HIV-Associated Vacuolar Myelopathy

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Overview

Vacuolar myelopathy is the most common chronic myelopathy associated with HIV infection. HIV-associated vacuolar myelopathy occurs during the late stages of HIV infection, when CD4+ lymphocyte counts are very low, often in conjunction with AIDS dementia complex, peripheral neuropathies, and opportunistic infections or malignancies of the central or peripheral nervous system (eg, cytomegalovirus, progressive multifocal leukoencephalopathy, lymphoma).

For patient education information, see the Immune System Center, Dementia Center, and Sexually Transmitted Diseases Center, as well as Dementia Due to HIV Infection and HIV/AIDS.

Pathophysiology

Several hypotheses have been proposed to explain the development of this common complication of HIV-1 infection. One hypothesis is infiltration by HIV-infected mononuclear cells that secrete neurotoxic factors, including cytokines, possibly in conjunction with neurotoxic astrocyte factors. A significant amount of scientific support exists for this paradigm. Transgenic mice that express HIV gene products in oligodendrocytes develop clinical and histologic features that resemble the human disease.

Although direct HIV infection of astrocytes and neurons is reported in the brain and dorsal root ganglia, it is not a major feature in vacuolar myelopathy.

The impaired ability to utilize vitamin B-12 as a source of methionine in transmethylation metabolism for myelin maintenance in the spinal cord may be a contributing factor.

Epidemiology and Prognosis

Before the introduction of highly active antiretroviral therapy (HAART), vacuolar myelopathy was seen in 5-20% of adult HIV patients in clinical studies and in 25-55% of adult HIV patients in histologic studies. Since the introduction of HAART, it is estimated that fewer than 10% of AIDS patients develop HIV myelopathy.

The prognosis in HIV patients with vacuolar myelopathy is poor. Most patients die within 6 months of developing symptoms.

Clinical Presentation

Vacuolar myelopathy typically presents as a slow progression of painless leg weakness, stiffness, sensory loss, imbalance, and sphincter dysfunction. Relapsing-remitting courses have also been described.[1]

Back pain is not a prominent feature. Arm function is usually normal except for advanced vacuolar myelopathy.

Vacuolar myelopathy is often associated with AIDS dementia complex and peripheral neuropathy. In such cases, patients have cognitive decline and distal limb pain and numbness.

Physical examination

The following may be noted on physical examination:

A discrete sensory level is usually absent; if present, this strongly suggests other causes of myelopathy.

Diagnostic Considerations

The differential diagnosis includes neurosyphilis. Other problems to be considered in the differential diagnosis of HIV-related vacuolar myelopathy include the following:

Diagnostic Tests

Electrophysiologic tests can confirm a clinical diagnosis of vacuolar myelopathy. Somatosensory evoked potential (SSEP) may be a valuable tool in the diagnosis of AIDS-associated myelopathy, particularly when myelopathy and peripheral neuropathy coexist.[2]

Other studies are used to identify or rule out other potential causes of myelopathy. CSF analysis can exclude infection with cytomegalovirus, varicella-zoster virus, herpes simplex virus, HTLV-1, and HTLV-2. CSF results are usually normal in HIV-1–associated vacuolar myelopathy.

Serum studies can determine vitamin B-12 and folic acid levels. In patients with borderline low B-12 levels, elevated homocysteine and methylmalonic acid levels are better indicators of a deficiency. B-12 levels are usually normal in vacuolar myelopathy.

A Schilling test, hematologic studies, and CD4+ lymphocyte counts may be indicated.

CT scan results are often noncontributory but may reveal unsuspected coexisting conditions such as extramedullary or intramedullary infections, neoplasms, degenerative disk disease, or degenerative joint disease of the spine.

Magnetic Resonance Imaging

MRI scans are often noncontributory but may reveal unsuspected coexisting conditions such as extramedullary or intramedullary infections, neoplasms, degenerative disk disease, or degenerative joint disease of the spine.

Spinal cord atrophy is the most common abnormal finding involving the thoracic cord with or without cervical cord involvement. T2-weighted MRI often shows symmetric nonenhancing high-signal areas, which are present on multiple contiguous slices and are usually symmetrical; these may result from extensive vacuolation.[3, 4, 5] Lesions may be confined to the posterior columns, especially the gracile tracts, or may be diffuse. (See the images below.)


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High-intensity lesion in the C2-C5 posterior spinal cord on T2-weighted sagittal MRI consistent with HIV myelopathy.


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High-intensity lesion in the posterior cervical cord on T2-weighted axial MRI consistent with HIV myelopathy.

Histologic Findings

Histologic findings may indicate multifocal, occasionally asymmetric vacuolation and myelin pallor involving the dorsal and lateral tracts more than the anterior and anterolateral tracts and involving the cervical and thoracic segments more than the lumbar segments or the brainstem, accompanied by astrogliosis. (See the images below.)


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Spinal cord from patient with vacuolar myelopathy that shows extensive spongiform changes in the white matter (Luxol fast blue stain) (contributed by ....


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Marked vacuolation is apparent in this Luxol fast blue stained photomicrograph (contributed by Dr. Beth Levy, Saint Louis University School of Medicin....

HIV-infected, activated, lipid-laden macrophages and microglia expressing interleukin-1 and/or tumor necrosis factor-alpha may be seen.[6, 7] On electron microscopy, intramyelinic or periaxonal vacuoles and, rarely, disrupted axons may be seen.

The histology resembles subacute combined degeneration from vitamin B-12 deficiency.[8]

Treatment & Management

Care for patients with HIV-associated vacuolar myelopathy is primarily supportive. Although no specific treatment is currently approved for this syndrome, viral control tailored to the individual patient's medical and viral history is important, as case reports showing clinical and radiologic improvement with highly active retroviral therapy (HAART) have been described.[9, 10, 11, 2]

A pilot study showed improvement in patients treated with L-methionine.[12] However, a randomized, double-blind, placebo-controlled study of 56 patients found that L-methionine was of no benefit.[13]

Refer the patient to a physical medicine specialist for spinal cord treatment and follow-up care.

Author

Niranjan N Singh, MD, DM, Associate Professor of Neurology, University of Missouri-Columbia School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Florian P Thomas, MD, MA, PhD, Drmed, Director, Regional MS Center of Excellence, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Ronald A Greenfield, MD, Professor, Department of Internal Medicine, University of Oklahoma College of Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Director of Neurology Clinic, St Louis ConnectCare; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Disclosure: Amgen Grant/research funds None

Chief Editor

Karen L Roos, MD, John and Nancy Nelson Professor of Neurology, Professor of Neurological Surgery, Department of Neurology, Indiana University School of Medicine

Disclosure: Nothing to disclose.

References

  1. Anneken K, Fischera M, Evers S. Recurrent vacuolar myelopathy in HIV infection. J Infect. Jun 2006;52(6):e181-3. [View Abstract]
  2. Tagliati M, Di Rocco A, Danisi F, Simpson DM. The role of somatosensory evoked potentials in the diagnosis of AIDS-associated myelopathy. Neurology. Apr 11 2000;54(7):1477-82. [View Abstract]
  3. Chong J, Di Rocco A, Tagliati M, et al. MR findings in AIDS-associated myelopathy. AJNR Am J Neuroradiol. Sep 1999;20(8):1412-6. [View Abstract]
  4. Santosh CG, Bell JE, Best JJ. Spinal tract pathology in AIDS: postmortem MRI correlation with neuropathology. Neuroradiology. Feb 1995;37(2):134-8. [View Abstract]
  5. Sartoretti-Schefer S, Blattler T, Wichmann W. Spinal MRI in vacuolar myelopathy, and correlation with histopathological findings. Neuroradiology. Dec 1997;39(12):865-9. [View Abstract]
  6. Eilbott DJ, Peress N, Burger H, et al. Human immunodeficiency virus type 1 in spinal cords of acquired immunodeficiency syndrome patients with myelopathy: expression and replication in macrophages. Proc Natl Acad Sci U S A. May 1989;86(9):3337-41. [View Abstract]
  7. Tyor WR, Glass JD, Baumrind N, et al. Cytokine expression of macrophages in HIV-1-associated vacuolar myelopathy. Neurology. May 1993;43(5):1002-9. [View Abstract]
  8. Petito CK, Navia BA, Cho ES, et al. Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N Engl J Med. Apr 4 1985;312(14):874-9. [View Abstract]
  9. Bizaare M, Dawood H, Moodley A. Vacuolar myelopathy: a case report of functional, clinical, and radiological improvement after highly active antiretroviral therapy. Int J Infect Dis. Jul 2008;12(4):442-4. [View Abstract]
  10. DiRocco A. HIV-associated myelopathy. Current Treatment Options in Infectious Diseases. Vol 5. 2003:457-465.
  11. Fernandez-Fernandez FJ, de la Fuente-Aguado J, Ocampo-Hermida A. Remission of HIV-associated myelopathy after highly active antiretroviraltherapy. J Postgrad Med. 2004;50(3):195-6. [View Abstract]
  12. Di Rocco A, Tagliati M, Danisi F, et al. A pilot study of L-methionine for the treatment of AIDS-associated myelopathy. Neurology. Jul 1998;51(1):266-8. [View Abstract]
  13. Di Rocco A, Werner P, Bottiglieri T, et al. Treatment of AIDS-associated myelopathy with L-methionine: a placebo-controlled study. Neurology. Oct 12 2004;63(7):1270-5. [View Abstract]
  14. Staudinger R, Henry K. Remission of HIV myelopathy after highly active antiretroviral therapy. Neurology. Jan 11 2000;54(1):267-8. [View Abstract]

High-intensity lesion in the C2-C5 posterior spinal cord on T2-weighted sagittal MRI consistent with HIV myelopathy.

High-intensity lesion in the posterior cervical cord on T2-weighted axial MRI consistent with HIV myelopathy.

Spinal cord from patient with vacuolar myelopathy that shows extensive spongiform changes in the white matter (Luxol fast blue stain) (contributed by Dr. Beth Levy, Saint Louis University School of Medicine, St. Louis, MO).

Marked vacuolation is apparent in this Luxol fast blue stained photomicrograph (contributed by Dr. Beth Levy, Saint Louis University School of Medicine, St. Louis, MO).

Spinal cord from patient with vacuolar myelopathy that shows extensive spongiform changes in the white matter (Luxol fast blue stain) (contributed by Dr. Beth Levy, Saint Louis University School of Medicine, St. Louis, MO).

Marked vacuolation is apparent in this Luxol fast blue stained photomicrograph (contributed by Dr. Beth Levy, Saint Louis University School of Medicine, St. Louis, MO).

High-intensity lesion in the C2-C5 posterior spinal cord on T2-weighted sagittal MRI consistent with HIV myelopathy.

High-intensity lesion in the posterior cervical cord on T2-weighted axial MRI consistent with HIV myelopathy.