Treatment strategies that control the previously described cascade of events leading to neuronal death may prove beneficial. Promising therapies include the use of interferon and interferon inducers, which have been shown to reduce mortality in mice infected by subcutaneous injection of WNV Morrey et al.
A preliminary report described three WNV patients with neurologic syndromes who showed improvement after receiving interferon alpha, thereby increasing optimism toward this treatment Sayao et al. Interferon gamma producing gamma-delta T cells also have been shown to prevent mortality from murine WNV infection Wang et al.
Other potential therapies include ribavirin, nucleic acids, RNA interference, antisense oligomers, peptides, imino sugars, and mycophenolic acid for a review, see Diamond, These agents act through distinct mechanisms and are moving through various stages of pre-clinical development.
The role of corticosteroids in WNV neuroinvasive disease is controversial, with concern that immunosuppressive effects may worsen outcome. However, high-dose steroids have been used to successfully treat a patient with WNV-associated acute flaccid paralysis Pyrgos and Younus, In addition, findings in 14 patients with acute infection suggest that intravenous dexamethasone may be the reason for shortening the acute phase of WNV meningoencephalitis and hastening patient recovery Narayanaswami et al.
However, both cases were characterized by an atypical temporal pattern of progressive symptoms or new deficits occurring several weeks after the onset of the acute illness. In most cases, WNV is thought to be cleared by an effective immune response after only several days of viremia. Accordingly, this relatively delayed progression of symptoms is more likely to reflect secondary injury from the downstream cascade of excitotoxic events and a secondary wave of inflammation.
In cases where the temporal course suggests that indirect immune-mediated mechanisms may be contributing to neuronal injury, a trial of high-dose corticosteroids seems justified. There also has been great interest in passive immunization with intravenous immune globulin IVIG for the treatment of patients with acute WNV infection. Immune serum frequently was used in the pre-antibiotic era to treat infectious diseases, and animal data indicate an important role for humoral immunity in controlling WNV infection Gea-Banacloche et al.
However, the study did not enroll enough cases to permit data analysis in the epidemic season. Nonetheless, neutralizing antibody therapeutics show promise in inhibiting WNV infection and preventing acute flaccid paralysis in vivo Diamond, , which justifies phase I and II studies using humanized or human monoclonal antibodies. Our observations and literature review suggest that patients with WNV infection who have muscle weakness or other neuromuscular signs and symptoms often are given erroneous diagnoses and may receive inappropriate, potentially injurious treatments.
Among patients referred to our rehabilitation center with WNV neuroinvasive disease, initial diagnoses that ultimately proved to be erroneous included evolving stroke, GBS, myopathy, food poisoning, endocarditis, sepsis, heat stroke, malingering, gastroenteritis, drug reaction, spinal cord compression, diabetic amyotrophy, and myocardial infarction.
Diagnostic studies and therapies directed at these erroneous diagnoses are typically ineffective and can produce significant morbidity. Hence, physicians should consider a diagnosis of WNV infection in any patient who presents with a febrile illness that progresses over several days associated with neurological signs or symptoms, especially during the summer months i.
Health care providers also need to be aware that the spectrum of neuromuscular manifestations may range from a poliomyelitis syndrome in the absence of overt fever or meningoencephalitis to subjective weakness and disabling fatigue.
This awareness will help to avoid less tenable diagnoses and inappropriate treatment. The differential diagnoses of WNV infection include other arbovirus encephalitides e. Louis encephalitis virus, Japanese encephalitis virus, Eastern, Western, and Venezuelan equine encephalitis viruses, tick borne encephalitis virus , other viral meningoencephalitides La Crosse virus, Murray Valley virus, coxsackievirus, echovirus, enterovirus , bacterial meningitis or encephalitis including Lyme disease and Leptospirosis , tick paralysis, and non-infectious conditions that affect brain or spinal cord e.
Poliovirus poliomyelitis should also be considered in the differential diagnosis if the patient resides in or travels to a polio-endemic region. However, in only four countries India, Afghanistan, Nigeria, and Pakistan remain polio-endemic see text footnote 1. In addition, poliovirus infection mainly affects infants or young children.
Although anterior horns are the major site of spinal cord pathology, inflammatory changes may also involve muscle fibers, peripheral nerves, spinal roots, and spinal sympathetic neurons and ganglia, contributing to the wide spectrum of neuromuscular manifestations of WNV infection.
Although there is no specific treatment or vaccine approved for human WNV infection, several drugs that can alter the cascade of immunobiochemical events leading to neuronal death may be potentially useful.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U. Front Neurol. Published online Mar Stokic 1.
Arturo Leis. Dobrivoje S. Author information Article notes Copyright and License information Disclaimer. This article was submitted to Frontiers in Neuromuscular Diseases, a specialty of Frontiers in Neurology. Received Oct 13; Accepted Feb This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License , which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
This article has been cited by other articles in PMC. Abstract The most common neuromuscular manifestation of West Nile virus WNV infection is a poliomyelitis syndrome with asymmetric paralysis variably involving one monoparesis to four limbs quadriparesis , with or without brainstem involvement and respiratory failure.
Keywords: West Nile virus, infection, poliomyelitis, fever. Open in a separate window. Figure 1. Figure 2. West Nile Virus Spinal Nerve Root Involvement Inflammatory changes in spinal cord gray matter also may extend into the spinal nerve roots to cause a myeloradiculitis Jeha et al.
West Nile Virus Peripheral Nerve Involvement West Nile virus can involve peripheral nerves although this manifestation is much less frequent than originally assumed during the outbreak, when weakness and acute flaccid paralysis were attributed to GBS or axonal polyneuropathy Nash et al. Neuromuscular Junction and Skeletal Muscle in West Nile Virus Infection West Nile virus has not been reported to cause a defect in neuromuscular transmission, but we have encountered three patients with WNV poliomyelitis who developed classic myasthenia gravis with positive acetylcholine receptor antibodies and a marked decremental response on repetitive nerve stimulation studies initial case reported in Leis and Stokic, West Nile Virus and Autoimmune Disease An unresolved issue that may have important neuromuscular implications is whether WNV infection can induce autoimmune disease Leis and Stokic, West Nile Virus Immunity and Pathogenesis Although postmortem examinations have confirmed WNV poliomyelitis and encephalitis, including patchy infection of neurons in the cerebral cortex, hippocampus, basal ganglia, cerebellum, and brain stem Doron et al.
Differential Diagnosis of Neuroinvasive West Nile Infection Our observations and literature review suggest that patients with WNV infection who have muscle weakness or other neuromuscular signs and symptoms often are given erroneous diagnoses and may receive inappropriate, potentially injurious treatments. Concluding Remarks Although anterior horns are the major site of spinal cord pathology, inflammatory changes may also involve muscle fibers, peripheral nerves, spinal roots, and spinal sympathetic neurons and ganglia, contributing to the wide spectrum of neuromuscular manifestations of WNV infection.
Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References Agrawal A. Human immunoglobulin as a treatment for West Nile virus infection. Guillain-Barre syndrome: an unusual presentation of West Nile virus infection. West Nile virus infection: MR imaging findings in the nervous system. AJNR Am. Unilateral brachial plexopathy associated with West Nile virus meningoencephalitis.
Electrodiagnostic features of acute paralytic poliomyelitis associated with West Nile virus infection. Muscle Nerve 29 , — Persistence of West Nile virus in the central nervous system and periphery of mice. The effects of West Nile virus on major histocompatibility complex class I and II molecule expression by Lewis rat Schwann cells in vitro. Flavivirus induces MHC antigen on human myoblasts: a model of autoimmune myositis?
Muscle Nerve 15 , — Prophylactic and therapeutic efficacy of human intravenous immunoglobulin in treating West Nile virus infection in mice. Bilateral diaphragmatic paralysis and related respiratory complications in a patient with West Nile virus infection. Thorax 59 , — West Nile virus disease: a descriptive study of patients hospitalized in a 4-county region of Colorado in Neuropathology of the brain and spinal cord in human West Nile virus infection.
Meningoencephalitis in a child complicated by myocarditis, quadriparesis and respiratory failure. The neuroanatomy of post-polio fatigue. West Nile virus. Clinical and neuropathological features of West Nile virus equine encephalomyelitis in Italy. Equine Vet. Pathologic and immunohistochemical findings in naturally occuring West Nile virus infection in horses. Acute flaccid paralysis syndrome associated with West Nile virus infection- Mississippi and Louisiana, July-August Viral-induced spinal motor neuron death is non-cell-autonomous and involves glutamate excitotoxicity.
West Nile virus neuroinvasive disease. Progress on the development of therapeutics against West Nile virus. Antiviral Res. Histopathologically proven poliomyelitis with quadriplegia and loss of brainstem function due to West Nile infection. Severe West Nile virus disease in healthy adults. Spinal cord neuropathology in human West Nile virus infection. West Nile virus: pathogenesis and therapeutic options. West nile virus RNA not detected in urine of 40 people tested 6 years after acute West Nile virus disease.
Polio myelitis due to West Nile virus. Clinicopathologic study and laboratory diagnosis of cases with West Nile virus encephalomyelitis. Rhabdomyolysis in a patient with West Nile encephalitis and flaccid paralysis. The role for intravenous immunoglobulin in the treatment of West Nile virus encephalitis. Possible benefit of intravenous immunoglobulin therapy in a lung transplant recipient with West Nile virus encephalitis.
Stiff-person syndrome following West Nile fever. Activation of divergent neuronal cell death pathways in different target cell populations during neuroadapted Sindbis virus infection of mice. Critical illness polyneuropathy.
Basis of neurovirulence in Sindbis virus encephalomyelitis of mice. West Nile virus infection. A new acute paralytic illness. Prognosis of West Nile virus associated acute flaccid paralysis: a case series.
Case Reports 5 , Occlusive vasculitis in a patient with concomitant West Nile virus infection. On July 24, , a low-grade fever, nausea, and vomiting, followed by shaking chills and sweats, developed in a year-old male Louisiana resident with a history of hypertension and coronary artery disease.
The next day, asymmetric weakness developed in the lower extremities, with no pain or numbness. Upper extremities were normal. No bowel or bladder dysfunction was present. The patient was hospitalized on July 29, and neurologic examination showed a flaccid, areflexic right lower extremity and a weak left lower extremity with diminished reflexes.
Results of strength and reflex testing of the upper extremities were normal. Sensory examination results were normal except for a mild decrease in sensitivity to pinprick, temperature, touch, and vibration in a stocking-and-glove distribution i.
A coarse bilateral upper extremity action tremor was noted. The patient had no headache, neck stiffness, or alteration of mental status Table 2. Admission laboratory values showed leukocytosis and CSF pleocytosis Table 3. Results of other diagnostic tests were unremarkable.
Postviral demyelination syndrome and viral-induced polyradicultis were considered, and IVIG , dexamethasone, and antibacterial and antiviral medications were administered without patient improvement. On day 15, the patient was discharged to a skilled nursing facility for rehabilitation. MRI of the cervical, thoracic, and lumbosacral spine obtained during rehabilitation was notable for showing mild cervical and lumbosacral spinal stenosis and foraminal restrictions from C3 through C7 and homogeneous enhancement of the nerve roots of the cauda equina consistent with meningitis.
Electrodiagnostic studies showed denervation in thoracic and lumbosacral myotomes, with no muscle activation in the right leg and reduced muscle activation in the left leg. Electrodiagnostic findings suggested a severe, asymmetric process affecting anterior horn cells or motor axons. Diffuse axonal polyneuropathy was not evident, despite a slight sensory loss in the distal extremities.
On August 2, , fever, headache, and neck stiffness developed in a year-old female Louisiana resident with a history of diabetes and degenerative disc disease; the next day acute weakness occurred in the right arm without pain, numbness, or paresthesias. She was hospitalized on August 4. On admission, physical examination documented fever, vomiting, encephalopathy, nuchal rigidity, and a bilateral rash on the lower extremities. Neurologic examination displayed a flaccid and areflexic right arm.
Her legs and left arm exhibited normal strength, reflexes, and coordination, with normal sensation in all limbs. A coarse tremor was noted in the chin, left arm, and legs Table 2. Laboratory findings included CSF pleocytosis Table 3. Differential diagnoses included meningoencephalitis with associated motor polyradiculopathy and monoplegia secondary to stroke. The patient was treated with antibacterial and antiviral medications.
MRI of the cervical spine showed multilevel degenerative disc disease. The patient remained lethargic until day 13, when mental status abruptly improved; right arm weakness persisted. On day 19, she was transferred to a rehabilitation facility. Electrodiagnostic studies showed absent CMAPs and profound denervation with no voluntary activation in muscles of the right arm.
Scattered denervation was also seen in the other three limbs. SNAPs had borderline amplitudes and conduction velocities bilaterally. The results were most consistent with a severe, asymmetric process affecting anterior horn cells or motor axons. The patient was subsequently transferred back to intensive care because her respiratory function was deteriorating, but she was not intubated. On August 11, , severe nausea, vomiting, headache, and diarrhea in the absence of fever developed in a year-old male Mississippi resident with a history of alcohol abuse; the next day, progressive right arm weakness developed.
He was hospitalized on August Neurologic examination on admission showed flaccid paralysis of the right arm and mild weakness of the right leg, with normal sensation in all limbs Table 2.
Laboratory values are shown in Table 3 ; a lumbar puncture was not performed. Acute stroke was diagnosed, and the patient was treated with heparin. Mental status changes, dysarthria, and dysphagia subsequently developed but resolved. Upon transfer to a rehabilitation center on day 12, the patient had paralysis and areflexia limited to the right arm, with normal sensation and diffuse tremor in all limbs. Electrodiagnostic studies showed markedly reduced motor responses in the right arm with normal sensory responses, consistent with a severe asymmetric process affecting anterior horn cells.
He reported no nuchal rigidity or mental status changes, although family members described him as intermittently confused. Neurologic examination showed a plegic and areflexic right leg and mild left leg weakness; sensation was intact throughout. A bilateral tremor of the upper extremities and jaw was noted Table 2. Laboratory abnormalities included a CSF pleocytosis Table 3. Results of an enhanced MRI of the spine suggested meningitis involving the conus medullaris and cauda equina.
Electrodiagnostic studies performed on day 4 demonstrated early denervation and absent activation in muscles of the right leg and reduced activation of muscles in the right arm. These findings were consistent with a severe, asymmetric process affecting anterior horn cells or motor axons. He was transferred to a rehabilitation facility on day 6 with no improvement of weakness. On September 1, , a previously healthy, year-old male Louisiana resident had onset of fever, headache, and nuchal rigidity followed the next day by dysphagia and bilateral arm and leg weakness that was worse on the left.
He was hospitalized on September 6 for acute respiratory failure and intubated. Neurologic examination showed normal cognition, asymmetric flaccid paralysis of the left arm and leg with absent reflexes, hyporeflexic weakness of the right arm and leg, and weakness of bulbar muscles Table 2.
A partial supranuclear gaze palsy, cogwheel rigidity, and bilateral Babinski signs were also evident. Admission laboratory findings showed peripheral leukocytosis and CSF pleocytosis Table 3.
Brain MRI showed increased T2 signal in the periaqueductal gray matter, substantia nigra, and trigeminal motor nuclei. On day 25, he was transferred to a long-term care facility with no improvement of limb weakness. The clinical and electrodiagnostic findings in these patients with WNV infection suggest involvement of spinal cord gray matter, specifically anterior horn cells, and a resulting acute poliomyelitis-like syndrome. All patients exhibited features typical for polio, including acute flaccid paralysis without paresthesias or sensory loss, marked asymmetric weakness, diminished or absent deep tendon reflexes in the affected limbs, and weakness that developed during an acute infectious process.
Other typical features of poliomyelitis included CSF pleocytosis in five of six patients with CSF examination, acute respiratory distress in four, and acute changes in bowel or bladder function in two. No patients had evidence of demyelinating polyneuropathy or myopathy. The absence of new sensory abnormalities localizes the disease process to the anterior horn cells or motor axons. While MRI signal abnormalities in the anterior spinal cord have been noted in patients with poliomyelitis 16 , 17 , these findings are inconsistent 18 , 19 , and the absence of such changes in our four patients in which imaging was performed does not preclude a diagnosis of a poliomyelitis-like syndrome.
Since immunization has eradicated wild-type poliovirus from the developed world, most cases of paralytic polio-like conditions in the United States have been linked to other RNA viruses, including echoviruses, enteroviruses, and coxsackieviruses Case reports have documented a poliomyelitis-type syndrome associated with other flaviviruses 21 — 23 , as well as anterior myelitis associated with WNV infection The assertion that WNV infection involves anterior horn cells and causes a polio-type syndrome has a pathologic basis.
The neuropathology of experimental WNV infection in monkeys was most pronounced in the cerebellum, medulla, and the cervical and lumbar regions of the spinal cord Anterior horn cells showed degeneration and neuronal cell death; conversely, no changes were seen in the oligodendroglia or peripheral nerves. Similarly, WNV-infected horses displayed multifocal polioencephalomyelitis, with involvement of the ventral and lateral horns of the thoracic and lumbar spinal cord 26 , WNV antigen was mainly localized within the gray matter of the spinal cord, with no lesions apparent in peripheral nerves or ganglia.
In WNV-infected birds, lesions and viral antigen were most prominent in the cerebellum and the gray matter of the spinal cord Three of the seven patients had acute flaccid paralysis without other findings, suggestive of severe central nervous system involvement caused by WNV infection. Physicians should suspect WNV infection in patients from areas where WNV is being transmitted and who have acute, painless, asymmetric weakness, even if unaccompanied by fever or apparent meningoencephalitis.
These therapies are ineffective for polio-like syndromes and can produce serious sequelae 34 — Continued surveillance and investigation of WNV-infected patients are needed to fully define the scope of clinical illness and determine the incidence of acute flaccid paralysis.
We reviewed data on 13 patients with WNV infection. Patients with muscle weakness were classified into one of three distinct groups based on clinical features.
Group 1 comprised five patients who developed acute flaccid paralysis, four with meningoencephalitis and one without fever or other signs of infection. Paralysis was asymmetric, and involved from one to four limbs in individual patients.
Electrodiagnostic studies confirmed involvement of anterior horn cells or motor axons.
0コメント