Rabies:

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Rabies Neuroimaging-Virus-Cytokine
Studies Laothamatas, Wacharapluesadee,
Lumlertdacha, Ampawong, Tepsumethanon,
Shuangshoti, Phumesin, Asavaphatiboon,
Worapruekjaru, Avihingsanon, Israsena,
Hemachudha Neuroimaging center - Ramathibodi
Hospital Queen Saovabha Memorial Institute Thai
Red Cross Society Department of Medicine
(Neurology), Chulalongkorn University
Hospital
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Laothamatas, et al American Journal
Neuroradiology 2003 Dog variant similar in
furious and paralytic rabies
3 paralytic 2 furious Serial Examinations
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Bat Variant
Pleasure and Fischbein Bat variant Arch Neurol
2000
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• MRI in human rabies
• Similar patterns in patients associated with bat
• and dog variants
• Similar patterns in patients with furious and
• paralytic rabies
• Preferential locations
• Blood brain barrier - intact (during noncomatose
  phase)
• (no contrast enhanced lesions seen)
• Similar patterns - is it due to timing of
  examination?

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2 paralytic dogs
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2 distinct MRI patterns

• PARALYTIC
• brainstem, hypothalamus, thalamus
• temporal, hippocampus
• FURIOUS
• widespread lesions
• NO CORRELATION BETWEEN SITE OF LESIONS AND
  LIMBIC SYMPTOMS

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1 Frontal, 2Temporal, 3Hippocampus,
4Parietal, 5Occipital, 6Midbrain, 7Pons,
8Medulla, 9Cerebellum, 10Thalamus,
11Basal ganglia, 12Caudate
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RABIES VIRUS DISTRIBUTION

• 2 paralytic and 1 furious
• virus RNA confined to brainstem
• thalamus-basal ganglia-caudate nucleus
• 1 paralytic
• also at temporal and hippocampus
• 1 furious
• widespread distribution
• NO CORRELATION BETWEEN CLINICAL
• MANIFESTATIONS AND SITES OF INFECTION
• ROUGH CORRELATION BETWEEN MRI AND VIRUS
  DISTRIBUTION

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Critical Elements

• Neuronal cells and paths are to be clean and
  clear (intactness of morphology and function) for
  further dissemination
• - Guigoni, Coulon, noncytolysis of rat
  motoneuron
• - Juntrakul, delayed mitochondrial cell
  death in cord and brainstem
• Explaining why rabies patient remains
  conscious and does not have limb weakness despite
  abundant presence of virus in brainstem and
  spinal cord.
• Needs not to be seen by any immune arms
• - Lafon, apoptosis of invading T cells,
  regulation of HLA-G1.
• - McKimmie, upregulation of TLR 3, 9
• - Prehaud, human postmitotic neurons produce
  IFN-beta
• - Blondel, Wang, Shutting off all
  innate/adaptive immunity

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Resident cells (microglia, astrocytes, neurons)

• TLR (4)
• IL1-beta, IL- 6/ 10/ 12, TNF-alpha
• (in response to viral infection and to
  IFN-gamma, IL-1 beta and TNF-alpha)

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Adaptive Immunity

• Th1 - IL-2/12 TNF IFN gamma
• Th2 - IL-4/5/6/10
• Th3 - TGF beta IL-10

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Other cytokines studied

• Cox-2, FGF
• MCP-1
• IL-8
• IL-18 (IFN gamma and GM-CSF inducer)
• GM-CSF
• VEGF

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• CNS immune responses are not that bad, BUT not
  early enough and not very efficient !!
• CNS immunity of paralytic is better than furious
• limiting the virus from spreading to other
  structures within CNS and from CNS to periphery
  (by nerves and lymph to LN) in paralytic
• explaining rapid progression and shorter
  survival period in human furious rabies patient
• ( 5 vs. 11.5 days in paralytic )

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Furious rabies

• Cellular immunity to rabies virus
• furious 6/9 vs. paralytic 0/7
• (Hemachudha, 1988)
• Related to more viruses emerged from CNS to
  periphery not because immuno-pathogenetic
• mechanisms play role in furious rabies

paralytic
furious
Furious rabies
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Invariably fatal

• Killing process begins, may be, even before CNS
  and peripheral immune responses develop