Reduced viral burden in paralytic compared to furious canine rabies is associated with prominent inflammation at the brainstem level

Background: The mechanisms that differentiate rabies infections into furious and paralytic forms remain undetermined. There are no neuropathological features in human brains that distinguish furious and paralytic rabies. This could be due to methodology and/or examination of specimens late in the disease course. In this study, postmortem examination of brain (5 furious and 5 paralytic) and spinal cord (3 furious and 3 paralytic) specimens was performed in 10 rabies-infected dogs, sacrificed shortly after developing the illness. Rabies virus (RABV) antigen (percentage of positive neurons, average antigen area in positive neurons and average antigen area per neuron) and RNA were quantified at 15 different central nervous system (CNS) regions. The distribution and degree of inflammation were also studied. Results: More RABV antigen was detected in furious rabies than paralytic in many of the CNS regions studied. Caudal-rostral polarity of viral antigen distribution was found in both clinical forms in order from greatest to least: spinal cord, brainstem, cerebellum, midline structures (caudate, thalamus), hippocampus, and cerebrum. In contrast, RABV RNA was most abundant in the cerebral midline structures. Viral RNA was found at significantly higher levels in the cerebral cortex, thalamus, midbrain and medulla of dogs with the furious subtype. The RNA levels in the spinal cord were comparable in both clinical forms. A striking inflammatory response was found in paralytic rabies in the brainstem. Conclusions: These observations provide preliminary evidence that RABV antigen and RNA levels are higher in the cerebrum in furious rabies compared to the paralytic form. In addition, brainstem inflammation, more pronounced in paralytic rabies, may impede viral propagation towards the cerebral hemispheres.