West Nile virus infection, presenting with flaccid monoparesis and meningoencephalitis
Clinical Summary: Spinal fluid collected from the lumbar puncture performed upon admission to the Houston Veterans Administration Medical Center was sent to the Houston City Health Department, where it was found to be positive for IgM for the West Nile virus (WNV) and negative for antibodies to the St. Louis Encephalitis virus.
IgM against WNV in the spinal fluid is considered to be diagnostic of acute WNV infection since IgM antibodies do not readily cross the blood-brain barrier, and therefore must be produced concurrently in the CNS [1, 2]. If a patient's serum tested positive for IgM or IgG antibodies, it would need to be repeated to show a significant rise in titers to diagnose acute WNV infection. Recent infection by, or vaccination for, a related virus (e.g. St. Louis Encephalitis, dengue, yellow fever, or Japanese encephalitis) can produce false positive IgM antibody tests. The most specific test for WNV is the plaque reduction neutralization test [2], and such neutralization tests are advocated after IgM-positive serum studies to confirm the diagnosis of WNV infection [3].
This was the first human case of West Nile virus infection confirmed in Texas.
The West Nile virus (WNV) is a member of the viral family named Flaviviridae [4]. It is a single-stranded RNA virus. There are two genera in this family, and WNV belongs to the second genus named flavivirus. The sixty-eight known flaviviruses are divided into eight antigenic complexes: WNV belongs to the Japanese encephalitis complex, which includes the viruses for Japanese Encephalitis and St. Louis Encephalitis. Most flaviviruses are transmitted via arthropods such as mosquitoes or ticks.
WNV was first isolated from a human in Uganda in 1937. It was endemic throughout the West Nile area before spreading throughout Africa, parts of Europe, Russia, India, and Indonesia [5].
There have been a number of epidemics of WNV infection. There were two outbreaks in Israel in 1951-1954 and 1957. The 1957 outbreak was the first time that meningoencephalitis was recognized as a manifestation of WNV infection. There was another epidemic in South Africa in 1974. Subsequently, there was a 20-year period of decreased activity before numerous outbreaks began in the 1990s [5]. The virus was first reported in the United States in 1999 with an outbreak in the New York City (NYC) area. There were 62 human cases and seven deaths. This was followed by 21 cases with two deaths in 2000 in the U.S., 66 cases with nine deaths in 2001 [6], and 1641 cases with 72 deaths in 2002 as of Sept 20, 2002 [7]. Eighty-four additional cases have been reported in Texas since our patient was reported in July; the vast majority have been in Harris County, which encompasses the city of Houston, and the immediately surrounding area.
Meek [5] and others [2] have noted three troubling trends in WNV epidemics. 1) There is an increased frequency of outbreaks involving humans and horses (11 since 1994). 2) There is an apparent increase in more severe human disease. Whereas neurologic impairment, for example, was not commonly reported previously, the Romanian epidemic of 1996 affected 393 patients, of whom 352 had meningitis, meningoencephalitis, or encephalitis. Finally, 3) there have been higher rates of bird mortality in association with recent human outbreaks. These observations suggest that a more virulent strain of West Nile virus may have developed [5].
In the US, the virus has been found in a number of species of birds, which may be natural reservoirs. It spreads predominantly via the Culex mosquito vector; however, the virus has been isolated from 42 other species of mosquito. In the NYC area, approximately 3.6% of mosquito pools tested positive for WNV [24]. Humans and horses are incidental hosts. WNV has been isolated from many other animals, including geese, cats, dogs, bats, rodents, rabbits, raccoons, and skunks.
The majority of persons infected with WNV have no symptoms. About 20% of infected people will develop a mild clinical illness after an incubation period of 3-15 days [8]. Less than one percent (1/150) will develop severe neurological disease [1, 2, 8]. In Queens, New York after the 1999 epidemic, 2.6% of the population had serologic evidence of exposure to WNV [8, 23]. Thus, the 59 diagnosed cases of meningoencephalitis were probably associated with about 8,200 additional cases of asymptomatic or minimally symptomatic WNV infection [23].
The treatment of WNV infection is supportive. No virus-specific treatment is available, and there are no controlled studies to guide us regarding the prophylactic use of corticosteroids, anticonvulsants, or anti-edema agents at this time [3].
Regarding prognosis, NYC Health Department follow-up one year after their 1999 epidemic revealed persistent symptoms of fatigue (67%), memory loss (50%), weakness (44%), depression (38%) and other findings [2]. Only 37% of patients reported full physical, functional, and cognitive recovery [3].
Several risk factors appear to influence the morbidity and mortality associated with WNV infection. Age over 75 years increases the relative risk of death by a factor of 8 [9]. Co-morbid illnesses, such as hypertension and diabetes mellitus, also appear to increase relative risk by two and five-fold respectively [9]. This may occur via facilitating viral crossing of the blood-brain barrier, thus increasing the brain's susceptibility to infection [9]. WNV infection has also been reported in an HIV-positive patient [10]; however, it is unclear whether such persons, or others with immunosuppressed states, are at increased risk for overt infection.
Two additional clinical risk factors predicting mortality are the presence of encephalitis with severe muscle weakness and a change in level of consciousness [2]. The case/fatality ratio in epidemics of the last eight years has been 4-14% with almost all deaths occurring among patients manifesting encephalitis [3]. Amongst encephalitis patients, the case/fatality ratio in the recent Israeli and NYC (1999) epidemics was 24% and 19% [3].
Our patient's risk factors for WNV infection included occupational exposure to mosquitoes (as he works outdoors on air-conditioners), and exposure to mosquito bites as he mows his large lawn. He also lives in a rural area where birds are known to be infected with WNV. Moreover, the first horse in the Houston area killed by WNV lived near the patient's home.
The typical presentation of WNV includes fever, headache, backache, and myalgias lasting 3-6 days [3, 4, 8]. The presentation also commonly includes pharyngitis, conjunctivitis, eye pain, nausea, vomiting, diarrhea, abdominal pain, and anorexia. Half of patients previously reported developed a maculopapular rash on the chest, back, and arms, but this has been less common in recent epidemics (~22% of cases [3]). Lymphadenopathy was more common in past epidemics, but is present in <5% in recent outbreaks [3]. WNV can also produce pancreatitis, hepatitis, myocarditis, or leukopenia. One occasionally observes hyponatremia [8]. Patients can also present with neurologic symptoms, as happened with this patient.
Neurologic involvement in West Nile virus infection can include encephalitis, meningitis, meningoencephalitis, optic neuritis, cranial nerve dysfunction, myelitis, polyradiculitis, ataxia, extrapyramidal signs, myoclonus, and seizures (uncommon) [8].
Head CT scans are usually normal, and in ~1/3 of patients the MRI demonstrates enhancement of the leptomeninges, periventricular areas, or both [8]. The CSF usually shows leukocytosis with lymphocytes (unless it is performed very early in the illness, in which case the CSF leukocyte count may not be elevated) and an elevation of CSF protein.
Most relevant to this case, WNV infection can also produce focal weakness that appears peripheral in origin. There is evidence to suggest that WNV produces this weakness by involving one or more anatomic loci within the lower motoneuron or motor unit. These loci may include axons, myelin, anterior horn cell bodies, and cranial nerve motor nuclei.
WNV infection is associated with a flaccid paralysis that resembles Guillain-Barre Syndrome (GBS) [5, 6, 9, 11, 12]. GBS-like syndromes have been associated with two other flaviviruses, the Japanese encephalitis virus and dengue virus [13, 14]. Paralysis and paresis with WNV was apparently reported only 3 times prior to the New York epidemic of 1999. One was a 1954 report of one patient with acute flaccid paralysis of the extremities after purposeful WNV inoculation as a treatment for refractory neoplasia. That patient recovered.
In the 1999 NYC epidemic, four of the five initial patients diagnosed with WNV encephalitis developed a flaccid paralysis, two had decreased DTRs, and three of them died [4]. The electromyography/nerve conduction studies (EMG/NCV) showed axonal neuropathies: two were polyneuropathies and two were motor with normal sensory examinations. Autopsies were obtained in all three patients that died, but the pathologic basis for the weakness is unclear. All three autopsy examinations showed encephalitis and microglial nodules [15]. Microglial nodules were found in the medulla, cerebellum, thalamus, and rarely in the cerebrum, especially hippocampus; nodules were located in both the gray and white matter. There was also evidence for mononuclear inflammatory infiltrates in 1) the leptomeninges; 2) perivascularly in the medulla and in some medullary cranial nerve roots; and 3) perivascularly with the medulla and thalamus being most involved. No mention was made of anterior horn cell or proximal root involvement, and no assays of peripheral nerves were reported.
Ultimately, the 1999 New York epidemic was associated with 59 hospitalizations. A complete report of these patients published in 2001 [9] indicated that there had been weakness in 16 patients, and flaccid paralysis in six. Four patients required ventilatory support. Nineteen patients had hyporeflexia (presumably those were the patients with weakness, though this was not specified) and four had hyperreflexia. Eight of 10 patients who underwent electromyographic and nerve conduction velocity studies (EMG/NCV) (which presumably included the six with flaccid paralysis) had evidence of axonal polyneuropathy. Decreased conduction velocities in motor or sensory nerves or both were noted on NCV studies, with diminished compound muscle action potentials. Fibrillations were noted on EMG studies. The conduction velocities and amplitudes from the EMG/NCV studies were not reported in detail, and thus it is difficult to compare the relative contributions of axonopathy versus demyelination.
A second mechanism for weakness is suggested by another report from that same NYC 1999 epidemic. A 69 year old patient had a GBS-like syndrome on presentation [11]. His EMG/NCV studies were consistent with demyelinating neuropathy with some secondary axonal involvement.
Reports from the 2000 NYC epidemic also suggested demyelination. That epidemic led to the hospitalization of 19 patients [12]. Three had weakness on examination. Six had abnormal reflexes, four of which were hyporeflexic. It is unclear whether the patients with hyporeflexia were the same patients that had muscle weakness, though presumably they were, and it is unclear which muscle groups were the weakest. An EMG/NCV study from a single infected patient with Parkinson's disease, diabetes and hypertension showed a moderate-to-severe demyelinating peripheral neuropathy.
In the Israeli outbreak of 2000, three cases of acute polyneuropathy were reported [16]. One patient had an isolated polyneuropathy, and two had additional evidence of meningoencephalitis. One of three patients studied had electrophysiologic testing that suggested a sensory-motor demyelinating neuropathy, while the other two patients had findings suggesting an axonal process.
A third mechanism that may account for weakness with WNV infection is a myelitis. Two "Letters to the Editor" published online in advance of the October 17, 2002 print version of the New England Journal of Medicine describe four patients with weakness associated with WNV infection [17, 18]: one from Louisiana and three from Mississippi.
All four patients presented with constitutional symptoms: all had fever, and some had chills, confusion, or myalgias. Then, each developed weakness. One patient had bifacial and then appendicular weakness [17]. Two patients had 3-extremity weakness, and one patient had monoparesis [18]. All had normal or nearly normal sensation. The three with more extensive involvement required mechanical ventilation. One had normal tendon reflexes [17], and three were areflexic in the involved extremities [18]. Two had bladder dysfunction. Three brain MRIs and one cervical MRI were normal in one study [18], and a complete spinal cord MRI was normal in the other [17]. CSF WBC counts were elevated in two instances and normal in another instance. The CSF protein was elevated all three times it was reported in these cases. Serial EMG/NCV studies between days 4 and 18 in the single patient report [17] showed a 25-50% reduction in motor amplitudes, with normal nerve conduction velocities. There was widespread increased spontaneous activity and severely reduced motor unit recruitment. In the other three patients, EMG/NCV studies showed reduced motor amplitudes and normal sensory responses. There was evidence of denervation on EMG that was focal in the case of monoparesis and scattered or widespread in the other two instances. No motor or sensory conduction velocities on the group of three patients were provided [18].
The two sets of authors interpreted their findings as supporting an anterior horn cell (AHC) location for the underlying pathology. In the single patient report [17], the authors concluded that the patient had "paralytic poliomyelitis, [which one could] distinguish from GBS? by the presence of fever, pleocytosis, and retained DTRs". In the other report [18], it was concluded that the patients had poliomyelitis based on "asymmetric flaccid paralysis, areflexia in all three patients, and two had bladder dysfunction and acute respiratory failure. Electrodiagnostic findings confirmed involvement of anterior horn cells or motor axons. These clinical and electrodiagnostic findings are classic features of poliomyelitis and strongly suggest that in humans, as in animals, the spinal cord gray matter is the target of West Nile virus."
This conclusion is important in suggesting that typical treatments for GBS, such as plasma-exchange, may not be appropriate for the treatment of GBS-like weakness associated with WNV infection.
It may be difficult via EMG/NCV studies alone to be certain that AHCs are involved as opposed to multiple motor roots, i.e., a polyneuritis. Ultimately, confirmation of this anatomic location will require pathological study of the spinal cord in such patients. Previous neuropathologic investigations of WNV cases did not examine AHCs [15, 19].
There is evidence in the veterinary literature supporting the hypothesis that AHCs could be involved in WNV-induced weakness. In birds killed in the 1999 NYC epidemic, pathologic investigation identified WNV in neurons and glial cells in the brain (especially Purkinje cells), and included the spinal cord [20]. Pathologic examination of the CNS of horses in Tuscany, Italy, killed by WNV infection in 1998, revealed a "nonsuppurative polioencephalomyelitis with constant involvement of the ventral horns of the thoracic and lumbar spinal cord" [21].
A fourth and related mechanism of lower motor neuron (LMN) weakness with WNV infection for cranial nerves (CNs) may be direct involvement of the motor CN nuclei or proximal roots. One report noted endoneurial mononuclear inflammation of the CN roots in two patients [19]. Another report from the 1999 NYC epidemic was a case-report of rhombencephalitis [22]. A 15 year-old adolescent presented with bifacial weakness, a depressed gag reflex, tongue fasciculations, and bilateral appendicular and truncal ataxia, with mildly increased tendon reflexes. One month later, he was improved, and at six months, his neurologic exam was normal. Other cases with similar CN involvement were reported in the Romanian (1996) and Russian (1999) epidemics.
It thus appears that weakness occurring in association with WNV infection could be due to axonal neuropathy, demyelinating neuropathy, or anterior horn cell/motor nuclei involvement, or combinations of the above.
Our patient appears to have an unusual complication of WNV infection, i.e. isolated flaccid paralysis of the right upper extremity. To our knowledge, isolated monoparesis has only been reported one time previously in association with WNV [18].
We investigated the anatomy of our patient's monoparesis. His weakness did not appear to be central in origin. Nonetheless, a brain MRI was performed because of his history of CNS trauma, the patient's stroke risk factors, the possibility of focal CNS involvement by encephalitis (though that is unusual with WNV), and the abnormalities noted on the head CT scan. MRI of the brain showed two focal regions of T2-weighted hyperintensity: one in the right frontal pole in the supraorbital region, and the other near the temporal horn of the left lateral ventricle just above the petrous ridge. Both were consistent with old contusions, and were not in locations that would explain the patient's monoparesis. Diffusion-weighted MRI did not show any areas of acute appearing abnormality. Moreover, the EEG did not show any areas of focal slowing.
Physical examination of the weak right upper extremity, which showed a loss of reflexes, was consistent with lower motor neuron (LMN) dysfunction. The patient also reported jumping muscles. However, fasciculations were not observed until hospital day #13 when they were noted in the first dorsal interosseus muscle. The EMG/NCV examination on hospital day #13 was also consistent with LMN dysfunction.
The nerve conduction velocities measured in the right upper extremity were normal (Median 50.4 and Ulnar 53.4). However, the compound muscle action potentials were diffusely reduced, including ulnar, axillary and musculocutaneous evoked potentials. The F-responses were also mildly prolonged: the Median F-response was 36.1 milliseconds stimulating at the wrist (normal<32 msec), and the Ulnar F-response was 34.2 milliseconds stimulating at the wrist (normal<32 msec). Sensory conduction studies were normal in both upper limbs, except for reduced right median and superficial radial sensory nerve action potentials recorded respectively from the second and first digit (upper trunk distribution).
The needle EMG exam showed moderate active denervation (1+ to 2+ fibrillations and positive sharp waves, and reduced recruitment patterns) with severe loss of voluntary motor unit potentials in right C8/lower trunk innervated muscles, and mild active denervation without clear loss of voluntary motor unit potentials diffusely in the right forearm and proximal upper limb muscles. The first dorsal interosseus muscle showed fasciculations. There was also mild active denervation in the right cervical and mid-thoracic paraspinal muscles. This study was interpreted as indicating right cervical and thoracic multilevel motor root lesions (polyradiculopathy) with probably the greatest involvement at the C8 root, with the possibility of a superimposed axonopathy affecting the upper trunk of the brachial plexus.
The EMG/NCV study was repeated one week later. We were particularly interested in testing whether the findings had progressed to a broader distribution. This second EMG/NCV on hospital day #20 did, in fact, show that there was now mild left cervical multi-root involvement despite a lack of associated symptoms. Moreover, despite a lack of lower extremity symptoms, there was also a mild, chronic, distal sensorimotor axonal and demyelinating polyneuropathy in those extremities.
As with two recent reports [17, 18], it was not possible to be entirely certain whether there was AHC or polyradicular involvement, or both. Thus, we performed a cervical MRI with and without contrast specifically looking at the ventral cord. It was normal. We also did an MRI of the brachial plexus after the first EMG/NCV study because it had suggested possible upper trunk involvement. The plexus MRI was also normal. Thus, the exact focus or foci of involvement producing weakness remains uncertain.
Our patient received supportive therapy. His strength improved over a period of weeks to grade 4/5 proximally and distally. His reflexes returned more swiftly, i.e., over a period of days.
This case highlights the need to consider West Nile viral infection in a patient presenting with a combination of encephalopathy and weakness. In our patient, weakness preceded the altered mental status by one week. At the time of onset of weakness, however, our patient did have signs of meningeal irritation (headache, fever, and neck pain). Reports in the literature indicate that weakness and encephalopathy can also present concomitantly.
This case is notable for its description of focal weakness, apparently of peripheral origin, in a patient infected by a flavivirus (West Nile virus). In their discussion, Kataki et al. call to attention the wide range of neurologic manifestations encountered in the most recent epidemic of West Nile viral infection. They discuss the available evidence that the spectrum of West Nile-associated disease, or perhaps the recognition of its various forms, may be changing. We thank Daniel Musher, M.D., of the Infectious Disease division of the Houston Veterans Administration Medical Center, and the Department of Medicine at Baylor College of Medicine, for his assistance with this case. We also acknowledge the assistance of Robert J. Kolimas, M.D., of the Neurology Service at the Houston Veterans Administration Medical Center, with the electrodiagnostic studies.
-- Dennis R. Mosier, M.D., Ph.D.
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