Model Number 346

Subacute Sclerosing Panencephalitis

Human Disease: Subacute Sclerosing Panencephalitis
Animal Model: Subacute Measles Virus Encephalitis in Ferrets

Reprinted from:

COMPARATIVE PATHOLOGY BULLETIN

19(2): 2,5-6, 1987

Contributed by Halldor Thormar, PhD and Hannah A. Brown, MS, The New York State Office of Mental Retardation and Developmental Disabilities, Institute for Basic Research in Developmental Disabilities, Department of Virology, Staten Island, New York 10314.

Subacute sclerosing panencephalitis (SSPE, Dawson’s inclusion body encephalitis, Pette and Doring’s panencephalitis, van Bogaert’s subacute sclerosing leukoencephalitis) is a rare central nervous system (CNS) disease of children and young adolescents caused by a defective measles virus.1,2 The disease begins with insidious behavioral changes and a decline in intellectual functions and progresses slowly to overt neurological signs. It ends in complete loss of cerebral functions and death, usually within one to two years. The time from acute measles infection until the onset of SSPE varies from a few months to more than 20 years. The human disease is not suitable for controlled experimental studies, and it is not possible to study pathogenic processes that take place before the onset of clinical signs. A number of laboratories have, therefore, attempted to develop animal models for SSPE.3-5

A defective cell-associated strain of measles virus (SSPE strain D.R.) was passed in brain cell cultures and inoculated intracerebrally (i.c.) into young adult male ferrets (Mustela putorius furo, Marshall Research Animals, Inc., North Rose, NY).6 Most of the ferrets developed acute fatal encephalitis from 3 to 12 days after inoculation. If the ferrets were immunized subcutaneously with 0.5 ml of live measles vaccine (Attenuvax, Merck, Sharp and Dohme, West Point, PA) 5 weeks before i.c. inoculation with strain D.R., only about half of them developed acute encephalitis. The remainder of the ferrets survived for 3 weeks or more and some developed a subacute measles virus encephalitis from 5 weeks to 8 months later.7

Biologic Features: Subacute measles encephalitis in ferrets is characterized by neurological signs which are similar to those seen in SSPE, i.e. tremors, seizures and paralysis, particularly of the hind legs. The disease lasts from a few days to several weeks and ends in death. Perivascular cuffings and infiltrations of inflammatory cells are widespread both in the white and gray matter of the brain and spinal cord (Fig. 1). Inclusion bodies have not been observed in neurons or glial cells.8 Cell-associated, defective measles virus has been shown to be wide-

Figure 1—Perivascular cuffings and infiltration of Inflammatory cells in the brain of a ferret with subacute measles encephalitis (H&E, X175). (Left)

Figure 2—Localization of measles virus antigen in infected brain cells of a ferret with subacute encephalitis. Avidin-biotin-peroxidase immunostaining with rabbit anti-measles hyperimmune serum (X350). (Right)

spread in the CNS, both by growing tissue from various areas of the brain and the spinal cord in explant cultures and by immunoperoxidase labeling of tissue sections using antisera against measles virus (Fig. 2).9

The sera and spinal fluids of ferrets with subacute encephalitis have measles virus antibodies in high titers. A number of studies such as determination of immunoglobulin G (IgG) to albumin ratios in sera and brain extracts and absorption of brain extracts with measles virus antigen have indicated that much of the measles antibody is synthesized within the CNS.’° This has been directly demonstrated by immunolabeling, using protein A conjugated to horseradish peroxidase.” Measles specific oligoclonal IgG bands are present in the spinal fluids and sera of ferrets with subacute encephalitis (Fig. 3). 12 The intensity of the bands correlates with the measles antibody titers. IgG from the spinal fluids and sera shows precipitating antibody activity against all the measles virus proteins except the matrix (M) protein.

Although strain D.R. has been used in most experiments with the animal model, other cell-associated SSPE measles virus strains have also been used with similar results.’3 Attempts to use intravenous inoculation instead of i.c. inoculation

For reference citation—Thormar, H. and Brown, H. R.: Subacute Scierosing Panencephalitis, Model No.

Migaki. Registry of Comparative Pathology, Armed Forces Institute of Pathology, Washington, DC (1987).