The Bay Area Reporter - March 4, 1996
Rob Sabados, ACT UP/Golden Gate Writers Pool

PML derives its name from the fact that it worsens (progressive), that it occurs simultaneously in multiple locations near blood vessels (multifocal), and that it attacks the white matter (leuko) of the brain (encephalopathy). Common symptoms include weakness, seizures, difficulty with speech and coordination, and changes in behavior and awareness. While PML is generally fatal, about ten percent of patients with PML, usually those with CD4 counts over 200, stabilize or improve. A 1995 Canadian study found an average survival time of 9.4 months for those with greater than 90 CD4 count and 3.6 months for those with less.

Researchers believe that PML is caused by the JC virus (JCV). JCV belongs to a family of pathogenic viruses called papova viruses. This family includes other pathogenic viruses such as human papilloma virus (HPV), which causes warts and has been linked to anal and cervical cancer. Multiple studies have determined that 70-90 percent of healthy adults, regardless of location or risk category, are infected with JCV. Despite this, PML occurs more frequently in women than men.

According to the Centers for Disease Control and Prevention (CDC), PML went from being the cause of death for 0.8 percent of PWAs in 1988 to 1.9 percent in 1992. PML also affects other people who are immunocompromised, such as organ recipients and people with cancer, particularly leukemia. The true incidence of PML is unknown, since people with PML are often misdiagnosed with and treated for more common opportunistic infections such as toxoplasmosis and cryptococcal meningitis. To further complicate the picture, many of the first "PML" cases were successfully treated with antibiotics, such as Bactrim (Septra, TMP/SMX), sulfadiazine, or pyrimethamine, suggesting that other opportunistic infections were responsible for the symptoms. Similarly, other viruses such as HIV and CMV can cause PML-like symptoms that respond to antiviral drugs, such as acyclovir. PML can also occur at the same time as other OIs, further complicating the diagnosis, as a definitive diagnosis of toxoplasmosis, for example, will discourage physicians from testing for PML, and vice versa.

They Can Find ...

Currently, the diagnosis of PML is made based upon brain biopsy and radiological findings. During a brain biopsy, a neurosurgeon removes a small piece of brain tissue so that it can be stained and examined under a microscope. Unfortunately, as many as 60 percent of brain biopsies yield inconclusive results, due to technical factors and the possibility that the small fraction of tissue removed doesn't contain the source of the problem. Understandably, both patients and physicians are often reluctant to utilize this highly invasive procedure. Still, studies such as ACTG 243, discussed below, require that patients undergo this procedure to confirm the diagnosis.

An alternative method of diagnosis is the use of magnetic resonance imaging (MRI) and computed tomography (CT) scanning. Of these two technologies, MRI seems to be the more effective, and can often be used differentiate between PML, multiple sclerosis, toxoplasmosis, and lymphoma. And these tests can be inconclusive, especially in people with a history of neurological problems or other OIs, requiring the patient to undergo a brain biopsy.

... With A New Test ...

When evaluating a patient's neurological problem, physicians generally order a spinal tap (lumbar puncture) to obtain cerebro-spinal fluid (CSF). While CSF cultures and microscopic examination can help rule out certain infections, they cannot detect PML.

Using the same PCR technology used to measure HIV viral load, researchers have been able to diagnose PML by measuring JCV levels in CSF collected as part of routine evaluations. Overcoming the problems with sensitivity that plagued early PCR tests, researchers, including Dr. Dawn McGuire at UCSF were able to accurately diagnose 92 percent of patients with PML, including 100 percent of those whose diagnosis was confirmed by biopsy. When CSF samples from patients who did not have PML were analyzed, the test was correct on 92 percent of samples. Those patients testing false-positive for PML all had risk factors such as HIV, chronic leukemia, or neurological deficits, and may be at risk for future PML.

Although it is not currently licensed, physicians have reported using this test for patients with symptoms suggestive of PML for whom a definitive diagnosis could not be made.

As spinal taps are decidedly unpleasant, and can cause complications such as severe headaches, researchers are continuing to look for alternatives. A new test, presented at the Third Conference on Human Retroviruses and Opportunistic Infections in January 1996, uses blood instead of CSF. Using this test, researchers found JC virus can, at times, be found at high levels in the blood. While JCV levels were higher in people with advanced HIV infection, JCV levels were independent of CD4 count. If PML is caused by reactivated virus being carried to the brain by blood, and not by JCV reactivating in the brain, JC virus screening may become as routine as CBCs and CD4 counts.

... But They Can't Treat

At present, the only treatments available or even being widely studied are high-dose AZT (zidovudine, Retrovir) and Ara-C (Cytosine arabnoside, cytarabine). The role and efficacy of these two drugs is unclear, as numerous small studies have yielded conflicting results. In San Francisco, the one and only PML-related clinical trial compares patients taking an antiretroviral to patients taking an antiretroviral and receiving Ara-C either intravenously or intrathecally. The intrathecal injection group has a small pump surgically attached to the base of base of the skull so that the Ara-C can be injected directly into the brain. This study, ACTG 243, excludes anyone who has used an antiretroviral other than AZT, ddI, or ddC.

As with many OIs for which no effective treatment exists, much of the literature consists of "medicine by anecdote." Many people with PML have claimed that drugs such as acyclovir, n-acetyl cysteine (NAC), peptide T; immune-system stimulators such as alpha interferon and beta interferon; and immunosuppressants such as dextramethasone and prednisone were able to improve their condition. Unfortunately, there have been no systematic studies of these agents.

Several neglected drugs may have efficacy in treating PML. For example, topotecan, owned by SmithKline Beecham, has shown in vitro efficacy against JCV. In response to pressure from ACT UP/New York and New York's PWA Health Group, topotecan's role as a chemotherapy and anti-viral drug is being explored. According to the New-York based PWA Health Group, Pharmacia & Upjohn has studied two related drugs, CPT-11 and SN-38, and made them available on a compassionate use basis. t

For more information about these drugs, including importing them for personal use, call PWA Health Group at (212)255-0520; ask for Notes from the Underground #29. For more information about topotecan, contact SmithKline Beecham's Sharyn Arnold at (215)741-7074 (voice) or (215)751-7655 (fax). Pharmacia & Upjohn, based in Kalamazoo MI, can be reached at (616)323-4000.

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