Download Neuroinflammatory Reflex

Neuroinflammatory Reflex
I M P L I C AT I O N S O N R H E U M AT I C D I S E A S E
Immunology
Neuroscience
#1 Neutrophil and monocyte recruitment to the site
of infection/injury
#2 Pathogen fragments and molecules involves with
tissue injury stimulate TLR and other pattern
recognition receptors
#3 Immune activation through NF-kappa-B
#4 Recruitment of adaptive immune cells
#5 Resolution of inflammation via resolving and lipoxins
Principles
• Bi-direction communication between the periphery
and the CNS
• Reflex like circuits exist to quickly respond to
inflammatory events
Vagal Physiology
• Afferent fibers transmit
information from
peripheral organs to the
brain
Vagal Physiology
• Efferent fibers originate
in the brain stem and
innervate organs to
control heart rate, GI
motility and immune
function
Vagal Physiology
•
Efferent vagus
nerve
communicates
with the splenic
nerve to suppress
excessive proinflammatory
cytokine
responses and
inflammation
Vagal Physiology
•
Acetyl- choline
suppresses endotoxinstimulated macrophage
release of TNF, IL-1b, IL-6
and IL-18
Vagal Physiology
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Afferents can stimulate the HPA axis and lead to
release of cortisol by the adrenal gland
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Pavlov Immunol Res
(2015) 63:38–57
Vagus Nerve Interventions
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Vagus Nerve Stimulator
18 pts for 84 days
stimulated up to 4x daily
57% achieved ACR50
30% resistant pts ACR50
28% DAS-28 remission
Frieda A. Koopman, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid
arthritis. PNAS, July 2016
Biologics
• Generally ~50% of the patients have clinically relevant
improvement (ACR20)1
1. Rheumatology (Oxford). 2013 Aug 14
Vagus Nerve Interventions
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Transcutaneous TENS device
Improves heart rate variability 20% in 15minutes
Has not been studied in rheumatologic disease
Inexpensive and safe
Jennifer A. Clancy, et al. Non-invasive Vagus Nerve Stimulation in Healthy Humans Reduces Sympathetic Nerve Activity. Brain Stimulation,
2014; DOI: 10.1016/j.brs.2014.07.031
Vagus Nerve Interventions
• Mid tech:
• Cryo helmets
• PEMF stimulators
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Low Tech:
Deep breathing
Facial ice bathes
Cold showers
Gargling
Valsalva
Laughing
Singing
Gagging
Endogenous Opioids and
Immune Function
Low Dose Naltrexone
• Monocytes isolated from RA/SLE patients have low
levels of beta endorphin
• Lower levels of beta endorphin are inversely correlated
with inflammatory markers
• Levels are 1/4 -1/8 of a normal healthy population
• WHY?
1. Wiedermann CJ, Sacerdote P, Mur E, Kinigadner U, Wicker T, Panerai AE, et al.Decreased immunoreactive beta-endorphin in mononuclear leucocytes frompatients with rheumatic diseases. Clin Exp
Immunol 1992;87:178–82.
2. Panerai AE, Vecchiet J, Panzeri P, Meroni P, Scarone S, Pizzigallo E, et al. Peripheral blood mononuclear cell beta-endorphin concentration is decreased in chronic fatigue syndrome and fibromyalgia but
not in depression, preliminary report. Clin J Pain 2002;18:270–3
Low Dose Naltrexone
• “The bio equivalent of an orgasm a day”- me
• Modulated opioid growth factor (OGF) production and
OGF receptors
• Immunomodulating rather then suppressive
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LDN
• Increasing beta endorphins and OGF sensitivity
decreases:
• IL1, TNFa production
• TLR4 activity
• Auto reactive T cell proliferation
• Glial activation
• Mitochondrial apoptosis
LDN
• Principles of prescribing
• 1.5mg caps PO HS x 7 nights, then 2 PO HS (3.0mg) x 7
nights, then 3 PO HS (4.5), then best tolerated dose
thereafter
• Use up to 6mg total dose depending on body weight
• In pediatric patients >18months: 0.1mg/kg dosage
• Avoid in pregnancy/early lactation
• Avoid concurrent narcotic prescriptions**
• **maybe