar syndrome was graded as mild, intermediate, or severe; patients with severe cerebellar syndrome could not walk due to trunk ataxia.

On admission, normal mental status was found in 63.4% of patients. The cardinal presenting symptoms were fever (95%), headache (63.6%), nausea and vomiting (68.4%), dizziness (52.6%), and maculopapular rash (15.8%). Meningeal signs were positive in eight patients (42.1%). More than half (62.5%) of patients had symptoms and signs suggestive of a cerebellar syndrome without cranial nerve involvement. In 25% of patients mild cerebellar syndrome was found; 12.5% of patients had intermediate and 25% had a severe cerebellar syndrome. Eleven patients (57.9%) had gait ataxia ranging from slight to severe trunk ataxia. Cerebrospinal fluid pleocytosis and elevated protein levels were present in 73.3% of patients. Four patients died, all of whom were older than 76, with severe background debilitating diseases. A statistically significant correlation was demonstrated between the severity of the cerebellar syndrome and the patient’s prognosis (in terms of morbidity and mortality).

“The most important laboratory findings were albuminaturia in almost half the patients, increased protein levels in 80%, and neurocytoses—either mononuclear or polycytoses—in 76%,” reported Dr. River. Cerebellar signs occurred in 62.5% of patients: 25% had mild cerebellar syndrome, 12.5% had moderate, and 25% had severe. Five of 19 had significant dysarthria; half of the patients had asymmetric, the other half had symmetric cerebellar syndrome. “The first question we wanted to ask was, ‘Does the presence of encephalopathy change, or have an impact upon, outcome at discharge?’

“Performing the appropriate tests on such a small group of patients, we got a P value of 40.1, suggesting that encephalopathy is associated with worse outcome at discharge,” he explained. “The second question we asked was, ‘Is cerebellar syndrome associated with a better or worse prognosis?’ ” Their results suggest that patients with a cerebellar syndrome had a better outcome at discharge.

“In our region, at least, cerebellar syndrome is a salient clinical feature of West Nile fever. The presence of cerebellar signs carries a good prognosis in contradistinction to the presence of encephalopathy,” Dr. River advised.

NR

—Heidi W. Moore

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