Waksman’s original suggestion (quoted by Richardson) that PML could be caused by viral infection of the CNS in patients with impaired immunologic responses proved to be correct. ZuRhein and Chou, in an electron microscopic study of cerebral lesions from a patient with PML later demonstrated crystalline arrays of particles resembling papovaviruses in the inclusion-bearing oligodendrocytes. The characteristic feature is enlargement of oligodendrocytes, some bizarrely shaped, with intranuclear inclusions. Since then a human polyomavirus, designated “JC virus” (initials of the patient, John Cunningham, who had Hodgkin disease, and from whom the virus was originally isolated), or JCV, has been shown to be the causative agent. JCV is ubiquitous, as judged by the presence of antibodies to the virus in approximately 70 percent of the normal adult population. It is thought to be dormant in the kidney or bone marrow until an immunosuppressed state permits its active replication. The virus has been isolated from the urine, blood lymphocytes, bone marrow, and kidney, but there is no clinical evidence of damage to extraneural structures except for rare instances of nephropathy. The surface receptor that facilitates viral entry into oligodendrocytes has been characterized.
The circumstance of PML in the context of immune treatment of multiple sclerosis has evinced great interest and is discussed in Chap. 35.
Anecdotal reports of the efficacy of various medications such as cytosine arabinoside, cidofovir, mirtazapine, interferon, and topotecan, either have not been tested in, or have failed to be sustained in larger trials. In HIV patients, aggressive treatment using antiretroviral drug combinations, including protease inhibitors, slows the progression of PML and has led to remission in almost half of cases, as in the large series reported by Antinori and colleagues. Several series found that the disease occurs with a CD4 count below 200 cells/μL, most often with counts below 50/μL and a higher count makes the diagnosis of PML unlikely, although up to 10 percent of patients have higher values. A review of this subject, particularly relating to HIV and PML, is in the article by Berger and colleagues. Although titled as if a guideline, it contains extensive authoritative current material.
Immune reconstitution inflammatory syndrome (IRIS) A special comment should be made regarding the transient but sometimes severe clinical worsening of PML that may occur during the initial treatment of HIV infection with antiretroviral drugs. This syndrome has been attributed to the emergence of acute inflammation surrounding the demyelinating lesions as a result of reconstitution of the immune system (immune reconstitution inflammatory syndrome or IRIS that has been mentioned in the section on the treatment of HIV). In support of this mechanism, there is a parallel blossoming of the lesions with gadolinium enhancement on MRI. Treatment with corticosteroids has been suggested and is said to allow survival and temporary remission of PML, although we have seen at least one dramatic exception. Judicious use of corticosteroids is implemented to mute this reaction.
This disease was first described by Dawson in 1934 under the name “inclusion body encephalitis” and extensively studied by Van Bogaert, who renamed it subacute sclerosing panencephalitis. It is now recognized to be the result of chronic measles virus infection. Never a common disease, the condition occurred until recently at a rate of about 1 case per 1 million children per year and now, with the introduction and widespread use of measles vaccine, it has practically disappeared.