Neuroinflammation, neuroautoimmunity, and the co-morbidities of complex regional pain syndrome

Abstract

Complex Regional Pain Syndrome (CRPS) is associated with non-dermatomal patterns of pain, unusual movement disorders, and somatovisceral dysfunctions. These symptoms are viewed by some neurologists and psychiatrists as being psychogenic in origin. Recent evidence, however, suggests that an autoimmune attack on self-antigens found in the peripheral and central nervous system may underlie a number of CRPS symptoms. From both animal and human studies, evidence is accumulating that neuroinflammation can spread, either anterograde or retrograde, via axonal projections in the CNS, thereby establishing neuroinflammatory tracks and secondary neuroinflammatory foci within the neuraxis. These findings suggest that neuroinflammatory lesions, as well as their associated functional consequences, should be evaluated during the differential diagnosis of non-dermatomal pain presentations, atypical movement disorders, as well as other "medically unexplained symptoms", which are often attributed to psychogenic illness.

Fig. 1

Potential autoantibody binding sites in CRPS patients for β2AR (beta(2)-adrenergic receptor) and M2R (muscarinic 2 acetylcholine receptor) autoautoantibodies. (images modified from The Inner Man™, Medical Illustrations Company LLC). a. β2AR and M2R sites in the central nervous system and heart: β2AR in cerebellum—(Reznikoff et al. 1986); β2AR in reticular formation—(Culmsee 2009); β2AR in sympathetic autonomic nervous system—(Katzung 2001), M2R in parasympathetic autonomic system and heart—(Katzung 2001) β2AR also in astrocytes and microglia (Mantyh et al. ; Wang et al. 2010) b. M2R distribution in pyramidal motor pathway to skeletal muscles M2R in motor cortex and thalamus—(Levey et al. 1991) M2R in peripheral nerves—(Katzung 2001)

Fig. 2

A conceptual model for functional pathophysiologies arising from neuroinflammatory tracks. Neuroinflammation leads to a loss of sensory gating, as well as excessive gain, in sensorimotor pathways. a. Normal sensory processing (dotted lines). GABAergic interneurons provide inhibitory tone at both first order and second order synapses. Non-activated microglia (M) lie in the CNS parenchyma. Leukocytes (L) and autoantibodies are present in the CNS vasculature. b. Peripheral injury initiates anterograde central sensitization. Microglial activation takes place in response to cytokines released at the terminals of injured primary afferents (first order synapse). Breakdown of the blood–brain barrier (or the blood-spinal cord barrier) allows activated leukocytes and autoantibodies to extravasate into the parenchyma of the CNS, leading to autoimmune mediated neuroinflammation. Release of Brain-Derived Neurotrophic Factor (BDNF) from plasma, endothelial cells, and activated microglia alter chloride homeostasis in post-synaptic neurons. Accumulation of intracellular chloride (yellow) results in synaptic conversion, changing GABAergic and glycinergic synapses from inhibitory tone to excitatory tone (Huberfeld et al. ; Price et al. ; Cooper and Przebinda 2011). Sensory gating is lost at the first order synapse. Graded sensory transmission is lost within the neural circuit. Upregulation (red) of excitatory transducers (e.g. glutamate receptors) results an increase in excitatory tone. Functional changes in the circuit result in a collapse of feedforward inhibition and filtering at the first-order synapse (pain gate in the nociceptive circuit) (Cooper and Przebinda 2011). Neuroimmune activation spreads to the second order synapse through the release of the cytokine CCL21 from the terminals of first order neurons (Saab and Hains 2009). Small sensory stimuli provoke large (thick dotted arrows) volleys in second order neurons. c. Central injury to the CNS can result in retrograde central sensitization via neuroimmune activation. Loss of inhibitory interneurons (grey outlines), either by autoimmune attack (e.g. Stiff-Person Syndrome) (Sandbrink et al. ; Rokocevic and Floeter 2012), or by metabolic crisis (e.g. hypoglycemia, hypoxia, or excitotoxicity), permanently reduces inhibitory tone in the sensorimotor circuit. These conditions, and/or the conditions illustrated in panel B, may contribute to post-traumatic dystonias, non-dermatomal pain distributions, autonomic, and/or somatovisceral disorders, in patients with autoimmune-mediated neuroinflammation, even after the initial neuroinflammatory event subsides

Fig. 3

A neuroinflammatory model for the generation of fixed dystonia. Injury to a peripheral nerve results in inflammation of motor neurons. Neuroinflammation is established in the spinal cord, ipsilateral and segmental to the peripheral nerve injury (Sigel et al. ; Lee et al. 2009). Retrograde migration of neuroinflammation (red arrow) occurs via corticospinal neurons, leading to a secondary neuroinflammation site in the motor cortex (Cooper 2011a). Loss of chloride-dependent inhibitory tone (similar to panel 2B) and/or an increase in excitatory tone in the cortical and spinal neuroinflammatory foci lead to tonic firing of segmental motor neurons. A neuroinflammation-mediated loss of intracortical inhibition in the motor cortex may also be required for the genesis of fixed dystonia. (images modified from The Inner Man™, Medical Illustrations Company LLC)