Patterns of blood-brain barrier breakdown in inflammatory demyelination

The evolution of the changes in the blood-brain barrier (BBB) in chronic relapsing experimental allergic encephalomyelitis (CREAE), a model of immune-mediated demyelination, has been studied by magnetic resonance imaging (MRI); gadolinium-DTPA (Gd-DTPA) was used to detect BBB breakdown by both quantitative and qualitative techniques. Animals with acute EAE were examined for comparison. In animals with CREAE an approximately linear relationship was found between the mean number of lesions enhancing with Gd-DTPA seen per MRI slice and the severity of clinical disability at relapse. In addition, a direct relationship was seen between the duration of clinical relapse and the duration of enhancement with Gd-DTPA for lesions associated with the relapse. Lesions studied in animals having entered a progressive phase of disease showed the most sustained BBB breakdown. These observations suggest that BBB breakdown is important in the development of clinical signs in inflammatory demyelination. In CREAE, areas of focal enhancement with Gd-DTPA could usually be clearly defined at a time of clinical relapse. In slices free of focal lesions, no abnormal Gd-DTPA leakage could be detected using a quantitative method. In contrast, in acute EAE no focal lesions were visible, but significant leakage was detected by measurement. No change was found in T2 relaxation times in CREAE or acute EAE. The pattern of BBB breakdown in inflammatory demyelination evolves from a diffuse shortlived disturbance in acute EAE to a more focal and prolonged breakdown in animals with chronic relapsing and progressive disease. The broad similarities in the pattern of BBB breakdown seen in CREAE and multiple sclerosis support the hypothesis that the initial vascular changes in the human disease are due to inflammation which could be mediated immunologically.