BALTIMORE — Surveillance programs for progressive multifocal leukoencephalopathy have many hurdles to clear before any become a reality in federal agencies or state health departments, despite concern over new cases that are associated with the use of monoclonal antibody therapies.

Dr. James J. Sejvar of the Centers for Disease Control and Prevention said that in addition to a lack of funding, attempts to conduct surveillance for progressive multifocal leukoencephalopathy (PML) are hampered by a lack of clear diagnostic criteria, a definition for a confirmed case, and case validation methods.

Dr. Sejvar, a neurologist and epidemiologist with the division of viral and rickettsial diseases at the CDC's National Center for Zoonotic, Vector-Borne, and Enteric Disease, described potential benefits and limitations of various approaches to PML surveillance at the annual meeting of the American Neurological Association.

Reports thus far have estimated that PML occurs in 1 of every 1,000 patients exposed to natalizumab (Tysabri), 1 of every 500 exposed to efalizumab (which has been taken off the U.S. market), and at an unknown, but probably lower, rate in patients exposed to rituximab (Rituxan).

National surveillance for PML could be conducted by making it a nationally notifiable infectious disease, establishing a national registry, or by gathering information from physicians, states, or laboratories.

A mechanism for surveillance still would need to have the capacity to determine a case definition of PML, which samples of patient data should be analyzed, the level of diagnostic certainty necessary for prompt reporting/confirming of cases, who should analyze patients' samples and data, and how it would be funded, Dr. Sejvar said.

NNIDs Designation

The CDC could add PML to the list of nationally notifiable infectious diseases (NNIDs), which are normally restricted to diseases with significant risk to public health. Although a rough infrastructure is already in place to add PML, and the condition would gain greater attention from physicians if it were added to the list, Dr. Sejvar said that “making it reportable doesn't mean it will be reported.”

Diagnosing PML is difficult in part because of inaccurate reporting of cases, which points to the need for methods for validating cases. PML is probably also underascertained in clinics, he said, noting that no simple laboratory test for it is available.

Dr. Sejvar said state governments are unlikely to view PML as a public health imperative that is worthy of the investments that would have to be made to conduct surveillance.

National Registry for PML

Another option would be for PML to be tracked in a national registry by the Agency for Toxic Substances and Diseases Registry (ATSDR). The congressionally mandated national amyotrophic lateral sclerosis registry that was recently developed with the ATSDR could serve as a template, Dr. Sejvar said.

“This would provide for an infrastructure to start to get a handle on PML and also allow for the collection of detailed clinical information.”

The registry would rely on self-reports by patients and entries from physicians, and would need funding and endorsement from various stakeholders, he said. Congress would have to be actively lobbied for a national PML registry.

Active, Physician-Based Surveillance

Surveillance for PML under the CDC's Emerging Infections Program, a network formed by the CDC and 10 state health departments covering 44 million people, would provide a relatively accurate estimation of incidence and prevalence. The EIP contains sites with many tertiary neurologic care institutes where patients with PML would be best diagnosed, Dr. Sejvar noted.

The proactive outreach approach of the EIP would provide direct contact with the neurologic community, but it is limited by the resources of its partners. Adding PML surveillance would require endorsement by principal investigators at all EIP sites, who are unlikely to view PML as important enough to add.

State-Based Surveillance

State-based surveillance by the CDC or ATSDR, performed in cooperation with the Council of State and Territorial Epidemiologists (CSTE), “may be one of the best options,” Dr. Sejvar said.

The CSTE is already involved in surveillance for Creutzfeldt-Jakob disease, another rare neurologic disorder that is difficult to diagnose. If PML surveillance was performed with CSTE, state surveillance officers would identify and report cases to the CDC. The CSTE would need to receive a proposal to add PML to its surveillance list and then endorse it.

There is also potential for collaborating with the National Prion Disease Pathology Surveillance Center to confirm cases pathologically, Dr. Sejvar said.

Laboratory-Based Surveillance

A system of laboratory-based surveillance is already used for other infectious diseases, particularly ones that can be readily identified in the lab and then reported to state health departments and the CDC. If a lab-based system was assembled, investigators could collect data rapidly from the relatively few labs that perform JC virus polymerase chain reaction assays, requiring minimal resources, Dr. Sejvar said.

However, lab-based surveillance would produce many false-negative results. Clinical data, which would be hard to obtain, would be necessary to interpret the lab data.

Potential Methods for PML Surveillance Programs Outlined