Correspondence

Spinal Cord Disease in West Nile Virus Infection

N Engl J Med 2003; 348:564-566February 6, 2003

Article

To the Editor:

Recent letters to the Journal from Leis et al.1 and Glass et al.2 (Oct. 17 issue) as well as reports by others3 have described a poliomyelitis-like syndrome occurring in patients with West Nile virus infection. In these patients, acute flaccid paralysis developed that was suggestive of involvement of anterior horn cells of the spinal cord, but the histopathology of the spinal cord was not described.

We report the histopathological findings from the spinal cord of an 81-year-old man with West Nile virus infection (positive serologic tests for IgM) who presented with a four-day history of fever accompanied by nausea, vomiting, and ataxia. Analysis of the cerebrospinal fluid showed a white-cell count of 1444 per cubic millimeter, with 85 percent neutrophils. Acute flaccid paralysis developed, and the patient died 11 days after presentation. Magnetic resonance imaging showed marked abnormal enhancement of the cauda equina.

At autopsy, mild cerebral edema was present, with evidence of meningoencephalitis. There was variable involvement of the spinal cord, with the lumbar cord being most affected. There was focal loss of anterior-horn neurons, accompanied by gliosis, occasional macrophages (CD68-positive), neuronophagia, and perivascular lymphocytes (Figure 1Figure 1Lumbar Spinal Cord Specimen from a Man with a Poliomyelitis-like Syndrome Associated with West Nile Virus.). Most of the lymphocytes were CD3-positive T cells, with a slight predominance of CD8 over CD4 cells. Elsewhere in the spinal cord parenchyma, there were focal microglial nodules and chronic perivascular inflammation with focal leptomeningitis. There was mild infiltration of anterior lumbar nerve roots by lymphocytes. The histopathological findings corroborate the clinical impression of involvement of the anterior horn cells of the spinal cord in poliomyelitis-like syndrome associated with West Nile virus.

Todd W. Kelley, M.D.
Richard A. Prayson, M.D.
Carlos M. Isada, M.D.
Cleveland Clinic Foundation, Cleveland, OH 44195

3 References

1. 1

   Leis AA, Stokic DS, Polk JL, Dostrow V, Winkelmann M. A poliomyelitis-like syndrome from West Nile virus infection. N Engl J Med 2002;347:1279-1280
   Full Text | Web of Science | Medline

2. 2

   Glass JD, Samuels O, Rich MM. Poliomyelitis due to West Nile virus. N Engl J Med 2002;347:1280-1281
   Full Text | Web of Science | Medline

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   Ahmed S, Libman R, Wesson K, Ahmed F, Einberg K. Guillain-Barré syndrome: an unusual presentation of West Nile virus infection. Neurology 2000;55:144-146
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To the Editor:

Leis et al. describe a disease due to West Nile virus infection as “poliomyelitis-like,” whereas Glass et al. describe it as “poliomyelitis.” It should be named “West Nile virus myelitis.” When the disease of the anterior horn of the spinal cord was discovered in patients with “infantile paralysis,” it was named “poliomyelitis” (from polios, meaning gray, and myelos, meaning marrow).1 But once its cause was named “poliovirus,” the term “poliomyelitis” took on the meaning of disease caused by poliovirus.1

Contrary to the statement of Glass et al., other flaviviruses do cause myelitis.2 Murray Valley encephalitis virus disease was once confused with poliomyelitis because of clinical similarities.2 Japanese encephalitis virus myelitis mimicking poliomyelitis, with anterior-horn disease confirmed by electrophysiological analysis, has been reported in Vietnam.2 Anterior-horn damage had been detected by histopathological analysis in patients with Japanese encephalitis virus disease.2 Other flavivirus diseases such as St. Louis encephalitis virus disease, Rocio virus infection, and tick-borne encephalitis, Powassan virus infection, and louping ill virus are also reported to cause spinal cord disease and muscle paralysis.2

Antibodies to poliovirus are seldom found, or are found in very low titers, in the cerebrospinal fluid,3 but antibody to West Nile virus was found in a high titer in the case reported by Glass et al., and deep-tendon reflexes were described as preserved. Tendon reflexes are lost in poliomyelitis and Japanese encephalitis virus myelitis and were lost in the three cases reported by Leis et al. In myelitis due to enterovirus type 70 and Japanese encephalitis virus, high cerebrospinal fluid antibody titers are also common.2,3 Thus, there must be differences in the site and nature of the disease, with local production of antibody in the central nervous system or loss of reflexes in most but not all types of viral myelitis.

T. Jacob John, F.R.C.P., Ph.D.
439 Civil Supplies Godown Ln., Kamalakshipuram, Vellore, 632 002, India
vlr_tjjohn@sancharnet.in

3 References

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   Sutter RW, Cochi SL, Melnick JL. Live attenuated poliovirus vaccines. In: Plotkin SA, Orenstein WA, eds. Vaccines. 3rd ed. Philadelphia: W.B. Saunders, 1999:364-408.
   

2. 2

   John TJ, Walker DH. Enterovirus infections, including poliomyelitis. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens & practice. Vol. 2. Philadelphia: Churchill Livingstone, 1999:1123-32.
   

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   Solomon T, Kneen R, Dung NM, et al. Poliomyelitis-like illness due to Japanese encephalitis virus. Lancet 1998;351:1094-1097
   CrossRef | Web of Science | Medline

Author/Editor Response

We applaud Kelley and colleagues for providing pathological confirmation of anterior-horn-cell involvement in West Nile virus infection in humans. In August and September 2002, we also conducted postmortem examinations in three patients with West Nile virus infection. Their clinical presentations included fever, chills, muscle weakness, and acute respiratory distress requiring mechanical ventilation. At autopsy, poliomyelitis (inflammation of the spinal cord gray matter) was the principal central nervous system finding in each case.1 The lesions varied from patchy gliosis and loss of neurons in the ventral gray matter to extensive perivascular cuffs of chronic inflammatory cells. The magnitude of the inflammatory infiltrate was most evident with the CD68 preparation, which stained histiocytes and microglial cells. Inflammatory cells were also clustered around dying anterior horn cells. The pathologic process is characteristic of viral infection involving neurons in the gray matter. Although different viruses, including other flaviviruses, can produce the same histopathological change, the pathological findings identify acute poliomyelitis as a cause of the muscle weakness and acute flaccid paralysis that is commonly seen2,3 in patients with West Nile virus infection.

The letter by John reflects a common belief that the term “poliomyelitis” refers exclusively to disease caused by poliovirus. However, the clinical syndrome of anterior poliomyelitis caused by many viruses is indistinguishable from that caused by poliovirus.4 Because the electrophysiological, spinal fluid, and histopathological findings may also be identical, the diseases must be differentiated on the basis of serologic studies or isolation of virus. It therefore becomes problematic to describe nearly identical syndromes that differ only in viral cause with the use of terms other than “poliomyelitis.” From a pathological perspective, it is particularly appropriate to describe inflammation (itis) of the spinal cord (myelos) gray matter (polios) as “poliomyelitis.” Accordingly, we now favor the term “West Nile poliomyelitis” rather than the term “West Nile virus myelitis” proposed by John, because it more accurately reflects the major clinical and pathological involvement of the spinal cord gray matter.

The preserved deep-tendon reflexes in the case reported by Glass and colleagues also perplexed us, since normal reflexes are not expected in the setting of profound muscle weakness due to lower-motor-neuron involvement. However, we cannot conclude that this finding reflects differences in the site and nature of the West Nile virus disease, as suggested by John. The cumulative clinical and electrophysiological data in this case still favor poliomyelitis as the cause of the patient's symptoms.

A. Arturo Leis, M.D.
Dobrivoje S. Stokic, M.D.
Methodist Rehabilitation Center, Jackson, MS 39216
dstokic@mmrcrehab.org

Jonathan Fratkin, M.D.
University of Mississippi Medical Center, Jackson, MS 39216

4 References

1. 1

   Leis AA, Fratkin J, Stokic DS, Harrington T, Webb RM, Slavinski SA. West Nile poliomyelitis. Lancet Infect Dis 2003;3:9-10
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2. 2

   Petersen LR, Marfin AA. West Nile virus: a primer for the clinician. Ann Intern Med 2002;137:173-179
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   Acute flaccid paralysis syndrome associated with West Nile virus infection -- Mississippi and Louisiana, July-August 2002. MMWR Morb Mortal Wkly Rep 2002;51:825-828
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   Noncompressive myelopathies. In: Byrne TN, Benzel EC, Waxman SG. Diseases of the spine and spinal cord. Oxford, England: Oxford University Press, 2000:266-313.
   

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   Natalie A. Prow, David N. Irani. (2007) The opioid receptor antagonist, naloxone, protects spinal motor neurons in a murine model of alphavirus encephalomyelitis. Experimental Neurology 205:2, 461-470
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   David N. Irani, Natalie A. Prow. (2007) Neuroprotective Interventions Targeting Detrimental Host Immune Responses Protect Mice From Fatal Alphavirus Encephalitis. Journal of Neuropathology and Experimental Neurology 66:6, 533-544
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   Lara E. Jeha, Gregory P. Hanes, Cathy A. Sila, Richard J. Lederman, Carlos M. Isada, Steven M. Gordon. (2005) Long-term Outcome of Patients With West Nile Virus Infection. Infectious Diseases in Clinical Practice 13:3, 101-103
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   N. K. Watson, R. E. Bartt, S. A. Houff, S. E. Leurgans, M. J. Schneck. (2005) Focal Neurological Deficits and West Nile Virus Infection. Clinical Infectious Diseases 40:7, e59-e62
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   A. Arturo Leis, Dobrivoje S. Stokic. (2005) Neuromuscular manifestations of human West Nile virus infection. Current Treatment Options in Neurology 7:1, 15-22
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   Christina Marciniak, Susan Sorosky, Christina Hynes. (2004) Acute flaccid paralysis associated with West Nile virus: Motor and functional improvement in 4 patients. Archives of Physical Medicine and Rehabilitation 85:12, 1933-1938
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   David B. Arciniegas, C. Alan Anderson. (2004) Viral encephalitis: Neuropsychiatric and neurobehavioral aspects. Current Psychiatry Reports 6:5, 372-379
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   Solomon, Tom, . (2004) Flavivirus Encephalitis. New England Journal of Medicine 351:4, 370-378
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    John D England, Arthur K Asbury. (2004) Peripheral neuropathy. The Lancet 363:9427, 2151-2161
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    Amer Al-Shekhlee, Bashar Katirji. (2004) Electrodiagnostic features of acute paralytic poliomyelitis associated with West Nile virus infection. Muscle & Nerve 29:3, 376-380
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    Tom Solomon, Hugh Willison. (2003) Infectious causes of acute flaccid paralysis. Current Opinion in Infectious Diseases 16:5, 375-381
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    Bennet I. Omalu, Abdulrazek A. Shakir, Guoji Wang, W. Ian Lipkin, Clayton A. Wiley. (2003) Fatal Fulminant Pan-Meningo-Polioencephalitis Due to West Nile Virus. Brain Pathology 13:4, 465-472
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    K. L. Roos. (2003) Fever and Asymmetrical Weakness in the Summer: Evidence of a West Nile Virus-Associated Poliomyelitis-Like Illness. Mayo Clinic Proceedings 78:10, 1205-1206
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    M. L. Flaherty, E. F. M. Wijdicks, J. C. Stevens, J. R. Daube, E. C. Chenworth, E. F. Helou, M. R. Sohail. (2003) Clinical and Electrophysiologic Patterns of Flaccid Paralysis Due to West Nile Virus. Mayo Clinic Proceedings 78:10, 1245-1248
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    A. Arturo Leis, Dobrivoje S. Stokic, Risa M. Webb, Sally A. Slavinski, Jonathan Fratkin. (2003) Clinical spectrum of muscle weakness in human West Nile virus infection. Muscle & Nerve 28:3, 302-308
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    S. I. Doron, J. F. Dashe, L. S. Adelman, W. F. Brown, B. G. Werner, S. Hadley. (2003) Histopathologically Proven Poliomyelitis with Quadriplegia and Loss of Brainstem Function Due to West Nile Virus Infection. Clinical Infectious Diseases 37:5, e74-e77
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    Richard T. Johnson, David R. Cornblath. (2003) Poliomyelitis and flaviviruses. Annals of Neurology 53:6, 691-692
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