Pain problems are a major component of consultative neurology. The perception of pain is complex and is composed of a discriminative component (location, quality, and intensity), an affective component (unpleasantness), and a motivational and emotional component (anxiety, depression, coping maneuvers). Each component has its unique circuitry.
Pain itself may be characterized as:
Specific modalities of pain are expressed in pain states. Hyperalgesia is defined as heightened sensitivity to a painful stimulus. Allodynia is pain that is elicited from a non-painful stimulus. In neuropathic pain conditions mechanical and heat hyperalgesia are cardinal features. Dynamic mechanical allodynia refers to pain elicited by a moving cutaneous stimulus (a wisp of cotton stroked across the skin) whereas static allodynia refers to pain elicited by pressure at ordinarily non-painful thresholds. Mechano allodynia is carried by A-beta fibers (myelinated 8-12 μ fibers). Thermal hyperalgesia is associated with A-delta fibers that convey cold and polymodal C-fibers that respond to heat, tissue destruction, and chemical stimuli. Mechanical and thermal hyperalgesia (particularly cold) are major modalities of peripheral neuropathic pain. Radicular conditions (disc disease, spinal stenosis, trauma to nerve roots) are primary causes of peripheral neuropathic pain. Pain is a very dynamic and plastic process in that chronic pain afferences actually change the response characteristic of pain transmission neurons (PTNs). In general, they become more responsive. Pain is a very sensitive modality in that only one C-fiber when stimulated during microneurography can convey location, quality, and intensity of a stimulus. It is now clear that immune mechanisms are important at many levels of pain production and maintenance (microglia, astrocytes and satellite cells).
As a general chain of events, a tissue-modifying stimulus triggers the firing of transient receptor potential (TRPV1, TRPVIII, and TRPA1) receptors on primary pain afferents. In turn, they initiate action potentials in C-fibers and A-delta fiber nociceptive neurons (cell bodies are in the dorsal root ganglia) that synapse in different lamina of the dorsal horn. These second order neurons give rise to spinothalamic and other afferents that activate the pain matrix. Specific aspects of inputs into PTNs induce both central and peripheral sensitization of the pain matrix, which modifies anatomic, physiologic and gene expression of pain pathways at all levels.
The skin is a complex sensory organ that also serves homeostatic and immunologic barrier functions. It is a neuroimmune cutaneous system that signals the sensory modalities of touch, pressure, temperature, and pain. As noted earlier, these primary modalities are modified in pain states (hyperalgesia, allodynia, and hyperpathia). All chronic pain conditions induce plasticity in pain transmission neurons. It is poorly recognized that there is a descending facilitating and inhibitory pain control system, the diffuse nociceptive inhibitory control (DNIC) system in experimental animals and in the patients’ conditioned pain modulation (CPM) system that modifies the transmission and physiology of pain transmission after a painful stimulus. This is a dynamic system that adjusts its sensitivity (thresholds) by complex mechanisms. Sensory transduction occurs following activation of primary intraepidermal nerve terminal C and A-delta nociceptive afferents. Activation of these primary intraepidermal nerve terminal C and A-delta nociceptive afferents is dependent on ligand activation of neuronal and non-neuronal skin cells of the neuroimmune cutaneous system (NICS). The epidermis is primarily composed of keratinocytes, melanocytes, Langerhans, and Merkel cells. These cells express sensor proteins and neuropeptides (substance P and calcitonin gene-related peptide) that are pivotal in nociception and neurogenic inflammation (vasodilation, plasma extravasation, and hypersensitivity). Keratinocytes comprise approximately 85% of dermal cells and form a tight junction with primary nociceptive nerve fibers. They express transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin (TRPA1) receptors. These channels are members of the transient receptor (TRP) superfamily of nonselective cation channels. TRPV1 channels are noxious heat-gated cation channels that are expressed on nociceptive primary afferents and also respond to protons, endogenous lipid ligands that include endocannabinoids, lipoxygenase, lysophosphatidic and linoleic acid metabolites as well as serotonin, bradykinins, prostanoids and reactive oxygen species (ROS) in the microenvironment following injury. These receptors (TRPV1 and TRPA1) are activated following injury or inflammation, depolarize nociceptive primary afferents in the skin whose central terminals project to the dorsal horn (DH) of the spinal cord. The dorsal root ganglia are composed of large diameter neurons that mediate mechanical modalities, small diameter neurons that mediate pain and temperature, as well as satellite cells that are similar to glial cells in the CNS. There are also blood vessels innervated by unmyelinated autonomic fibers in the DRG. Following injury, there is upregulation of various receptors on the neuronal elements of the DRG and under specific conditions cause sprouting of sympathetic fibers from the blood vessels. These fibers may form basket-like terminals around nociceptive and large mechanosensitive neurons. The spinal nerve-blood barrier and that of the DRG is not as tight as the blood-brain barrier. This is important in the pathophysiology of neuropathy caused by chemotherapy (direct toxic injury from cis-platinum and paclitaxel in the DRG) as well as autoimmune attack from activated lymphocytes and other cellular agents. In the skin, keratinocytes, macrophages, TRPV1-expressing nociceptors release nerve growth factor (NGF), prostaglandins (particularly E2), pro-inflammatory cytokines (IL-1, IL-6, and transforming growth factor beta 1 (TGFΒ1) as well as chemokines which sensitize (lower the threshold to fire) of primary afferent nociceptors. In many instances, after the nociceptors are exposed to the above noted “inflammatory soup,” they fire spontaneously which is the origin of spontaneous pain in many chronic neuropathic pain syndromes.
Nociceptive afferents are principally unmyelinated (1μ C-fibers) and thinly myelinated (1-4μ) A-delta fibers. The A-delta fibers signal location, intensity, cold and the lancinating quality of pain (epicritic qualities or fast pain). C-fibers are slowly conducting, transmit a burning quality of pain, and are poorly localizing (second pain).
The transmission and processing of painful inputs to the pain matrix is critically dependent on the properties of ion channels that are expressed on A-delta and C-fiber afferents. These include voltage-gated ion channels and leak channels that in concert regulate resting membrane potential, set, and maintain the action potentials and firing properties of pain transmission neurons. A major cause of chronic neuropathic and inflammatory peripheral pain is due to dysregulation of ion channel expression caused by tissue and nerve injury that enhances pain transmission and neuronal excitability. Afferent nociceptive signals due to activation of specific receptors and ion channels on peripheral nerve endings of A-delta and C-fibers are propagated and synapse in the extremely complex circuitry of the spinal cord dorsal horn. These afferents release glutamate and substance P that activate second order neurons that ascend to CNS processing ensembles that process pain signals.
The physiological properties of pain transmission neurons are critically dependent on the expression density and function of their ion channels that define:
1.The resting membrane potential
2.The initiation of the action potential
3.Depolarization and repolarization kinetics
4.The refractory period
5.Transmitter release from their central terminals on second order neurons in the dorsal horn
The relevant ion channels that determine these properties are:
1.Voltage-gated sodium, potassium and calcium channels
2.Leak channels
3.Ligand gated channels
4.Transient receptor potential channels
Particularly important for stimulus detection, initiation of action potentials in pain afferents and synaptic transmission are:
1.Nav 1.7 and Nav 1.8 isoforms of voltage-gated sodium channels
2.N-type calcium channels
3.Transient receptor potential channels
The sodium channel isoforms Nav1.7, 1.8, and 1.9 that are essential for the physiologic properties of peripheral nerves do not interfere with CNS or cardiac function and have been extensively studied as targets for pain pharmacology. Mutations in the gene that code for the Nav1.7 channel have demonstrated its role in human pain. It is expressed in peripheral neurons, the dorsal root ganglia (DRG), trigeminal and nodose ganglia as well as sympathetic ganglia neurons. It is activated by slow depolarizations that are close to resting membrane potential and sets the gain of nociceptor afferents. It is upregulated in inflammatory pain states, accumulates in neuromas, and is essential in ectopic impulse generation under these conditions. Genetic studies and functional profiling of mutant channels (from mutations in the SCN9A gene that encode the Nav 1.7 channel) have demonstrated its function in inherited erythromelalgia. In this condition, patients experience severe pain (burning and aching) from innocuous warm stimuli. The missense mutations were shown to increase the activity of the channels and to increase their response to small depolarizing stimuli. Other gain of function mutations in the Nav 1.7 channel impair channel inactivation and are associated with paroxysmal extreme pain disorder. These patients suffer rectal pain that in later life may be experienced in periorbital and perimandibular areas after a stimulus to the lower body. Autosomal recessive mutations of the Nav 1.7 channel may demonstrate insensitivity to pain. In this condition, patients do not produce functional Nav 1.7 channels. The exact role of the channel and its location in this deficit has not been determined. A polymorphism in the gene has been associated with hyperexcitability of DRG pain transmission neurons.
Gain of function variants of Nav 1.7 channels enhance activity by: (1) impairing slow inactivation or (2) impairment of both fast and slow inactivation, (3) enhancing activation by producing a persistent (non-activating) current. These physiologic changes lower the action potential threshold of DRG pain transmission neurons, increase their firing frequency, and cause abnormal spontaneous firing that is also thought to be a mechanism for evoked and spontaneous pain in patients with peripheral neuropathies.
The Nav 1.8 channel has been associated with painful peripheral neuropathies. It is expressed in DRG pain transmission neurons, their axons and in trigeminal and nodose ganglion neurons. It has depolarized voltage dependence, which renders it relatively resistant to inactivation during neuronal depolarization. It is a major component of the action potential upstroke (its inward current) and confers repetitive firing of depolarized neurons. It has a role in both inflammatory and neuropathic pain. Gain of function mutations in Nav 1.8 channels have been associated with approximately 5% of patients with painful neuropathies by causing hyperexcitability and spontaneous discharge of DRG pain transmitting neurons (PTNs).
The Nav 1.9 channel is expressed in DRG pain transmission neurons, the trigeminal ganglion neurons, and nociceptors of the myenteric plexus. It produces a non-inactivating current that is activated at hyperpolarized potentials close to the resting membrane potential. It prolongs and increases small depolarizations that increase DRG PTN excitability. It appears to be important in inflammatory pain as inflammatory mediators increase its current.
The Nav 1.3 channel may be important for neuropathic pain, as it has been shown to:
1.Produce a persistent current that responds to small depolarizations
2.Is active close to the resting membrane potential
3.Is positioned to amplify small nociceptive afferences
4.Is rapidly inactivated which supports repetitive firing
Potassium channels regulate resting membrane potential and action potential repolarization in PTNs. They are divided into:
Decreased voltage-gated potassium channel function causes increased PTN firing and spike duration as well as decreased spike threshold. Experimental evidence in neuropathic pain models support a strong contribution of Kv channels as inhibitory to pain signaling in nociceptive afferents.
Two-pore potassium channels (K2P) support a hyperpolarized resting membrane potential through their effects on leak potassium currents. K2P channel subtypes that include TRESK, TRAAK, TASK and THIK channels are expressed in DRG PTNs. They are important regulators of primary nociceptive afferent fiber excitability often to mechanical and heat stimuli (hallmarks of neuropathic pain).
Calcium activated potassium channels (Kca) are a determinant of after-hyperpolarization that follows an action potential and thus neuronal firing frequency and pattern. Kca channels include large (BK), intermediate (IK) and small (SK) channels: all of which when activated limit pain transmission neuronal discharge. There is decreased expression of SK and IK channels in human DRG PTNs after nerve injury that would increase their neuronal firing.
Recent experimental studies demonstrate decreased BK channel expression to brain derived neurotrophic factor (BDNF) – mediated down regulation at the transcriptional level. Microglia are activated after peripheral nerve injury and may be the source of the BDNF. Sodium activated potassium (Kna) channels are also involved in after-hyperpolarization and are important in the regulation of firing rate adaptation.
In summary, voltage-gated, ion-activated or leak potassium currents inhibit afferent pain signaling.
Neurons express multiple types of voltage-gated calcium channels (Cav channels) that are the primary source of depolarization-induced calcium increase in PTNs. N-type calcium channels are high voltage-activated channels that trigger neurotransmitter release in the dorsal horn.
T type Cav channels regulate afferent pain signaling whose mechanisms include:
1.The support of rebound burst activity induced by increasing the activity of co-localized Nav channels
2.An upregulation of Cav 3.2 channels in Aδ fibers (involved in mechano-transduction)
3.Interaction with the proteins of synaptic release which promote low threshold neurotransmitter release at specific dorsal horn synapses
Several gene families encode calcium-activated chloride currents that regulate neuronal excitability. Experimental studies of DRG neurons demonstrate that these chloride currents may be involved in after-depolarizations following neuronal discharge.
Hyperpolarization activated cyclic nucleotide-gated (HCN) channels are activated and open at negative membrane potentials and are a component of neuronal excitability and rhythm generation. Their four subtypes are expressed in DRG PTNs. Blockade of the channel decreases mechanical allodynia in both inflammatory and neuropathic pain models.
Nociceptive signals are modified prior to their arrival at the spinal cord dorsal horn. Primary sensory neurons (in the DRG), their terminals in the skin and peripheral tissues as well as adjacent host-defense cells (satellite cells) release a variety of proteins and peptides that effect nociceptive afference to the dorsal horn. Lipid-derived mediators are a major component of this peripheral gating mechanism by their interaction with nociceptor afferents, macrophages, mast cells, and keratinocytes. In general, most nociceptors are polymodal as they can signal different modalities of harmful stimuli. Nociceptor subclasses express distinctive membrane ion channels, receptors, and intracellular signaling proteins. After tissue and nerve terminal damage, these transduction molecules induce hyper-excitability in nociceptive afferents, which is called peripheral sensitization. As noted earlier, the clinical manifestations of this sensitization is mechanical and thermal allodynia in which innocuous mechanical and thermal stimuli are perceived as painful and hyperalgesia in which a mildly noxious stimulus is perceived as very painful. Peripheral sensitization is often accompanied by neurogenic inflammation. This vasodilatory response is caused by the release of substance P and calcitonin gene-related peptide (CGRP) from the activated C-fiber nociceptor primary terminals.
Nociceptors respond to endogenous proalgesic factors that are rapidly released following injury or are produced slowly during inflammatory states, tumor growth, or peripheral neuropathy. The first wave of proalgesic substances that may affect nociceptor terminals after injury are ATP and ADP leaked from damaged cells and bradykinin released from plasma globulin during blood clotting. Both activate excitatory receptors on primary nociceptive afferents. A later group of sensitizing and proinflammatory molecules includes substance P, CGRP, and lipid-derived mediators released by primary afferent nociceptor fibers and host-defense cells. Other proinflammatory mediators are prostaglandin E2 (PGE2) and prostacyclin (PGI2). They activate specific G protein-coupled receptors on nociceptive afferents that increase membrane excitability and amplify the release of SP and CGRP. Essential components of this signaling cascade are the enzymes cyclooxygenase 1 (Cox)-1 and Cox-2 which convert arachidonic acid into PGH2 the common precursor of all prostanoids.
Enzymatic and non-enzymatic conversions of membrane-derived polyunsaturated fatty acid (PUFA) oxidation form other lipid molecules that excite nociceptors and include:
1.Hydroxylated derivatives of linoleic acid
2.Hepoxilin A3
3.PGE2-glycerol ester
4.Prostamide F2α
5.Lysophosphatidic acid
6.Lysophosphatidyl inositol
A clear role of lipid-mediated signaling in the induction and maintenance of neuropathic pain is well established.
Recent experimental evidence demonstrates that bioactive lipids may also decrease and modulate pain initiation. These analgesic lipid mediators include:
1.Endogenous cannabinoids
2.Lipid-amide agonists of peroxisome proliferator-activated receptor–α (PPAR-α)
3.Products of oxidative PUFA metabolism.
Reactive oxygen species (ROS) are chemical species that contain oxygen and include peroxides, superoxides, hydroxyl radicals, and singlet oxygen. They are formed as a natural by-product of the normal metabolism of oxygen. They have major roles in cell signaling and homeostasis. If ROS increase dramatically they may damage cell structures and this process is known as oxidative stress.
The reduction of molecular oxygen (O2) produces superoxide (.O2) which is the precursor of most other reactive oxygen species.
The hydroxyl radical is extremely reactive and removes electrons from molecules in its vicinity that produces a free radical from the affected molecule. This creates a propagating chain reaction. H2O2 is more damaging than the hydroxyl radical due to its lower reactivity which gives it more time to enter the nucleus of the cell and react with its DNA.
ROS are produced intracellularly primarily by:
As noted, ROS are produced by multiple mechanisms that depend on the cell and tissue type.
The process of oxidative phosphorylation that creates ATP involves the transport of protons (hydrogen ions) across the inner mitochondrial membrane along the electron transport chain (ETC). Electrons undergo a series of oxidation-reduction reactions that occur in the proteins of the chain such that each acceptor protein along the chain has a greater reduction potential than the previous protein complex. The oxygen molecule is the final destination of electrons passing along the chain. Under normal conditions, oxygen is reduced to water. In approximately 0.1-2% of electrons that pass through the chain, oxygen is prematurely and incompletely reduced to make the superoxide radical. Electron leakage occurs primarily in complexes I and III. The superoxide molecule may inactivate enzymes or cause lipid peroxidation in its hydroperoxyl HO2 form.
If mitochondria are severely damaged from environmental conditions (toxins, chemotherapeutic agents, anoxia) the cell undergoes apoptosis or programmed cell death. The surface of mitochondria contains layered Bcl-2 proteins that detect mitochondrial damage and activate BAX proteins that produce holes in the mitochondrial membrane. Cytochrome C leaks from the ruptured membranes and binds to APAF-1 (apoptotic protease activating factor 1) that is free in the cytoplasm. ATP in the mitochondrion provides the energy for the binding of APAF-1 and cytochrome C to form apoptosomes. Apoptosomes bind and activate caspase-9, also in the cytoplasm, which then cleaves the proteins of the mitochondrial membrane. The resulting protein denaturation ends in phagocytosis of the cell.
The interaction of .O2 with nitric oxide produces NO-peroxynitrate. Under physiologic conditions the antioxidant defense system primarily composed of manganese superoxide dismutase MnSOD, catalase, glutathione thioredoxin and glutathione peroxidase reduce superoxide to water and molecular oxygen. If the antioxidant defense system is over-whelmed by a large increase of ROS, formation of peroxynitrate and other ROS increases and causes oxidative stress. Peroxynitrate causes a bioenergetics failure of mitochondria by altering and disrupting metabolic enzymes, mitochondrial electron transport proteins (thus reducing the production of ATP), ATP synthase and membrane transport proteins. Its damage of MnSOD causes a feed-forward reaction that increases its own production, which further increases superoxide.
1)There is leakage and loss of electrons (ē) primarily from mitochondrial complexes I and III
2)In neuropathic pain models:
a)mtROS are elevated in spinal neurons, microglia and astrocytes.
b)NOX-1, 2 (derived from NADPH oxidase) are expressed at the cellular membrane level and produce .O2 after phosphorylation of a cytosolic subunit
c)NOX-1 derived from NADPH oxidase:
i)Translocates PKCΕ to the membrane which enhances transient receptor potential vanilloid (TRPV1) activity in the DRG
d)NOX-2 derived from NADPH oxidase:
i)Primarily expressed in phagocytic cells (macrophages and microglia) is upregulated after peripheral nerve injury (PNI) and induces .O2. Its expression may be initiated by Toll-like receptors (TLRs)
ii)Decreases TNF but induces IL-1β and demonstrates the expression of the neuronal injury marker ATF3
iii)In NOX-2 deficient mice there is decreased expression of Iba on peptidergic axons and a decrease of proinflammatory cytokines
iv)Increases gene expression of proinflammatory cytokines in the DRG
e)NOX-4 (derived from nicotinamide dinucleotide phosphate, NADPH):
i)Is expressed by DRG neurons on both myelinated (A-fibers) and C-fibers
ii)It is also expressed by microglia, astrocytes and macrophages
iii)Its expression in cellular organelles (endoplasmic reticulum, ER) produces the ROS H2O2
iv)NOX-4 may decrease the neuronal proteins MPZ and PMP22 after nerve injury (shown in experimental sciatic nerve injury)
1)Positive effects:
a)Induction of host defense genes
b)Mobilization of ion transport systems
c)Platelets that are involved in wound repair and blood homeostasis release ROS that recruit platelets to the site of injury. A link is established to the adaptive immune system by ROS recruitment of leukocytes
2)Damaging Effects of ROS:
a)Damage of DNA and/or RNA
b)Oxidation of polyunsaturated fatty acids in lipids (lipid peroxidation)
c)Oxidation of amino acids in proteins
d)Mediation of apoptosis
e)Oxidative deactivation of specific enzymes via oxidation of cofactors
f)Mitochondrial damage
3)In the pain state – ROS:
a)Activate Ca/CaMKII in glutamatergic neurons
b)Induce presynaptic inhibition of GABAergic neurons
c)H2O2 increases action potentials of DRG neurons by activating cGK1α that increases neurotransmitter release from A-delta and C-fiber terminals of primary afferent neurons in the DH
Nitrosylation is the covalent incorporation of a nitric oxide moiety into another molecule. S-nitrosylation is the covalent attachment of NO to a cysteine residue that forms an S-nitrosothiol (SNO). S-nitrosylation is a post-translational protein modification that is a widespread signaling mechanism and is the primary driver of NO bioactivity. S-nitrosylation is targeted, reversible, spatio-temporally restricted and is important for a host of cellular functions. An important function is the allosteric regulation of proteins by both endogenous and exogenous sources of NO. It is the prototype redox-based signaling mechanism.
NO action in regard to nociceptive transmission is complex and often opposing. In several pain models neuronal NO (neuronal) at high concentrations in the spinal cord increases pain sensitivity while pharmacologic inhibition and genetic deletion decrease it. Expression of neuronal nitric oxide synthase (nNOS) in sensory neurons is upregulated following peripheral nerve injury. Low concentrations of NO in the spinal cord have been shown to attenuate allodynia after nerve injury. NO may increase the anti-nociceptive effects of opioids, NSAIDs and the NO-releasing derivative of gabapentin (NCX8001) at peripheral transduction sites. NO-dependent activation of ATP-sensitive potassium channels may be a component of peripheral analgesia. These KATP channels are expressed in metabolically active tissues and are complex. They are hetero-octamers and have four regulatory SUR subunits (SUR1, SUR2A, or SUR2B) as well as four ATP-sensitive pore forming inwardly rectifying potassium channels (Kir6.x) with subunits (Kir6.1 or Kir6.2). The ratio of cellular ADP/ATP determines their opening that allows them to function as metabolic sensors thus linking cytosolic energetics with cellular functions. In both the central and peripheral nervous system KATP channels are a component of the regulation of neuronal excitability, neurotransmitter release and ligand effects. S-nitrosylation regulates Na+ channels and acid-sensing channels in DRG neurons, the NMDA receptor channel complex. Ca2+ activated K+ channels that are all-important in pathologic pain states. It has been demonstrated that nitric oxide activates ATP-sensitive potassium channels in sensory neurons by direct, S-nitrosylation.
Nitric oxide is a diffusible gas that is synthesized from L-arginine by NOS-1 (neuronal), NOS-2 (inducible), and NOS-3 (endothelial).
The activation of the NMDA receptor with its associated increased intracellular calcium induces the transcription of nitric oxide synthase.
1.Nitration and phosphorylation of NMDA subunits that increase intracellular calcium concentration
2.Decrease glutamate transporter (GLT-1) that increases its concentration at the synapse
3.Nitro-oxidative products decrease GAD-67 GABAergic DH neurons and decrease GABA release
4.Increase calcium influx and increase synaptic currents
5.Decreases glutamine synthesis
1.TRP channel activation initiates the pain signal and concomitantly releases co-localized vasoactive neuropeptides (substance P (SP) and calcitonin gene related peptide (CGRP) to cause neurogenic inflammation
2.Induce post-translation modifications of proteins and lipids that drive pain
3.Mitochondrial DNA is a target for oxidation and nitration
4.Nitro-oxidative species trigger release of proapoptotic factors disrupting organelle dynamics in mitochondria
5.Toll-like receptors bind to a variety of endogenous danger signals that include those released from nitro-oxidative damaged mitrochondria. They also activate NF-kB and MAPKs pathways
6.NOX derived ROS (from NADPH-oxidase) are second messengers for NF-kB and p38MAPK
7.The Toll-like receptor 2-NOX-1 interaction:
a.Upregulates adhesion molecules via the chemokine CCL3 which induces transendothelial cell migration
8. Mitochondrial derived ROS:
a.Activate the NLRP3 inflammasome that proteolytically activates the inflammatory cytokine IL-1B
1.Mitochondria are critically involved in energy production (ATP), lipid synthesis, apoptosis and cellular calcium homeostasis
2.NOX and NOS derived ROS disrupt mitochondrial homeostasis. There is increased metabolism during pain states that has been demonstrated to induce a bioenergetics crisis with consequent degeneration of nociceptive primary afferent fibers
3.Mitochondria are a target of oxidation and nitration
4.Peroxidated lipid end-products:
a.Form reactive aldehydes that induce covalent modifications (adducts) with an array of mitochondrial proteins that include mitochondrial antioxidants
5.Nitro-oxidant species:
a.Release pro-apoptotic factors
b.Nitric oxide decreases fusion and fission of mitochondria
c.Decreased mitochondrial homeostasis is affected by:
i.Translocation of Bcl-2 associated x protein from the cytosol to the mitochondrial membrane that activates apoptotic pathways
1)In the course of tissue and/or nerve injury all forms of pain are induced that include:
a)Nociceptive
b)Inflammatory
c)Neuropathic
i)Neuropathic pain states have a component of inflammatory pain that fades as the neuropathic pain states become predominant
2)At the site of tissue injury in addition to the release of hydrogen ion, serotonin, bradykinin, prostanoids – glia and immune cells release TNF alpha, IL-1B and BDNF (brain-derived neurotrophic factor)
3)Mechanisms for increased inflammation-induced neuronal hyperexcitability:
a)Increased glutamate release from the terminals of nociceptive primary afferent fibers (A-delta and C-fibers)
b)Increased AMPA post synaptic primary nociceptive fiber expression
c)Phosphorylation of NMDA subunits that increase the receptor permeability to Ca2+ ions
d)Down-regulation of astrocyte glutamate transporters
e)Decreased GABA and glycine release from inhibitory interneurons
f)Decreased K-Cl co-transporter KCC2 on postsynaptic terminals
g)Nitro-oxidative species:
i)Regulate the production of proinflammatory mediators:
(1)NF-kB and p38MAPK are induced and increase the transcription of proinflammatory cytokines
h)Degrade NF-kB and p38MAPK phosphatases and thus maintain their concentration
i)Increase neuron to glia signals from released metalloproteinases
j)Increased TLR signaling:
i)Bind DAMP (damage-associated molecular pattern) that includes DNA and N-formyl peptides from damaged mitochondria
ii)ROS are second messengers for TLR signaling
iii)There is a rapid respiratory burst after activation of TLR2 and 4 from direct interaction of intracellular domain of NOX1,2 and 4 enzymes that is essential for NF-kB and p38MAPK dependent cytokine production
iv)Disruption of blood-brain barrier (BBB) tight junctions
v)TLR-NOX1 interaction via the chemokine CCL3 upregulates adhesion molecules
vi)Increase of lipid rafts by activation of NOX enzymes
vii)Increased transcription of TLRs
viii)ROS activate the inflammasome (protein complexes that cause proteolytic activation of the inflammatory cytokine IL-1B)
ix)Mitochondria are a source of ROS that activate inflammasomes (NLRP3). Nitro-oxidative species induce calcium influx that activates NLRP3 inflammasomes through the receptor TRMPM2
x)Transcription of NOX/NOS enzymes is upregulated by TLR4 and 9 as well as by NF-kB and p38MAPK
xi)ATP signaling via P2X7R (released from neurons) activate NOX2 in a calcium-p38 dependent manner
A major component of central sensitization occurs in the spinal cord dorsal horn. Persistent and intense nociceptive afferent input from nociceptive afferents induces maladaptive neuroplasticity in the synapses of pain projecting neurons primarily of the spinothalamic tract. During the course of this maladaptive neuroplasticity, long-term potentiation (LTP) of excitatory postsynaptic currents is seen in spinothalamic pain projecting neurons while long-term depression (LTD) develops in GABAergic interneurons to the same nociceptive input.
Increasing experimental evidence supports a major role of reactive oxygen species in increasing pain transmission following peripheral nerve injury. A major effect of increased levels of reactive oxygen species (ROS) is the down regulation of GABA transmission in the dorsal horn following nerve and spinal cord injury. Lack of GABAergic inhibition of pain projecting neurons is a major factor in enhanced pain transmission in neuropathic pain states.
In the brain the development of LTP or LTD is posited to be caused by the frequency of stimulation. In the spinal cord cell type specific LTP develops in spinothalamic tract pain projecting neurons while LTD occurs in GABAergic dorsal horn neurons from the same nociceptive stimulus. Recent studies support the hypothesis that specific ROS subtypes are instrumental in cell type-specific synaptic plasticity. Superoxide radicals are posited to cause the induction and maintenance of spinothalamic pain projecting neuron LTP and DH GABAergic LTD, while hydroxyl radicals are essential for GABAergic DH LTD induction and maintenance.
1)TRPV1 (transient receptor potential family vanilloid 1:
a)Expressed as C-fiber primary nociceptive afferents
b)Linoleic acid metabolites that are created during production of eicosanoids are endogenous TRPV1 agonists when oxidized
c)TRPV1 receptors are:
i)Are activated directly by modified proteins and lipids
ii)Are activated during thermal and mechanical hyperalgesia which are major components of neuropathic pain
2)TRPV2:
a)Is a non-selective calcium permeable cation channel that is part of the Transient Receptor Potential ion channel superfamily of receptors
b)It is physiologically activated by heat via free intracellular ADP-ribose acting in concert with free intracellular calcium. Oxidative stress (an accumulation of ROS that overwhelms anti-oxidant mechanisms) induces the enzyme PARP (Poly ADP-ribose polymerase) that activates the channel
3)TRPM2 is expressed by neurons, monocytes, macrophages, microglia and T cells. It is directly activated by nitro-oxidative species
a)In turn, it activates MAPK and nuclear factor K light chain enhancer of activated B cell, (NF-kB) important for the production of proinflammatory cytokines
b)The channel is directly activated by H2O2 and cytosolic ADP-ribose generated from damaged mitochondria
c)The channel is vital for activation of spinal microglia and for macrophage infiltration into the spinal cord after peripheral nerve injury
d)It activates ERK/MAPKs and induces nuclear translocation of NF-kB that is critical for the production of proinflammatory cytokines and chemokines
4)TRPA1:
a)Is a member of the transient receptor potential channel family and contains 14N-terminal ankyrin repeats
b)It is activated by both reactive and non-reactive compounds
c)It is expressed by pepetidergic C-fibers and is activated by modified proteins and lipids
d)A missense mutation of TRPA1 causes hereditary episodic pain syndrome
1)Carbonylation are reactions that induce carbon monoxide into organic and inorganic substrates
2)Modifications of the side chains of histidine, cysteine and lysine in proteins to carbonyl derivatives (aldehydes and ketones) are caused by oxidative stress
3)Nitro-oxidative species induce protein carbonylation and membrane phospholipid peroxidation and nitration. These reactions produce reactive aldehydes exemplified by acrolein that directly activate TRPA1 receptors. After spinal cord injury, acrolein is elevated in both the dorsal root ganglia and the dorsal horn that may contribute to spinal cord injury pain.
4)At the site of injury the following compounds contribute to neuroexcitability:
a)H2O2
b)Peroxynitrate
c)Carbonylated proteins
d)Peroxidated and nitrated lipids
e)Reactive aldehydes
An antioxidant is a molecule that inhibits the oxidation of other molecules. As noted earlier, oxidation is the loss of electrons during a reaction by a molecule, atom or ion. Oxidation occurs when the state of a molecule, atom, or ion is increased (loss of electrons).
Reduction is its opposite (gain of electrons) by a molecule, atom or ion. As noted above, the major producers of ROS during metabolism that occur in components of the pain matrix are:
1)NADPH oxidase (NOX)
2)Nitric oxide synthase (NOS)
3)Mitochondrial metabolism with loss of electrons from complex I and III
The ROS generated by these reactions in the course of energy production are damaging to multiple cellular functions and if not controlled may destroy the cell. The cell has evolved a complex network of antioxidant metabolites and enzymes that prevent oxidative damage to DNA, protein and lipids. In general, these systems prevent the ROS from being formed or assist in their removal prior to their causing cell damage. The major ROS generated that must be controlled are hydrogen peroxide (H2O2), the superoxide anion (.O2), nitrosative species and the hydroxyl radical.
The hydroxyl radical is very unstable and reacts rapidly and non-specifically with most biological molecules. The hydroxyl radical is derived from hydrogen peroxide by metal-catalyzed redox reactions such as the Fenton reaction. As noted above, ROS induce chemical chain reactions exemplified by lipid peroxidation, the oxidation of DNA, and proteins. Damage to proteins results in enzyme inhibition, denaturation and protein degradation.
The superoxide anion is a by-product of several steps in the mitochondrial electron transport chain. In particular, the reduction of coenzyme Q in complex III forms a highly reactive free radical as an intermediate Q-. This intermediate is unstable and leads to electron transfer directly to oxygen that forms the superoxide anion. Peroxide is produced from the oxidation of reduced flavoproteins in complex I.
Antioxidants are classified as hydrophilic (soluble in water) or lipophlic (soluble in lipids). Water-soluble antioxidants interact with oxidants in the cytosol and the blood plasma. Lipid-soluble antioxidants protect cell membranes from lipid peroxidation. Both species have a spectrum of concentrations in body fluids and tissues. Glutathione and ubiquinone are primarily confined within cells while uric acid is more evenly distributed. Interactions between antioxidants and their metabolites and enzyme systems may be both synergistic or independent. The effect of the antioxidant depends on its concentration, the reactivity of the specific reactive oxygen species and the state of other antioxidants with which it interacts.
1)Activation of Antioxidant Genes:
a)Nuclear factor Nrf2 (erythroid-derived 2) –like 2 is a transcription factor that is encoded by the NFE2L2 gene. It is a basic leucine zipper (bzip) protein that regulates the expression of antioxidant proteins
b)It is expressed in neurons, macrophages, astrocytes, Schwann cells and microglia
c)Under homeostatic conditions Nrf2:
i)Nrf2 is anchored to the cytoplasm by binding to Kelch-like ECH-associated protein I (Keap1):
(1)Keap1 sequesters cystosolic Nrf2 and ubiquinates it for degradation
d)Under conditions of oxidative stress, Nrf2 is released and translocates to the nucleus where it binds to antioxidant response element (ARE) to elicit expression of more than 200 antioxidant genes
e)The major antioxidants in pain states include:
i)Superoxide dismutase (SOD)
ii)Cytosolic SOD2 in mitochondria
iii)Catalase
iv)Glutathione
v)Heme oxygenase
f)Another mechanism that contributes to antioxidant defense is the chelation of transition metals. This process prevents them from catalyzing the production of free radicals. The ability to sequester iron is particularly important and is effected by transferrin and ferritin
1)Glutathione is a cysteine-containing peptide synthesized in cells from its constituent amino acids. Its antioxidant properties derive from the thiol group in its cysteine moiety that is a reducing agent and is reversibly oxidized and reduced. It is maintained in its reduced form intracellularly by glutathione reductase. It has a central role in maintaining intracellular redox potential.
1)A major defense against oxidative stress is an interacting network of antioxidant enzymes systems:
a)Superoxide released from oxidative phosphorylation is converted to hydrogen peroxide and then water by further reduction. This pathway is first catalyzed by superoxide dismutase and then requires catalases and peroxidases
1)Superoxide dismutases (SODs):
a)Are a family of enzymes that catalyze the degradation of the superoxide anion into O2 and H2O2
b)In humans, the copper/zinc SOD is present in the cytosol. Manganese SOD is located in mitochondria
2)Catalase:
a)Catalyzes the conversion of H2O2 to water and O2 in concert with a manganese or iron cofactor
3)Peroxiredoxins:
a)These are peroxidases that catalyze the reduction of peroxynitrate, organic hydroperoxides and hydrogen peroxide
1)The thioredoxin system is composed of thioredoxin and thioredoxin reductase
2)Its active site has two closely located cysteines in its CXXC motif that cycle between an active dithiol form (its reduced state) and an oxidized disulfide form
3)It is an effective reducing agent and scavenges ROS and maintains other proteins in a reduced state
4)Active thioredoxin (after being oxidized) is regenerated by thioredoxin reductase utilizing NADPH as an electron donor
1)This system includes glutathione, glutathione reductase, glutathione peroxidases and glutathione S-transferases:
a)Glutathione peroxidase contains four selenium cofactors that catalyze the degradation of H2O2 and organic hydroperoxides
b)There are four different glutathione peroxidase isoenzymes in animals with glutathione 1 peroxidase being the most abundant. It scavenges H2O2. Glutathione peroxidase 4 primarily acts upon lipid hydroperoxides. Glutathione S-transferase primarily affects lipid peroxides.
In cardiovascular disease, the oxidation of low-density lipoprotein (LDL) is particularly important in initiating atherogenesis. In both chronic and acute pain states, ROS are a major component of pain projection neuron hyperexcitability.
1)IL-10 and TGF-B counter-regulate proinflammatory signaling in neuropathic pain states:
a)IL-10 and TGF-B decrease NOX-2 activity and increase antioxidant production
b)A2A/A3 (adenosine) decreases NOX activity and drives the production of anti-inflammatory cytokines and antioxidants
1)NOX activity is increased by morphine:
a)The downstream mediators are posited to be superoxide and peroxynitrate
b)There is a possible interaction between mu-opioid receptors and TLRs which would increase the production of ROS
c)Nitro-oxidative signaling disrupts endogenous opioid analgesia in supraspinal sites that are important for descending nociceptive inhibitory control (DNIC) and conditioned pain modulation (CPM)
d)Nitration of metenkephalin in the RVM has been posited
As noted in this short overview of some aspects of somatic neuropathic pain, a great deal of information is known. Molecular mechanisms that control these basic cascades are rapidly being demonstrated and will undoubtedly lead to insights that will lead to better somatic neuropathic pain management.
Clinical diagnosis, experience, and judgment will be buttressed but will remain the cornerstone of treatment.
Neuronal and non-neural cells in injured areas produce endocannabinoids (arachidonic acid derivatives) that suppress nociceptor sensitization and neurogenic inflammation. They activate CB1 and CB2 cannabinoid receptors that are Gi/o protein-coupled receptors. CB1 expression is seen in nociceptive and non-nociceptive neurons in the DRG, trigeminal ganglion as well as macrophages, mast cells and epidermal keratinocytes.
Both CB1 and CB2 receptor activation have pleiotrophic effects that include:
1.Inhibition of voltage gated calcium and acid-sensing (ASIC) channels
2.Decrease of the calcium current evoked by capsaicin activation of TRPV1 channels
3.Block nerve growth factor induced TRPV1 sensitization
Peripheral CB1 mediated mechanisms suppress nociceptive behavior in pain models and decrease CGRP release. The second cannabinoid receptor CB2 has 40% homology with CB1 and has receptors on cells of hematopoietic origin, which include those that interact with nociceptive afferents (macrophages and mast cells). In experimental pain models, CB2 expression is upregulated in the DRG after nerve injury. CB2 agonists attenuate calcium transients induced by capsaicin in human DRG neurons. Endocannabinoid lipids also interact with TRPV1 channels and G protein-coupled GPR55 receptors.
Anandamide and 2-arachidonyl-n-glycerol (2-AG) are well-characterized lipid mediators that are produced by enzyme-mediated hydrolysis of phospholipid precursors in cell membranes. Anandamide is active near its site of production and is inactivated by carrier-mediated endocytosis followed by the serine hydrolase fatty acid amide hydrolase cleavage to arachidonic acid and ethanolamine. Anandamide may also be transformed by Cox-2 to proalgesic prostamides. Increased anandamide is produced by calcium influx into nociceptors or to activation of Toll-like receptor-4 (TLR-4) in macrophages. Anandamide at the site of injury activates CB1 receptors that modulate nociceptive input to the spinal dorsal horn (DH). In contradistinction to anandamide, 2AG is formed from the hydrolysis of phosphatidylinositol-4,5 biphosphate (PIP2). The Β-isoform of Phospholipase C (PLC-Β), activated by Gq-coupled receptors, hydrolyses PIP2 into 1,2-diacyglycerol (DAG) which in turn is converted by diacyl-glycerol lipase-α (DGL-α) to 2-AG.
2-AG mobilization in the brain and spinal cord is regulated by transducing Gq proteins and is essential in the descending modulation of pain that is associated with acute stress.
In summary, endocannabinoid lipids are rapidly recruited to areas of peripheral injury to dampen nociceptive afferent signaling.
PPAR-α is activated by ligand binding that produces the formation of a multi-protein complex comprised of the retinoid X receptor (RXR) and variable sets of protein activators. When activated it binds to responsive elements on DNA that enhance the transcription of anti-inflammatory proteins while concomitantly decreasing the activity of proinflammatory transcription factors by transrepression.
The transcriptional regulators that are modified by PPAR-α activation include:
1.Nuclear factor kB (NF-kB)
2.Signal transducers and activators of transcription (STATs)
3.Activator protein 1 (AP1)
4.Nuclear factor of activated T cells (NFAT).
These changes in gene expression occur over a matter of hours to days. PPAR-α is expressed in DRG PTNs, macrophages and other host defense cells which when activated suppress pain behaviors in neuropathic pain models. It appears to have a role in the tonic control of inflammatory and nociceptive pain. The rapid analgesic action of PPAR-α ligands (within minutes) and experimental studies suggest that it is involved in the regulation of calcium-activated potassium channels primarily ΒKCa (KCa1.1) and intermediate-conduction IKCa (KCa 3.1) channels. Both channels modulate the excitability of primary sensory neurons.
Oleoylethanolamide (OEA) and palmitoylethanolamides are produced by cleavage of distinct membrane phospholipids, N-oleoyl-PE and N-palmitoyl-phosphatidyl ethanolamine. The reaction is catalyzed by N-acyl PE-specific phospholipase D (NAPE-PLD) which is the same enzyme that induces anandamide release in neurons. Macrophages produce OEA, PEA and mono and polyunsaturated fatty acid amides (FAE) that inhibit inflammatory responses by activating PPAR-α. It has been posited that both in macrophages and pain transmission neurons, the cysteine hydrolase N-acylethanolamine acid amidase (NAAA) are converted into fatty acid and ethanolamine to limit their activity. OEA and PEA are tonically produced by DRG neurons and skin cells. Tissue damage has been shown to suppress FAE mobilization. It is possible that endogenouse FAE signaling at PPAR-α receptors is a tonic inhibitor of nociceptive and inflammatory responses to injury.
An exudate at a site of injury evolves during the course of an inflammatory reaction. Initially there is a high concentration of proinflammatory lipid mediators that include: (1) prostanoids (PGE2 and PGI2) and (2) leukotrienes (LTB4).
Over time, these mediators are supplanted by lipid molecules that:
1.Inhibit neutrophil infiltration
2.Clear cellular debris
3.Enhance antimicrobial activity of epithelial cells
4.Stimulate wound healing.
These bioactive lipids also are a component of the normalization of nociceptive signaling by binding to selective surface receptors on DRG PTNs and immune cells.
Epoxygenated fatty acids derived from the enzymatic activity of the cytochrome P450 system catalyze the oxygenation of long-chain PUFAs that include arachidonic, eicosapentaenoic (EPA) and docosahexaenoic acids (DHA). Their oxygenation produces bioactive epoxide-containing fatty acids (EpFAs). They are active near their sites of synthesis and regulate vascular tone and inflammation. They are metabolized by enzyme-soluble epoxide hydrolase (sEH) into 1,2 hydroxy fatty acids, which have properties different from their substrate. Experimentally, they have been shown to modulate nociceptive signaling.
Lipoxins are derived by enzyme-mediated oxygenation of arachidonic acid. They manifest transcellular biosynthesis that involves interaction among different cell types that make contact during an inflammatory response. A well-studied member of this class of mediators, LX4A4 may dampen nociceptive signaling by activating the ALX/FPR2 or CB1 receptors on PTNs.
Resolvins and protectins are generated by complex multistep oxygenation of membrane PUFAs (EPA and DHA) rather than arachidonic acid. They demonstrate pro-resolving, immune-modulating and anti-nociceptive effects.
Bioactive lipid mediators may modulate nociceptive input to the pain matrix in three stages:
1.Endogenous PPAR-α agonists (primarily OEA and PEA) may be involved in setting the threshold for nociceptive afferent activation by:
a.Regulating transcriptional activity of the NF-kB complex
b.Opening membrane ion channels of primary nociceptive afferents
2.During injury endocannabinoids are formed that suppress the effects of proalgesic molecules and attenuate nociceptor excitability
3.During healing, products of oxidized PUFA substrates that include lipoxins and resolvins help to return nociceptive thresholds to baseline.
As noted earlier, the transmission of pain involves subsets of thinly myelinated Aδ and unmyelinated C fiber afferent discharge from DRG pain transmission neurons (PTNs) that activate second-order DH spinothalamic and spinobulbar projection neurons.
The DH is a gating center that utilizes interacting excitatory and inhibitory ensembles of interneurons in its complex circuitry to process nociceptive inputs. Excitatory interneurons are essential for the physiologic and pathologic transmission of sensory input to projection neurons. Inhibitory neurons gate these afferents.
Lamina I and II comprise the superficial dorsal horn (DH). Lamina I is composed of heterogeneous types of spinothalamic and spinobulbar projection neurons. Lamina II, the substantia gelatinosa, has an outer and inner region that contains specific local excitatory or inhibitory interneurons. The deep dorsal horn, lamina III to V contains both interneurons and projection neurons (WDR, wide dynamic range neurons). Different subtypes of primary afferents from the DRG neurons project to lamina specific regions onto both projection and interneurons. There are descending projections from pain modulating areas of the brainstem and other CNS ensembles to pain projecting neurons.
There are two primary nociceptor subtypes differentiated by their neurochemical profiles. Painful heat stimuli are transmitted by nociceptive C-fiber afferents that contain SP and calcitonin gene-related peptides (CGRP). They synapse on both projection and interneurons of lamina I and outer lamina II. These nociceptive afferents express TRPV1 (respond to heat, protons and capsaicin). TRPA1 (transient receptor potential ankyrin I) on C and A-delta fibers that are activated by irritant chemical stimuli. Non-peptidergic C nociceptive afferents transmit mechanical pain and synapse on interneurons of inner lamina II. The non-peptidergic afferents express lectin 1-B4. Both types of afferents have L-glutamate as their primary neurotransmitter. Co-localization of SP is particularly important in NMDA expressing pain-projecting neurons. Low-threshold C mechanoreceptors have been associated with a pleasant touch that primarily expresses tyrosine hydroxylase and the vesicular glutamate transporter subtype 3. Myelinated large diameter AΒ afferents from low mechanical threshold mechanoreceptors mediate discriminative touch exemplified by two point discrimination and stereognosis. These low threshold AΒ mechanoreceptors express δ-type opioid receptors and synapse on different neuronal populations from inner lamina II to V. Thermoreceptors comprise C and Aδ fibers. C-fibers terminate in layer I and II while Aδ fibers synapse in lamina I and V. Thermal sensation depends on temperature-dependent activation of specific TRP and cation channels. The projection neurons of the DH transmit sensory information by spinothalamic pathways and parallel tracts whose neurons are located in lamina I and III-V and receive afferences directly and by excitatory interneurons.
Lamina I contains the majority of spinothalamic projection neurons that include:
1.Nociceptive-specific neurons that transmit heat or mechanically evoked pain
2.Neurons that respond to innocuous cooling
3.Neurons that encode noxious heat, pinch, and cold.
These lamina I neurons are multipolar or fusiform in shape and express the neurokinin-1 receptor (NK1R) activated by substance P (important for central sensitization of PTNs). These neurons convey location, quality, and intensity of pain and contribute to its emotional valence via parallel spinothalamic pathways. They project primarily to thalamic ventral posterolateral, posteromedial, and posterior inferior nuclei that in turn relay to the primary (SI) and secondary (SII) somatosensory cortex. The posterior component of the ventral medial thalamic nucleus projects to the dorsal posterior insular cortex. NK1R lamina I neurons also project to the lateral parabrachial nucleus that connects with the amygdala and hypothalamus and the periaqueductal gray (PAG) an essential component of the circuitry involved in central pain processing. Other afferences that include glutamatergic projections from excitatory interneurons in lamina II modulate nociceptive lamina I projection neurons. Pyramidal neurons in lamina I synapse with non-nociceptive low-threshold C mechanoreceptors and with C afferents that express TRMP8 receptors that signal innocuous cooling. Peripheral inflammation induces upregulation of NK1R receptors on pyramidal neurons that may allow them to signal noxious sensation.
The deep dorsal horn neurons are found in Rexed laminas III-V and are known as wide dynamic range neurons (WDR). They respond to both innocuous and tissue-damaging stimuli, have large receptive fields, and code stimulus intensity. The innocuous inputs to these projection neurons arise from large diameter (12-20μ) AΒ afferents. Lamina III WDR neurons have NK1R receptors and long dorsal dendrites that project into lamina I-II and are activated by peptidergic primary afferents. They also synapse with excitatory interneurons of deep lamina II that are nonpeptidergic nociceptive afferents. Lamina V neurons are a major component of the spinothalamic tract as well as projecting to the amygdala and hypothalamus that are involved in the affective component of pain processing.
Dorsal horn interneurons are located in lamina I-III with their major concentration in lamina II. They are heterogeneous in regard to morphology, neurochemical profile, physiologic properties, and connectivity.
The morphologic types include:
1.Islet cell (the predominant type)
2.Central
3.Radial
4.Vertical (which are excitatory or inhibitory)
Inhibitory interneuron neurotransmitters are GABAergic and glycinergic and in some instances, both. The majority of inhibitory interneurons have islet cell morphology. Radial, vertical, and central cells are primarily excitatory interneurons and utilize L-glutamate as their neurotransmitter.
Inhibitory neurons are comprised of subpopulations of GABAergic and glycinergic ensembles that make up approximately 1/3 of the neurons of the DH. GABAergic and glycinergic interneurons may coexpress parvalbumin, neuropeptide y, dynorphin, galanin or neuronal nitric oxide synthase. These different ensembles of interneurons have specific neurophysiological properties and afferent input.
Excitatory interneurons are divided into different groups dependent on differential expression of:
1.Vesicular glutamate transporters
2.Somatostatin
3.Somatostatin 2A
4.Opioid or glutamate receptors
5.Protein kinase Cv
6.Gastrin-releasing peptide
7.Calretinin
They receive specific primary afferents as exemplified by vertical interneurons that are the target of low-threshold AΒ and Aδ and C mechanoreceptors while interneurons that express vesicular glutamate transporter 3 or protein kinase Cv synapse with low-threshold AΒ mechanoreceptors. Excitatory interneurons have varied firing patterns primarily set by A-type Kv4 channels.
Nociceptors are modality specific. Peptidergic substance P, TRPV1 expressing nociceptors carry heat pain and synapse in the superficial dorsal horn on NK1R-expressing lamina I projecting neurons and neurons in outer lamina II. These afferences are also to either excitatory or inhibitory interneurons. Nonpeptidergic C afferents synapse with all types of excitatory interneurons and may not synapse with inhibitory interneurons directly. Μu-opioid receptors are expressed on peptidergic afferents and δ-opioid receptors are demonstrated on nonpeptidergic afferents.
Nociceptive afferents synapse directly with spinothalamic projection neurons and form a feed-forward circuit by means of excitatory interneurons. This circuitry is extremely complex as exemplified by heat and mechanically induced pain. NK1R expressing nociceptive lamina I neurons synapse with peptidergic afferents that encode heat pain but also synapse with a polysynaptic nonpeptidergic pathway composed of mechanosensitive fibers that encode mechanical pain. The sequential activation of this pathway entails: (1) activation of excitatory interneurons of lamina II (central interneurons) that activate (2) vertical cells in outer lamina II that in turn (3) project to the NK1R spinothalamic neurons in lamina I. These pathways provide the anatomical basis of the polymodal response of lamina I spinothalamic projection neurons to mechanical and heat noxious stimuli. Vertical excitatory interneurons in outer layer II receive direct Aδ nociceptor projection and there is also a nociceptive projection to the neurons of the deep dorsal horn (WDR) in which lamina II excitatory interneurons relay nonpeptidergic C fibers to neurons in lateral lamina V (WDR neurons).
Low-threshold mechanoreception is able to activate pain-projecting neurons of the superficial dorsal horn to cause dynamic and static mechanoallodynia that are prominent features of neuropathic pain. Low threshold AΒ mechanoreceptors synapse with and activate excitatory interneurons in lamina III that express vesicular glutamate transporter-3 and project to protein kinase Cv-expressing interneurons of inner lamina II. There is then sequential activation of central interneurons in inner lamina II, vertical interneurons in outer lamina II and terminal projections to NK-1 expressing pain projecting neurons of lamina I. The direct Aδ and C-fiber mechanical input concomitant with excitatory interneuron mediated low threshold mechanoreceptor afference to the vertical excitatory interneurons of outer lamina II is posited to be the anatomical basis of mechanical allodynia. Another possible contributory pathway for mechanoallodynia is the C-fiber tactile low threshold C-mechanoreceptors that also project to inner lamina II and through excitatory interneurons may modulate the wide-dynamic nociceptive projection neurons of lamina I and V. During baseline conditions, low-threshold mechanoreceptors are blocked from activating nociceptive projection neurons by surround feed-forward inhibition.
A gate control mechanism that reduces the transmission of mechanical, itch and nociceptive transmission to spinothalamic projection neurons is provided by local DH inhibitory interneurons.
The gate control theory of Melzack and Wall posits that large fibers that transmit innocuous stimuli synapse with and activate inhibitory neurons of the substantia gelatinosa that in turn inhibit the pain projecting neurons of the dorsal horn. It has been suggested that parv-albumin-expressing inhibitory GABA / glycinergic islet cells that are located in inner lamina II – IV are the anatomical basis for this pain dampening mechanism because they are the target of low-threshold primary afferents. Another contribution to this mechanism may be from islet cell interneurons that receive projections from low-threshold mechanosensitive C fibers. Dorsal horn inhibition may be effected both pre and postsynaptically. Inner lamina II and III GABAergic interneurons inhibit primary myelinated afferents that block low-threshold afferences to excitatory interneurons. Islet cell inhibitory interneurons modulate descending mono-aminergic input to pain transmission neurons. As noted in the gate control theory noxious stimuli may inhibit inhibitory neurons that would increase pain transmission. Compatible with this proposal has been the demonstration that direct projections from nociceptive substance P-containing fibers to inhibitory islet or central interneurons are activated by noxious stimuli enhance pain transmission by inhibiting a subset of other inhibitory islet cell interneurons.
The dorsal horn is a major gate in the CNS for the modulation and processing of nociception. In general, chronic neuropathic pain results from lesions of the somatosensory system that causes peripheral and central sensitization. Spinothalamic systems are primarily involved. Peripheral sensitization is a manifestation of maladaptive neuroplasticity caused by the expression and dysfunction of a wide spectrum of cation channels in nociceptors that include TRPV1 and voltage-gated sodium (Nav1.7, 1.8, 1.9 and 1.3) channels in response to axon injury or different forms of tissue damage. Calcium channels control transmitter release in the dorsal horn as well as neuronal activity of pain projection neurons and plasticity in chronic pain states.
In the spinal cord during nociceptive afferent stimulation, there is co-release of substance P and calcitonin gene related peptides (CGRP) and glutamate on pain projecting neurons (PTNs). These neurotransmitters activate both neurokinin (NKR1) and N-methyl-D-aspartate (NMDA) receptors in chronic pain states which combined with loss of local DH and supraspinal inhibition causes hyper- excitability of pain transmission neurons. Major manifestations of central sensitization are windup (temporal summation) induced by specific Aδ and C-fiber discharge from tissue and nerve damage and long-term potentiation (LTP) from high-frequency stimulation. Homosynaptic LTP is the persistent increase in synaptic strength of excitatory glutamatergic synapses on dorsal horn projection neurons. Prolonged nociceptive stimulation may induce heterosynaptic LTP, long lasting facilitation of dorsal horn neurons to non-nociceptive AΒ or C-fiber afferences. Heterosynaptic LTP causes the change (facilitation) of adjacent non-activated synapses (by the nociceptive barrage) that: (1) expands the stimulus sensitive receptive fields beyond the area of the damaged tissue. LTP occurs both pre and post synaptically primarily by calcium mediated mechanisms.
In the post-synaptic pain transmission neuron there is calcium influx from:
1.L-type voltage-gated Cav1.2 channels
2.NMDA receptors (whose magnesium block has been lifted)
3.Ca2+ release from intracellular stores (primarily the endoplasmic reticulum)
The intracellular Ca2+ release may also be induced by metabotropic glutamate receptors or the tyrosine kinase B receptor that is activated by brain-derived neurotrophic factor (BDNF). The increased intracellular calcium activates enzymatic cascades mediated by protein kinases such as calcium calmodulin kinase II and extracellular signal-related kinase.
These enzymatic-mediated transformations cause:
1.Upregulation of α-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA) receptor expression and recruitment to the post synaptic membrane
2.Activation of transcription and local translation of synaptic proteins
3.Growth and structural changes of dendritic spines
Presynaptic mechanisms of central sensitization cause increased glutamate release from C afferents enhanced by nitric oxide that is generated from protein kinase G mediated activity.
Hyperexcitable spinal dorsal horn pain projection neurons demonstrate:
1.Reduced firing thresholds
2.Increased receptive field size
3.Spontaneous discharge
4.Greater evoked activity
Along with LTP, ‘windup’ is a major manifestation of central sensitization and is the increase in neuronal response to a constant stimulus. It is also known as temporal summation. It is induced by Aδ and C-fiber input to pain projecting neurons but once induced enhances responses to both nociceptive and low-threshold mechanical afferences (inputs). In general, if the nociceptive drive onto central pain projecting neurons is blocked, there is a slow return of pain projection neuronal response to baseline levels. Some degree of peripheral afference is needed to maintain central sensitization.
The characteristic properties of sensitized nociceptors are:
1.Spontaneous discharge (frequently termed ectopic)
2.A lowered activation threshold for thermal and mechanical stimuli (particularly in neuropathic pain states)
3.Increased discharge following suprathreshold stimulation.
The spontaneous barrage from sensitized nociceptors causes neuropathic central sensitization.
A subset of dorsal horn pain projecting neurons that contain the NK1 receptor (substance P) are responsible for windup of PTNs but also for activation of the brainstem projections of the rostral ventral medullary nucleus (RVM) and the PAG that modulate descending inhibition and facilitation of pain transmission. A loss or inadequate diffuse noxious inhibitory control (DNIC) modulation of pain transmission has been demonstrated in many chronic neuropathic pain conditions. Sensitized spinal circuits are restricted to the projection zones of the affected nerves. Descending nociceptive controls may be diffuse, bilateral, and nonsegmental.
As noted earlier, experimental peripheral axotomy demonstrates sprouting of AΒ afferents into lamina I and outer lamina II. After a nerve injury, there may be a phenotype switch in which there is upregulation of expression of substance P on low threshold afferents. Still, evidence is lacking for substance P activation of NK1R receptors in nociceptive PTNs of lamina I. Prolonged noxious stimulation causes extracellular receptor-activated kinase (ERK1) mediated phosphorylation and downregulation of Kv4.2 channels in PTNs, increasing their excitability.
Loss of DH inhibition is one major mechanism underlying central sensitization. It also occurs at multiple levels of the pain matrix. Mechanisms that contribute to loss of GABAergic and glycinergic inhibition in the dorsal horn may follow axonal or nerve injury.
They include:
1.Excitotoxic damage
2.Long-term depression (LTD)
3.Reduced efficacy of GABAA or glycine receptor channels
4.Activation of TRPV1 receptors that induce LTD of excitatory input from myelinated afferents to inhibitory neurons.
In addition, peripheral axonal injury may initiate CA2+-dependent signaling that causes a general down regulation of the excitatory projections of Aδ and C-fibers to GABAergic neurons.
Recent experimental studies have demonstrated a major role of spinal cord microglia in the induction and maintenance of chronic pain by release of mediators that modulate the plasticity of synaptic response in inhibitory and excitatory pain circuitry throughout the pain matrix. Microglia have been shown to reduce the efficacy of inhibition at the spinal cord level by secretion of BDNF that down regulates the potassium chloride exporter in lamina I neurons. This mechanism is based upon a depolarization shift in the equilibrium chloride potential such that chloride current flows from the PTN (depolarizing the cell) which reduces the efficacy of GABAA and glycine receptor-mediated inhibition.
The molecular mechanisms that lead to amplification of nociceptive signals at the level of afferent input and the central sensitization of pain transmission neurons are rapidly unfolding and are starting to unravel some of the questions in regard to pain vulnerability and resistance.
Dermatomes and Sclerotomes
A dermatome consists of the primary neurons of the DRG and their peripheral and central afferents that include cutaneous and visceral endings. Each dermatome is segregated as it enters the spinal cord: the medial fibers that are primarily myelinated and are mechanosensitive, and the lateral are pain and temperative fibers (segregation of the spinal roots at the dorsal root entry zone (DREZ)). Each dermatome maintains a specific topography throughout its projections in the CNS (brainstem, thalamus, and cortex).
A sclerotome refers to pain projection pathways from bones, ligaments, and fascia that project slightly differently from the dermatomal pattern. After traversing the dorsal root entry zone, C-fibers innervate the specific spinal segment, but also approximately two spinal segments rostrally and caudally by means of Lissauer’s tract. There is thus overlap of sensory pain dermatomal innervations. There is a small contralateral segmental DH innervation through the anterior commissures.
The dorsal horn is cytoarchitecturally organized into Rexed layers (laminae). A-delta fiber afferents synapse in lamina I and the outermost lamina II cells. There are also important synapses from A-delta fibers in lateral lamina V. Large mechanosensitive (heavily myelinated) fibers synapse in layers III and IV. The primary synaptic connections of C-fibers is in lamina I and the substantia gelatinosa (Rexed layer II). C-fiber collaterals project to the intermediolateral column (ILC) and the motor neurons of Rexed layers IX. Cells in lamina VII (primarily motor interneurons) and lamina VIII (autonomic neurons) also respond to painful stimuli. These neurons receive projections from the DNIC (descending pain-modulating system; principally from the rostral ventral medullary neurons). Rexed layer VII motor interneurons also synapse segmentally with C-fibers. Reflex connections from C-fiber afferents to motor neurons in IX and autonomic neurons of the intermediolateral column (ILC) are activated in pain states. There are sympathetic chemical connections at the site of injury, where released norepinephrine may excite upregulated sympathetic alpha-receptors on nociceptive afferents, as well as plastic sympathetic upregulations within the DRG. In addition to the secondary neurons (pain projecting neurons PTN) of Rexed layers I and II (the primary neurons are in the DRG), the neurons of lateral Rexed layers V and VI are pivotal for many of the secondary modalities of pain sensation seen in neuropathic pain states.
Neurons in these layers are wide dynamic in range:
1.They receive low threshold mechanoreceptive input (LTM; A-beta myelinated afferents)
2.Sympathetic afferents
3.Temperative (C-fiber; heat; A-delta cold fiber afferents) and nociceptive specific projections.
Integration of these afferent inputs determines if these neurons will depolarize.
The secondary axons of Rexed layers I, II (inner /outer layers), lateral V and VI form the major components of the lateral spinothalamic tract. The spinal thalamic tract (STT) decussates in the anterior spinal commissure and ascends contralaterally as the spinothalamic tract that synapses at brainstem and thalamic levels. Pain and temperature fibers decussate approximately at two segmental levels rostral to their level of entry. Therefore, there is a drop of pain and temperature sensations on the trunk of approximately two levels with spinal cord injury (often slightly higher posteriorly). Sacral fibers are outermost in the tract while those carrying cervical and arm pain are most medial. There is also segregation by modality.
The modalities may be segregated superiorly to inferiorly in the STT:
Medially placed anterolateral fascicular fibers comprise the spinoreticular thalamic pathway. It projects to the reticular core of the medulla and midbrain and synapses in the medial (DM) and intralaminar nuclei of the thalamus (centralis medialis, lateralis, and zona reticularis). This paleospinothalamic system synapses with the nucleus gigantocellularis, parabrachial nucleus, midbrain reticular formation, periaqueductal gray (PAG) and hypothalamic nuclei. Other fasciculi of the medial anterolateral pathway synapse with the brainstem reticular core by a series of short interneuronal projections. There is also a direct spinohypothalamic pathway.
The medial fasciculi of the spinothalamic pathway conduct pain from the gastrointestinal tract, periosteum, and peritoneum. There is some evidence that deep visceral pain may also be carried in a deep pathway in the posterior columns. It has been proposed that this primarily medial pathway (slowly conducting with widespread diffuse core and limbic projections) is for the affective components of pain. The direct fast conducting spinothalamic pathway projects to the ventroposterolateral (VPL) and ventroposterior medial (VPM) nuclei of the thalamic vertebrobasilar complex (VB). This system projects primarily to SI of the primary sensory cortex. This pathway mediates the discriminate aspects of pain (quality, localization, and intensity): it is generally referred to as the lateral pathway.
Visceral pain from the esophagus, stomach, small bowel, and proximal colon project via the vagus nerve that projects to the nucleus tractus solitaries (NTS).
The direct spinothalamic tract separates into two major divisions before synapsing in the thalamus (as noted above, it gives off collaterals to many nuclei in the brainstem as it ascends): the lateral division synapses in the VPL and some posterior nuclei, while the medial division synapses are in the intralaminar complex and submedius nucleus. As noted above, the spinoreticularothalamic pathway synapses with the parafascicular and centrolateral thalamic nuclei. Thus they overlap medial spinothalamic projections. The intralaminar fiber projections also overlap with direct spinothalamic projections.
Projections from the dorsal horn are widespread and overlapping. The lateral system, the discriminative pain pathway, is primarily composed of dorsal horn projections to the VB complex (VPM and VPL) of the thalamus and consequently to the primary sensory cortex. The affectual pain circuits comprise components of the reticular formation, the parabrachial nucleus, the amygdala, insular cortex, anterior cingulate gyrus, and SII. Both of these circuitries are commonly referred to as the pain matrix that encodes the discriminative, affective and motivational components of the perception of pain.
The primary excitatory neurotransmitter in pain transmission neurons (PTNs) is glutamate. There is a contribution from aspartate and kainate. Na(V)1.7 sodium channels are pivotal for initiation of the action potential while a variety of potassium and HCN (hyperpolarization-activated cyclic nucleotide gated) channels return the membrane to its resting potential. HCN channels are activated with membrane hyperpolarization and conduct an inward excitatory current. Dorsal horn inhibitory interneurons utilize GABA-B and glycine, as their inhibitory neurotransmitters. The potassium chloride co-transporter is essential for inhibition in the DH. It functions under physiologic conditions to decrease intracellular chloride in pain transmission neurons. Thus if it is defective, afferents from inhibitory neurons that release GABA-B onto PTNs would depolarize (excite) PTNs as chloride would follow its electrochemical gradient (leave the cell) and the membrane potential would fall to threshold levels. The NMDA receptor (N-methyl-D-aspartate) is extremely important for plastic changes in the DH that occur in chronic pain states. They are a class of ionotropic glutamate receptors. NMDARs that have slow deactivation kinetics, are highly Ca2+ permeable, and require partial depolarization to relieve their external Mg2+ channel block. C-fibers coexpress substance P and calcitonin G-related peptide in addition to glutamate. Thus, a continual C-fiber input to NMDA receptors depolarizes these receptors due to the release of the neuromodulator SP, which depolarizes the receptor enough to release its Mg2+ channel block and allow sodium and calcium influx. Additionally, under conditions of a continuous C-fiber input lateral synaptic NMDA receptors move to the synapse and acquire more AMPA channels. The increased calcium concentration in the PTN activates calcium calmodulin II which in turn activates P38 mitogen-activated kinase (MAPK) and extracellular regulated kinase (ERK) 1/2 to effect gene expression through cyclic AMP response element (CREB transcription factor). The phosphorylation and dephosphorylation of intracellular enzymatic cascades determine PTN excitability. The induction of new protein synthesis by activation of CaMKII and ultimately the CREB transcription factor is a major cause of neuronal plasticity in chronic pain states.
Radicular trauma from disc and degenerative osteoarthritic conditions, as well as autoimmune disease, are major causes of chronic neuropathic pain. In the area of injury, the microenvironment that includes protons, bradykinin, leukocytes, serotonin, prostaglandin, and ROS (i.e. an “inflammatory soup”) induces peripheral nociceptive afferent terminal sensitization. C-fiber activation (from the inflammatory milieu) induces phosphorylation of ERK in small DRG neurons (PTN). C-fiber stimulation also induces phosphorylation in MAPKs and extracellular signal-regulated kinases (ERKs) in neurons with myelinated fibers. These intracellular enzymatic cascades lower the firing threshold of the C-fiber and A-delta fiber nociceptors. Prolonged nociceptive afferent input from C-fibers (primarily the mechanical insensitive ones) induces central sensitization in the DH and other components of the pain matrix. Central sensitization refers to the increased synaptic efficacy in PTNs (pain transmission neurons at all levels of the pain matrix) that follows intense peripheral noxious stimuli from tissue injury or nerve damage.
Central sensitization is manifested by:
This physiological state is similar in physiologic parameters to long-term potentiation (LTP) and depression (LTD) that are important for memory and learning.
In parallel with the molecular changes in pain transmission neurons is activation of segmental microglia. Chemokines released from activated neurons (fractalkine) as well as extracellular adenosine triphosphate (ATP) play pivotal roles in the physiology of PTNs. Microglia express several subtypes of P2XR (purine receptors) which contribute to pain signaling in the spinal cord under pathologic conditions such as neuropathic pain. Activated microglia secrete inflammatory cytokines which both induce and maintain neuropathic pain and contribute to central sensitization.
As noted earlier, nociception is transmitted to the superficial lamina of the dorsal horn (lamina I and II) by thinly myelinated Aδ fibers and unmyelinated C-fibers. The former transmit sharp well-localized epicutic pain and the latter poorly localized and often delayed burning pain. AΒ larger myelinated fibers synapse in the deeper layers of the dorsal horn (primarily lamina III and IV) on projection neurons and excitatory and inhibitory interneurons. There is an anatomical link that is polysynaptic to pain projection neurons of the superficial dorsal horn that is strongly repressed by inhibitory interneurons (GABAergic and glycinergic) under normal circumstances. AΒ fibers carry mechanical sensation and proprioception and not pain. The complex neural networks of the dorsal horn are modulated and modified under pathological conditions of tissue inflammation and nerve injury. The loss of function of inhibitory neurons in the dorsal horn circuitry or reduced effectiveness of GABAergic and glycinergic inhibition is a major component of neuropathic pain.
Glial cells are astrocytes, oligodendrocytes and microglia and are approximately 70% of all cells in the CNS. Microglia, the resident macrophages of the CNS, are derived from macrophages of the yolk sac and are widely distributed throughout the central nervous system. They have small cell bodies with branched and motile processes that monitor their local milieu. They respond rapidly to stimuli that include inflammation and damage to both the peripheral and central nervous system. Activated microglia progress through a stereotypic series of changes in morphology, gene expression, function and number. They synthesize and release cytokines and other chemical mediators that induce immunologic responses and also alter the function of neurons. The morphological changes in microglia after activation are cell body hypertrophy, thickened and retracted processes, an increase in number and upregulation of their markers CD11b and Iba1 (ionized calcium-binding adapter molecule-1). Signaling neuronally derived molecules for microglial activation include:
1.Monocyte chemoattractant protein-1 (MCP-1 or CCL2), and
2.Metalloproteinase-9 (MMP-9)
These molecules are upregulated in the dorsal root ganglion after peripheral nerve injury and, when experimentally administered intrathecally in normal rats, induce microglial activation and allodynia. The substrates for MMP-9 are thought to include fractalkine, interleukin 1Β and tumor necrosis factor-α. Microglia express a receptor for the cytokine interferon -γ (IFN-γ R) which when stimulated changes their morphology and increases their number. The source of IFN-γ has not been identified but appears to be important in transforming microglia into an activated state. The glycoprotein CSF 1 also has been demonstrated to activate microglia. Toll-like receptors, type I transmembrane signaling proteins that recognize pathogen associated molecular patterns are also a component of microglial activation.
Microglia are also important for the detection and removal of apoptotic neuronal debris. Following nerve injury, activated microglia are recruited to the dorsal horn (often to the specific segment of the spinal cord that supplies the injured dermatome) by chemokine and ATP signaling. They survey and modify sensory afferent input for damage by extension and movement of their processes. This is effected by ion channel activation, modulation of membrane potential, changes in cell volume and ion concentration and induces phagocytosis. The relevance of these mechanisms in neuropathic pain states has not been determined.
Peripheral nerve injury, and to a lesser degree inflammatory pathologies, cause dramatic upregulation of the ATP receptor P2X4 and the chemokine receptor CX3CR1 in spinal cord microglia. The signaling from activated microglia to dorsal horn neurons, both local circuit and pain projecting, is an essential component of both the induction and maintenance of neuropathic pain. A major mechanism for this effect is the activation of P2X4Rs that cause the synthesis and release of brain derived neurotrophic factor (BDNF) which causes an alteration of the transmembrane anion gradient in a subpopulation of dorsal horn lamina I neurons by down regulation of the neuronal chloride transporter KCC2. This causes an increase of Cl- ion concentration within these neurons and when GABA or glycine is released onto these neurons Cl- ion flows down its electrochemical gradient (less negative Cl- intracellularly) which depolarizes the cell. The result is aberrant nociceptive output and a decrease of inhibitory tone that normally suppresses the polysynaptic pathways that connect AΒ input to lamina I pain-projecting neurons. This mechanism has been posited as a cause of the mechanical hyperalgesia and allodynia that is characteristic of neuropathic pain states. Recent experimental work has demonstrated that interferon regulatory factor-8 is an essential transcription factor for P2X4R upregulation. It is expressed in lymphocytes and dendritic cells. After peripheral nerve injury IRF-8 is selectively upregulated in microglia. Suppression of the upregulation of spinal IRF8 decreases PNI induced tactile allodynia. It has also been demonstrated that IRF8 induces the expression of genes associated with microglial activation including those involved in the upregulation of P2X4R. Other recently identified transcription factors that regulate microglial function include IF5, the E26-transformation-specific family transcription factor PV.1 which has been shown to control the function and phenotype of human brain microglia. Runt-related transcription factor 1 also regulates the activity state of microglia and is upregulated in spinal cord microglia after peripheral nerve injury. In order to effectively bind its ATP ligand, P2X4Rs need to be expressed on the cell surface. Trafficking of P2X4R receptors from intracellular compartments occurs when microglia are stimulated by Toll-like receptor 1 agonists lipopolysaccharide or the Ca2+ ionophore ionomycin. The chemokine CCL2 also increases P2X4R on the cell surface putatively by exocytosis of P2X4R-containing lysosomes. It is clear that microglial P24XRs are dynamically regulated and their increased expression on the cell surface may increase the responsiveness of microglia to extracellular ATP.
Activation of various cell surface receptors in spinal microglia induces intracellular signaling cascades. Activation of P38 MAPK (mitogen activated protein kinase) is an important component that leads to neuropathic pain after tissue and nerve injury. Cathepsin S through fractalkine and its receptor signaling and P2Y12R have been shown to be involved in P38 MAPK signaling. P38 MAPK is primarily activated in spinal cells that express the microglial markers CD11b / OX-42 and Iba1. P38 activation peaks in the first week after peripheral nerve, ventral root and spinal cord injury and remains elevated (after PN1) for three weeks. Minocycline, a nonselective microglial inhibitor, decreases neuropathic pain in animal models by inhibiting p38. MMP-9, ATP and the chemokines CCL2 and fractalkine which are released from DRG neurons from nerve injury-induced discharge, which activate spinal cord microglia. Studies have shown that both C-fiber activity and large myelinated AΒ fibers activate microglia after nerve injury. In addition to P38 MAPK extracellular signal-regulated protein kinase (ERK) is increased in the superficial dorsal horn following peripheral nerve injury. Upregulation of ERK 1 and 2 are seen first in dorsal horn neurons shortly after injury, then in microglia for several days and in astrocytes after 3 weeks.
The phosphorylation of p38 in microglia after activation of the P2X4 receptor increases the synthesis and release of BDNF and the cytokines IL-1Β, IL-6, and TNFα in part by the activation of the transcription factor NF-kB. TLR4 activation by lipopolysaccharide also activates p38 MAPK and induces IL-1Β release.
Experimentally blocking spinal p38 in pain models:
1)Decreases upregulation of IL-1Β,
2)Decreases C-fiber-evoked responses, N-methyl-D-aspartate receptor mediated responses
3)Suppresses wind-up in wide-dynamic range dorsal horn neurons,
4)Decreases the inhibitory tone of the dorsal horn by decreasing GABAA receptor-mediated currents.
The released pro-inflammatory cytokines have a major modulatory role in excitatory or inhibitory synaptic transmission in the superficial dorsal horn circuitry. In experimental rat models of spinal cord injury, inhibition of ERK suppresses the hyperresponsiveness of pain projecting neurons by reducing the synthesis of prostaglandin E2.
Recently, an ion channel of the TMEM 16 family (anoctamins) of transmembrane proteins have been described that have pleiotropic functions that include ion transport, phospholipid scrambling (translocation of phospholipids between the two monolayers of a lipid bilayer of a cell membrane) and regulation of other membrane proteins. TMEM16A (anoctamin-1) functions as a Ca2+-activated Cl- channel that has physiologic functions in transepithelial ion transport, smooth muscle contraction, olfaction, phototransduction, nociception and control of neuronal excitability. The Ca2+ activated channel has either anion or non-selective cation permeability.
In both in vivo and ex vivo preparations, microglia from TMEM16F conditional knockout mice demonstrate:
1)Absence of mechanical hypersensitivity after peripheral nerve injury
2)Decreased phagocytosis by spinal microglia
3)Altered morphology
4)Deficits of activation markers
5)Diminished branch motility and phagocytic ability
This evidence supports a role for phagocytic activity of microglia after nerve injury in the altered nociceptive processing that causes neuropathic pain.
Activated microglia have altered expression of genes that upregulate cell-surface receptors (P2X4R being primary) and intracellular signaling molecules (p38 MAPK as primary) that produce and secrete diffusible factors that include BDNF and proinflammatory cytokines that modulate pain processing in the dorsal horn of the spinal cord.
The individual pain experience is extremely complicated and involves many brain areas, their reciprocal connectivity and modulation. The subjective experience of pain is modulated by cognitive, affective, and contextual factors which complicates the delineation of a primary core area for the perception of pain. Early imaging studies supported a major role of the insular cortex for encoding and processing nociception. Many studies have demonstrated that the neural correlate of pain is associated with the concomitant activation of the thalamus, primary and secondary somatosensory cortices (SI and SII), insula, anterior cingulate cortex (ACC) and the prefrontal (PFC) cortices.
In order to overcome the power deficits of many small imaging studies of various pain states and to capture 3 dimensional (3D) spatial information derived from voxel-based data the meta analytical method of activation likelihood estimation (ALE) was developed.
The method:
1.Provides statistical integration of voxel-based data across multiple studies and
2.Allows an estimate of activation likelihood of a given area in a pain state
A quantitative assessment of brain regions involved in pain processing reveals that the insula, ACC, SII and the thalamus are activated by pain irrespective of modality and body part both in patients and healthy controls. The predominance of insular and anterior cingulate cortex (ACC) activations supports their essential role in pain processing and the experience of pain. The likelihood of activation includes the entire insular cortex with peaks in its anterior portions. The dorsal-posterior insula has been posited as the area of cortical representation of nociception, the anterior insula is associated with the integration of affective and interoceptive states. Present data supports the anterior insula as the essential cortex for the subjective experience of pain. It has been posited that the posterior insula is a non-specific relay for sensory information and codes its stimulus intensity. Neuroanatomical evidence suggests that the right anterior insula is a component of the afferent system for the interoceptive representation of pain. The anterior insula (AI) has been posited to code the homeostatic state of the body and to integrate it with the motivational drive to restore homeostasis and body protection. The anterior insula is activated during the perception of empathy for pain (watching pain in others). The anterior cingulate cortex is a limbic cortex that receives the same spinothalamic tract input as the anterior insula. The anterior insula and the ACC are frequently activated concomitantly and it has been suggested that AI is the site of pain awareness and the ACC is the site for the initiation of a behavioral response (pain avoidance). The ACC is associated with the emotional-motivational aspects of pain. ACC activation is associated with the unpleasantness of pain rather than its intensity. The AI, ACC and the thalamus are activated across pain modalities that suggest that they are components of a core network of brain areas involved in pain processing.
Chronic pain causes maladaptive neuroplasticity that is reflected by: 1) structural, 2) functional and 3) neurochemical brain alterations. Pain patients are less likely to activate the anterior insula and the thalamus than healthy control subjects. This has been posited to represent disrupted interoception that may be a cause for the absence of pain inhibitory activation during evoked pain. It has also been suggested that the less likelihood of a pain patient to activate AI and the cingulate gyrus may indicate a ceiling effect as the patient has continuing nociceptive input to nociceptive processing areas and is unable to increase the activation further (from experimental pain protocols). The above results, i.e. failure to activate AI, the cingulate cortex, and the thalamus support a proposed shift from the lateral discriminative pain system to the medial system that processes the affective-motivational aspects of pain during the process of pain chronification. The thalamus demonstrates structural changes, decreased activity during rest and attenuated pain-evoked activation during several categories of pain. These findings support the hypothesis that pain pathophysiology involves thalamocortical dysrhythmia.
The prefrontal cortex is an important brain region for inhibitory control of pain as demonstrated by its function during the reappraisal of pain and placebo analgesia. Recent studies have demonstrated a less likelihood to activate parts of the middle-frontal gyrus in pain states that may reflect decreased activation of the brain’s inhibitory circuitry.
In summary: 1) functional brain mapping supports an essential rule for the insula and ACC in the perception of pain and 2) there is decreased activation in the anterior insula, cingulate cortex and thalamus in chronic pain patients when compared to healthy controls.
Peripheral nociceptors are more easily sensitized to thermal than mechanical stimuli. The manifestations of peripheral sensitization are:
1)Reduced thresholds
2)Increased suprathreshold responses
3)Spontaneous discharge
TRPV1 (transient receptor potential cation channel subfamily V member 1) is a transient receptor protein ion channel primarily responsive to heat and protons. After phosphorylation via multiple pathways, it is a major cause of peripheral sensitization to its ligands and heat. In inflammatory conditions, its activation threshold on C-fibers may be below body temperature causing them to discharge and producing spontaneous pain. If the receptor is repeatedly stimulated with mildly noxious heat stimuli it loses the phasic component of its response as well as its ability to generate action potentials due to a decrease of heat-induced inward currents. Nociceptors adapt with prolonged constant stimulation.
Peripheral sensitization and receptor fatigue are mechanisms of modulation of nociceptive input in the peripheral nervous system. Fatigue occurs with mild stimuli and sensitization with possible tissue damaging stimuli. Central sensitization in most instances requires a continuous afferent nociceptive drive to be maintained. Peripheral sensitization is a major mechanism of this nociceptive afference.
Lamina I-II neurons of the superficial dorsal horn respond to nociceptive specific afferent input. The pain projecting neurons of the deep dorsal horn respond to thermal, chemical and mechanical stimuli as well as to a broad range of intensities from the afferent input of peripheral nerves. The slow temporal summation of nociceptive neurons in the deep dorsal horn is termed “wind-up”. During wind-up, repetitive stimulation at low frequencies (more than 1 impulse every three seconds), induces an increase of the wide dynamic range neuron (WDR) evoked response and post-discharge with each stimulus. “Wind-up” is induced by C-fiber input in WDR neurons and not high threshold or nociceptive specific neurons that only respond to nociceptive input. It is not induced by A-fiber afferences. “Wind-up” may be a mechanism to compensate for peripheral receptor fatigue. During prolonged low-frequency stimulation “wind-up” evolves into long-term depression in which synaptic efficacy is decreased. “Wind-up” is induced by activation of NMDA receptors after the magnesium block has been removed by depolarization of the neuron from C-fiber released substance P. There are no neuropeptides in AΒ fibers - which explains why low threshold afferences are unable to induce “wind-up”. The major effect of NMDA activation is its permeability to calcium. After activation, the increased calcium concentration activates calcium calmodulin dependent kinases (CaMKI/II) and ERK that along with other intracellular cascades increase synaptic glutamate efficacy.
Spinal nociceptive neurons are both tonically inhibited from local circuit GABAergic and glycinergic interneurons and also receive stimulus evoked inhibitory control projections (DNIC) from the rostral ventral medullary nucleus (RVM) located in the caudal medulla and the periaqueductal gray (PAG) nuclei of the midbrain. The RVM may also be excitatory to nociceptive DH neurons utilizing serotonin as the ligand for the 5HT3 receptor. The effects of DNIC are widespread and are a reflection of the wide dynamic range neurons that they target. They are also known as convergent neurons as they respond to all somatosensory modalities that includes thermal, chemical and mechanical. They may be projection neurons or interneurons for polysynaptic reflexes. The receptive fields of WDR neurons have a gradient of sensitivity, the center responding to any mechanical stimulus (including hair movement and light touch) while the periphery responds only to noxious stimuli. WDR neurons also receive afferences from viscera, muscles, and joints. This convergence of inputs allows them to monitor both the interface with the external environment and the internal milieu. WDR neurons have a dynamic physiology as the size of their peripheral fields and their output may change due to the evoked plasticity of both excitatory and inhibitory segmental processes. These WDR neurons are strongly inhibited when a nociceptive stimulus is applied to any part of the body that is beyond their excitatory receptive field. DNIC projections only modify convergent wide dynamic neurons and the inhibition is usually triggered only by a nociceptive conditioning stimulus. There is evidence that the level of pain induced by the conditioning stimulus may be associated with the degree of DNIC or conditioned pain modulation. A larger area for conditioning stimulation causes stronger pain inhibition posited to be due to spatial summation.
Recent experiments utilizing compression for conditioned pain modulation have been effective in inducing DNIC pain inhibition. The DNIC inhibition is potent, affects all of the physiological functions of the WDR neuron, and persists for some time after withdrawal of the test stimulus. A-delta and C-fibers are the primary afferences that trigger DNIC. DNIC anatomically is subserved by the parabrachial nucleus and the subnucleus reticularis dorsalis and possibly the nucleus raphe magnus via its on and off cells. The DNIC has been shown to modulate both “Off “and “On” cells in the RVM, the major component of the spino-bulbar-spinal inhibitory loop.
The posited function of this circuitry is to enhance spatial contrast of a pain signal by lateral inhibition that accentuates the most relevant and strongest nociceptive input for processing and response programming.
The brain can control its own ascending nociceptive afference. The RVM receives descending projections from the PAG that in turn is modulated by the hypothalamus, amygdala, and areas of the cerebral cortex. This allows cognitive and affective processes to modify pain processing at a spinal level. This is exemplified by the placebo affect in which expectation and conditioning can decrease dorsal horn excitability. As noted above, the posterior insular cortex is essential for coding the intensity of a painful stimulus while the anterior insula and anterior cingulate cortices are important for the integration of the affective and interoceptive aspects of the pain experience. The prefrontal cortex, the primary and secondary motor cortices are all components of the pain processing system and the programs to avoid tissue injury that reach the spinal level through dorsal lateral pathways of the spinal cord. Pain states activate the contralateral thalamus whose activity can be modified by transcranial cortical stimulation of the contralateral motor cortex. Maladaptive plasticity of the cortex has been clearly demonstrated in phantom limb pain. Cortical pain inhibition is primarily effected by modulation of the spino-bulbar-spinal loop of the caudal brainstem centered in the RVM.
Approximately 30% of patients with neuropathic pain respond to approved therapies. Presentation of sensory pain symptoms vary but patients can be characterized by different symptomatic pain profiles or phenotypes. A major goal of neuropathic pain management is to develop mechanism-based treatments. The differentiation of neuropathic pain from nociceptive pain is critical in this determination. Quantitative sensory testing combined with various screening questionnaires and the clinical evaluation are the platforms for the determination of sensory profiles in neuropathic pain patients.
The pain DETECT questionnaire is validated and consists of seven pain sensory symptom items, one pain course pattern item and one pain radiation item. The pain DETECT questionnaire has been shown to be effective in identifying neuropathic pain of varying etiologies and in determining pain intensity and its relationship to health status. It is also able to characterize specific symptom clusters by sensory symptoms.
Somatosensory abnormalities in patients with neuropathic pain syndromes utilizing quantitative sensory testing (QST) of the German Research Network in Neuropathic Pain protocol demonstrated:
1.A shift to hyperalgesia for nociceptive pain
2.Hypoesthesia for non-nociceptive parameters
3.Thermosensory or mechanical hypoesthesia was more frequent than hypoalgesia
4.Mechanical hyperalgesia (blunt pressure, pinprick) was more frequent than thermal hyperalgesia, dynamic mechanical allodynia, paradoxical heat sensations or wind up
5.All sensory alterations were demonstrated in each neurological pathology but with different frequencies
6.Thermal and mechanical hyperalgesias occur most frequently with complex regional pain syndrome and peripheral nerve injury
7.Allodynia was frequent with postherpetic neuralgia
8.Postherpetic neuralgia and central pain had subgroups with either mechanical hyperalgesia or mechanical hypoalgesia
9.In central pain and polyneuropathy there were often combinations of gain and loss whose most frequent combination was thermal / mechanical loss without hyperalgesia
10. Mixed loss with mechanical hyperalgesia was noted in peripheral nerve pathology
11. Mechanical hyperalgesia without sensory loss is characteristic of trigeminal neuralgia
1.Persistent pain with hyperalgesia to heat that is restricted to the area of tissue injury supports the mechanism of peripheral sensitization:
a.Nociceptors have lowered thresholds to heat and a low pH
b.The pain persists for up to a day and is limited to the site of the injury
c.Peripheral sensitization and fatigue are localized to the stimulated nociceptors and even to the stimulated part of the receptive field
2.Hyperalgesia to punctate stimuli (pinprick) and dynamic mechanical allodynia (light brushing) which may extend one or two segments above and below the area of tissue damage, is supportive of central sensitization. It may be long lasting and is frequently associated with spread. Receptive fields of central neurons expand and afferences that were not sufficient to discharge dorsal horn neurons are now capable of doing so. The loss of inhibition of local circuit DH GABAergic and glycinergic interneurons may no longer tonically inhibit AΒ polysynaptic pathways so that mechanical stimuli are able to drive pain projecting neurons of lamina I of the dorsal horn
3.Pain in a specific body region may be inhibited by AΒ large myelinated fiber activation only during the stimulation, is consistent with the gate control hypothesis
4.Pain inhibition from A-delta fiber activation is confined to the stimulated body part and is consistent with long-term depression (LTD). Synaptic efficacy of first order DH pain projecting neurons is attenuated due to decrease of presynaptic neurotransmitter release or decrease in postsynaptic receptor density; LTD is induced by small, slow rises in postsynaptic calcium levels. The calcium concentration in the postsynaptic cell is a major determinant whether LTD or LTP is effected. LTD is a localized effect that can last for hours
5.Widespread pain that may involve the entire body associated with mechanical hyperalgesia is suggestive of deficits in descending inhibitory controls or supraspinal facilitation by modulation of the RVM nucleus. The duration of the effects outlasts the conditioning stimulus for a few minutes
Major advances have been made in an understanding of the molecular basis of neuropathic pain. In the future, there will be individualized mechanism based pain therapy.
As noted above, chronic neuropathic pain is extremely complex at all levels and engages:
(1)Sensory discriminative components
(2)Affective motivational components
(3)Cognitive components
It is a perception unique to each individual, dependent on genetics, a past pain history and present context. Acute pain activates different circuitry than chronic pain and there are many mechanisms leading to the chronification of acute pain. Central sensitization and pain modulation occur in the brainstem and spinal cord that are now starting to be imaged with high field 7 Tesla and MRI technology.
The neuroimaging modalities that are used to study the brain networks that underlie both acute and chronic pain include PET, EEG/ magnetoencephalography (concomitantly with imaging), single photon-emission computed tomography (SPECT/CT) and various MRI techniques, most recently including arterial spin labeling (ASL).
The major chronic pain states reported with these techniques include:
(1)Chronic low back pain
(2)Fibromyalgia
(3)Osteoarthritis
(4)Complex regional pain syndrome (CRPS)
(5)Phantom limb pain
(6)Chronic migraine
(7)Chronic pelvic pain
(8)Peripheral neuropathy
In addition, many experimental reports in rodents and healthy volunteers have allowed manipulations of the painful stimuli with neuroimaging and anatomical correlation. Neuroimaging has also given insight into the modulation of the pain experience, including attention, the anticipation of pain, empathy, placebo effects, meditation, emotional state (fear/anxiety), and reward aspects of pain relief.
Structural changes in the brain parenchyma occur with chronic neuropathic pain primarily demonstrated by voxel-based and cortical thickness analysis. CRPS, fibromyalgia, migraine, temporomandibular joint disorder, and chronic low back pain demonstrate regional increases and decreases in gray matter density and cortical thickness. These structural changes are demonstrated in the insular cortex, somatosensory cortices, motor cortex, and parietal cortices. Subcortical structural changes occur in the thalamus and basal ganglia. Possibly influencing the cognitive components of pain are alterations in the prefrontal cortex, hippocampus and amygdala (emotional regulation). Reversal of gray matter density in specific chronic pain entities are reported with effective therapy. The exact clinical correlation and meaning of these structural changes has not been elucidated. Gray matter changes are noted to increase over 3 years and to be correlated with increased low back pain in the face of minimal stress. Detailed evaluation of white matter connectivity between nodes of brain circuitries are obtained with the use of MRI tractography and fractional anisotrophy in various chronic neuropathic illnesses. Combined voxel-based morphometry and diffusion tensor imaging are utilized to evaluate the interactions between gray matter nodes and white matter alterations.
There is no specific brain area that solely encodes a painful stimulus. In the past, the dorsal posterior insular cortex was thought to be the major pain encoding cortical area. More recently, a core “pain matrix” that includes the thalamus, posterior and anterior insular cortex, SII, the ACC (anterior cingulate cortex), the PAG and central nucleus of the amygdala are thought to be the major pain encoding areas. The discriminatory components of acute pain are subserved by the lateral nuclei of the thalamic ventrobasal complex and project to SI and SII. The medial pain system of the pain matrix projects from the parabrachial nucleus and medial thalamic nuclei to the anterior cingulate area, which encode emotional aspects of pain, direct attention to the painful stimulus, the unpleasantness of pain and assigns response priorities. In chronic painful conditions there is a shift to the affective, emotional and reward circuitry which includes the mPFC (dorsal) - amygdala – nucleus accumbens. At a cellular level it has been shown that there is release of endogenous opioids in the rostral anterior cingulate region that is necessary for the release of dopamine in the NAc for relief of chronic pain. Functional studies have also demonstrated increased connectivity of the mPFC and the nucleus accumbens (NAc) in chronic neuropathic pain.
Intensity coding of pain is correlated with increased activity (fMRI) in the SI and posterior insular cortex in CRPS, low back pain and fibromyalgia when painful stimuli are applied to an affected area. Structural alterations during painful stimuli in chronic neuropathic pain disorders are also seen in SII and are thought to be a component of higher order sensory processing and integration. The primary motor, premotor, and supplementary motor cortices as well as the cerebellum are activated in fMRI studies in chronic neuropathic pain. Areas of the PFC that include the ventromedial PFC, the dorsolateral PFC and the orbitofrontal cortex are associated with alteration of cognitive processes and chronic pain. The temporo-parietal junction (a multimodal sensory area), precuneus, and posterior cingulate cortex demonstrate functional MRI alterations during chronic neuropathic pain. These are areas of the default mode network that is usually activated during mind wandering, introspection and self-referential thought (during the absence of a task). It is suggested that abnormalities in the DMN may be more apparent with chronic neuropathic pain.
Brain areas related to the affective and emotional components of pain – its unpleasantness and aversiveness include the anterior insular and anterior cingulate cortex that demonstrates altered function in chronic neuropathic pain states.
The psychological aspects of pain processing, which include fear and emotional states, demonstrate alterations in the central nucleus of the amygdala (fear processing) and alterations of the hippocampus that affect memory related circuitry.
Recent studies with high field MRI 7 Tesla technology demonstrate that brainstem components of the descending pain modulating system (DPMS) are active both during the development and during maintenance of central sensitization produced by the capsaicin model of experimentally produced neuropathic pain. Involvement of the DPMS is shown to be a mechanism in placebo anesthesia (its inhibitory action). This function (placebo anesthesia) can be blocked by naloxone.
A recent study demonstrates that the periaqueductal gray may integrate aversive prediction errors that may be important in aversive learning. Clearly, thalamic lesions are implicated clinically in central pain syndromes. Altered motor and general connectivity may be affected by changes in basal ganglia structure and function during chronic pain. The ventral tegmental area (dense projections to the nucleus accumbens) is gaining attention as alterations of the reward and affective components of the pain experience predominate in chronic neuropathic pain states.
Static and dynamic mechanical allodynia and, to a lesser degree, thermal hyperalgesia and allodynia are major components of neuropathic pain. The most disturbing component of neuropathic pain, however, is spontaneous pain.
Patients with varying have lesions of the neuraxis that include spinal brainstem, thalamic and cortical lesions that developed mechanical allodynia on one side of the body, were evaluated with fMRI. Innocuous mechanical stimuli were delivered to the affected and normal side of the body. Brush and cold rubbing of the unaffected side of the body are not painful and activate the contralateral SI and SII somatosensory areas and the insular cortex. The same innocuous stimuli applied to the allodynic side of the patient’s body evoke activity in similar parts of the somatosensory system, are extremely painful, and demonstrate lesser activation of SII and the insular cortices. There is increased activation of the contralateral SI and primary motor cortex (MI), and in the ipsilateral hemisphere (to the allodynic side), and increases of activation in the parietal operculum (SII), SI, and the insular cortex. There is additional activation of the premotor and motor areas, including MI, the supplementary motor area, the posterior parietal cortex, and the mid-anterior cingulate cortex of the ipsilateral hemisphere. It is postulated that the ipsilateral hemisphere may be a component of the shift from normal mechanical sensation to allodynia following deafferenting CNS lesions. The affected areas primarily link attention (posterior parietal cortices) and motor control (midanterior cingulate cortex). Under normal circumstances, the contralateral insular cortex and SII are activated by innocuous cold stimuli. The insular cortex receives spinothalamic afferences from the VMpo nucleus of the thalamus and from laminar I projecting neurons that are activated by cold.
A great deal of recent neuroimaging research in pain has focused on the inherent and altered connectivity between nodes and within brain circuitry. The advantage of resting state fMRI is that the acquisition of data can be acquired while chronic neuropathic pain patients are quietly resting in the MRI scanner. This data more closely reflects the natural state of brain activation during spontaneous pain (the most disturbing element of neuropathic pain). Resting state MRI investigates the degree of functional connectivity between nodes (nuclei of the “pain matrix”) which is correlated with low frequency oscillations between these areas. The networks that are altered during chronic pain are:
(1)The default mode network (DMN) that is active at rest (task free state)
(2)The salience and sensorimotor networks that are active during various stimuli and are related to sensory and motor processing.
Different neuropathic pain conditions are shown to specifically activate components of the DMN. In patients with chronic low back pain there is decreased DMN connectivity within the medial PFC, posterior cingulate cortex and amygdala. In fibromyalgia there is greater connectivity between the DMN and the executive and salience circuitries. In addition, fibromyalgia patients demonstrate greater connectivity between the DMN and the insular cortex than that which is seen in healthy controls. Fibromyalgia also demonstrates a spectrum of alterations between the insular and other cortical areas. In chronic pain states, there are altered low-frequency oscillations that include the primary somatosensory cortex (SI), the supplementary motor area (SMA), the dorsolateral prefrontal cortex (DLPFC) and the amygdala. In CRPS, there is decreased resting state functional connectivity in the DMN and increased connectivity in sensory and motor areas with other pain processing areas.
Tracey reports unexpected findings in phantom pain, rather than loss of sensory input that would be characterized by structural and functional degeneration of the deprived sensorimotor cortex. If patients are asked to move the lost extremity rather than imagine its movement, there is preserved function of these areas. It is further shown that the lip area does not invade the adjacent hand area. It has been posited that phantom pain is associated with reduced integrational functional connectivity in the primary sensorimotor complex. In light of these findings, direct transcranial stimulation is utilized effectively to manipulate this aberrant functional connectivity to relieve pain in patients with phantom pain. This treatment effect buttresses the functional relevance between sensorimotor cortical plasticity and pain.
An extremely important aspect of neuroimaging in the study of chronic neuropathic pain is the demonstration (Balilhi) that both functional and structural (white matter properties) in cortico-limbic areas influence the risk for the development of chronic neuropathic pain. He demonstrated that increased connectivity between the mPFC (dorsal) and the amygdala and nucleus accumbens (NAc) differentiates persistent and recurrent back pain patients from patients who have less persistent back pain. Complicated fMRI studies show that relief from treatment interventions may be related to:
(1)Increased activity of baseline reward circuits in response to evoked pain
(2)Increased trait reward responsiveness.
This system (functional reward system) may also be a component of the mechanism of opioid analgesia and its activation may be necessary for the success of treatments that alleviate neuropathic pain. On a cellular level, it is shown experimentally that endogenous opioid release in the rostral anterior cingulate cortex is required for dopamine release in the NAc for analgesia of chronic neuropathic pain. Surprisingly, in another study focusing on the reward system in chronic pain, reports that only 20% of relief is needed for a significant benefit.
Tonic and slowly varying neural states are difficult to image. Neuroimaging with arterial spin labeling (ASL) may overcome this challenge and allow insight into long lasting perceptual experiences. The use of advanced acquisition ASL techniques recently demonstrates a major role of the contralateral dorsal posterior insular cortex in tracking ongoing pain. These studies demonstrate a brain region that is active over a continuous period and is correlated with the intensity of pain due to manipulation of the nociceptive stimulus.
Magnetic resonance spectroscopy is also used to define aspects of neuropathic pain. Its application in patients with fibromyalgia versus controls demonstrates increased glutamate/glutamine in the posterior insular cortex. Pressure pain thresholds are negatively correlated with the peaks of glutamate/glutamine. Furthermore, pregabalin, which is a partially effective treatment for FM, also lowers the concentration of glutamate/glutamine in the posterior insular cortex.
Intense research from worldwide laboratories has built an experimental and clinical base that is starting to unravel the underlying mechanisms of neuropathic pain. These studies will hopefully lead to a mechanism-based and personalized treatment options for neuropathic pain patients.
Nerve roots exit and enter the spinal cord through the neural foramina. These are bony canals of varying length depending on the spinal segment. The contents of the neural foramina (canals) are the spinal nerve roots, recurrent meningeal nerves, and radicular blood vessels. The anatomical boundaries are the pedicles inferiorly and superiorly, anteriorly the intervertebral disc and vertebral body and posteriorly the facet joint. The superior and inferior facets are lined by synovium. The dorsal root ganglia (DRG) are in the foraminal canals.
The blood supply to a spinal nerve root derives from the corresponding radicular artery. At the root entry zone, blood vessels lie on the surface of rootlets and in inter-radicular spaces. Capillary density is high in the ventral root entry zone. In osteoarthritic degenerative conditions, facet joints are frequently remodeled by hypertrophic bone expansion. Tropism occurs whereby the facet rotates into the foraminal exit canals and the lateral recess. This process impinges on the exiting nerve root at its level. The facet joints are innervated by branches of the posterior primary ramus of the spinal nerve root. The clinical effect of degeneration of the annulus pulposus and the posterior longitudinal ligament are not well categorized. Both structures receive nociceptive innervations. Extruded disc material induces an inflammatory response around the nerve root eliciting the expression of IL-1, IL-6 and tumor necrosis factor-alpha that directly depolarize nociceptive C-fibers and A-delta afferents. Dorsal root ganglia have a less permeable blood-nerve barrier than the blood brain barrier. This is important in the context of chemotherapy-induced radiculopathy and autoimmune processes such as Sjogren’s syndrome or paraneoplastic processes. The cell bodies in the DRG for PTNs may thus be directly affected in the course of these disorders.
Radicular pain is caused by depolarization of A-delta and C-fiber nociceptive afferents. A-delta primary nociceptive afferents (1-4 μ) cause lancinating well-localized pain in the expected dermatome. With root irritation, the lancinating pain is frequently followed by a deep aching pain that has a burning quality. This second pain is mediated by 1μ unmyelinated slowly conducting C-fibers. Sympathetic discharge elicited by somatic sympathetic reflexes may amplify and drive this pain in chronic conditions. The usual radicular pain radiates within its specific dermatome. However, it may be appreciated in only part of the anatomical confines of the dermatome. Thus, an L5 root injury may be felt just or predominately in the lateral thigh or great toe and not the lower back.
The pain is usually increased by mechanical maneuvers that increase intraspinal pressure or stretch the nerve root. The nervi nervorum that innervate the nerve sheath are sensitized so that a mechanical stimulus of the root rather than a tissue destructive one in the dermatome will depolarize them (basis for the straight leg-raising test and other provocative stretch maneuvers).
There is segregation of spinal root afferents at the dorsal root entry zone (DREZ). Medial dorsal root fibers carry proprioception, vibration, and light touch. Lateral dorsal root fibers (closest to the area dorsolaterally where discs extrude) carry lancinating pain (A-delta fiber mediated), cold (A-delta fiber), temperature and burning pain (C-fiber). Lesions that affect the dorsal root entry zone are, in general, painful. Lesions peripheral to the DRG in the neuronal exit canals cause numbness. Lesions of the medial branch of the posterior primary division of the dorsal root are associated with numbness and paresthesias (1½ inches laterally from the spinous process). Meningeal afferents from the dorsal root innervate the dura at each spinal segmental level. These are the recurrent branches of Spurling. The L5 branch is particularly relevant as its referred pain is to the top of the thigh when it is stimulated (often mistaken for L1, L2, L3 root pain).
Ventral root lesions cause segmental weakness. If these axons are injured, there will be associated atrophy and fasciculation along with weakness of the innervated muscles. Early with compressive or irritative lesions, reflexes may be enhanced. This has been posited to result from the differential susceptibility of inhibitory afferents in the ventral root. In the lower extremity (if reflexes are increased), the examiner must always be aware of compressive or intrinsic spinal cord lesions that may injure the corticospinal tract and disinhibit neurons below the lesion level.
The vertebral bodies are connected by intervening discs and partially supported by the anterior and posterior longitudinal ligaments. The posterior elements from the vertebral bodies are composed of the pedicles, laminae, and dorsal spine. The transverse dorsal spinous processes are the origin and insertions of the paraspinal musculature. The ligamentum flavum is on the ventral surface of the laminae, and the posterior longitudinal ligament runs dorsally on the vertebral body. The dentate ligament connects the spinal cord to the dura. The interspinous ligaments connect the spinous processes and facet joints. The facet and sacroiliac joints have a synovial lining. Spine stability depends on the integrity of its skeletal and ligamentous components as well as active muscular support from the paraspinal musculature. The L5 vertebral body is the load segment for the lower spine (subject to the weight of the upper body). The skeletal and ligamentous structures are most vulnerable at movement segments (C5-C6 cervically and L5-S1 in the lumbar spine). If a segment is fused, the next uppermost spinal segment becomes the movement segment. Stress on bone activates osteoblasts and molecular mechanisms that remodel bone. This is evidenced by endplate increased bone density (Modic's sclerosis). Transforming growth factor beta-1, osteoblast and osteoclast activation, and complicated bone metabolism are all important in this process. Voluntary and reflex activity of the paraspinal, sacrospinalis, abdominal, gluteus maximus and hamstring musculature not only support the spinal column but adjust their activity following pathologic processes. These adjustments change gait and posture, which in turn modify load and stress points in the vertebral column.
After the exit of the lumbar spinal roots from the cord, they course downward in the subarachnoid space prior to entering the exit foraminal canals. The area on the inner surface of the pedicle (area prior to the entrance of the foraminal canal) is known as the lateral recess. This area may be compromised by congenitally shortened pedicles (common in achondroplasias and other congenital bony dysostoses) or extruded disc fragments.
The lateral lumbar intervertebral canals are complex osteofibrous, neurovascular tunnels whose configuration is modified by degenerative change in the intervertebral disc and degenerative arthritic changes in the facet joints and the canal itself. Their shape and morphometric features are dependent on their level, vary individually, and change with age dependent degeneration.
In the epidural compartment that lies behind the vertebral bodies is a sagittal membrane that connects the deeper layer of the posterior longitudinal ligament (PLL) with the posterior midline of the vertebral body. This connection may be total or partial. Its clinical significance is that it prevents disc material (that has been extruded) from moving to the contralateral side. Meningovertebral ligaments connect the dura with the PPL, which prevents movement of the dura from the spinal canal. These ligaments vary in size from loose areolar structures to clear individual ligaments and may be midsagittal or more laterally placed. A double cross vault structure has been described between the PPL and the dura matter from L3 to the termination of the dural sac. Meningovertebral ligaments may also contain extruded disc material.
The subpedicular notch of the upper vertebra is the widest part of the canal (shaped like an inverted teardrop) and is often referred to as the neural foramen. The anterior wall of the intervertebral canal is composed of the posterolateral components of two articulating vertebrae and the intervening disc. The anterior inferior morphology of the intervertebral foramen depends on the apophyseal rings and the disc that often bulges physiologically at the lumbar level. The posterior wall of the nerve root canal is composed of the ligamentum flavum, the pars interarticularis of the dorsal vertebra and the superior articular facet of the ventral vertebra.
Nerve sleeve morphology is level dependent, has a variable oblique course from the thecal sac to the outer third of the intervertebral canal. Anomalous lumbosacral nerve roots have a variable course and often originate from an abnormal high or low position from the spinal cord. There may be conjoined roots (most often associated with an abnormal nerve root sleeve), a double set of nerve roots, or an anastomosis between nerve roots of adjacent levels. The dorsal root ganglion (DRG) may be variably placed in the intervertebral foramen. At L4 and L5 levels, the DRGs tend to be intraforaminal. The S1 DRG is intraspinal. An intraspinal position makes the ganglia more susceptible to compression from a superior articular facet or disc bulging. Extra-
foraminal positions of the DRG have been reported at L4 and L5.
The sinuvertebral nerve has a recurrent course through the lateral neuro vertebral canal and supplies the laterodorsal outer annulus of the disc, the PLL, the anterior 2/3 of the dural sac and the anterior vascular plexus.
Other blood vessels that traverse the neurovertebral canal include:
1.Anterior and posterior spinal canal branches
2.Anterior and posterior radicular branches
3.Veins of the anterior and posterior internal vertebral venous plexus.
At each segment, there are one or two thick and one to four thin sinuvertebral nerves (SVNs) that originate close to the connection of the rami communicantes to the spinal nerve. The thin SVNs have extensive ramifications that form a network in the floor of the central lumbar canal that supplies the PLL. The PLL is posited to play a role in spinal proprioception and nociception and may be vulnerable to extruded proalgesic disc material. Adjacent to the semivertebral nerves, small branches from the rami communicates join the dorsal ramus in association with the segmental artery that enters the neural canal. The sympathetic nerve plexus and the SVNs inside the anterior longitudinal ligament are a network of nerve fibers that surround the intervertebral discs and the vertebral bodies. The dorsal ramus innervates the facet joints at the corresponding level and one below prior to its muscular and cutaneous innervations.
In summary, the principal innervation of the intervertebral disc is the sinuvertebral nerves. They are recurrent branches of the ventral spinal nerve rami that re-enter the intervertebral foramina and are formed by a somatic root from the ventral ramus and a sympathetic root from a grey ramus. The dorsal ramus, especially its medial branch innervates posterior structures that include the multifidus muscle and the facet joint.
The lumbar vertebral body is innervated primarily by nerves that enter through the basivertebral foramen on its posterior surface, are associated with blood vessels, and are concentrated in its center. The pattern of innervation closely follows that of the bone blood supply. Vertebral endplate nerves take origin from the basivertebral nerve trunk. The vertebral periosteum is lightly innervated but does not pierce the anterior or lateral cortices of the vertebral body. The sympathetic nerves that supply the vertebral body and accompany the nutrient artery through the BVF take their origin from semivertebral nerves that branch from the sympathetic trunk. They occupy the intervertebral canal and supply the posterior longitudinal ligament and the posterior annulus of the disc. The innervation of the posterior border of the endplate originates from the sinuvertebral nerves. The anterolateral periphery of the endplate is sparsely innervated. Immunohistochemical testing demonstrates that the sinuvertebral nerves of the vertebral body are CGRP positive (a nociceptive marker). Several reports have shown that elevated interosseous pressure causes pain in low back pain patients that can be relieved by vertebroplasty. This result has been posited to be associated with destruction of this innervation.
A detailed study of the sinuvertebral nerves at the craniovertebral junction undertaken because of their possible involvement in whiplash injury demonstrated that:
1.SVNs at C0-C1, C1-C2 and C2-C3 intervertebral levels arise from two roots, a somatic root from either the spinal nerve or ventral ramus and a sympathetic branch from the vertebral artery plexus or the superior cervical ganglion
2.C2 and C3 innervate the majority of structures of the cranio-vertebral junction and the basi-occiput, and that the C1 SVN supplied a small component of the atlanto-occipital joint.
All three SVNs followed an ascending and descending intraspinal course associated with the arterial supply of the cervical vertebral junction (CVJ).
The intervertebral discs are located between vertebral bodies and are composed of a nucleus pulposus, annulus fibrosis, and cartilaginous endplates. Their blood supply is only to the cartilaginous end-plates. They are innervated only in the outer annulus fibrosus by branches of the sinuvertebral nerve from the ventral rami of the spinal nerve or from the grey rami communicantes. They are derived from the mesodermal notochord and a great deal of their metabolism is through the cartilaginous endplates. The constituents of a disc are collagen and elastin fibers and aggrecan. The annulus fibrosus is attached to the vertebral endplates. The cartilaginous endplate is a 0.1 – 1.6 mm hyaline cartilage layer. It is a semi-permeable membrane that allows diffusion between disc nuclear cells and the vertebral vasculature and restricts proteoglycan movement to the disc space. As a disc ages, it loses osmotic pressure in the nucleus, and with dehydration loses height which affects the ligamentum flavum, facet joints and the morphology of the neural foramina.
The pathology of disc disease with aging is:
(1)“End-plate-driven” that involves endplate defects and inward collapse of the annulus fibrosus
(2)“Annulus-driven” which involves a radial fissure of the annulus fibrosus with leakage of nucleus pulposus proteoglycans and or disc prolapse
A far lateral disc protrusion may just entrap the exiting nerve root that will affect the corresponding spinal segment. A more medial extrusion may compress the exiting nerve root and the next lower root as it descends prior to its exit.
All parts of the body surface are innervated by a nerve root and a peripheral nerve and have a specific pattern of referred pain. Thus, sensory complaints may be overlapping such that a particular pain distribution may be composed of a root, nerve, or plexus distribution as well as its referred pattern. The sensory patterns may be difficult to discern in the face and extremities. Further complicating sensory patterns are the radiations of sclerotomes and those of the posterior rami of the lower back. Each body part receives some overlapping root rostral and caudal innervations, and there is further overlap in the dorsal horn as noted above from Lissauer’s tract.
The V1-V3 divisions of the trigeminal nerve (V) are well demarcated. The C2-C3 roots comprise the preauricular nerve that innervates the side of the face overlapping V2 and V3. C2 involvement alone innervates an area just anterior to the ear. C2-C3 roots comprise the lesser occipital nerve which innervates the back of the head. C3-C4 comprises the post auricular nerve that innervates the ear and portions of the parietal skull. Cervical roots C3 primarily innervates the neck and C4 the trapezius ridge. C5 innervates the top of the shoulder. C6 innervates the thumb and index finger, C7 primarily the third and 4th finger and C8 the little finger. Thoracic roots T1 innervates the lower forearm and T2 the inner humerus. T4 innervates the nipples, T10 the umbilicus and L1 the groin. Lumbar roots L2 and L3 innervate the anterior thigh while L5 innervates it laterally. The cap of the knee is L3, the inner knee L4 and the outside of the knee are innervated by L5. A strip of the inner lower leg is innervated by L4. The outside of the lower leg and foot is innervated by S1. L5 innervates the great toe and top of the foot. The bottom of the foot medially is L5 and laterally is S1. The medial posterior thigh is L3 and more laterally S3. The anus is usually presented as being innervated by sacral roots S5 roots. Saddle areas are primarily S2-S4. A sclerotome is derived from an enlage somite. During development, the somite develops into a variety of different structures. These include disks, cartilage, joint capsules, and ligaments that refer pain to the body surface in specific patterns. In general, when a portion of a sclerotome is irritated by a mechanical or chemical stimulus (rupture of a disc, facet, and ligament irritation from disc material) pain may be experienced as originating from the dermatome innervated by a nerve although it originated from the facet. Sclerotogenous pain is often reported as a dull ache and is diffuse.
A primary mechanism of referred pain is somatic and visceral convergence. The skin surface and a specific internal organ are innervated by the same DRG. In the instance of referred pain from the spine, pain may be projected to visceral or other structures in the territory innervated by lumbar and upper sacral roots. Pelvic and abdominal viscera may refer pain to the spine. Sclerotomal pain radiations from the upper part of the lumbar spine may be referred to the medial flank, groin, hip and anterior thigh. This occurs most often (my experience) from discogenic disease at L5-S1. The literature supports irritation of the superior cluneal nerves (that are derived from the posterior divisions of the first three spinal nerves) which innervate the upper buttocks as a source of referred pain. It has been proposed that pain radiations into the lower buttocks and posterior thigh originate from lower lumbar and upper sacral roots. As a general rule, referred pain: 1) has the same intensity as local pain; 2) stretch maneuvers that increase local pain similarly exacerbate referred pain.
Pain referred to the spine from visceral processes may be posturally related but are not influenced by back movement. A common functional relationship of root irritation and visceral activity is micturition and defecation initiated by L5-S1 root irritation.
Local pain in the spine is caused by pathological processes of the facet joint, ligaments, periosteum, capsule of apophyseal joints, and the annulus fibrosis. If there is pain from annulus fibrosis stretch or tear is debated. It is innervated by nociceptive fibers and disc contents initiate an immune response that may induce the release of inflammatory cytokines (IL-1, IL-6, and TNF-alpha among others) that theoretically could irritate nociceptive afferents.
Pain from these spinal structures is:
1.Higher lumbar root pathology is usually caused by:
a.Autoimmune Processes
b.Connective tissue diseases
c.Diabetes mellitus
d.Vasculitides
e.Congenital defects
f.Metastases
g.Meningeal disorders
2.Lower root involvement (L4-S1) is usually caused by:
a.Degenerative disc disease
b.Lumbar spondylosis
c.Spondylolysis
d.Lumbar spondylolisthesis
e.Spinal stenosis
f.Facet hypertrophy and tropism
g.Lateral recess syndrome
h.Surgical procedures
i.Congenital lesions
j.Ligamentous cysts
k.Carcinomatosis of the meninges
l.Metastatic disease (gastrointestinal tract)
1.Tumor (metastatic and carcinomatosis of the meninges)
2.Trauma (lumbosacral junction)
3.Arachnoiditis
4.Congenital abnormalities
5.Diabetes mellitus
6.Collagen vascular and autoimmune processes
1.Lumbosacral transitional vertebra (LSTV) is the most common congenital anomaly of the lumbosacral spine
2.Its prevalence has been estimated at 7% to 30% of the general population
1.The prevailing view is that there are no clinical consequences of the lesions
2.Some others describe:
a.Pain may arise from the disc above the defect, from the contralateral facet or an anomalous articulation
1.Sacralization of the lowest vertebral body or lumbarization of the upper-most sacral vertebra
1.MRI:
a.Disc degeneration above the LSTV (reported)
b.An association with spina-bifida
c.Subtypes (Castellvi classification)
d.A fusion of the fifth lumbar vertebral body to the sacrum or separation of the first sacral segment (creating 6 rather than 5 lumbar segments); importance is identification of the correct level for spinal surgery
1.Failure of the neural tube to close during the fourth week of embryogenesis creates the most common severe birth defect in the USA
2.Incidence of approximately 1 in 2000 births
3.Spina bifida:
a.A neural tube malformation that involves the spinal cord and vertebral arches
b.Severe forms:
i.There is protrusion of the spinal cord and or the meninges through a defect in the vertebral arch
1.Clinical features depend on the level of the defect
2.Spinal cord clinical symptomatology starts at the defect level and usually includes:
a.Leg paralysis
b.Urinary and fecal incontinence
c.Anesthesia of the affected segment and below this level
d.Orthopedic anomalies of the hips, knees and feet
e.Associated neurological complications:
i.Hydrocephalus
ii.Arnold-Chiari type II malformations
1.Mutations in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR) genes have been linked to the disease
2.Disturbance of the development of the embryonic tail bud
3.Spinal cord abnormalities may include:
a.Overdistension of the central canal
b.Duplication or splitting of the spinal cord
c.Diplomyelia or diastematomyelia
d.Tethering of the sacral end of the spinal cord
4.Associated defects:
a.Sacral agenesis
b.Anorectal and urogenital system anomalies
1.Associated rarely with a subcutaneous mass, cutaneous hyperpigmentation over the defect
2.Lack of fusion of the laminae of one lumbar or sacral vertebra
3.Facet joint or pedicle anomalies that include:
a.Asymmetry of facet joints
b.Narrow lateral recess
c.Short pedicles
1.Congenital absence of the lumbosacral articular facet joint is rare; the L5-S1 is affected in approximately 80% of patients
2.May be associated with conjoined nerve roots
1.May cause spinal instability
2.Conjoined nerve roots may be associated with clinical signs and symptoms referable to the involved roots
1.Possible defect in a neural arch ossification center has been posited
1.Approximately 0.25% of patients may have conjoined nerve roots in the normal population; most commonly at L5-S1
2.Conjoined nerve roots have been reported with anomalies of the vertebral arch, spondylosis, spondylolisthesis and bifid sacrum
3.Myelography with CT:
a.Absence of the facet joint
4.3D-CT evaluation:
a.Demonstrates the articular process
5.Rare congenital absence of the posterior elements of the spinal column have been reported
1.Congenital scoliosis is the failure of normal vertebral development during the 4th to 6th week of gestation
1.Radicular pain from nerve root entrapment
2.Pain occurs both on the convexity and concavity of the curve
3.Concavity pain is posited to be generated by impingement of the facets. This frequently occurs at the apex of the lumbar curves at L3-L4 or L2-L3
4.Spinal stenosis pain:
a.Usually, it is present with lumbar or lumbosacral deformity
b.Patients develop postural change. They lean forward, develop a flat back and slightly bend their knees with walking
5.Patients may also have radicular pain from spondylolisthesis and degenerative disc disease
1.Scoliosis is a developmental defect in the formation of the mesenchymal component of the vertebrae
2.Failure of formation:
a.A normal fully segmented hemivertebra (normal disc space above and below
b.Semisegmental hemivertebra:
i.The hemivertebra is fused to the adjacent disc on one side
c.In segmented hemivertebra:
i.The hemivertebra is fused to the vertebra on each side
d.An incarcerated hemivertebra:
i.The affected vertebra is fused within the lateral margins of the vertebrae above and below
e.Unincarcerated hemivertebra:
i.Laterally positioned
f.Wedged vertebra
3.Failure of Segmentation:
a.Block vertebra:
i.Bilateral bony bars
b.Bar body:
i.A unilateral unsegmented bar is common
4.Mixed:
a.A unilateral unsegmented bar with contralateral hemivertebra
b.Progresses the most rapidly
5.Associated conditions with congenital scoliosis:
a.May occur in isolation
b.Occur with systemic anomalies in approximately 60% of patients which include:
i.Cardiac defects – 10%
ii.Genitourinary defects – 25%
iii.Spinal cord malformations
iv.Associated syndromes that include:
1.Alagille syndrome
2.VACTERL syndrome
3.Jarcho-Levin Syndrome / spondylocostal dysostosis
4.Klippel-Feil syndrome
1.Renal ultrasound or MRI
2.Echocardiogram
1.MRI:
a.All patients with congenital scoliosis need evaluation of the complete neuroaxis to rule out associated anomalies that occur in 20-40% of patients and include:
i.Chiari malformations
ii.Tethered cord
iii.Syringomyelia
iv.Diastematomyelia
v.Intradural lipoma
2.3DCT
a.Best delineates posterior bony anatomy
1.Definition: a spinal deformity with a Cobb angle of more than 10o in the coronal plane in a skeletally mature patient
2.Separated into 3 major categories:
a.Type I (primary degenerative scoliosis):
i.Disc or facet joint arthritis that affects the spinal column asymmetrically
b.Type II (idiopathic adolescent scoliosis) which progresses into adulthood:
i.Combined with secondary degenerations
ii.Surgical or no surgical treatment
c.Type III (secondary adult curves) in addition to:
i.Oblique pelvis due to leg length differences or hip pathology
ii.Idiopathic, neuromuscular or congenital scoliosis
iii.Lumbosacral junction asymmetry
1.Similar radicular pain that is seen with congenital scoliosis
2.Severe pain from spondylolisthesis, spinal stenosis, degenerative disc disease and facet syndrome
1.Scoliosis will develop in approximately 30% of patients ages 50-54 that have a greater than 10o curve
2.Degenerative spine pathologies
3.Rare spinal cord tumors that differentially involve the spinal cord with asymmetric destruction of anterior horn cells that innervate paraspinal muscles (C shaped curve)
4.Osteoporosis and osteomalacia with fractures and remodeling of bone
5.Degenerative translational vertebral shift with pelvic obliquity
1.Measurement of metabolic bone disease to evaluate osteoporosis
2.Sed rate and C-reactive protein
1.Radiographs determine:
a.The pelvic incidence:
i.The angle of incidence is the algebraic sum of the pelvic tilt (PT) and the sacral slope (SS)
ii.The pelvis does not change after adolescence and directly influences pelvic alignment that include the parameters of pelvic tilt and sacral slope, sagittal spinal balance and lumbar lordosis
b.Prognostic features for curve progression include:
i.Increasing intervertebral disc degeneration
ii.An intercrest line through L5
iii.Apical lateral vertebral translation >6mm
2.MRI:
a.Excellent for evaluation of disc and soft tissue degenerative changes
b.Excellent delineation of nerve root exit impingement, subluxation and canal parameters
3.CT / myelography:
a.Delineation of the continuity of the contrast column
b.Flexion and extension views delineate dynamic changes associated with spinal stenosis
c.Delineation of the dural sac
1.Increased angulation of the spine
1.Posturally-induced low back pain
2.Radiculopathy at the segmental level (usually L3-L5)
3.Signs of central or lateral spinal stenosis
4.Neural claudication symptoms
1.Increased compression of the apophyseal joints
2.Increased anterior shear force at the lumbosacral junction
3.Possible precursor to spondylolisthesis
4.In the context of metabolic bone disease (primarily osteoporosis) it is combined with asymmetric arthritic disease or vertebral fracture
5.Asymmetric degeneration leads to spinal load imbalance with bone remodeling and further degenerative changes
6.Destruction of facet joints, joint capsules, disc and ligaments
7.There is frequent multisegmental instability
1.MRI and CT evaluation:
a.Facet joint degenerative changes (hypertrophy and tropism); thickened ligaments
b.Central and lateral spinal stenosis
c.Disc desiccation with degeneration and loss of disc height
2.Measurement of the lordosis angles in relation to the superior most vertebra
3.A sharp angle of L5 in relation to S1; the closer the angle is to the 180o plane > traction on L4, L5 and the S1 nerve roots
1.The most common form of nonlethal skeletal dysplasia
2.Genetics:
a.Mutation of the fibroblast growth factor receptor 3-gene (FGF-R3) that maps to chromosome 4p16.3 and is autosomal dominant
3.Prevalence is 0.36 to 0.6 per 10,000 live births
1.Short stature
2.Disproportionately shorter limb bones
3.Narrow trunk
4.Macrocephaly
5.Prominent forehead and flattened midface
6.Short broad hands; trident fingers
7.Neurological complications:
a.Cervicomedullary spinal cord compression (foramen magnum stenosis)
b.Sleep apnea
c.Disordered respiration
d.Myelopathy
e.Hydrocephalus
f.Ligament laxity
8.General medical complications:
a.Musculoskeletal
b.Cardiorespiratory
c.Ear, nose and throat
9.80% of individuals are symptomatic by age 60
10.Radiculopathy with claudication (often due to spinal stenosis at T12-L1)
11.Compressive cervical myelopathy
1.Narrow spinal canal
2.Short pedicles
3.Narrowed exit foramina
4.Block vertebra
5.Abnormal chondrocyte proliferation in the growth plate
1.Sleep studies to evaluate disordered respiration and sleep apnea
2.MRI:
a.Evaluation of the foramen magnum and T11-L1 spinal stenosis
b.Congenital canal stenosis
1.Developmental lumbar spinal stenosis is a maldevelopment primarily of the dorsal spinal elements:
a.Short pedicles
b.Trefoil bony spinal canal
1.Similar clinical symptomatology as acquired stenosis with neurogenic cauda equina claudication
2.Cervical and lower lumbar radicular pain
3.Presentation is at an earlier age than acquired forms
4.Subtle clinical signs of spondylosis
1.Multilevel involvement with L3, L4 and L5 levels most severely involved
2.Severe stenosis at L1, L2 and S1 is rare
1.MRI:
a.Shorter pedicle length
b.Smaller cross sectional spinal canal area
c.Block vertebra
d.Narrowed exit foramina
1.The lateral recess may be the principal site of pathology in lumbar canal stenosis
2.Anatomy:
a.Bordered laterally by the pedicles, posteriorly by the superior articular facet and ligamentum flavum and anteriorly by the vertebral body, endplate margin and disc margin
b.It is funnel shaped and is narrowest in its cranial extent at the superior portion of the pedicle.
1.Radicular signs and symptoms
2.If the compression is in the intervertebral foramen, extension of the trunk in conjunction with ipsilateral side bending and rotation reproduces the symptoms
1.Two morphologic forms cause root compression in the lateral recess:
i.Fibrous and hyaline cartilage and cancellous bone
ii.Intramembranous bone formation possibly due to segmental instability
1.CT measurement of the posterior edge of the vertebral body and the anterior part of the articular facet in the pedicular slice at the level of the upper vertebral platform:
a.Lateral recess stenosis occurs when the nerve root is trapped in the bony margins of the lateral recess or exit foramen
b.Narrowing is diagnosed when the anterior-posterior dimension is below 4mm
1.Traction of the conus medullaris and cauda equina by a tight thickened filum terminale
2.Two clinical categories:
a.Asymptomatic in childhood and presents for the first time in adult life
b.Patients with pre-existing static skeletal/neurologic abnormalities that progress in adult life
1. Pes cavus (uni or bilateral)
2. Cutaneous stigmata (strawberry hemangioma; cutaneous dimple) over the sacrum
3. Back pain; may have anal and perianal pain; genital or diffuse leg pain
4. Motor and sensory radicular deficits of lumbar and sacral roots
5. Sphincter alterations
6. Symptomatic with specific positions; particularly the dorsal lithotomy position
7. Symptomatic following delivery or vaginal surgery (primarily due to the dorsal lithotomy position)
8. Urodynamic features:
a.Hyperreflexia of the bladder (neurogenic bladder)
b.Internal and external detrusor dyssynergia
c.Decreased bladder sensation and compliance
d.Hypocontractility of the detrusor muscle
9. General hyperreflexia of both upper and lower extremities
10. Associations with tethered cord:
a.Terminal syringomyelia (caudal 1/3 of the spinal cord)
b.Diastematomyelia
c.Lipoma of the conus and lipomyeloschisis
d.Unilateral pes cavus
1. Combination of thickening of the filum terminale with:
a. Low or dilated conus medullaris
b. Spinal lipoma
c. Dermoid cyst
d. Diastematomyelia
e. Hydromyelia
f. Sacral agenesis
1. MRI:
a. Tethered cord; tip of the conus medullaris is below the body of L2 instead of the L1-L2 disc space
b. Most commonly associated with intra or extradural lipoma
1.Type I and II:
a.One or more nerve roots exit the thecal sac at a more cranial (Type I) or caudal (Type II) level
2.Type III:
a.Two or more nerve roots emerge from the thecal sac through a closely adjacent dural opening
3.Type IV:
a.Two or more roots emerge from the dural sac as one nerve trunk
4.Type V:
a.Two or more nerve roots are connected by an anastomotic branch after exiting the dural sac
1.Anomalies occur primarily at L4-L5
2.20% of patients have other lumbosacral anomalies; rarely congenital absence of a facet joint on the side of the anomaly
3.They may be asymptomatic
4.May be associated with failure of back surgery for herniated disc or spondylosis as they are less mobile
5.In association with lumbar spondylosis and foraminal stenosis
a.The affected roots are compressed between the transverse process of the last lumbar segment and sacral ala (S1) or in various relationships to the inner side of the pedicle and facet joint
6.Conjoined lumbosacral roots:
a.Are found in approximately 1% of lumbar disc operations
b.Most often at L5-S1
c.Often not associated with a herniated disc
1. Two adjacent nerve roots that share a common dural envelope during their course from the dural sac
2. The incidence by CT, MRI and myelography vary widely 2-17% in patients studied with spine imaging
1.The dorsal roots may be more commonly involved than the ventral roots
2.Bifurcation occurs close to the intervening pedicles; they then enter their respective foramina
3.Abnormal root anastomosis is caused from a connection of a band of nerve fibers or a distal union in a common sheath
4.There is decreased mobility of the root which increases its risk of neuropractic or direct injury during neurosurgical procedures
1. Features typical of conjoined roots include:
a. MRI:
i. Equal density of the nerve root anomaly and the thecal sac
b. Asymmetry of the subarachnoid space (pouching out) in the axial view at the level of the anomaly that may be above the intervertebral disc space
c. Possible specific MRI signs:
i. Asymmetric morphology of the anterolateral corner of the dural sac
ii. Intervening extradural fat between the asymmetric dura and the nerve root
iii. Visualization of the entire course of the nerve root at the disc level
iv. Focal lateral recess and foraminal stenosis
1.Lumbar synovial cysts arise from the zygapophyseal joint capsule
2.“Juxtafacet cysts” (also encompasses ganglion cyst) are similar clinically but differ histologically and may represent a spectrum of the same degenerative process
3.Possibly a cause of 1% of patients with low back pain
4.The greatest prevalence is in the seventh decade of life
1.The majority of spinal synovial cysts are at the L4-L5 level
2.Cysts may be asymptomatic
3.Present with radicular pain, neurogenic claudication or cauda equina syndrome
4.Back pain usually precedes compression symptoms
5.Myelopathy symptoms have been reported in cysts above L1-L2
1.The synovial cysts have a lining of synovial cells and arise from the facet joint
1.MRI:
a.The modality of choice; it has a 90% sensitivity compared to 70% with CT scanning
2.Low intensity signal on T1 weighted images and high-intensity signal on T2-weighted sequences. The signal varies depending on the concentration of proteinaceous material or blood in the cyst
3.Adhesion of a lumbar synovial cyst to the dura can cause a dural tear with a subsequent CSF fistula
1.Aging of the ligamentum flavum is associated with thickening and loss of elasticity
2.Most ligamentum flavum cysts are located laterally within the spinal canal
3.It is a well-defined elastic structure that is composed of 80% elastic and 20% collagen fibers rarely seen in other ligaments
4.Intraspinal ligamentum cysts primarily are found in the lower lumbar area at L4-L5 and may be associated with degenerative spondylolisthesis
1.The majority of symptomatic cysts present with radicular symptoms that mimic disc disease
2.Spinal stenosis
1.Cysts of the ligamentum flavum are embedded in the inner surface of the ligament and are not related to the facet joint
2.Pathogenesis is posited to occur from ligamentous and fibro-collagenous degeneration
3.There are changes in proteoglycans, loss of elastic fibers, an increase in collagen tissue and mucinoid degeneration in the ligament
4.The cysts may hemorrhage due to mechanical stress
1.MRI:
a.The modality of choice; on T1-weighted sequences they have variable signal intensity
b.T2-weighted sequences demonstrate high signal intensity
2.Synovial cysts may have a calcified rim that does not occur with ligamentum flavum cysts
3.The CT characteristics of synovial cysts are:
a.Cystic formation that may have a calcified wall
b.They are located adjacent to facet joints
c.Often demonstrate degeneration
4.CT characteristics:
a.The cysts are adjacent to the ligamentum flavum
b.Rarely demonstrate intraluminal hemorrhage
c.Calcium pyrophosphate crystals have been demonstrated in the ligament in patients with radicular pain
1.Juxta-articular cysts (ganglion and synovial cysts)
2.Ligamentum flavum cysts
3.Arachnoid cysts
4.Perineurial cysts
5.Dermoid cyst
6.Infectious cyst
7.Granuloma
8.Intraligamentous amyloid deposition
9.Ossification
10.Juxta facet joint cysts
a.The cysts are located in the perineural space between the endoneurium and perineurium
b.Type I cyst:
i.Extradural meningeal cyst without spinal nerve root fibers
ii.Type II
1.Spinal extradural meningeal cyst with spinal nerve roots
ii.Type III
1.Spinal intradural meningeal cysts
a.Fluid filled lesion with low signal on T1-weighted sequences and high signal in T2 weighted images
10.Bilateral symptoms and sphincter (overwhelmingly bladder) dysfunction most often occur with large midline disc extrusion that compresses the cauda equina
4. Knee jerk decreased
10.Tenderness with compression over the fourth lumbar lateral process and between the fourth and fifth spinous space, the ligaments and laterally in the sciatic notch
In general, the L1-L3 roots are not affected by disc disease, as they are not motion segments.
They are involved by:
1.Diabetic plexopathy
2.Ilioinguinal neuropathy
3.Genitofemoral nerve injury from:
a.Surgical procedures (hernia, catheterization of the femoral artery) and intra-abdominal surgical procedures
b.Lymphoma
c.Retroperitoneal hematoma
d.Autoimmune processes.
4.Rarely the roots are involved in high impact injuries (MVA accidents, falls, and skiing injuries).
5.Differential diagnosis includes:
a.Lumbosacral plexopathy and medical causes of radiculopathy:
i.Metastasis
ii.Autoimmune disorders
iii.Metabolic disorders (diabetes mellitus)
iv.Infectious diseases (HIV, CMV, and brucellosis)
i.Thickening or nodularity of the skin
ii.Hair loss
iii.Neurogenic edema
1.Sequestered intervertebral disc fragments are able to migrate both intra and extradurally within the spinal canal
2.Free disc fragments are often misinterpreted as a neoplastic mass
3.Unusual sequestered disc fragments have an incidence of 0.4%
1.Posterior epidural migration of a lumbar disc fragment:
1.Fibrocartilage with degenerative features that include:
a.Increased chondrocyte density
b.Mucoid degeneration
c.Vascular proliferation and granular change
2.Anatomical barriers that limit disc fragment migration include:
a.Sagittal midline septum (septum posticum) that is between the vertebral body and the posterior longitudinal ligaments (prevents the movement of the disc fragment across the midline)
b.Peridural or lateral membrane which is posterolateral and attaches to the free edge of the PLL which restricts posterior migration of a free disc fragment
1.MRI:
a.Disc fragments may show different patterns of contrast enhancement
b.There may be no disc space protrusion
c.Peripheral enhancement of the disc fragment is due to the inflammatory response with vascular granulation tissue at the disc periphery
1.Factors involved in the initiation and progression of disc disease include:
a.Age
b.Abnormalities of load
c.Decreased nutrient supply
d.Hereditary
2.The change of the cellular microenvironment with disc degeneration includes:
a.Loss of proteoglycan
b.Loss of disc height
c.Tears in the annulus fibrosus
d.Associated spinal stenosis
e.Neoinnervation
f.Hypermobility of the affected segment
g.Inflammation
3.Nerve fibers are found in the inner layers of the annulus fibrosus and nucleus pulposus in patients with low back pain. Innervation of the inner disc is only seen in painful discs and not normal discs
4.In patients disc lesions normally occur in the posterior portion of the disc
5.Recent studies in human prolapsed disc material have demonstrated upregulation in IL-2.
6.IL-2 promotes extracellular matrix degradation as well as:
a.Increased expression of type I collagen
b.It is a disintegrin
c.Metalloproteinase with thrombospondin motifs and matrix metalloproteinases
d.IL-2 decreases aggrecan and type II collagen expression levels
e.It is posited that nucleus pulposus inflammatory cytokines are severely toxic to both disc cells and nerve fibers
f.759 proteins from the annulus fibrosus and 692 proteins from the nucleus pulposis have been identified in the proteome map of these tissues. 73 annulus proteins and 54 proteins from the nucleus pulposis are differentially regulated from normal discs and those that are degenerated
g.The differentially expressed proteins are components of cell adhesion, cell migration and interleukin 13 signaling pathways
1.MRI:
a.Delineates the herniated nucleus pulposis (HNP). It is a focal, asymmetric protrusion of disc material beyond the annulus. The HNP is most often hypointense
b.High intensity signal may be seen in the posterior annulus on T2 weighted sequences
c.Sagittal MRI delineates the relationship between the HNP, abnormal facets to exiting nerve roots within the neural foraminal exit canals
d.Delineates sequestered disc fragments
2.CT:
a.Is utilized in patients who are unable to undergo MRI due to a pacemaker or other internally implanted metal
b.In subligamentous herniation, HNP is a smooth displacement of the disk margin into the neural foramen or the spinal canal. It effaces the epidural fat and displaces the dural sac
3.Myelography with CT delineates the relationship between the nerve root sleeve and the nerve itself to surrounding bony structures
1.A congenital bony defect in the pars interarticularis (the junction of the pedicle with the lamina; often bound by cartilage)
2.Frequently encountered in young athletic patients but may be seen at all ages
3.A predisposition to fracture or disjunction with slight trauma or repetitive motion
1.May be asymptomatic in many patients
2.Spinal instability
3.Atrophy of the gluteal muscles if associated with spondylolisthesis
4.Local back pain at the level of involvement
5.Radiculopathy
1.Developmental or acquired stress fracture often secondary to low-grade trauma
2.Classification:
a.Type 1:
i.Congenital abnormality of L5 or the upper sacrum with displacement of the L5 vertebra on the sacrum
b.Type 2 (isthmic):
i.A stress fracture of the pars interarticularis (fatigue fracture IIA); elongation IIB or acute fracture (IIC)
c.Type 3 (degenerative)
i.Remodeling of the articular processes
d.Type 4 (traumatic)
i.Acute fracture of the vertebral arch that may occur separately from the pars
e.Type 5 (pathologic)
i.Generalized or focal bone disease that affects the vertebral arch
1.CT:
a.Multislice CT with multiplanar reformatting is effective for detecting the bony defect. It is not sensitive for delineating early edema without a fracture line
2.MRI:
a.Excellent for the detection of early bone marrow edema when a visible fracture line is not detected
b.May identify associated nerve root compression
1)Spondylolisthesis is the forward translation of one vertebral body over its inferior one
2)Bilateral spondylolysis predisposes to spondylolisthesis. The vertebral body, pedicles, and superior facets slip forward. The degree of slippage is usually graded by the percentage of displacement relative to the lower vertebra
3)Slippage in non-severe traumatic patients is L5 over S1 or L4 over L5
4)There may be progression of spondylolysis to spondylolisthesis occurs in adult patients
5)Low grade spondylolisthesis is less than or equal to 50% of the inferior vertebra; high grade spondylolisthesis is greater than 50% slippage (almost always requires surgical correction)
6)Average age of adult spondylolisthesis patients (>21 years of age) in a retrospective review with grade III, IV or V was 35 years (range 21 – 88 years)
1)Atrophy of the gluteal muscles innervated by L4, L5, S1
2)Weakness of the gluteus maximus, anterior tibialis, extensor hallucis longus is often prominent
3)Radicular pain occurs most often in L4-S1 distributions
4)Flexion and extension maneuvers are painful; patients have pain on standing rather than sitting (more common with discogenic disease) and are unable to wear high heels
5)Rare bladder involvement
1)Types I-V (dependent on the degree of slippage)
2)Congenital hypoplasia of the pedicle
3)High grade dysplastic isthmic spondylolisthesis
1.Rare patients described with 2 DCT have congenital hypoplasia of the lumbosacral pedicles (pediatric)
2.Spondyloptosis:
a.100% subluxation of a superior vertebral body over its inferior one
b.Spinal segment is lodged in the anterior or posterior space of the adjacent segment
c.Complete disruption of structural elements of the vertebral column and the adjacent paravertebral soft tissues (associated with severe neurologic deficits)
d.CT scan:
i.A horizontal oriented defect in the pars interarticularis that interrupts the complete bony ring of the posterior elements
ii.Demonstrates degenerative bony changes, congenital and dysplastic forms of the disease
e.MRI scanning:
i.High signal intensity in the pars interarticularis on T2 weighted sequences that indicates fluid, a pseudoarthrosis or bone edema
ii.Lumbar paraspinal muscle morphometry in adult isthmic spondylolisthesis:
(a)Patients demonstrated higher cross-sectional areas (CSAs ) of the erector spinae muscle; the multifidus (MF) had lower (dCSA) in patients than controls
(b)Posited that isthmic spondylolisthesis have selective atrophy of the multifidus muscle and compensatory hypertrophy of the erector spinae muscles
1)Spinal stenosis refers to degenerative changes in bone, joints, and ligaments of the spine that narrow the spinal canal. These changes reach clinical significance more rapidly if there is congenital canal narrowing and small intervertebral foramina
2)Compression of lumbar and sacral roots are a consequence of these degenerative changes
1)Fluctuating aching and lancinating pain in the buttock, sciatic nerve distributions
2)Pain is exacerbated by prolonged sitting (>30-45 minutes) standing or walking (2-3 blocks). There is relief with rest. Severe patients have constant pain, but obtain some relief with a change in posture.
3)“Neurogenic claudication” causes:
a)Gradual onset of weakness and heaviness of the legs associated with walking often associated with asymmetrical buttock and calf pain (neurogenic cramps” or “Charlie horse”)
b)Pain is relieved with rest. It is a deep ache rather than a squeezing burning sensation
c)The numbness may begin in one leg, spread to the other and ascend if walking or exercise continues
d)If the condition is severe patients may attain relief by squatting, lying flat with the legs flexed at the hips and knees (opens up the canal)
e)Posture is forward flexed at the hip; the swing phase of gait may be restricted
f)Rare urinary incontinence and impotence
g)There are often concomitant cervical degenerative changes that compress the spinal cord such that knee and ankle reflexes are preserved. Ankle reflexes may be lost with exercise but return with rest
h)Degenerative spondylolisthesis with pain radiating into the thighs with flexion and extension of the spine occurs if the slippage is at L4 over L5 or L5 over S1. The involved root compression causes paresthesia, sensory loss, weakness, and reflex loss.
i)Lumbar stenosis has been associated with the syndrome of painful legs – moving toes which causes:
i)Burning lower leg pain
ii)Sinusoidal rhythmic toe movements that most often begin asymmetrically but may spread to the contralateral extremity
1)The spinal roots are compressed by the vertebral body anteriorly, the facet joints laterally and the ligamentum flavum posteriorly
2)Spondylolisthesis increases the stenosis in the anteroposterior dimension
3)A spinal root may be compressed by “tropism” of a degenerated facet, overgrowth of an inferior or superior facet, against the floor of the intervertebral canal
1)MRI:
a)Patients have a shorter pedicle length which causes a smaller cross-sectional spinal canal area (pedicle length of 6.5 mm and cross-sectional area of 213 mm)
b)The canal stenosis is distributed uniformly throughout the lumbar spine in congenital spinal stenosis
c)Degenerative spinal stenosis:
i)Protrusion of discs at affected levels
ii)Facet hypertrophy
iii)Hypertrophy of the ligamentum flavum
iv)CSA (cross-sectional area) of the dural sac is often less than 80 mm2
v)Associated degenerative spondylolisthesis
vi)Narrowed nerve root foramina
vii)Nerve root sedimentation sign:
(1)A positive sign is the absence of nerve roots sinking to the dorsal portion of the dural sac
1)Coccydynia or coccygodynia definition:
a)A painful syndrome in the region of the coccyx
2)The coccyx is composed of 3-5 vertebrae some of which may be fused
3)It attaches to the sacrum from two dorsal grooves being either a symphysis or as a true synovial joint
4)It has attachments to the gluteus maximus, the coccygeal muscle and the anococcygeal ligament
1)Pain at the end of the spine exacerbated by mechanical stimuli such as sitting, bicycling, rowing and riding
2)Patients may have L4-S1 root radiations (particularly in younger patients)
3)If roots are compromised, a pelvic tilt and atrophy of the gluteus muscle may be present
1)Fracture, subluxation from mechanical trauma
2)Abnormal mobility
3)Disc degeneration at sacrococcygeal and intercoccygeal segments
4)Coccygeal spicule (bony excrescence)
5)Rare osteomyelitis or tumor
6)Extracoccygeal disorders that can cause coccygeal pain include:
a)Pilonidal cysts
b)Perianal abscess
c)Hemorrhoids
d)Radiations from nerve root involvement of the lumbosacral spine, sacroiliac joints, piriformis muscle and involvement of the sacrum (metastasis)
e)Visceral involvement of pelvic organs
1)Lateral x-ray of the coccyx in the standing and sitting position:
a)Hypermobility
b)Fracture
c)Subluxation
d)Metastasis
e)Osteomyelitis
2)MRI:
a)Disc abnormalities; extrusion of the nucleus pulposis or endplate abnormality
b)Abnormalities of the coccyx tip that are located in the surrounding soft tissue and include:
i)Venous dilatations
ii)Soft tissue inflammation
iii)Vertebral bone edema
1)Lumbar zygapophyseal or “facet joint” pain is a major cause of chronic low back pain
2)Osteoarthritic degeneration causes irritation of the nociceptors that innervate the synovial membrane, hyaline cartilage, bone or fibrous capsule of the facet joint
3)Afferents from the facet joint are carried by the medial branch of the dorsal rami of the nerve root
1)Low back and radicular pain that is most often unilateral
2)Component of spinal stenosis pain
3)The pain is not relieved by position change
4)The pain is exacerbated by stress on the facet joint caused by retro- or lateral flexion of the spine; at the time the pain may be exacerbated by standing or walking
1) Osteoarthritic degeneration of the joint with bony hypertrophy
1)It is controversial whether tropism, an asymmetry in orientation of a facet (rotates into or compresses the intervertebral foramen) is a preexisting developmental phenomenon or is secondary to progressive remodeling of the joint
2)Tropism may increase disc degeneration and degenerative spondylolisthesis
1) Sprains are ligamentous injuries that are most often the result of a sudden extremely forceful muscle contraction or trauma
2) Strains are partial or complete tears of the muscle – tendon unit most often from a violent muscle contraction
1)When there is severe pain and paraspinal muscle spasm, the segmental nerve roots or their terminals may have been over stretched or otherwise injured
2)Recurrent aching pain in lumbar areas. Rarely there may be radiation into the buttocks and posterior thigh (never below the knee)
3)No weakness, sensory loss or reflex changes
4)Complaints of stiffness that are aggravated by specific movements
5)Range of motion particularly in flexion is decreased and painful
1)Acute trauma does not cause degenerative disc or bony structural disease (in the course of repetitive movement, it may be by means of the molecular mechanisms that trigger bone remodeling). It may exacerbate pain by nerve root compression against osteophytes in foraminal canals, increasing the bulge of an annulus fibrosa or mechanically stimulating the nervi-nervorum of the nerve sheath and root sleeves or the A-delta and C-fibers within the nerve sheath.
2)The lumbar spine and the hips are extensively involved in spine mobility; L4 and L5-S1 bear the highest loads and are the primary motion segments. They are most often involved in sprain and strain spinal injury
3)Load-bearing sprain and strain injuries most often occur during the most forceful coupling patterns as exemplified by lateral bending with flexion-extension and axial rotation with lateral bending.
4)The translatory and rotary stability of the spine is maintained by the ligaments. Specific ligaments may contribute more to the translator or rotary component of spinal stability depending on loading characteristics
5)The strength of a ligament is proportional to its cross-sectional area; in general, a ligament with greater cross-sectional area provides a greater component of stability and is displaced less during physiological loading
6)All major ligaments may be involved either by severe direct trauma or repetitive motion. They include:
a.The anterior and posterior longitudinal ligaments
b.Ligamentum flavum
c.Intertransversal capsular ligaments
d.Capsula ligaments
e.Interspinous ligaments
f.Supraspinosus ligaments
7)The posterior ligaments are most frequently injured
1)CT and MRI:
a)To rule out disc or nerve root involvement
The lumbar spine is comprised of a mobile segment of five vertebrae between primarily immobile thoracic and sacral segments. The rib cage and intercostal musculature stabilize the thoracic spine, while the sacral segment is stabilized by its attachment to the ilium. Lumbar vertebrae are longer and heavier than those of the thoracic and cervical spine, and other distinguishing features from these spinal segments include:
During flexion, there is compression of the intervertebral disc anteriorly and the spinal canal is widened. Sliding occurs laterally in the articular process of the zygapophyseal joints. Flexion is restricted by the posterior ligamentous complex and the dorsal spinal musculature. Extension of the lumbar spine causes posterior compression of the disc and narrowing of the spinal canal associated with sliding movement of the zygapophyseal joint. Extension is limited by the anterior longitudinal ligament, ventral spinal musculature and the lamina and spinous processes.
Lateral bending compresses the disc on the concave side and separates the zygapophyseal joint associated with the over-riding of the joint on the concave side. Lateral bending is limited by the intertransverse ligaments.
Rotation of the lumbar spine compresses annulus fibrosus fibers of the intervertebral discs and is restricted by the facet joints and the iliolumbar ligaments.
1)The National Spinal Cord Injury Registry report shows that:
a)40% of spinal injuries are caused by motor vehicle accidents
b)20% by falls
c)40% by gunshot wounds, during contact sports, industrial and agricultural accidents
1)Patients present with severe pain, muscle spasm, deformity and neurologic deficits related to the level of injury
2)Fractures of the thoracolumbar junction frequently cause conus medullaris and lumbar nerve root damage.
3)Fractures that compress the conus medullaris cause:
a)Paralysis of pelvic floor muscles
b)Autonomous neurogenic bladder
c)Constipation
d)Impaired erectile and ejaculation function
e)Asymmetric saddle anesthesia
4)Complete damage to the sacral spinal cord causes:
a)Loss of bowel and bladder control
b)Paralysis of sacrally innervated muscles of the lower extremity; often higher lumbar roots are concomitantly damaged that allows some flexion at the hip and partial flexion and extension at the knee with preserved knee reflexes. Sensation in lumbar dermatomes may be preserved.
5)Lower lumbar fractures cause solitary or multiple root deficits. A cauda equina syndrome may occur in the face of central disc herniation, fracture-dislocation and burst fractures.
1)Compression of the lumbar and sacral roots below the L3 vertebral level
2)Radicular pain in lumbosacral root distributions; it is often asymmetric and unilateral and is increased with Valsalva maneuvers
3)There is flaccid, hypotonic and areflexic paralysis in:
a)Glutei muscles
b)Posterior thigh muscles
c)Anterolateral muscles of the leg and foot
4)Asymmetric sensory loss in the saddle distribution. This involves the anal, perineal and genital regions and may extend to the anterolateral leg and lateral foot
5)The Achilles reflex (primarily S1-S2 segments) is lost and there is variable decrease of the patellar reflex (L2-L4).
6)Sphincter involvement is similar to that which occurs with conus medullaris lesions
1)Cauda Equina:
a)Early pain
b)Late sphincter involvement
c)Asymmetrical sensory examination
2)Conus Medullaris:
a)Early and severe sphincter and sexual dysfunction
b)Late pain
c)More symmetrical sensory loss
1)Specific fractures:
a)“Burst” fracture of a vertebral body
b)Pedicle, laminar or spinous process may be asymmetrically fractured
c)Loss of height of a vertebral body by wedge or compression forces
2)If the patient falls and lands on his feet, calcaneal and hip fractures may be associated
1)Plain radiography determines:
a)Alignment
b)Identification of vertebral body margins
c)The spinolaminar line
d)Articular facet joints
e)Interspinous distance
f)Position of the transverse processes
g)Oblique views for:
i)Pars interarticularis fractures
ii)Facet subluxation
h)Abnormalities of alignment include:
i)Disruption of the anterior or posterior vertebral body lines
ii)Disruption of the spinolaminar line
iii)Rotary dislocation of facets
iv)Kyphotic angulation (misalignment and bony fractures)
v)Widening of the interpeduncular distance and disruption of the posterior margin of the vertebral body are signs of vertebral disruption
vi)Narrowing of a disc space
(1)A concomitant of a flexion injury
(2)Occurs at the level above the fractured vertebra
vii)A severe posterior ligament injury:
(1)Widening of a facet joint
(2)Complete baring of the facet
(3)Increase of the interspinous distance
2)Computed tomography:
a)Best defines complex fractures and involvement of posterior elements
b)Tridimensional reconstructions:
i)Define the extent of canal compromise
ii)Define posterior element fractures
3)Magnetic resonance imaging:
a)Excellent visualization of the spinal cord and ligamentous structures
b)T2-weighted sequences have high signal intensity in the spinal cord in areas of injury and edema
c)The anterior and posterior longitudinal ligaments may be identified on T1 and T2 weighted sequences
1) The setting is almost always a high-impact rotary injury of the spine
1)Severe pain and muscle spasm at the site of injury
2)Associated paraspinal muscle injury with retroperitoneal hemorrhage causes:
a)Severe pain at the injury site from sacrospinalis or paraspinal muscle hemorrhage
b)Pain in the side, often with radiation to the groin
c)A quiet patient whose position of comfort is often lying on the side with flexed legs
d)Proximal > distal leg weakness
e)Loss of the knee and ankle jerks on the affected side (depending on the level of the fracture and consequent retroperitoneal bleeding)
f)Seven to 10 days following the injury there are signs of blood breakdown products in the skin and subcutaneous tissue of the affected flank (Grey Turner’s sign)
1)Fractured and displaced transverse processes at the affected level
2)Hemorrhage into the sacrospinalis, paraspinal and rarely the psoas muscle
3)Retroperitoneal hemorrhage
1)Radiographs and CT:
a)Define the fractured and dislocated transverse process
b)Define malalignment and associated vertebral structural damage
2)MRI:
a)To evaluate disc, ligamentous and associated muscle hemorrhage and retroperitoneal blood
1)Definition: a low bone mass with micro-architectural deterioration that leads to decreased bone strength with an increased susceptibility to fracture
2)Among insufficiency fractures associated with osteoporosis vertebral fractures are the earliest and most common
3)Approximately 20-25% of Caucasian women and men >50 years of age suffer a vertebral fracture
4)Vertebral fractures are a predictor of subsequent insufficiency fractures: one vertebral fracture confers a much higher risk of sustaining another
1)A bone mass density (BMDT-score ) greater than 2.5 at the femoral neck is normal; many patients suffer vertebral fractures at this normal level
2)A large percentage of fragility fractures of the lumbar spine are missed clinically
3)Onset of sudden thoracic or lumbar pain, most often lancinating if a nerve root is involved
4)Multiple vertebral fractures lead to kyphosis, loss of height, chronic pain and loss of spine mobility
1)There is an imbalance between bone resorption and formation
2)Remodeling of bone is constant with approximately 10% of bone mass undergoing the process at any time point
3)The activation of osteoclasts is regulated by molecular signals of which receptor activator of nuclear factor kappa – B ligand (RANK1) is prominent. It is secreted by osteoblasts
4)The interplay of molecular signaling of osteoprotegerin (OPG) and RANK1 are determinants of bone turnover
5)Trabecular bone has active turnover and develops decreased bone density and disrupted microarchitecture
6)Weak spicules of trabecular bone break (“microcracks”) and are replaced by weaker bone
1)Radiography:
a)Cortical thinning and increased radiolucency of bone
b)Vertebral height decrease (vertical deformity (T4-L4))
2)Dual-energy x-ray:
a)Dual-energy x-ray absorptiometry (DXA) is the present standard evaluation
i)Osteoporosis can be diagnosed if the bone mineral density is less than or equal to 2.5 standard deviations below that of a 30-40 year old healthy woman. This is computed as a T-score
3)MRI:
a)Differentiation of benign from malignant fractures
b)Benign fracture characteristics:
i)Maintenance of some normal marrow signal
ii)No involvement of posterior elements
c)Fluid sign or gas within the vertebral body
d)Low intensity band along the fractured end endplate (the fracture line)
e)No tissue mass in the paravertebral or epidural space
1)Osteoporosis
2)Metastasis:
a)Pedicle involvement
b)Vertebral body involvement
c)Does not involve the disc
3)Corticosteroid use
4)Hyperparathyroidism (primary and more frequently associated with kidney disease)
5)Type-2 Diabetes
6)Myeloma (often multiple vertebrae are affected)
7)Hemangioma (often hemorrhage; trabecular pattern on radiographs)
8)Various bone cysts
9)Prolonged heparin use (fish mouth endplates)
1. A primary benign bone lesion; it constitutes 10% of all primary benign bone tumors and 3% of all primary bone tumors
1.Most often they are seen in the first 3 decades; 3x more common in men
2.Predilection:
a.Long bones; particularly of the lower extremities
3.Major symptom is pain:
a.Localized and more severe at night
b.May be exacerbated or relieved by movement
c.Relieved by non-steroidal anti-inflammatory drugs (block prostaglandin activation of primary nociceptors in the lesion) and not by narcotics
d.Scoliosis occurs in 70% of patients when it involves the spine:
i.The most common cause of painful scoliosis in adolescents particularly if located in the thoracic or lumbar spine
e.If located in a pedicle, it may involve the exiting nerve root
1.A highly vascularized nidus of connective tissue surrounded by sclerotic bone
2.The nidus is approximately 10 mm in diameter which is smaller than that seen in an osteoblastoma
1.CT is the best diagnostic modality to visualize the nidus
2.MRI:
a.Increased signal intensity on T2-weighted sequences or enhanced T1-weighted sequences
i.Correlates with the degree of vascularity of the fibrovascular nidal stroma
ii.Correlates with the quantity of osteoid substance within the nidus
iii.Visualizes the soft tissue and bone marrow around the nidus
1. The major tumor to be differentiated is osteoblastoma
1.Cervical vertebrae are rarely affected
2.Similar clinical signs and symptoms to osteoid osteoma
3.More aggressive than osteoid osteoma and erosion into the vertebral artery has been reported; blindness has been reported from occlusion of the posterior cerebral artery
4.May extend into the neuronal exit foramina
1.Similar to that of osteoid osteoma although a major differential point is these lesions are usually larger than 2 cm whereas osteoid osteomas are less than 2 cm
1. Histological features are similar to those of an osteoid osteoma except they are larger than 2 cm
1.The most common benign bone tumor
2.35% to 50% of benign bone neoplasms and 10% to 15% of all primary bone tumors
1.Involvement of the spine occurs in 2 to 5% of patients; male>female 2.5:1
2.Spine involvement is often seen in the setting of multiple osteochondromatosis
3.Usual occurrences are in long bones
4.Usual spine predilection is for cervical or upper thoracic levels
5.Patients described at L4 and L5 with radicular involvement
6.Often asymptomatic
1.A developmental enchondromatous hyperplasia
2.Formation of cartilage-capped bony protrusions from a bony focus
a.Epidural extension
b.Expansion of the involved vertebra
c.Spontaneous epidural extension
d.Pathologic burst fracture
1. Giant cell tumor
2. Aneurysmal bone cyst
3. Metastasis
1.A benign non-neoplastic expansible cystic bone lesion
2.Most common location is long bones but approximately 12-30% involve the spine
3.Lumbar spine is the most frequent location followed by the thoracic spine; 2% involve the cervical spine
4.Incidence is 114/100,000 people; age (1-59 years)
1.Most frequently encountered between 10-20 years of age
2.Most commonly found in the metaphyseal areas of long bones
3.Presenting symptoms:
a.Well defined somatic pain, stiffness, and swelling
b.Pathologic fracture may cause spinal cord compression and radiculopathy
a.Pedicle and vertebral body integrity
4.MRI:
a.Multilocular cysts that are fluid filled; T2-weighted sequences have high-intensity signal
b.Multiple cysts may have varying signal intensities on T1 and T2-weighted sequences due to different oxidation levels of blood and their breakdown products
1.Pain and swelling at the lesion site are the most common symptoms
2.The tumor may be locally aggressive and impinge on a nerve root
3.Skull lesions (often sphenoid and temporal bones, rarely the occiput) produce symptoms by their location
1.Osteoclastic-like nuclear giant cells in a fibrohistiocytic stroma between osseous spicules
2.May also have foreign body-like giant cells
3.Histiocytes may be positive for CD68
4.Endochondral ossification
a.Ground glass appearance; cytic lesion
b.Expands bone
a.T1-weighted sequence equal intensity with muscle; T2-weighted sequence slightly intense signal
1.Chondroblastoma
2.Chondrosarcoma
3.Aneurysmal bone cyst
4.Dermoid cyst
5.Eosinophilic granuloma
6.Pigmented villonodular synovitis
1.Congenital non-neoplastic lesions that originate from totipotent ectodermal cells which remain within the developing neural tube
2.Starts between the 3rd and 5th weeks of gestation
3.In approximately 50% of patients, there is a dermal sinus tract
1.Cysts are usually intradural in the lumbar and sacral spine
2.Symptoms may occur from tethering of the spinal cord in association with congenital nerve root abnormalities
3.Rupture causes chemical arachnoiditis
4.Infection of the cyst or sinus tract causes meningitis
5.May occur at the site of meningocele repair
6.Rarely they develop after a lumbar puncture or trauma
1.MRI:
a.T1 and T2 weighted sequences demonstrate variable signal intensities according to the tissue in the cyst
1.Contains epidermis, hair follicles and sebaceous glands, that are derived from residual embryonic cells
1.Eosinophilic granuloma (EG) is one of the Langerhans cell histiocytosis
2.Incidence of 1:150,000 people / year
3.The most common site is the skull; vertebral involvement is approximately 7%
4.EG is a self-limited disease
1.Most often patients are younger than 15 years of age
2.In addition to the skull and vertebrae, the pelvis, mandible and ribs may be involved
3.Thoracic vertebrae are most often affected followed by lumbar (35%) and cervical vertebrae (11%)
4.Male to female is 2-5:1
5.Usually, the neurologic deficits are rare:
a.Pain may occur at the site
b.Spinal cord compression may occur from cervical tumors
c.Radiculopathy
1.Single or multiple skeletal lesions
2.Lung involvement
3.Accumulation of pathologic Langerhans cells
4.Anti-CD1a immunolabeling
1.Lytic lesion often with osteoblastic activity on X-ray and CT
2.PET evaluation has 90% sensitivity and a specificity of 65%-80%
a.False positive results occur from benign disease with an inflammatory component such as fibrous dysplasia or aneurismal bone cysts
b.Low-grade tumors
1.Rare tumors with an incidence of one/million people
2.Approximately 4% of primary malignant bone tumors and 20% of primary spine tumors
3.Divided into:
a.Clival (skull base)
b.Sacrococcygeal
c.Cervical, thoracic and lumbar
d.Almost equal distribution by site
4.Sacrococcygeal tumors have a male predominance of 2:1
5.Brachy gene in chordoma:
a.A diagnostic marker that differentiates the tumor from myoepithelioma and chondrosarcoma
6.Classification:
a.Notochordal hamartomas
i.Benign counterpart of chordoma
b.Chondroid chordoma:
i.5-15% of all chordomas
ii.Spheno-occipital areas of the skull base
c.Differentiated chordoma:
i.Less than 10% of chordoma
d.There is a correlation between the histological characteristic of a chordoma and its ability to metastasize:
i.Chondroid chordomas are the least aggressive while de-differentiated chordomas are the most aggressive
1.Sacral chordomas:
a.May be associated with large exophytic soft tissue masses
b.Bowel and bladder dysfunction (sacral roots)
c.Severe back pain; painful sacral mass
d.Intralesional surgery has a high rate of recurrence
1.Physaliferous cells are characteristic; foamy appearance of the cytoplasm that contains multiple vacuoles which ultra-structurally are divided into smooth-walled and villous
2.Tumors stain for vimentin, the S-100 protein, epithelial membrane antigen and low molecular weight cytokeratins
3.Chondroid chordomas:
a.Histological features of both chordoma and chondrosarcoma
i.Approximately 1/3 of cranial chordomas
ii.Express chordoma markers
4.De-differentiated chordoma:
a.Sarcomatous regions comprised of spindle-shaped polygonal cells
b.Metastasizes late
1.MRI:
a.T2-weighted sequences demonstrate a hypointense, non-enhancing, interosseous lesion
1.Liposarcoma is a common adult soft tissue sarcoma composed of three histologic subtypes:
a.Well and de-differentiated
b.Myxoid/round cell
c.Pleomorphic
2.Z1C1 overexpression:
a.A transcription factor important for neuronal development
1.Well-differentiated and de-differentiated liposarcomas occur:
a.Retroperitoneum > extremities > para-testicular areas and trunk; invasion of the lumbosacral plexus and individual roots
b.Motor and sensory loss in the plexi and roots that are involved.
2.De-differentiated tumors may metastasize (lungs primarily)
3.Retroperitoneal tumors may be >30 cm and invade viscera and the lumbosacral plexus; local reoccurrence is common
4.Myxoid/round cell tumors:
a. Translocation of chromosome 12 and 16
b.Interferes with adipocyte differentiation; abundant extracellular myxoid tissue
c.Present in younger patients and its primary location is the proximal lower extremities
d.Metastasizes to the skeleton, lumbosacral roots and pelvic plexi
5.Pleomorphic liposarcoma:
a.Chromosomal gains, losses, duplications, and rearrangements have been described
b.Usually, present with lower extremity involvement; rarely the retroperitoneum and mediastinum
c.Resembles a non-adipocytic soft tissue sarcoma (malignant fibrous histiocytoma)
6.All types may involve lumbar and sacral roots
1.Dependent on subtype
2.Pleomorphic liposarcoma resembles a non-adipocytic soft tissue sarcoma (malignant fibrous histiocytoma)
3.Myxoid/round cell liposarcoma:
a.Abundant extracellular myxoid tissue
4.Well and de-differentiated tumors:
a.Adipocytomas (WD Type)
b.DD Types have an adipocyte-rich region that is demarcated from highly cellular spindle cell area
1. Intradural lesion that may diffusely invade the vertebral bodies and encase the cauda equina
1.Primitive neuroectodermal tumors (PNET) and Ewing sarcoma are in the same family of malignant small, round cell neoplasms whose origin is soft tissue or bone.
2.Usual sites for EWS-PNET are the chest wall, pelvis, and the extremities
3.Incidence rate is approximately 3 patients/1,000,000 people
4.Approximately 10% of EWS arise in extraskeletal soft tissue
5.Caused by rearrangements involving the EWS gene on chromosome 22q 12 and fusion partners from the ETS oncogene family; 95% of EW sarcoma family tumors have fusion of the central exons of the EWSR1 gene (Ewing Sarcoma Breakpoint Region 1)
1. The tumor may arise from the pedicles of L4-5, and L5 S1
2. Primarily involves lumbar and sacral roots in the spine
3. Cerebral and lung metastasis occur
1.Poorly differentiated small round cell tumors
2.ES and PNET represent a single entity
3.Light microscopy reveals small round blue cells with hyperchromatic nuclei and minimal cytoplasm
4.EWS-PNETs co-express:
a. CD99 (the glycoprotein MIC2) and vimentin
1. CT scan EWS-PNETs:
a.Heterogeneous masses that invade surrounding tissue including bone
2. MRI:
a.The mass is isointense to muscle on T1-weighted sequences and hyperintense on T2-weighted sequences
1.Osteosarcoma is the most common primary malignant bone tumor in children and young adults
2.Older adults are usually affected by sarcomatous transformation of Paget’s disease of bone
3.Incidence of 1/100,000 people
1.A painful mass lesion
2.Pathologic fracture
3.Secondary causes include:
a.Ionizing radiation
b.Hereditary:
i.Retinoblastoma
ii.Paget’s disease of bone
iii.Enchondromatosis
iv.Hereditary multiple exostoses
v.Fibrous dysplasia
4.Presents between 5 and 30 years of age; a second peak occurs in the fifth and sixth decade
5.Pathologic fracture of vertebrae and compressive myelopathy and radiculopathy
1.A malignant spindle cell neoplasm that produces osteoid
2.Classified into 4 subtypes:
a.Osteoblastic
b.Fibroblastic
c.Chondroblastic
d.Telangiectatic
3.Classification is based on the predominant type of tumor matrix
1.Radiographs:
a.An ill-defined mixed sclerotic and lytic lesion that arises in the metaphyseal region of the involved bone
b.Destruction of the bone cortex
c.Soft tissue mass with ossification
d.Periosteal new bone formation with elevation of the cortex (Codman’s triangle)
2.CT assessment is superior to MRI for assessment of new bone formation
3.MRI:
a.T1 and T2 weighted sequences with fat suppression for the extent of bone and soft tissue involvement
b.Macroscopic tumor emboli may be found in regional large vessels
c.Telangiectatic osteosarcoma may present as a sacral mass
1.Less than 10% of chondrosarcomas are in children; 0.5% of low-grade tumors arise from benign chondroid lesions
2.They are 27% of all primary bone tumors
3.Central tumors arise in the medullary cavity or periosteum
1.Most patients present between 40-70 years of age
2.Patients with Ollier disease, Maffucci syndrome, and hereditary multiple exostoses have a higher incidence
3.Insidious worsening pain that is most pronounced at night
4.Approximately 20% present as a pathologic fracture
5.Primary sites are the shoulder, pelvis or proximal femur
6.Rare spinal compression from pathologic fracture or radiculopathy
1. May arise from an osteochondroma
2. Enchondroma (secondary chondrosarcoma)
3. Giant cell tumor
4. Bone cyst
1.Metastatic tumors are the most common neoplasms of the intraspinal canal and nerve roots
2.Locations:
a.Epidural > leptomeningeal > intraspinal
3.Epidural metastases occur primarily from direct extension of metastatic vertebral tumors; rarely a metastasis grows through the intervertebral foramina or directly metastasizes to the epidural space
4.Radiculopathy is secondary to direct compression by the tumor, metabolic and cytokine expression or a pathologic fracture that compresses the cauda equina
5.Differential diagnosis of common tumors that metastasize to vertebrae:
a.Lung
b.Breast
c.Prostate
d.Ovary
e.Melanoma
f.Renal cell
g.Sarcoma
h.Multiple myeloma
6.The most frequent sites of metastases are: thoracic > 70%; lumbosacral > 20%; cervical 10%
1.Local pain is the initial symptom. It is particularly evoked by mechanical stimuli (percussion over the involved vertebra)
2.Radicular pain:
a.Thoracic metastasis usually present with bilateral radicular pain
b.Lumbosacral roots most often have a unilateral presentation
c.Cervical spine:
i.C8-T1 (from Pancoast) tumor or metastasis may present with C8/T1 radicular pain, a Horner’s syndrome and anhidrosis or hyperhidrosis.
ii.C8-T1 innervates the eye and T2 is the level for extremity sympathetic innervations (irritation or destruction)
d.Herpes Zoster may be reactivated at the site of the lesion
e.Deep boring pain that is worse at night
f.Weakness, sensory loss, and atrophy with depressed or absent reflexes at the affected level
1.Malignant features by MRI:
a.Ill-defined lesion margin
b.Pedicle involvement
c.Heterogeneous enhancement pattern
d.Irregular nodular paravertebral soft tissue lesion
e.Erosion of the end plate
f.Star burst pattern of fracture is more likely traumatic
1.Cortical fractures of the vertebral body without cortical bone destruction
2.Retropulsion of a bone fragment of the posterior cortex of the vertebral body into the spinal canal
3.Fracture lines within the cancellous bone of the vertebral body
4.Intervertebral vacuum phenomena
5.Thin diffuse paraspinal soft tissue mass
1.The posterior portion of the vertebral body is involved
2.Concomitant vertebral body and pedicle involvement
3.Extensive abnormalities that involve the vertebral body and vertebral arch, but spare the pedicle are benign
4.Destruction of the anterolateral or posterior cortical bone of the vertebral body
5.Destruction of the cancellous bone of the vertebral body
1.Multiple vertebral levels are involved
2.The most common metastatic lesion
3.Thoracic vertebrae > lumbosacral > cervical spine
4.Cortical and cerebellar metastasis are often concomitant
5.A common cause of carcinomatosis of the meninges
6.Rarely anti-Yo[HT1] antibodies with paraneoplastic cerebellar degeneration
7.Often bilateral lumbosacral roots are involved
8.Rarely anti-‘Hu’ antibodies and associated limbic encephalitis and anterior horn cell disease
1.Pain radiates to the low back usually diffusely but may have a dermatomal distribution
1.Unilateral lumbar spine dull ache
2.Radiations to the groin, labia and testicles
3.Involvement is frequently of the upper lumbar roots
4.May be associated with a very dense vertebra
1.Pain radiates to the central thoracic spine
1.Thoracic or lumbar pain
2.Pain radiates to the lower abdomen, groin, anterior thigh, or flank
3.Characteristic tumors located retroperitoneally are lymphomas, renal cell carcinoma, and Schwannoma
1.Malignant cells exit the primary tumor, attach to, degrade the proteins of the extracellular matrix, and metastasize via the bloodstream, the lymphatics or directly to adjacent tissue.
2.Specific cancers spread to particular tissues that may be mediated by chemokines and transforming growth factor beta
3.Critical mechanisms for growth of metastases include:
a.Angiogenesis
b.Endothelial progenitor cells incorporation into tumor vasculature
c.Tumor cell mobility
d.Epigenetic regulation:
i.Histone modifications
e.Exosome factors
1.Destructive lesions of the vertebral body and particularly the pedicle and posterior elements; an osteoid osteoma (benign) may also affect the pedicle
2.The disc space is not involved
3.Multiple vertebral involvement suggests multiple myeloma, breast or lung metastasis
4.Involvement of the sacrum is characteristic of colon cancer
5.Multiple osteoblastic vertebral lesions suggest prostatic metastasis
6.A single dense vertebra on plain X-ray may occur with leukemia or lymphoma
7.Other MRI characteristics helpful in differentiating benign versus malignant vertebral fractures include:
a.Posterior cortical bulging:
i.74% of malignant lesions versus 45% of benign lesions
ii.Epidural mass formation was seen in 77% of malignant lesions and 25% in benign lesions
iii.Pedicle enhancement:
1.93% of malignant lesions and 39% of benign lesions (may occur with osteoporotic fractures)
1.Ependymomas (myxopapillary)
2.Glioma of the filum terminale
3.Neurofibroma of the cauda equine
4.Cauda equina tumors:
a.Hemangioblastoma
b.Paraganglioma
c.Ganglioneuroma
d.Schwannomatosis
e.Neurofibroma
5. Intraspinal pericytoma
1)The mean annual incidence of peripheral arterial disease is increasing
2)Patients with critical limb ischemia (CLI) have a high risk of cardiovascular disease that includes myocardial infarction, stroke and death
3)Vascular insufficiency of peripheral nerves and nerve roots is grossly underestimated
1)Exercise induced (intermittent) or rest pain
2)Thigh and calf muscles are predominately involved
3)Burning and squeezing quality of the pain that improves with rest and recurs with further exercise
4)Hip and buttock pain with walking
5)Ischemic rest pain of the lower extremity:
a)Primarily in the foot and toes
b)Buerger’s disease affects the medial foot
c)The pain is worse at night
d)Relieved by dependency
e)Always in the context of severe peripheral vascular disease
6)Leriche syndrome:
a)Atheromatous occlusive disease of the infrarenal aorta, common iliac arteries or both
b)Hip and buttock claudication
c)Impotence
d)Decreased peripheral lower extremity pulses
1)Atherosclerosis of large and medium sized lower extremity blood vessels
2)Coral reef aorta:
a)Calcified plaques in the visceral part of the aorta; plaques cause decreased perfusion of the lower extremities, visceral ischemia and renovascular hypotension
3)Microembolization from the endoaortic calcified mass causes the “blue toe” syndrome
4)Critical limb ischemia is caused by:
a)Severe atherosclerotic disease
b)Thromboembolic disease
c)Thromboangiitis obliterans
d)Vasculitis
e)Cystic adventitial disease
f)Popliteal entrapment
g)All processes may affect the nutrient supply to nerve roots
1) Arteriography to delineate the level and extent of arterial atherosclerosis
1)Rarely occurs with the increased use of MRI and CT for the diagnosis of back pain rather than myelography with contrast
2)The use of water-soluble contrast material if myelography is necessary rarely causes adhesive arachnoiditis
1)Intractable low back and leg pain and paresthesia of the involved nerve roots that is exacerbated by position
2)Burning pain, often encompassing several roots predominates over motor weakness
1)The arachnoid membrane is thickened over the cauda equina
2)It has been described in the setting of:
a)Lipid contrast use during myelopathy
b)Repeated epidural blood patches
c)Operative procedures
d)Infections
e)Subarachnoid hemorrhage
f)Epidural anesthesia
3)Chronic inflammation of the arachnoid layer of the meninges
4)Possible immune features
1)MRI:
a)Thickened meninges in the spinal canal with clumped nerve roots
2)CT / myelography:
a)Clumping and adhesion of nerve roots
1)Is a chronic inflammatory disorder characterized by spondylitis, sacroiliitis, peripheral joint involvement
2)Extra-articular manifestations include:
a)Uveitis
b)Inflammatory bowel disease
c)Psoriasis
d)Cardiovascular disease
3)Approximately 95% of patients are histocompatibility antigen HLS-B27 positive
1)Low back pain is an early complaint. It often radiates to the posterior thigh and groin
2)Limitation of movement is constant and progressive; severe early morning stiffness or an increase in stiffness after periods of inactivity
3)In later stages, some patients develop cauda equina compression
4)Pain in the thorax and sternum with coughing or other Valsalva maneuvers
5)Progressive flexion at the hips and flexion spine deformity which may exacerbate gait difficulty
1) Investigation of the IL-23 and Th17 axis that drives immune activation and chronic inflammation by the differentiation and activation of Th17 cells
1)X-ray:
a)Destruction of the sacroiliac joint
b)Bony bridging of the vertebral bodies (“bamboo spine”)
c)Dilatation of the lumbar thecal sac
d)Fracture dislocation of the spine at all levels from minor trauma (flexion extension injuries are most common cervically)
e)Destructive vertebral lesions; correlated with the return of pain after a period of quiescence or if the pain is localized
1)Abdominal aortic aneurysms occur most commonly in patients over 50 years of age, men more commonly than women, who are hypertensive, smoke and have heart or blood vessel disease
2)Marfan and Ehlers-Danlos are the most common genetic illnesses in which they occur
3)Most, approximately 85%, occur below the kidney
4)AAA have an incidence of 2% in males over the age of 65
5)An aneurysm less than 5.5 cm have a one year rupture risk of less than 1%
1)The great majority of aneurysms are asymptomatic
2)As the aneurysm expands, there may be pain in the chest, lower back or scrotum
3)A pulsatile sensation in the abdomen
4)Pain may occur at lumbosacral root levels
1)Aneurysms greater than 7 cm have a 33% chance of rupture with a mortality rate of 85-90%
2)Smoking is a major risk factor
3)In the tunica media and intima histologic analysis reveals:
a)Accumulation of lipids in foam cells
b)Extracellular free cholesterol uptake
c)Calcification
d)Adventitial inflammatory infiltrate
4)The basic mechanism has been posited to be proteolytic degradation of the tunica media by the increased expression and activity of matrix metalloproteinases
5)The serine protease granzyme B may also contribute to rupture by cleaving decorin that disrupts collagen and decreases the tensile strength of the adventitia
1)X-ray of the abdomen may reveal calcification in the walls of the aorta (approximately in 50% of patients)
2)Ultrasonography is the screen for AAA
3)CT scan has close to 100% sensitivity
4)Rarely plain x-ray or CT delineates erosion of vertebrae particularly at the T10-L1 level
1)The usual organisms are staphylococci, mycobacteria, streptococcus equisimilis and rarely fungi
2)Vertebral osteomyelites are responsible for 2 – 4% of all bone infections
3)Infections may have a predilection for children and the elderly
1)Subacute or chronic back pain that is exacerbated by movement and is not relieved by rest
2)Mechanically sensitive area (percussion) over the spine in the involved segments or the patient has severe limitation of movement. Pain may be severe with slight motion
3)Radicular pain may occur if the nerve root is affected
4)General symptoms include fever, night sweats, difficulty moving from a standing to sitting position
5)Patients may be afebrile and may not have leukocytosis
1)Destruction of bone trabeculae with inflammatory changes
2)Paravertebral mass (abscess)
3)Involvement of the vertebral body and the disc. Cancer does not breach the disc space. Fistula with drainage may be at a distance from the infected vertebrae which may occur with tuberculosis. Kyphosis (Pott’s disease) is rare in the west but occurs in developing countries with spinal tuberculosis: the usual sites are the lower thoracic and upper lumbar vertebrae.
1)Elevated sed rate and C-reactive protein is the rule
1)Involvement of the disc space as well as the vertebral body
2)Trauma and postoperatively, the discs may be directly infected. In the case of vertebral osteomyelitis the bone infection is primary and then spreads to the disc
3)Subacute bacterial endocarditis (SBE) may be associated with severe back pain and demonstrate no changes on MRI
1)Usually a severe pyogenic infection of the epidural space that requires immediate neurosurgical intervention and antibiotic treatment
2)Spinal epidural abscesses occur in 0.2 to 2 patients per 10,000 hospital admissions
3)The most common cause is hematogenous spread from a septic focus or by extension from osteomyelitis
4)The most common organism is staphylococcal infection
5)Most infections occur in patients between 30 to 60 years of age
6)Risk factors include diabetes mellitus, trauma, intravenous drug abuse, lumbar puncture, epidural injections / catheters and following laminectomy
1)Low grade fever with severe localized pain over the involved segment that is mechanically sensitive (percussion)
2)Radicular component may supervene
3)Paraplegia, anesthesia below the affected level with sphincter dysfunction occur in later stages (spinal cord involvement)
1) Pus and or inflammatory granulation tissue between the dura mater and the vertebral column
2) The infection is most frequent at the thoracolumbar levels (epidural space is larger); it is more frequently located posteriorly than anteriorly
1)Leukocyte count (1,500-42,000 / mm3)
2)Increased sed-rate and C-reactive protein
1.MRI yields the greatest diagnostic accuracy
1.May localize to the involved segment by hematogenous spread of a systemic infection (exemplified by urinary tract infection)
2.Following lumbosacral spinal procedures with concomitant osteomyelitis and spread into the disc space
1)Staphylococcus aureus is the most common organism; Escherichia coli and Proteus species are common in patients with urinary tract infections
2)Gram negative species are the most common organisms in i.v. drug abusing patients
3)Concomitant medical conditions are:
a)Diabetes
b)HIV infection
c)Steroid use
d)Cancer
e)Chronic renal failure
4)The disc is nourished by direct diffusion from the adjacent vertebral body endplate. Septic emboli lodge in the metaphyseal arteries (end arteries) that causes infarctions of the endplates that is followed by infectious spread into the disc space
5)Spread may also occur through Batson’s plexus
1)Increased sed-rate and C-reactive protein
2)Leukocytosis
3)Following operative procedures, staphylococcus aureus and epidermidis as well as Streptococcus species are the most common causative species
1)MRI:
a)Delineated characteristics include:
i)Location
ii)Osseous involvement
iii)Anterior versus posterior spinal location
iv)Soft tissue and iliopsoas involvement
b)Increased signal intensity on T2-weighted sequences with gadolinium enhancement noted in the disc space. Destructive enhancing bone lesions are demonstrated in patients with vertebral osteomyelitis
1.Clinical features depend on the specific underlying medical condition, whether the process is primarily demyelinating or axonal, the tempo of the underlying process and its extent
2.Most of the autoimmune processes are generalized while those due to infection are localized
3.Carcinomatous involvement affects the mental status and cranial nerves
1)CMV in the later stages of a severe HIV infection
2)Lyme disease
3)Herpetic infection
4)Carcinomatosis of the meninges
5)Guillain-Barre syndrome and other autoimmune neuropathies
6)Lumbosacral plexitis
7)Sarcoidosis
1)Sed rate and C-reactive protein are increased in both infective and autoimmune processes
2)Specific antigens for GBS and its variants
1)MRI:
a)Hypertrophic nerve roots in many autoimmune illnesses
b)Contrast enhancement of affected nerve roots
c)Some congenital neuropathies manifest hypertrophic nerve roots (cauda equina) that cause a compressive neuropathy
a)Spinal cord infarction
b)Myelitis
c)Compression fractures
d)The Guillain-Barre syndrome
1)Coagulation parameters
2)Sed rate and C-reactive protein
3)CSF evaluation if infection is suspected with PCR
1)MRI
a)High signal intensity of the parenchymal spinal cord on T2-weighted sequences
i)Dorsal views if an AVM is etiologic
ii)Surround T1 hypointense ring (hemosiderin) suggests cavernous hemangioma
i.May be associated with cranial neuropathy (uni or bilateral VII, rarely other cranial nerves and meningitis)
ii.Single or asymmetric multiple root involvement
i.Affects lumbar and sacral roots
ii.Most commonly encountered in severely affected HIV patients (CD4+ count of < 50 mm3)
i.Rapidly progressive cauda equina syndrome
ii.Leg weakness, paresthesia and saddle region sensory loss, sphincter dysfunction, progressive weakness to flaccid paralysis
iii.Severe low back pain
iv.Polymorphonuclear pleocytosis with elevated protein and viral titers in the CSF; positive PCR
v.Gadolinium enhancement on MRI of involved roots in 50% of patients
vi.If acute neurologic symptoms and signs need to rule out:
1.Infection or many other lesions of the cauda equina and conus medullaris
2.Lymphomatous infiltration of the lumbosacral roots
3.Syphilis (in an HIV-infected patient)
4.Herpes simplex (type II with sacral root involvement)
5.HIV-related polyradiculopathy
vii.Herpes virus 8 (lumbar and thoracic roots)
viii.EBV (isolated nerve roots)
ix.Tuberculosis (cold abscess):
1.L1-L3 roots
2.Some ethnicities have primarily cervical root involvement (Asian patients)
a.Dorsal root entry zone is the site of infection
b.Pachymeningitis cervicalis > lumbosacral involvement
c.Tabetic pain:
i.Thoracic > lumbosacral roots
ii.May simulate a thoracic or abdominal visceral emergency
a.Involvement is overwhelming in the cervical cord
b.Isolated roots may be involved
i.Occurs in the thoracic > lumbosacral > cervical cord
ii.Chronic lesions occur in the thoracic cord
iii.Infecting organisms:
1.Staphylococcus aureus
2.Gram-negative rods
3.Anaerobes
4.Skin flora (spinal operations)
5.Mycobacterium
6.Fungi
i.IV drug abuse
ii.Spinal surgery
iii.Diabetes mellitus
iv.Epidural steroids:
1.Recent fungal contaminant of steroid injections
v.Epidural catheters:
1.Prolonged use for neuropathic pain patients
vi.Immunocompromised patients
i.Onset often occurs with severe back pain; delayed from the onset of the infection
ii.Spinal cord compression, infarction or parenchymal infection
iii.Deep boring midline pain in the spine with sudden radicular component
iv.Cauda equina involvement
v.Fever, leukocytosis and elevated sed rate
vi.MRI may demonstrate gadolinium enhancement of the involved roots
i.Patients > 60 years of age
ii.Present with pain of neuropathic quality usually of the distal extremities
iii.Prominent weakness
iv.Concomitant weight loss
v.Thoracoabdominal nerve root involvement
a.Proximal L1-L3 nerve root involvement; all roots may be affected
b.Asymmetric involvement
10.All collagen vascular disease
11.Carcinomatosis of the meninges
12.Mixed collagen vascular disease
1.Endometriosis:
a.Endometrial tissue is adherent to pelvic nerve roots (L5-S5)
b.Catamenial cyclical pain with bleeds from the aberrant tissue and irritation of the lumbosacral roots
2.Laparoscopy for pelvic and abdominal processes with root injury:
a.L1-L3 > involvement than L5-S1 roots
3.Epidural catheter trauma:
a.Prolonged exposure to bupivacaine (directly toxic to the nerve root)
b.Direct trauma to the root during catheter insertion
4.Arachnoiditis:
a.General Characteristics:
i.Clumped scarred nerve roots in the dorsal sac (MRI evaluation)
ii.Occurs following multiple surgeries or hemorrhage during myelography with pantopague. Water-soluble contrast has eliminated this cause.
b.Clinical Manifestations:
i.Severe burning pain in several root distributions > motor weakness
ii.No exacerbating or relieving factors
iii.Asymmetric reflex loss
5.Spina Bifida:
a.May be associated with congenital defects of the pedicles, facets, and foraminal exit canals
b.Conjoined nerve roots
6.Mxyopapillary Ependymoma:
a.Asymmetric lumbosacral nerve root involvement
b.Lower extremity weakness
c.Bowel, bladder, and sexual dysfunction
7.Dropped Metastasis:
a.Medulloblastoma
8.Traumatic nerve root avulsion:
a.Severe trauma (often motorcycle accidents)
b.Most often cervical nerve roots and the brachial plexus are injured
c.MVA affect lumbosacral roots and the lumbosacral plexus
9.Plate fixation and pedicle screw displacement
10.Complications of epidural and spinal anesthesia:
a.General Characteristics:
i.Toxic effects of anesthetic (usually 0.25% bupivacaine)
ii.Direct injury by needle or catheter
iii.Subarachnoid injection of anesthetic during epidural procedures
iv.Contamination of anesthetics with detergents, chemicals or organisms (bacteria or fungal)
v.Epidural abscess
vi.Risk of epidural anesthesia is increased with:
1.Lumbar spinal stenosis (“Pooling”) of bupivacaine around nerve roots
2.Inadvertent subarachnoid injection of high volume of anesthetic
3.A combination of general and epidural anesthesia
4.Advanced age
b.Clinical Manifestations:
i.Radicular pain and weakness
ii.Lower extremity myoclonus and severe spasm
iii.Cauda equina syndrome
iv.May clear after days to weeks (the cauda equina are peripheral nerves and have regenerative capacity)
1.Cervical spine roots exit horizontally from the spinal cord to the neural exit foramina
2.The ventral and dorsal roots join just distal to the DRG (which most often is in the vertebral foraminal exit canal) and form a spinal nerve; the dorsal ramus supplies the paraspinal muscles (its origin is just distal to the DRG) as well as the cutaneous innervation of 1 – 1 ½ inches lateral to the spinous process
1)C1-C2 level:
a)There is no disc between C1-C2
b)Ligaments and joint capsules resist excessive motion at this level
c)Cervical spinal nerve I only carries motor fibers
d)It arises from the spinal column above the C1 vertebra
e)It innervates:
i)Geniohyoid muscle (hypoglossal nerve)
ii)Thyrohyoid muscle (hypoglossal nerve)
iii)Omohyoid muscle (Ansa cervicalis)
iv)Sternohyoid (Ansa cervicalis)
v)Rectus capitis anterior muscle
vi)Partial innervation of the longus capitus muscle
vii)Rectus capitis lateralis muscle
viii)Partial innervation of the splenius cervicis muscle
ix)Rectus capitis posterior major muscle
2)C2 nerve root:
a)Motor innervation:
i)Similar muscles innervated by C1 that move the head and neck and include:
(1)Longus capitis
(2)Rectus capitis
(3)Obliquis capitis
(4)Longissimus capitis and cervicis
(5)Rotatores
(6)Semispinalis
(7)Multifidi
(8)Intertransversari
ii)A small supply to the sternocleidomastoid muscle which is primarily innervated by the spinal accessory nerve
iii)It innervates the skin of the scalp at the top of the head, over the top of the ear and the parotid gland
iv)It forms part of the greater occipital nerve
3)C3 Nerve Root:
a)Motor innervation:
i)Paresis of the scalene and levator scapulae
ii)Innervation to:
(1)Infrahyoid muscles
(2)Semispinalis capitis
(3)Cervicis
(4)Longissimus capitis and cervicis
(5)Intertransversari rotatores
(6)Multifidi
iii)Some innervation of the diaphragm
iv)Some innervation of the trapezius muscle that is primarily innervated by the spinal accessory nerve
b)Sensory innervation of the lower occiput, the angle of the jaw and the upper neck
c)In addition to motor and sensory symptoms, irritation of the root may cause the red ear syndrome. This represents neurogenic edema from the release of vasoactive neuropeptides (SP and GCRP).
d)The red ear syndrome has also been described with temporomandibular joint syndrome and thalamic lesions
4)Cervical Root 4:
a)Motor innervation:
i)Scalene and levator scapulae
ii)Rhomboid muscles
iii)Trapezius
iv)Sternocleidomastoid muscles
v)Diaphragm
b)Sensory innervation:
i)Innervation of the lower neck and parts of the trapezius ridge
ii)No reflex deficit
5)Cervical Root 5:
a)Motor innervation:
i)Levator scapulae
ii)Rhomboids
iii)Serratus anterior
iv)Supraspinatus
v)Infraspinatus
vi)Deltoid
vii)Biceps and brachioradialis
viii)Some diaphragmatic innervation
b)Sensory innervation:
i)Neck, shoulder and upper arm pain
ii)Cap of the shoulder
iii)Lateral arm
c)Depressed biceps and brachioradialis reflex
6)Cervical Root 6:
a)Motor innervation:
i)Serratus anterior
ii)Biceps
iii)Pronator teres
iv)Flexor carpi radialis
v)Brachioradialis
vi)Extensor carpi radialis longus
vii)Supinator
viii)Extensor carpi radialis brevis
b)Sensory innervation:
i)Pain in the lateral arm and dorsal forearm
ii)Loss of sensation on the lateral forearm
iii)Loss of sensation in the first and second digits
c)Depressed biceps and brachioradialis reflex; “inverted radial reflex”
7)Cervical root 7:
a)Motor innervation:
i)Serratus anterior
ii)Pectoralis major
iii)Latissimus dorsi
iv)Pronator teres
v)Flexor carpi radialis
vi)Triceps
vii)Extensor carpi radialis longus
viii)Extensor carpi radialis brevis
ix)Extensor digitorum
b)Sensory innervation:
i)Pain in the dorsal forearm; rarely a radiation to the middle digit
ii)Some sensory loss in the third and part of the fourth digits
c)Depressed triceps reflex:
i)Rarely, patients may have pseudomyotonia of the hand from misdirection of C7 fibers after root injury. The patient has normal muscle relaxation of the hand but on extension of the fingers, there is paradoxical flexion.
8)Cervical Root 8:
a)Motor innervation:
i)Flexor digitorum superficialis
ii)Flexor pollicus longus
iii)Flexor digitorum profundus I-IV
iv)Pronator quadratus
v)Abductor pollicis brevis
vi)Opponens pollicis
vii)Flexor pollicis brevis
viii)Lumbricals
ix)Flexor carpi ulnaris
x)Abductor digiti minimi
xi)Opponens digiti minimi
xii)Flexor digiti minimi
xiii)Interossei (dorsal and ventral)
xiv)Abductor pollicis
xv)Extensor digiti minimi
xvi)Extensor[HT2] carpi ulnaris
xvii)Abductor pollicis longis
xviii)Extensor pollicis longus and brevis
xix)Extensor indicis
b)Sensory innervation:
i)Medial forearm and hand
ii)Fifth digit
c)Depression of the finger flexor reflex
1)Often there is an insidious onset of signs and symptoms at the segmental level
2)There are intradural communicating fibers between adjacent segments of the posterior roots. The connections are densest between a specific cervical segment and the adjacent caudal root. Therefore a lesion may be one level higher than its actual location
3)Prefixed and postfixed brachial plexi may also alter root localization
4)Cervical root compression and syndromes are often incomplete
5)Lateral discs may cause weakness without pain particularly prominent with discs at the fifth and sixth segmental levels
6)All patients with pain have limitation of movement of the neck to all planes (particularly with hyperextension)
7)The pain is exacerbated with Valsalva maneuvers and with downward pressure on the head when it is in extension
8)Manual traction and abduction of the arm tend to relieve pain (opens the neural exit foramina)
9)Large and central disc herniations may compress the spinal cord:
a)The central disc herniation may be painless
b)Bilateral hand numbness and paresthesias may occur
c)Paresthesias of the chest wall below the compression level may be appreciated
d)Stiffness and hyperreflexia of the legs is produced by disinhibition of the corticospinal tracts
e)The C7 nerve root is involved in approximately 70% of patients with HNP. The C6 root is involved in 20% and rarely the C5 and C8 roots are involved in the remaining 10% of patients
1)C1-C2:
a)There is no disc between C1-C2
2)C2-C3 intervertebral disc space:
a)Rarely trauma induces C2-C3 disc extrusion
b)Nonspecific neck and rarely shoulder pain most often; rarely radicular lancinating pain that radiates to preauricular areas and the lateral neck
c)A retro-odontoid disc may result from an upper migrating disc fragment
d)Concomitant cord injury may cause motor and sensory symptoms below the disc level
3)C3-C4 intervertebral disc space:
a)Disc herniations at this level are rare
b)May present with no or minimal pain
c)May cause a myelopathy
d)Hand numbness may be a prominent symptom
4)C4-C5 intervertebral disc space herniation:
a)The C5 root is affected
b)Pain is felt across the trapezius ridge to the shoulder
c)There is weakness of the supra and infraspinatus, deltoid and biceps manifested by:
i)Inability to abduct the arm (first 10-20o) and rotate it externally (supra and infraspinati) when the shoulder is adducted
ii)Slight biceps weakness
iii)Depressed biceps reflex
iv)Area of sensory loss over the deltoid muscle
5)C5-C6 intervertebral disc space herniation:
a)The C6 root is affected from a laterally placed disc
b)Pain in the trapezius ridge and cap of the shoulder
c)Sensory radiations are to the anterior upper arm, radial forearm, thumb and index finger
i)Other sensory manifestations include:
(1)Tenderness above the scapular spine as well as the supraclavicular fossa and in the biceps muscle
d)Motor manifestations:
i)Weakness of forearm flexion (biceps)
ii)Deltoid weakness manifested with poor arm abduction
e)Diminished or absent biceps and supinator reflexes
6)C6-C7 intervertebral disc space herniation:
a)The affected root is C7
b)Pain radiates to the shoulder blade, scapular spine, posterolateral upper arm; less commonly to the elbow, dorsal forearm, index and middle fingers. Rarely, all fingers are numb
c)Other radiations include:
i)Pectoral and axillary areas
ii)Tenderness is pronounced over the medial scapular border, the supraclavicular fossa and the triceps muscle
d)There is weakness of the extensors of the forearm and often the wrist; the triceps is weak
e)Decreased triceps reflex
7)C7-T1 intervertebral disc space herniation:
a)The C8 root is affected
b)Pain radiates along the medial side of the forearm; sensory loss is in the distribution of the medial cutaneous nerve of the forearm and of the ulnar nerve in the hand (half of the 4th finger and all of the 5th finger)
c)Weakness is primarily in the intrinsic hand muscles supplied by the ulnar nerve that include:
i)Flexor digitorum profundus, third and fourth lumbrical, muscles of the hypothenar eminence, adductor pollicis, flexor pollicis brevis and the interossei
d)The triceps reflex may be slightly depressed
1)Abnormalities of the cervical spine posterior arch are rare and are most often found incidentally
2)This defect may also occur in the thoracic, lumbar and sacral spine
3)The defect occurs on either side and is almost always unilateral
4)C6 is the most common level of occurrence (39%0 and C5 with 27%)
1)Most patients are asymptomatic
2)Headache and cervical pain
3)Radicular pain has been described in the upper extremities
1)Failure of development of the ventral chondrification center during the sixth week of gestation
2)Absence of the pedicle and the lateral mass
3)Dysplasia of the inferior articulating facet at the adjacent level that causes anterior displacement
1)MRI:
a)Useful to eliminate soft tissue injury associated with traumatic subluxations
2)Radiographs:
a)An enlarged neural foramina due to the absence of the pedicle and posterior displacement of the articular mass of the affected vertebra
b)Dysplastic posteriorly displaced articular facet and lamina
c)Dysplastic transverse process
d)Associated anomalies include:
i)Spina bifida occulta
ii)Vertebral body fusions
e)Misdiagnoses include spinal tumor, bone tumor and fracture dislocation
1)Developmental anomalies of the axis are common
2)Anomalies of the posterior elements are rare and include:
a)Invagination of the lamina of C2
1)Progressive myelopathy
2)Mechanical neck pain from cervical root irritation
3)A case report associating absence of C2 vertebra posterior elements with atlanto-axial dislocation and basilar invagination
1)Failure of dorsal migration of cells from the second spinal sclerotome
2)Failure of chondrification that leads to failure of formation of the neural arch
1)Radiographs
a)Anterolisthesis of C2 over C3
b)Hypertrophied spinous process of C3
1)Prevalence is 1 in 65,000 live births
2)Accounts for 4.5% of all patients with craniosynostosis
3)Approximately 98% of patients have specific missense mutations in the linker between the second and third extracellular immunoglobulin domain of the FGFR2 gene that maps to chromosome 10q26
1)In early life:
a)Headaches and vomiting due to increased intracranial pressure
b)Stridor and sleep apnea
c)Visual deficits due to corneal injury from exposure conjunctivitis
d)Most patients have cognitive impairment although some have normal intelligence
2)Flattened asymmetrical face
3)Maxillary hypoplasia
4)Extremity and digit malformations that include:
a)Coalition of distal phalanges with synychia of the hands
b)Short humeri
5)Multiple CNS anomalies that include:
a)Megalencephaly
b)Absence of the corpus callosum
c)Ventriculomegaly
d)Gyral abnormalities and hypoplastic white matter among others
6)Dermatological features include:
a)Hyperhydrosis
b)Brittle nails
c)Hypopigmentation
d)Hyperkeratosis in the plantar surfaces among others
7)Cardiovascular defects include both atrial and ventricular defects:
a)Tetralogy of Fallot
b)Atrial and ventricular septal defects
c)Dextrocardia among others
8)Gastrointestinal, genitourinary and respiratory features and anomalies are common
1)Multiple CNS anomalies that include:
a)Megalencephaly
b)Absence of limbic structures and agenesis of the corpus callosum
c)White matter, convolutional and gyral convolutional anomalies
2)Aplasia or ankylosis of shoulders, elbow and hip joints
3)Rhizomelia
4)During early infancy (< 3 months) there is premature closure of the coronal suture; the lamdoidal sutures are normal
5)The syndactyly is a keratinocyte growth factor receptor (KGFR) mutation
1)98% of patients have a missense substitution mutation in exon 7 of FGFR2
1)MRI:
a)Delineates the cranial deficits that include:
i)Prominent convolutional markings,
ii)Enlarged ventricles
iii)Crowded foramen magnum
iv)Deficient septum pellucidum
v)Agenesis of the corpus callosum
b)Spinal radiographs:
i)Spinal fusion at C3-C4 and C5-C6 is most common
ii)Multilevel fusion occurs in approximately 20% of patients
iii)Spina bifida occulta is seen in ~7% of patients
iv)Atlanto-axial subluxation occurs in 7% of patients
1)Beare-Stevenson syndrome (may have FGFR2 mutations)
2)Carpenter syndrome
3)FGFR3-associated coronal synostosis
4)Jackson-Weiss syndrome
5)Pfeiffer syndrome
6)Saethre-Chotzen syndrome
1)There are several different classifications. Naquib classification:
a)Type I: two sets of block vertebrae with open intervening spaces that can sublux gradually or with acute trauma
b)Type II: craniocervical anomalies with occipitalization of the axis and basilar invagination; causes increased mobility at the craniocervical junction, possible foramen magnum encroachment; may also be associated with Arnold-Chiari malformation and syringomyelia
c)Type III: Fusion of one or more levels with associated spinal stenosis
2)The usual presentation is in childhood but it can present in later life
3)Incidence is 2 patients per 1000 patients (Danish study); 0.71% incidence in 1400 skeletons (Washington University School of Medicine study)
4)Klippel-Feil syndrome-1 is caused by heterozygous mutations in the GDF6 gene on chromosome 8q22
5)Additional forms of Klippel-Feil syndrome include:
a)AR mutation in the MEOX1 gene on chromosome 17q21
b)AD mutation of the GDF3 gene on chromosome 12p13
c)AR mutation due to mutation of the MYO18B gene that maps to chromosome 22q12
1)Upper cervical spine involvement tends to present earlier than lower cervical involvement
2)Short neck with decreased range of movement
3)A low hairline occurs in 40-50% of patients
4)Rotational loss is usually greater than loss of flexion and extension
5)May present with torticollis and facial asymmetry
6)Occipitocervical anomalies
7)Scoliosis may be seen in a significant proportion of patients
8)Cervical spinal stenosis
9)A Sprengel anomaly occurs in 20-30% of patients
a)Omovertebral bone which is an osteocartilaginous connection that tethers the scapula to the spine
b)Radicular pain primarily from midcervical root involvement
1)The cross-sectional area of the spinal cord is smaller in KFS patients from C2-C7
2)In older patients complete fusion is more prevalent at C2-C7
3)Fusion of the posterior elements is more common than anterior element fusion
4)An arrest of normal vertebral development may affect appositional bone development
5)Associated deficits:
a)Deafness
b)Vocal cord impairment
c)Cleft palate (AD pattern)
6)Defects of post-otic neural crest cells (PONC)
1)Hearing evaluation
1)Radiographic features:
a)Vertebral fusion at varying levels of the cervical spine
b)Anterior-posterior narrowing of the vertebral bodies (Wasp-Waist sign)
c)Focal canal stenosis C2-C7 (some patients)
d)Hemivertebrae
e)Spina bifida occulta
f)Scoliosis
g)Sprengel’s deformity
2)CT:
a)Better image features demonstrated than on plain radiography
b)Delineates canal stenosis
3)MRI:
a)Delineates canal stenosis and cord compression
b)Rare anterior cervical meningomyelocele
1)Cervical spondylosis is a degenerative disease of the cervical spine that affects the:
a)Vertebral bodies
b)Intervertebral discs
c)Nerve roots
d)Spinal cord
e)Facet joints
f)Longitudinal ligaments
g. Ligamentum flavum
2)It is the most frequent cause of spinal cord pathology in patients older than 55 years of age; >80% of men and women over 50 years of age have some radiologic features of the disease
3)Possibly starts earlier in men than women
4)In young patients it may be secondary to an abnormality in a joint between the vertebrae
1)Chronic suboccipital headaches
2)Pain may be localized to the neck or radiate to the shoulder, scapular border (medial) or to the arm
3)Compression of the nerve roots causes radicular pain; the C6 root is the most commonly affected from degeneration at the C5-C6 interspace; the next most common roots affected are C7 and then C5
4)Cervical myelopathy:
a)Has an insidious onset and is most common in 50-60 year old patients
b)The sphincters are rarely involved at presentation
c)Signs and symptoms occur from involvement of:
i)The corticospinal, posterior column, cerebellar and spinothalamic tracts
ii)Motor deficits from corticospinal and anterior horn cell dysfunction
iii)Central spinal cord syndrome
(1)Due to lamination of the corticospinal pathways the arms are more affected than the legs
iv)Brown-Sequard syndrome
v)Upper limb pain with a component of spinal cord compression
d)Unusual manifestations:
i)Glove-like sensory loss
ii)Concomitant tandem cervical and lumbar stenosis. There are almost always degenerative changes at both levels
iii)Complex gait abnormalities; tandem gait is difficult in most patients from a combination of peripheral lower extremity proprioceptive loss and compression of the dorsal columns and spinocerebellar pathways
iv)Lhermitte’s sign
1)Forward flexed neck with limitation to all planes of movement; particularly severe in extension
2)Spurling’s sign in which radicular pain is exaggerated by extension and lateral bending of the neck toward the side of the lesion (further compromising the nerve root exit foramina)
3)Rarely Lhermitte’s sign can be elicited
4)Atrophy of the C5-C6 innervated muscles, particularly the biceps; prominent trapezius muscle spasm and hypertrophy
5)Often atrophy of the median forearm musculature
6)Fasciculations that are spontaneous or mechanically induced in the shoulder girdle musculature
7)Weakness is more prominent proximally than distally
8)Sensory loss in affected dermatomes is less prominent than weakness
9)Inability to perform tandem gait
10) An inverted radial reflex with striking the biceps tendon. This requires two lesions:
a)Compression above the C5-C6 level usually by a spondylitic bar at C4-C5
b)Osteophytes that block the C5-C6 intervertebral foramen
c)Sensation enters the disinhibited spinal cord (from compression at C4-C5) by higher C3-C4 and lower roots from vibration of the arm when eliciting the bicep’s reflex
d)There is no induction of the biceps reflex due to the osteophytes at C5-C6 but the disinhibited spinal cord fires at C8-T1 eliciting finger flexion
e)Extremely rarely there is extension of the arm rather than flexion due to activation of C7 (triceps)
11) There are almost always concomitant signs of lumbosacral radiculopathy
12) Cortical spinal release phenomena in the form of Hoffman’s and Babinski signs are present with spinal cord compression
13) Increased reflexes in the upper and lower extremities below the level of the lesion (disinhibited spinal cord)
14) Broad based and spastic gait
1)Radicular arteries may be compressed in the dural sleeves
2)Contribution from a congenitally small canal
3)Intervertebral discs dehydrate and lose elasticity with age which leads to fissure formation
4)Ligaments become less elastic and develop traction spurs
5)The disc space narrows, the annulus bulges and the facets override which increases motion at that level which exacerbates the process
6)There may be concomitant disc herniation
7)Annulus bulging, facet hypertrophy and ligamentous thickening narrow the spinal canal
8)Overriding of the uncinate processes and their hypertrophy compresses the ventrolateral component of the nerve exit foramina. Facet hypertrophy and degenerative changes narrow the dorsal component of the foramina:
a)Thinning and fragmentation of the articular cartilage that leads to exposure of subchondral bone which leads to fibrosis, increased bone formation and cystic changes
b)Loss of articular cartilage leads to new bone formation (osteophytes)
1)EMG:
a)Delineates the involved roots
1)Radiographs:
a)Delineates uncovertebral and facet joint hypertrophy, the neural exit foramen, the intervertebral disc spaces and osteophytes
b)Flexion-extension views are important in instances of instability
2)MRI:
a)Excellent delineation of neural elements
b)Better evaluation of any parenchymal spinal cord pathology
3)In selected patients myelography with CT delineates the relation of nerve roots to bone
1)The AP diameter of the normal adult male cervical cord is 17-18 mm at levels C3-C5. The lower cervical levels measure 12-14 mm. Stenosis has a mean AP diameter of less than 10 mm and diameters of 10-13 mm are relatively stenotic in the upper cervical canal
2)The confines of the cervical spinal canal are:
a)Laminae and ligamentum flavum posterolaterally
b)The pedicles anterolaterallly
c)Discs and the vertebral bodies anteriorly
d)Extension of the neck reduces the overall canal area by 2-3 mm
e)Central cervical spinal compression is due to bulging of the disc annulus, hypertrophy of the ligamentum flavum and spondylitic bony overgrowth
f)Movement in congenital or acquired stenosis exacerbates the condition. The anterior roots are compressed between the annulus margins and spondylitic bony hypertrophic bars. In the posterior canal, hypertrophic facet joints and thickened infolded ligamentum flavum distort and compress dorsal roots.
g)Neural elements are tethered anteriorly against the protruding disc annulus and spondylitic bony overgrowth in hyperflexion
h)Lateral cervical stenosis is caused by encroachment of the lateral recess on the neural exit foramina due to hypertrophy of the uncovertebral joints, the lateral disc margin and facet hypertrophy
1)If there is primary central spinal cord compression, there is minimal pain but weakness and sensory loss below the level of compression
2)Radicular pain at affected levels from concomitant nerve root compression
3)Often there are depressed biceps and brachioradialis reflexes. The inverted radial reflex is often present (due to concomitant spondylitic changes at C4 and C5-C6)
4)Poor tandem gait due to compression of the dorsal and ventral spinocerebellar tracts (both serve the legs while the cuneocerebellar tract provides coordinative functions for the arms and fingers and is not often affected to the same degree)
5)Minimal atrophy of C5-C6 innervated musculature
6)Neurogenic bladder may occur late in the course of the disease
1)A congenitally small canal with short pedicles; acquired spondylosis
2)Disc degeneration, bulging and extrusion with concomitant facet and uncovertebral joint osteoarthritic overgrowth of bone
3)Hypertrophy and calcification of the posterior longitudinal ligament that is more common in Asian patients
1)EMG:
a)Delineates the levels of radicular involvement
1)MRI:
a)Grading system according to the T2-weighted sagittal images:
i)Grade 0: absence of canal stenosis
ii)Grade 1: subarachnoid space obliteration exceeding 50%
iii)Grade 2: spinal cord deformity
iv)Grade 3: spinal cord signal change
2)CT:
a)Needed when there are complications and contraindications for MRI studies (metal implants and cardiac pacers)
1)Degenerative lumbar spondylolisthesis is common in elderly patients
2)Cervical spondylolisthesis is most often caused by trauma
3)The injuries that lead to this condition include:
a)Traumatic spondylolisthesis of the axis (hangman’s fracture)
b)Uni or bilateral facet dislocation and fracture subluxation
c)Classification system for degenerative cervical spondylolisthesis:
i)Type 1: most common, occurs adjacent to relatively stiff spondylotic cervical levels
ii)Type II; occurs within spondylotic cervical segment
1)Decreased cervical range of motion
2)The affected levels are primarily C3-C4 and C4-C5
3)Neck pain is the initial symptom that may be associated with occipital radiations
4)Radicular symptoms
5)A combination of myeloradiculopathy
1)Trauma with hangman’s fracture of the axis
2)Bilateral or unilateral facet dislocation and fracture
3)Degenerative osteoarthritis with hypertrophic facet arthropathy that causes joint erosion, marginal osteophytes and subluxation; disc degeneration has been posited to be pivotal. Other evidence suggests that thinning of the facets and narrowing of the joint space is primary
4)Rare causes include:
a)Renal osteodystrophy
b)Congenital absence and hypoplasia of the C6 pedicles with C6-C7 spondylolisthesis
1.Radiographs:
a.A large proportion of patients are demonstrated to be unstable with flexion and extension at involved levels
b.Horizontal displacement (in 217 patients) averaged 3.9 mm
2.MRI:
a.Delineates the location and extent of neurological compression at the level of the spondylolisthesis
1.EMG:
a.Delineates the affected roots
1)Tarlov (perineural) cysts are common and most often incidental findings in the lumbosacral spine
2)Rarely perineural cysts are symptomatic in the cervical roots
3)A Tarlov cyst is formed within the nerve root sheath at the dorsal root ganglion
1)Radicular pain at the affected level that is exacerbated by Valsalva maneuvers
2)Rarely, compressive cervical myelopathy
1)The major histologic feature of the Tarlov cyst is the presence of nerve fibers in the cyst wall
2)The mechanisms posited for cyst formation include:
a)Ball-valve formation from a hemosiderin deposition caused by blockage of venous drainage of the perineurium and epineurium (traumatic theory)
b)Congenital arachnoid proliferation along existing nerve roots
1)MRI:
a)Isotense lesion on T1-weighted sequences; A hyperintense signal on T2 weighted images
b)Displacement of the spinal cord
1)Neuralgic amyotrophy is an acute painful multiple mononeuropathy that most often involves the upper brachial plexus
2)It may be restricted to one fascicle of one nerve, plexus or root
3)Hereditary neuralgic amyotrophy is primarily linked to chromosome 17q25.3. It is caused by heterozygous mutation in the SEPT9 gene.
4)It is AD.
1)Acute and recurrent episodes of brachial plexus weakness and atrophy most often preceded by severe pain in the affected arm
2)Usually it is asymmetric and involves plexi in a patchy distribution. It may involve the cervical and lumbar plexus as well as cranial nerves
3)There is amyotrophy and sensory loss
4)It is usually monophasic, autolimited and does not lead to a generalized polyneuropathy
1)It may be restricted to one fascicle of one nerve or root
2)May be triggered by infection
3)Axonal neuropathy
4)Possibly episodic patients are affected on an autoimmune basis
1)EMG:
a)A severe axonal neuropathy
1.Most often affects the C8-T1 roots or the proximal trunk of the brachial plexus
1)EMG:
a)Nerve conduction studies demonstrate attenuated compound muscle action potentials of the abductor policis brevis and often loss of sensory nerve action potential of the medial antebrachial cutaneous nerve
1)Radiographs:
a)Cervical rib is demonstrated
1)Anatomy of the thoracic outlet:
a)The sterno-costovertebral space:
i)The most proximal part of the thoracic outlet tunnel which is bounded
(1)Anteriorly by the sternum
(2)Posteriorly by the spine
(3)Laterally by the first rib
ii)The subclavian artery and vein as well as the C4-T1 roots of the plexus transverse the space
iii)Nerve roots have exited the spine but have not formed trunks
iv)Associated structures include:
(1)The apex of the lung and the pleura
(2)Sympathetic trunk
(3)Jugular vein
(4)Lymphatics of the neck
(5)Rarely the space is congenitally narrowed
i.Behind the artery
ii.Between the artery and the brachial plexus
iii.Entire base of the scalene triangle (traps the neurovascular bundle)
iv.Anterior insertion may merge with insertion of the middle scalene muscle (20% of patients)
v.The C5 and C6 roots may traverse the anterior scalene muscle rather than descend between the anterior and middle scalene muscles
i.Interdigitation of anterior and middle scalene muscles occurs in 70% of symptomatic patients
ii.Adherence of C5 and C6 roots to the middle scalene muscle may occur and places these roots under traction when the arm is moved
1)The dorsal root of C2, C3 and C4 are frequently injured from flexion-extension injury (whiplash)
2)C8-T1 roots are most often involved from congenital anatomical predisposition
3)Damage to cervical roots occurs during transaxillary first rib resection:
a)C8-T1 roots are most frequently involved
b)C5, C6 roots are most often damaged with scalenectomy and neurolysis procedures (supraclavicular approach)
4)Surgical trauma:
a)C5, C6 and C7 roots are most often affected with the repair of multi-level spondylosis, spondylolisthesis and disc decompression
b)Instrumentation that requires plates and pedicle screws
5)High impact trauma (MVA, falls, contact athletics)
6)Injury by epidural catheterization with bupivacaine >0.25% or by trauma by the catheter itself
1)There is immediate pain that worsens over time and may spread extra-territorially (peripheral and central sensitization)
2)Pain radiations:
a)Preauricular nerve territory (C2, C3 roots). The radiation overlaps with V2 and V3 radiations of the trigeminal nerve for which it may be confused
b)Postauricular nerve territory (C2-C4 roots). This territory covers the ear, overlaps with C2 at the angle of the jaw and radiates to the parietal and occipital areas of the skull
c)Specific radiations of C2 in isolation is to the base of the occiput, the angle of the jaw, parietal scalp and to the brow. The brow radiations are common with cough or Valsalva maneuvers with underlying Chiari malformations and with severe cervical spondylosis
d)Greater and lesser occipital nerve distributions (C2, C3, C4) posterior root damage with radiation of pain to the basiocciput and occipital areas of the scalp that is associated with migraine headache
3)Motor manifestations:
a)Flexion extension injury may damage the ansa hypoglossi:
i)Causes slight weakness of the sternocleidomastoid muscle as most of its innervation is derived from the spinal component of cranial nerve XI. Spasm of the muscle may be severe.
ii)Weakness of the suprahyoid muscles that are located above the hyoid bone in the neck and include the digastric, stylohyoid, geniohyoid and mylohyoid:
(1)Dysfunction of elevation of the hyoid and widening of the esophagus during swallowing
iii)Slight weakness of the scalene and trapezius muscles
4)Autonomic dysregulation occurs (usually adrenergic sympathetic overactivity) particularly with C8, T1 and T2 injury. The former causes sympathetic innervation to the face and eye while the T2 sympathetic ganglion is the primary innervation to the arm
5)Rotary subluxation of a facet joint presents with:
a)Pain at the segmental level
b)Torticollis (to the affected side)
c)Segmental root weakness
6)Complex Regional Pain Syndrome I and II (CRPS)
a)CRPS occurs most frequently after injury of small nociceptive afferents in soft tissue (type I) or injury of a specific nerve (type II)
b)Hyperalgesia and thermal and mechanical allodynia; loss of sensation both may occur in a regional distribution
c)Autonomic Dysregulation:
i)Temperature change ( in general, in the early stages there is increased warmth and later there is coolness)
ii)Hyper or hypohidrosis
d)Movement disorder:
i)Difficulty initiating movement
ii)Dystonia
iii)Weakness
iv)Tremor
v)Atrophy
e)Severe spreading pain that involves multiple roots (regional)
f)Dystrophic changes in the nails, hair and integument
4. The face rather than the ear may show similar signs
a)Traumatic Injuries:
i)Nerve root avulsion:
(1)High impact motor vehicle injury
(2)C5-C6 roots are the most often affected
ii)Rotary subluxation of facet joints; jumped facet joints
iii)Spondylolisthesis:
(1)Middle cervical segments are most often involved
iv)Rare disc herniations (overwhelmingly disc disease is a degenerative process; trauma frequently exacerbates existing disease)
b)Traction injuries:
i)Whiplash (severe flexion – extension injury)
ii)Neuropraxis (Class I):
(1)Interruption of nerve conduction without disruption of axon continuity:
(a)A physiologic block of nerve conduction
(b)There are sensory and motor deficits distal to the injury
(c)The endoneurium, perineurium and epineurium are intact
(d)There is no Wallerian degeneration
(e)There is no conduction across the injured area
iii)Axonotmesis (Class II)
(1)Loss of the continuity of both axon and its myelin sheath. The epineurium and perineurium are preserved:
(a)Wallerian degeneration occurs distal to the site of injury
(b)There are motor and sensory deficits distal to the injury
(c)EMG changes include:
(i)Lack of nerve conduction distal to the injury
(ii)Fibrillation and sharp waves are detected 2 to 3 weeks following the injury in denervated muscles
iv)Neurotmesis (Class III):
(1)Severance of the entire nerve fiber
(2)Wallerian degeneration occurs distal to the injury
(3)Severe sensory, motor and autonomic dysfunction of the innervated territory of affected fibers
(4)EMG and NCV parameters are similar to axonotmesis. There is no conduction distal to the injury
(5)Surgical injury to nerve roots during disc, spondylosis, spondylolisthesis and transaxillary and supraclavicular first rib resections
c)Congenital Anomalies that affect cervical roots:
i)Hypoglossal duct cysts
ii)Branchial cleft cysts
iii)Short and absent pedicles
iv)Achondroplasia
v)Basilar impression
vi)Platybasia
vii)Cervical syrinx
viii)Arnold Chiari malformations
ix)Cervical syringomyelia
x)Klippel-Feil Syndrome
xi)Rib-Band syndrome of Gilliat
1.EMG
1.Ultrasound
2.MRI microneurography
3.CT evaluation if there is bony involvement
i.3-5 mm in children
ii.1-2 mm in adults
1.Acromegaly
2.Mucopolysaccharidosis:
a)Morquio’s Syndrome has concomitant absence or hypoplasia of the odontoid process
3.Posterior ligament ossification syndrome
4.IgG-4 syndrome - a form of pachymeningitis
5.Hirayama syndrome (ligament laxity at lower cervical levels with spinal cord compression)
10.Chondrosarcoma (rare):
11.Ewing’s sarcoma:
12.Pancoast tumor:
i.Breast cancer
ii.Sarcoma following breast X-RT
13.Lymphomatous B-cell tumors:
a.Diffuse radiculopathies
14.Post x-ray treatment sarcoma:
a.Follows x-RT for breast cancer most frequently
b.Involves roots of the brachial plexus C8, T1 >C5, C6
c.May be delayed in onset from the last treatment by years
d.Associated with myokymia in the irradiated arm
e.Associated with skin changes that include hyperpigmentation, telangiectasia and proliferative endarteritis
f.MRI reveals hypertrophy and swelling of the trunks and cords of the brachial plexus that enhance with contrast
15.Neuromyotonia with Hodgkin’s disease:
a.Rippling fasciculation in the innervated muscles of the affected nerve roots
b.Anti-TA antibodies may be detected in the serum
16.Mixed salivary gland tumors:
a.Infiltrate C1-C4 roots
b.“Sugar coated” roots
17.Parotid gland tumors:
a.VIIth nerve most frequently involved
b.Cervical C2-C4 roots are involved less frequently
c.Swollen parotid glands noted in diabetes mellitus, mumps, HIV, tumors, and uremia
18.Salivary gland cylindroma:
d.Cervical C1-C4 roots are infiltrated
e.May have concomitant cranial nerve involvement
i.Ophthalmoplegia (III)
ii.Ramsay Hunt syndrome (VII)
i.Progressive outer retinal necrosis (PORN)
1.C5, C6 > C4, C5 > C8, T1 are the most commonly involved roots (cervical)
2.Clinical symptomatology:
a.Grouped vesicular eruption in a dermatomal distribution
b.Sensory loss in a dermatomal pattern to all modalities; severe pain in the affected dermatome
c.Atrophy, weakness much less than sensory alterations (subtle)
d.May have dermatomal sensory alterations weeks to occasionally months prior to the vesicular eruption and there may be no eruption (herpes sine herpete); there is often burning pain in the affected dermatome
1.Spontaneous lancinating pain
2.Deep continuous ache with lancinating exacerbations in the involved dermatome
3.Decreased sensory threshold to pinprick, touch or temperature of the dermatome
4.Allodynia to both static and dynamic mechano and thermal stimuli of the neighboring dermatomes but at times of the affected dermatome
1.Anti-VZV IgM antibody in the serum or CSF
2.Anti-VZV IgG antibody in CSF
3.Detection of VZV DNA in blood mononuclear cells or CSF
4.VZV DNA is detected in CSF in blood MNCs during neurological involvement
10.Sacral HSV infection can be associated with meningeal inflammation as aseptic meningitis
11.The lesions have a painful erythematous base and may be dermatomal or can be regional that involve several roots
12.The encephalitis involves the medial temporal lobe most severely, the frontal and insular cortex less often:
i.Widespread bilateral and asymmetrical necrosis in the temporal lobes
ii.Most often affected are the anterior parts of the parahippocampal, fusiform, inferior and middle temporal gyri
iii.Intense reactive inflammatory changes around the necrotic tissue
1.Lyme disease is caused by infection with the spirochete Borrelia burgdorferi and the immune response that it elicits
2.The disease is transmitted to humans from infected ticks of the genus Ixodes
i.Musculoskeletal system:
1.Inflammatory arthritis that may begin as a polyarticular process that evolves into a large joint monarticular process
2.Approximately 2/3 of patients have recurrences 2.5 months apart
ii.Neurologic complications include:
1.Occurs in 5-20% of patients
2.Cranial neuropathy most often uni or bilateral VIIth nerve paralysis (3% of patients)
3.Meningitis and encephalopathy
iii.Cutaneous manifestations:
1.Multiple erythema migrans lesions: erythematous macules (1-5 cm) that may be oval; they are evanescent and do not expand over days
2.Borrelial lymphocytoma; a bluish red nodular lesion that occurs:
a.Ear lobe in children
b.In adults it is seen in the areola of the nipple, scrotum, nose and the extremities
c.The heart may be involved
i.Chronic progressive encephalomyelitis
ii.Unilateral or bilateral VIIth nerve palsy
iii.C5, C6 cervical roots are the most often affected
iv.Decreased cognitive function (controversial)
1.Approximately 20,000 patients are reported annually in the USA; endemic areas are the coastal northeast, California and the Great Lakes region.
2.The disease is transmitted to humans by the bite of the Ixodes scapularis and pacificus ticks. It is posited that the tick has to feed for at least 36 hours for transmission to occur (for Borrelia burgdorferi).
3.Pathology in the knee joint may be prominent in stage 3
4.B. garini is the isolate in many cases of lymphocytic meningoradiculitis (Bannwarth syndrome) and white matter lesions. This is rare in North America.
5.A novel species of bacteria Borrelia mayonii has been isolated from patients in the upper Midwest. It has been associated with nausea and vomiting, diffuse rash and high spirochetemia
10.Spinal anatomy allows a bacterial infection to migrate to different vertebral levels.
1.Initial presentation is with neck pain and stiffness
2.Fever
3.Insidious onsets include disorientation, headache, sore throat and pain with swallowing
4.During evolution of the process patients develop quadriparesis and sensory loss as well as radicular pain at the involved segmental levels
1.Sedimentation rate, C-reactive protein and white blood count
1.Acute poliomyelitis is caused by small RNA viruses of the enterovirus genus Picornaviridae
2.The virus has a single-stranded RNA core that is surrounded by a protein capsid that has no lipid envelop thus making it resistant to lipid solvents and gives it stability at a low pH
3.Type 1 of its antigenic strains cause approximately 85% of patients that become paralyzed
1.Infection of the spinal cord and or the brainstem
2.The virus first multiplies in the oropharynx and then spreads to the mucosa of the ileum and Peyer’s patches; most infections are enteric rather than neurotropic
3.Hemorrhagic necrosis of anterior horn cells of the spinal cord with atrophy of spinal nerve roots
1.Approximately 25 to 50% of patients that have recovered from paralytic polio develop new muscle weakness and pain several decades after the original illness
1.Pain in the originally affected muscles and the newly weak muscles
2.Weakness returns in formerly weak muscles; increased weakness may occur
3.Severe fatigue
1.The illness may be sporadic or secondary to heterozygous mutations in the SEPT9 gene that maps to chromosome 17q25. It is an autosomal dominant condition
2.The disorder is classified as a brachial plexitis rather than a cervical root disorder
1.The illness is also known as hereditary neurologic amyotrophy (HNA)
2.The sudden onset of severe lancinating pain in the upper trunk brachial plexus distributions (primarily C5, C6 and C7 root territory) is most characteristic
3.The painful episodes may be recurrent and are followed by weakness and atrophy of the affected muscles
4.In the SEPT9 hereditary form there may be associated dysmorphic features that include:
a.Hypotelorism
b.Long nasal bridge
c.Facial asymmetry
d.Cleft palate
5.Attacks have been described as triggered by infections, immunizations and increased use of the affected arm
1.Primarily affects the upper trunk of the brachial plexus or one of the peripheral nerves that innervate the shoulder girdle. Rarely, it affects the middle cord and lower trunks and the suprascapular, long thoracic, and axillary nerves.
2.The etiology is controversial. Approximately 25% of patients have had a preceding viral infection and 15% a preceding immunization
3.The pathology is axonal
1.Mutational analysis of the SEPT9 gene
2.EMG:
a.An axonal process with positive sharp waves and fibrillation potentials in affected muscles
b.NCV are usually normal but sensory amplitudes are decreased
1.EBV
2.Hepatitis C
3.West Nile
4.Coxsackie (particularly serotype 6 and 9)
5.Adenovirus
6.Enterovirus
7.Zika virus
1.Diabetic amyotrophy is much more common in L2-L4 roots
2.Putative involvement of the vasa vasorum in addition to axonopathy and demyelinating features of the polyneuropathy
3.May be bilateral; the second event occurs 6-8 weeks following the first
1.C5, C6 roots are most commonly involved
2.Overwhelming a motor neuropathy with severe atrophy and wasting of the involved muscles
3.Sensory symptoms > than signs may be patchy; often out of a dermatomal distribution
1.Rare root involvement
2.May have associated skin rash
1.C5, C6 roots primarily are involved following cervical cord treatment
2.Myokymia may be prominent
1.May affect all cervical roots
1.Sicca complex:
a.Autoimmune etiology
b.May have patchy anhidrosis and sensory loss out of a dermatomal distribution
2.Probable dorsal root ganglionopathy
3.May involve definable cervical roots
1. Arteritis of the vasa vasorum that supply cervical nerve roots
1.Nerve root (on the root itself)
2.Dural AVM with accompanying compression of the nerve root
1.Venous congestion from severe cervical spondylosis or an extruded disc
2.Concomitant venous congestion of the spinal cord (myelomalacia) and the nerve root:
a.Postulated that veins over the nerve root cause mechanical pressure on the sensitized root that awakens patients with disc disease in the early morning
1.Arteriovenous malformation involving the anterior spinal artery
2.Cervical nerve roots and the spinal cord may be compressed
1.Arteriovenous malformation of an extremity
2.Enlargement of the bone and soft tissue components of the extremity
3.Enlarged epidural veins and their tributaries may compress segmental nerve roots
1.Hemosiderin deposits on nerve roots:
a.Radiculopathy
b.Cranial nerves I and VIII may be concomitantly involved
c.Caused by repeat bleeding from aneurysms, cavernous hemangiomas or rarely telangiectasias
d.Demonstrated by gradient ECHO or susceptibility weighted MRI sequences
1.Clumping together and scar formation of nerve roots:
a.Secondary to:
i.Multiple surgeries
ii.No longer seen from myelography due to the use of water-soluble contrast media
1.Severe burning pain in several dermatomal distributions
2.Usually a regional rather than a clear radicular pattern
3.CT/myelography demonstrates clumping of nerve roots or a featureless dural sac
4.Minimal weakness; burning pain predominates
5.Asymmetric reflex loss
6.Rare bladder involvement
7.Rarely caused by aneurismal rupture of a vertebral or anterior spinal artery
1.MRI demonstrates gadolinium enhancement of the scar
i.Pain is usually the most prominent symptom
i.Vertebral body star fracture (radiation of fracture lines from the center of the vertebral body)
ii.Bilateral radicular pain
iii.Fractured bone fragment may be displaced into the spinal canal or foraminal exit area
iv.Concomitant spinal cord direct injury and compression
i.Severe high impact trauma (most often MVA)
ii.Bilateral radicular pain
iii.Associated severe spinal cord injury
1.Account for approximately 0.5% of disc protrusions
2.Thoracic discs are rare because they are not at motion segments which is thought to be a major mechanism for degenerative changes
3.The lower four thoracic discs are the most commonly affected
1.May occur suddenly from heavy lifting, high impact MVA and concomitantly with spinal cord injury
2.Dull boring midline ache with episodes of radicular lancinating pain
3.Intercostal or abdominal radiations
4.The pain is exacerbated by specific movements and Valsalva maneuvers
5.Radicular pain may be associated with signs of compressive myelopathy (paraparesis, sphincter disturbance and Babinski sign)
6.Upper thoracic disc herniations may radiate to the cervical spine and lower thoracic herniations to the lumbar spine
7.Pain may also be referred to the retrogastric, retrosternal and inguinal areas
8.Annular tears may have specific referral patterns:
a.Anterior tears may refer to the ribs, chest wall, sternum and rarely viscera
b.Lateral tears to musculoskeletal sites
c.Posterior annulus tears local back pain
9.Sensory symptoms are the presenting complaint in approximately 25% of patients
10.Weakness is the presenting complaint in approximately 17% of patients
11.Incontinence of urine is the presenting symptom in 2% of patients. Rare bowel incontinence
1.Degenerative changes similar to those of cervical and lumbar disc
1.Medical evaluation of an underlying medical condition if clinically relevant (diabetes, amyloidosis, hereditary collagen disease)
1.Radiographs and CT:
a.Jumped facet joint:
i.Overriding of the inferior over the superior facet joint
ii.Places traction on or directly injures the segmental root
b.Rotary subluxation of the facet joint:
i.The facet joint is twisted; the synovial interfacet is breached
c.MRI:
i.Delineates soft tissues, ligaments and parenchymal spinal cord pathology
1.Syringomyelia is a fluid filled cavity within the spinal cord. It can occur with or without communication with the IVth ventricle
1.Atrophy at the segmental level
2.Early hyperhidrosis followed by anhidrosis of the affected segments
3.Severe lancinating radicular pain
4.Dissociated sensory loss at the segmental level (destruction of the spinothalamic fibers as they decussate in the anterior ventral commissure)
5.Long tract motor and sensory signs below the syrinx
6.Charcot joints of the shoulder, elbow or wrist
7.Scoliosis
8.Impaired sphincter function late in the course of the illness
9.Dysesthetic and radicular pain is most prominent in the neck and shoulders but also can affect thoracic roots
1.Associated with Chiari malformations
2.Trauma
3.Small posterior fossa
4.Platybasia and basilar invagination
5.Arachnoid cysts, rhombic roof, vascularized membranes and post-inflammatory membranes
6.Cavitation of spinal cord gray matter; continuous with or adjacent to the central canal; an inner layer of gliosis
1.MRI:
a.Imaging of the rostrocaudal extension of the spinal cord
b.Gadolinium enhancement differentiates scar, disc material and tumor
2.CT:
a.To assess the spinal canal particularly if the syrinx is traumatic
3.Myelography:
a.Delineates widening of the spinal cord and subarachnoid block
4.Post traumatic syrinx:
a.A further cystic degeneration of the spinal cord
b.Usually there is a 2 to 3 segment loss of function above and below the level of injury
c.Bilateral root involvement at the involved segmental level
1.Occurs in approximately 50% of patients after thoracotomy; approximately 30% of patients have pain 4 to 5 years following their procedure
1.Prolonged and often refractory and neuropathic pain of the involved roots or intercostal nerves
1.Elements of both neuropathic and myofascial pathology
2.Retraction of muscle or direct radicular and nerve injury
1.Sed rate and C-reactive protein (thoracic epidural catheters are utilized for pain relief and may cause an abscess or meningitis)
1.CT and MRI:
a.To delineate infection or structural lesion that affects the intercostal nerve
1.Affects predominantly elderly and middle-aged men with type 2 diabetes
2.In some series it affects the right side > than the left
3.It is often seen with cervical and lumbosacral radiculoplexus neuropathy
1.Most commonly occurs in elderly type II diabetics; median age range (32-83) for cervical radiculoplexus neuropathy approximately 20% also had thoracic involvement
2.Right side more often affected than the left (abdominal wall)
3.Usually involves 3-5 adjacent nerve roots between T6 and T12
4.It may be accompanied by profound weight loss
5.It may have an abrupt onset
6.Patients present with severe abdominal or chest radicular pain; at times the pain is out of a dermatomal distribution
7.The process is usually monophasic but in approximately 20% of patients it is recurrent
8.Weakness of affected intercostal and abdominal muscle
1.Infarction or ischemia of the thoracic nerve roots (vasa vasorum); a microvasculitis
2.Nerve biopsy in patients with concomitant cervical radiculoplexus:
a.Axonal degeneration, multifocal fiber loss
b.Focal perineurial thickening
c.Vessel wall inflammation
d.Epineural perivascular inflammation
e.Hemosiderin deposition
f.Involves motor, sensory and autonomic fibers
1.Type II diabetes with increased blood sugar
2.CSF:
a.Mildly elevated protein (70 mg/dl)
3.EMG:
a.Associated axonal neuropathy with paraspinal denervation
b.Some patients had associated upper, medial and lower brachial plexus involvement
1.MRI:
a.In those patients with concomitant upper extremity pain there may be bilateral brachial plexus involvement (contrast enhancement)
2.Ultrasound:
a.Swelling of affected roots
1.Is an autosomal dominant disorder due to mutations in the transthyretin gene that maps to the long arm of chromosome 18
2.It is characterized by extracellular deposition of transthyretin-derived amyloid fibrils in peripheral and autonomic nerves as well as the heart, gastrointestinal tract, kidneys, eyes and the connective tissue of the carpal and tarsal tunnels
3.TTR is a transport protein for thyroxine and retinol
4.It is primarily synthesized in the liver
1.Neuropathic involvement includes:
a.Sensorimotor and autonomic neuropathy
b.Lower and upper limb involvement
c.Carpal tunnel syndrome (TTRL58H variant)
d.TTR variants may cause CNS disease that includes:
i.Spastic paraparesis
ii.Nystagmus
iii.Leptomeningeal / cerebrovascular deposits that are associated with seizures, subarachnoid hemorrhages and dementia
e.Late-onset patients have preservation of unmyelinated fibers that may be responsible for neuropathic pain
f.Denervation of segmental thoracic discs may cause Charcot joints and radicular (thoracic) pain due to root irritation
1.TTR mutations accelerate TTR amyloid formation by destabilizing the native tertiary and quaternary structure of the protein that induces conformational change. This process leads to dissociation of its tetramers into partially unfolded species that then self-assemble into amyloid fibrils.
1.Congo red material in sural nerve biopsy or that of an affected organ
2.PCR molecular genetic testing to determine the specific variant
1.Alkaptonuria is an autosomal recessive disease caused by mutations in the HGO gene that maps to chromosome 3q1 which encodes homogentisic acid oxidase which catabolizes homogentisic acid (HGA)
2.The enzyme deficiency causes the accumulation and deposition of HGA in cartilage
3.Exogenous ochronosis is a bluish black pigmentation of the skin from phenol, trinitrophenol, benzene and hydroquinone
1.Dark urine in diapers, black cerumen and axillary pigmentation prior to age 10
2.Ear cartilage degeneration by the fourth decade
3.Gray-black scleral rings may be noted in the third decade
4.Arthropathy develops in the third and fourth decades
5.The knee, hip and shoulder joints develop the major arthropathy
6.The first manifestation may be the intervertebral disc degeneration of the lumbar spine which may also be seen in the thoracic spine
7.Degeneration of thoracic spine intervertebral discs may cause radicular pain
1.Accumulation and deposition of HGA in cartilage causes its weakness and brittleness that leads to inflammation and degenerative changes
2.HGA undergoes oxidation / polymerization reactions that produces a melanin-like pigment
3.HGA induces oxidation of serum and chondrocyte proteins
4.Mechanisms of action include:
a.HGA-induced proteome alterations
b.Lipid peroxidation
c.Thiol depletion
d.Amyloid production
e.Oxidative stress and protein oxidation
1.Increased levels of homogentisic acid in the urine, blood and other tissues
2.Molecular genetic testing
1.Radiographs:
a.Calcification and degeneration of multiple thoracic discs – “Rugger-Jersey” appearance
b.MRI:
i.Evaluation of affected joints
1.Shield sensory loss on the chest wall
2.Associated with distal dying back (length-dependent) dying back neuropathy of the extremities
3.Single or multiple dermatomal involvement of the chest wall or abdomen
4.Sensory loss or pain in the distribution of the ventral rami of the spinal nerve or the dorsal ramus of the spinal nerve, the paravertebral territory; the sensory loss may be in various combinations of these territories of the thoracic spinal nerves
1.Acute inflammatory demyelinating polyneuropathy (AIDP):
a.Gd1b, Gal-Nac-GD1a antibodies
b.Small fiber involvement may be associated with regional and focal severe pain
2.Chronic inflammatory demyelinating polyneuropathy (CIDP)
3.Sjogren’s disease:
a.May be primarily a dorsal root ganglionitis
b.Involvement of the dorsal primary ramus or its medial or lateral divisions
4.Sicca complex:
a.Dry eyes, mouth serous membranes
b.Segmental and regional sensory loss and anhidrosis
5.Radiculopathy with increased sed rate:
a.A poorly defined process
b.Usually the lumbosacral roots are involved
1.Malignancies:
a.Leukemia:
i.Acute presentation from bleeding into a nerve root
ii.Hodgkin disease and non-Hodgkin disease lymphoma:
1.Insidious and progressive nerve root involvement
2.Paraneoplastic mechanisms
iii.Carcinomatosis of the meninges:
1.Mental status alterations
2.Cranial nerve involvement
1.Anterior mediastinal tumors (rarely involve thoracic roots):
a.Thymoma and thymic carcinoma are usually locally invasive
b.Thymic carcinoid (associated with multiple endocrinopathy syndrome type I (MEN)
c.Thymic lipoma
d.Hodgkin and non-Hodgkin lymphoma (NHL)
2.Primary mediastinal germ cell tumors:
a.Mature teratoma
b.Seminoma
c.Nonseminomatous germ cell tumors
3.Posterior mediastinal tumors:
a.Peripheral nervous system benign and malignant neoplasms are more frequent in the posterior mediastinum
b.They develop from peripheral nerves, sympathetic and parasympathetic ganglia as well as neural tube embryonic remnants and include:
1.Schwannoma
2.Neurofibroma
3.Melanotic Schwannoma
4.Ganglioneuroma
5.Granular cell tumor
6.Malignant melanocytic nerve sheath tumor
7.Neuroblastoma
8.Neurofibrosarcoma (non-Recklinghausen disease)
4.Metastatic disease (similar to those that affect cervical roots)
5.Multiple myeloma (primarily affect roots by vertebral collapse and compression of the neural root exit foramina)
6.Osteoclastic myeloma
7.Plasmacytoma
8.Paget’s disease (sarcomatous degeneration)
9.GI cancer (sacral bone involvement with colon cancer); lumbar and sacral roots > thoracic root involvement
10.Giant articular bone cyst (vertebral fracture)
11.Osteoid osteoma:
a.Refractory to narcotics but responsive to prostaglandin inhibitors
b.Involves the posterior elements of the vertebral body (pedicles and facets)
c.Radicular symptoms
12.Vertebral body sarcoma
13.Chondrosarcoma
14.Enchondroma:
a.Involve the nerve root exit foramina
b.Approximately 4% involve thoracic vertebrae
15.Brown bone cyst:
a.Occurs with hyperparathyroidism
b.Bone resorption, fractures and radicular pain
16.Hemangioma of the vertebral body:
a.Most often they are incidental findings (on MRI T2-weighted sequences)
b.May weaken the vertebral body
c.The lesions are extremely vascular
d.May compress the exiting nerve root
17.Thoracic meningioma in women:
a.Extremely rare location for a meningioma in men
b.Increased growth of the tumor in pregnancy and with breast cancer
18.Schwannoma:
a.Typically enlarges the foraminal nerve root exit canal
b.Scalloping of the affected vertebral body (a sign of chronic pressure)
c.A dumbbell tumor (both enlarging the nerve root and expanding in the intradural extramedullary space)
19.Neurofibroma
20.Melanotic Schwannoma:
a.Some tumors are part of the Carney syndrome
b.May have dumb-bell characteristics on MRI
c.Melanin granules in tumor cells
21.Hemangiopericytoma of the thoracic spine
a.Most often found in the cranial cavity
b.Very rare in the spine but when they occur they are intradural extramedullary in location
c.They invade nerve roots and cause radicular pain
i.Enhancement of the disc with contrast on MRI
ii.The vertebral body is spared: there is often pre and postvertebral ligament inflammation (enhancement with gadolinium on T1 weighted sequences)
iii.Disc space infection causes severe lancinating radicular pain; minimal movement initiates pain (touching the patient’s bed)
iv.Spinal cord involvement by contiguous spread or by venous infarction
v.Gram-negative disc space infection following surgery:
1.Involvement and signs of infection may be delayed for up to six weeks from the procedure
2.Pain, swelling, erythema and edema at the operative site
3.Invariably high sed rate and C-reactive proteins
i.Acute kyphotic angulation
ii.Occurs from vertebral body collapse and loss of disc integrity
iii.May cause spastic paraparesis
The cervical plexus is composed of the anterior rami of C1-C4 that are derived from the C1-C4 cervical segments of the spinal cord. It lies behind the sternocleidomastoid muscle and anteriorly to the scalenus medius and levator scapulae muscles. The plexus anastomoses with the accessory nerve (XI), the hypoglossal nerve (XII) and the sympathetic trunk. The nerves derived from the cervical plexus innervate the back of the head, overlap with the cutaneous territory of the Vth nerve and are synergistic in head flexion and swallowing physiology. The branches of the cervical plexus emerge from the posterior triangle of the neck midway on the posterior border of the sternocleidomastoid muscle.
The terminal cutaneous branches of the cervical plexus are:
1.The greater occipital nerve, which innervates the skin of the posterior scalp, is the terminal branch of the dorsal ramus of C2 with a contribution from C3.
2.The lesser occipital nerve is derived from the anterior divisions of C2 and C3 and innervates the mastoid process and lateral head; the mastoid innervations overlap that of the sensory innervation from cranial nerve VII.
3.The greater auricular nerve (C2-C3) which innervates:
a.The skin of the lower cheek and the mandible (overlaps V2, V3)
b.The auriculotemporal and buccinator terminal nerves of cranial nerve V (overlaps).
c.It also innervates the neck below the external ear.
4.The cutaneous branches of the transverse colli nerves (C2-C3) which innervate the neck (primarily anteriorly).
5.The supraclavicular nerve (C3-C4) which innervate the skin of the supraclavicular fossa (immediately above the clavicle). May cause misdiagnosis with localizations of spinal cord injury levels.
6.C1 is a purely motor root.
7.Anatomical variants include:
a.Great auricular nerve communication with the mandibular nerve
b.Spinal accessory nerve communication with C2.
The innervations of the muscular branches of the cervical plexus is derived from the ansa hypoglossi:
1.A loop formed by C1 which curves with the hypoglossal nerve and joins the fibers from C2 and C3 roots that innervate infrahyoid muscles:
a.Sternohyoid
b.Omohyoid
c.Sternothyroid
d.Thyrohyoid
e.Geniohyoid
These muscles are synergistic in head flexion and swallowing physiology:
1.The phrenic nerve which innervates the diaphragm (C3- C5); C4 is the dominant root.
2.Branches to the middle scalene (C3-C4) that affects:
a.Lateral neck flexion
b.Levator scapulae muscles (C3-C4); rotation of the scapula.
3.Branches to the spinal accessory nerve that include:
a.C2 to the sternocleidomastoid muscle.
b.C3-C4 to the trapezius muscle.
c.These branches course with CNXI.
4.Swallowing function
a.Hyolaryngeal complex
An important component of the pharyngeal phase of swallowing is the elevation of the hyolaryngeal complex. This is accomplished by the submental muscles (mylohyoid, geniohyoid and anterior digastric and the thyrohyoid muscles). Hyolaryngeal elevation displaces the larynx above the food bolus, shortens the pharynx, and opens the upper esophageal sphincter. The hyolaryngeal complex is comprised of the hyoid bone, thyrohyoid membrane and the laryngeal cartilages that are the attachment site for the cricopharyngeus muscle; the cricopharyngeus muscle forms the upper esophageal sphincter. Other muscles that may contribute to the elevation of the hyolaryngeal complex are the posterior digastric, stylohyoid, and long pharyngeal muscles.
Anatomically, an anterior and posterior sling of muscles suspends the hyolaryngeal complex and along with the thyrohyoid muscle, elevates it during swallowing. The anterior component of the sling is composed of the mylohyoid, geniohyoid, and anterior digastric muscles that insert on the hyoid bone. The posterior digastricus and stylohyoid may also contribute to the anterior sling. The posterior ring is composed of the long pharyngeal muscles that include the stylopharyngeus, salpingopharyngeus and palatopharyngeus muscles that are stabilized by the levator veli palatini. The distal posterior ring muscles insert on the posterior edge of the thyroid cartilage and lateral pharyngeal walls proximal to the upper esophageal sphincter. The thyrohyoid muscle is intrinsic to the hyolaryngeal complex and approximates the thyroid and hyoid bone.
In summary, the submental muscles (mylohyoid, geniohyoid, and anterior digastric) and the thyrohyoid muscle primarily elevate the hyolaryngeal complex that opens the upper esophageal sphincter during the pharyngeal phase of swallowing. The ansa hypoglossi of the cervical plexus is pivotal in the innervations of many of the muscles required for the pharyngeal phase of swallowing.
1.The sensory component of the cervical plexus is frequently injured by “whiplash” traction injuries that are often misdiagnosed. The sensory components, particularly C2 and C3 are most often involved although the motor components of the ansa hypoglossi may also be injured
1.Sensory loss primarily in the territories of the greater and lesser occipital nerves and the great auricular nerve
2.Complex regional pain syndrome type I and II of the face and ear with associated:
a.Neurogenic edema and autonomic dysregulation:
i)Swelling
ii)Erythema
iii)Hyperhidrosis
3.Dysfunction of the external esophageal sphincter and the muscles innervated by the ansa hypoglossi
1.Trauma usually causes a neuropractic injury
2.The cervical plexus may also be injured by:
a.Penetrating injuries
b.Carotid endarterectomy or radical neck dissection for malignancy
c.Tumors
1.MRI:
a.To delineate specific pathologies in the neck
2.Ultrasound:
a.Delineates the anatomy of the plexus
1.Innervates the skin of the occiput (posterior scalp)
2.The greater occipital nerve (GON) is the medial branch of the dorsal ramus of the C2 spinal nerve. The GON takes a downward lateral course and is covered by the splenius capitis, the longissimus, and the semispinalis muscles. Rarely, it may course within the inferior oblique muscle. It pierces the semispinalis capitis muscle and emerges into the scalp through the aponeurotic fibrous attachment of the trapezius muscle and the sternocleidomastoid muscle to reach the superior nuchal line
3.The nerve splits and its medial branch innervates the occipital skin while its lateral branch innervates the area behind the pinna below the superior nuchal line.
4.The GON emerges through the semispinalis muscle 3 cm below the occipital protuberance and 1.5 cm lateral to the midline. The nerve is rarely compressed between the posterior arch of C1 and the lamina of C2. Variations of GON are usually in the vertical axis.
1.The six major compression points along the course of the nerve:
a.The most proximal (deepest point) is between the semispinalis and the obliquus capitis inferior adjacent to the spinous process
b.At the entrance into the semispinalis muscle
c.At the nerve exit from the semispinalis muscle
d.At the entrance of the nerve into the trapezius muscle
e.Where the nerve exits the trapezius fascia insertion into the nuchal line
f.The area where the occipital artery crosses the nerve at the distal region of the trapezius fascia
2.Neurofibroma
3.Direct trauma
1.Ultrasound:
a.Delineation of the nerve
2.MRI
a.To delineate a structural lesion
1.The LON takes origin from the dorsal ramus of C2 and rarely from C3
2.It ascends along the posterior border of the SCM muscle, near the cranium it perforates the deep fascia to ascend over the occiput to innervate the skin and communicates medially with GON. The nerve usually exits the posterior border of the SCM superior to the exit of the great auricular nerve, 6 to 7 cm lateral to the midline and 4 to 6 cm caudal to a line that connects the lowest points of the external auditory canal.
3.The upper back muscles of the cervical region are innervated by:
a.Branches from the dorsal rami of the second and third cervical nerves
b.Branches that arise from the posterior cervical plexus, a series of loops between the first and second and the second and third dorsal rami. Rarely there is a loop to the fourth dorsal rami.
4.There are articular branches of the C2-C3 facet joints that arise from communicating branches between the third occipital nerve and the C2 dorsal ramus
1.Pain and paresthesias of the mastoid, lateral and posterior head and lower portion of the occiput[HT3]
2.The symptoms are most often in the C2 distribution
1.Associated with flexion-extension or rotary injury of the neck (motor vehicle accidents, falls, and athletic injuries).
2.Very frequently associated with upper trunk (C5-C6) brachial plexus traction injuries.
3.Lacerations
4.Surgical procedures of the posterior triangle of the neck.
5.It is most often a neuropractic injury
6.Areas of nerve compression:
a.Zone 1:
i.Emergence of the LON from deep to or behind the SCM muscle
b.Zone 2:
i.The cephalic ascent of the LON along or posterior to the SCM
c.Zone 3:
i.Caudal to the nuchal line
1.Ultrasonography for delineation of the anatomy (areas of compression) and pathology of the nerve
2.MRI:
a.To delineate underlying pathologies that include:
i.Trauma
ii.Fibrositis
iii.Myositis
iv.Fracture of the atlas
v.Compression of the C2 nerve root
vi.C1-C2 arthrosis syndrome
vii.Atlantoaxial lateral mass osteoarthritis
viii.Hypertrophic cervical pachymeningitis
ix.Cervical cord tumors
x.Chiari malformation
xi.Neurosyphilis
1.The medial branch of the posterior division of the third cervical nerve gives off the third occipital nerve while coursing under the trapezius muscle
2.The nerve pierces the trapezius muscle, lies medial to the greater occipital nerve with which it communicates
1.Pain in the skin of the lower part of the occiput
2.A trigger for migraine headaches
1.Medical evaluation of underlying pathologies
1.Ultrasonography to delineate the anatomy of the nerve and possible zones of compression
2.MRI:
a)To delineate underlying pathologies
1.Originates from the cervical plexus. It is composed of branches of spinal nerves C2 and C3
2.It winds around the posterior border of the SCM, perforates the deep fascia, ascends beneath the platysma muscle to reach the parotid gland to divide into anterior and posterior branches
3.The anterior branch innervates the skin over the parotid gland and communicates with the VIIth nerve within the gland
4.The posterior branch innervates:
a.The skin over the mastoid and the back of the ear (except its upper part)
b.Lobule and lower concha of the ear
c.Communicates with the auricular branch of the vagus and the posterior auricular branch of VII
1.Paresthesias and pain in the lower cheek, lower pinna of the external ear (overlaps the auriculotemporal nerve of the Vth cranial nerve)
a.Irritation of this nerve causes:
i.Neurogenic inflammation and vasodilation of the pinna; the probable genesis of the “red ear” syndrome (C3 root is involved).
ii.C-fibers within the nerve release substance P (which interacts with mast cells that release histamine) and calcitonin gene-related peptide. The former (SP) causes endothelial plasma leakage and the latter (CGRP) vasodilation of the affected vessels
1.Damaged during surgical procedures to the neck or face:
a.Facelift
b.Parotid surgery
c.Carotid endarterectomy
d.Traction injury from MVA and falls (neuropractic pathology)
e.Lacerations and gunshot wounds
1.Ultrasound guided
1. Innervation of the anterior and upper neck (C2-C3 roots)
1. Pain in the anterior and upper neck
1.C1 nerve:
a.The C1 nerve does not innervate cutaneous tissue on the body surface
b.It supplies deep somatic tissue in the suboccipital area that includes:
i.The short muscles of the occipital triangle (through its dorsal ramus)
ii.The SCM and trapezius muscle
iii.Atlanto-occipital joint (by its ventral ramus)
iv.The sinuvertebral nerve of C1 innervates:
1.Median atlantoaxial joint
2.Dura matter of the posterior fossa
3.Vertebral artery
4.This innervation is in conjunction with the sinuvertebral nerves of C2 and C3
2.C2 nerve:
a.The dorsal ramus of C2 innervates the splenius capitis and semispinalis capitis to become the greater occipital nerve
b.The ventral ramus supplies:
i.Articular branches to the lateral C 1 / 2 joint
ii.Prevertebral muscles, SCM and trapezius
3.C3 nerve:
a.The dorsal ramus of the C3 nerve divides into 3 major branches:
i.The lateral branch:
1.Innervates the splenius capitis, cervicis and longissimus capitis
ii.Deep medial branch:
1.Innervates the semispinalis cervicis and multifidus
iii.The superficial medial branch:
1.Also known as the third occipital nerve
2.Innervates the C2-C3 zygapophyseal joint
3.Suboccipital cutaneous innervation
1.May be involved with viral infections that include Parsonage –Turner syndrome or neuralgia amyotrophica.
2.Rarely involved with traction injury but not infrequently damaged with scalenectomy and neurolysis procedures in thoracic outlet surgery (lies adjacent to the middle scalene muscle).
3.Aortic aneurysm (compression)
4.Intrathoracic neoplasm (infiltration)
5.Enlarged mediastinal lymph nodes
6.Subclavian vein or internal jugular vein catheterization (direct trauma)
7.Central vein catheter placement
8.Breast cancer (neck metastasis); if associated with damage to the sympathetic chain and recurrent laryngeal nerve it is Payne Syndrome.
9.Injured during coronary by-pass surgery (neuropraxis or dissection of the internal mammary artery)
10.Clipped in association with the inferior vena cava during liver transplantation
11.Amyotrophic lateral sclerosis
12.Diabetes mellitus
13.Critical care neuropathy (difficulty removing a patient from mechanical ventilation)
14.Mediastinal X-RT
15.Herpes Zoster
16.AIDP
17.Injury after radio-frequency denervation of cervical medial branches
i.Superior and middle pharyngeal constrictor muscles
i.Longus capitis and colli muscles
ii.Prevertebral fascia
iii.Second and third cervical vertebrae
1. Direct injury from surgical and dental procedures
2. Head and neck X-RT for malignancy
3. Associated with brachial plexus and cervical plexus neuropractic injuries.
The brachial plexus derives from the anterior primary rami of spinal segments C5, C6, C7, and T1. It is approximately 0.5 cm long in adults and extends from the spinal column to the axilla. Its detailed anatomy in this course is important as to which of its components are injured or affected by its varied pathologies. It is divided into roots, trunks, divisions, cords, and branches. The C5-C6 roots coalesce to form the upper trunk; the C7 primary anterior ramus forms the middle trunk and the anterior primary rami of C8-T1 the lower trunk. In approximately 60% of patients, the C4 spinal root is a component of the upper trunk. In this instance, the plexus is prefixed, as all of the spinal root contributions are placed up one level. In this situation, the T1 spinal root of the lower trunk is less prominent. In approximately 7% of patients, C5 contributes minimally to the plexus and spinal roots are shifted down one level. If this occurs, T2 contributes to the lower trunk and C7 to the upper trunk.
The C5-C6 roots course downward and coalesce to form the upper trunk between the scalenus medius and scalenus anterior muscles. The anterior division of the upper and middle trunk fuses and forms the lateral cord, while the anterior division of the lower trunk becomes the medial cord. The three posterior divisions of the upper, middle, and lower trunks form the posterior cord.
The brachial plexus is in close proximity to mobile components of the neck and shoulder that make it susceptible to traction injuries. The trunks are superficial in the supraclavicular fossa. The lower trunk is adjacent to the subclavian artery and the apex of the lung. The divisions of the plexus are retroclavicular and lie between the clavicle and the first rib. Infraclavicularly, the cords surround the axillary artery and are close to the proximal humerus and the glenohumeral joint. Cords are situated below the clavicle in the axilla and are the longest components of the plexus. There are anatomic variations between the cords.
The spinal nerves derived from the cords and trunks may be purely sensory, motor or mixed sensory motor. The nerves that arise directly from spinal roots include the dorsal scapular nerve, the long thoracic nerve, and a branch to the phrenic nerve. The subclavian and suprascapular nerves arise from the upper trunk. The subscapular and thoracodorsal nerves arise from the posterior cord that terminates as the axillary and radial nerves. The proximal medial cord gives rise to the motor branch that innervates the medial pectoral muscle. The distal medial cord gives rise to the medial brachial and medial antebrachial cutaneous nerves. The medial cord gives a small branch to the median nerve and makes up the ulnar nerve. The proximal portion of the lateral cord gives rise to the lateral pectoral nerve. The termination of the lateral cord is the musculocutaneous nerve. It also gives off a lateral branch that joins the branch from the medial cord to form the median nerve.
The median, ulnar, radial, axillary nerves take origin in the peripheral axilla. The proximal portions of the median, ulnar, and radial nerves are adjacent to the proximal humerus and the axillary artery. Plexus trunks form at the lateral border of the anterior and middle scalene muscles.
The major blood supply of the brachial plexus derives from the subclavian artery. The supraclavicular components of the plexus are supplied by the ascending cervical, deep cervical and the superior intercostal arteries. The roots are supplied by branches from the vertebral artery. The infraclavicular plexus and cords are supplied by the subclavian, axillary, and subscapular vessels.
1.The phrenic nerve:
a.As noted earlier, the major root that innervates the diaphragm is C4.
b.It receives contributions from C3 and C5.
c.The phrenic nerve crosses the anterior scalene muscle to enter the thorax.
2.Dorsal scapular nerve: arises from the C5 nerve root immediately after it emerges from the intervertebral foramen, courses between the middle and posterior scalene muscle to innervate the levator scapular and the major and minor rhomboid muscles.
3.The long thoracic nerve arises from the C5, C6 and C7 roots, descends along the lateral chest wall to innervate the serratus anterior muscle
1.The suprascapular nerve arises from the upper trunk, descends posteriorly between the omohyoid and the trapezius muscle, through the scapular notch to innervate the supra and infraspinatus muscles.
2.Nerve to the subclavius muscle: May arise from the C5 root or the upper trunk to innervate the subclavius muscle that lies between the clavicle and the first rib.
3.Medial pectoral nerve: Arises from the medial trunk whose major roots are C8 and T1. It innervates the pectoralis major and minor muscles.
The major roots contributing to the nerve are C5, C6, and C7. The nerve usually arises from the lateral cord.
Anatomic variations occur and include the origin from the anterior division of the upper and middle trunks.
The primary roots of the nerves are C5 and C6. The upper and lower subscapular nerves arise from the posterior cord in the axilla. The subscapularis nerve innervates the subscapularis muscle; the lower subscapular nerve innervates both the subscapularis and the teres major muscles.
The major roots comprising the nerve are from C5-C7. The primary root is C7. The nerve takes origin from the posterior cord to innervate the latissimus dorsi muscle.
Anatomic variants include origins from:
1.The radial nerve
2.The axillary nerve
The nerve originates from the medial cord to innervate the medial upper arm above the elbow.
Medial cutaneous nerve of the forearm usually arises from the medial cord. An anatomic variant is an origin from the medial cutaneous nerve of the arm. It innervates the medial forearm to the wrist.
The musculocutaneous nerve is the termination of the lateral cord. It innervates the coracobrachialis, biceps brachii, and the brachialis muscles. Its major contributing roots are C5 and C6. In some patients, there is a contribution from C7. It terminates as the lateral cutaneous nerve of the lateral forearm from the elbow to the wrist.
A lateral branch fuses with a branch from the medial cord to form the median nerve.
An anatomic variant in a small number of patients includes:
1.An origin of the nerve from the anterior division of the upper trunk.
a.In this instance, the lateral branch to the median nerve arises from the middle trunk.
The axillary nerve is one of the terminal branches of the posterior cord and is primarily composed of the C5 and C6 spinal nerves. It traverses the quadrilateral space (teres major inferiorly, triceps laterally, the humerus medially, and the teres minor superiorly). It innervates the teres minor and deltoid muscles. Its cutaneous branches innervate the lateral proximal arm over the deltoid muscle.
The spinal nerves that comprise the radial nerve are from C5-C8. T1 contributes in approximately 10% of patients. It is the termination of the posterior cord. A branch arises in the axilla, the posterior cutaneous nerve, which innervates the posterior upper arm to the elbow. In the upper arm, it descends medially to the humerus between the medial and long heads of the biceps muscle in the spinal groove. Its branches in the upper arm innervate the medial, lateral, and long heads of the triceps brachii and the anconeus muscle. At the lateral aspect of the upper arm (after exiting the spinal groove), it innervates the brachioradialis, extensor carpi radialis longus and a small component of the brachialis muscle (whose main innervation is the musculocutaneous nerve). It gives off the posterior antebrachial cutaneous nerve that innervates the posterior forearm. At the elbow, it divides into the sensory superficial radial nerve and the motor posterior interosseous nerve. The posterior interosseous nerve traverses the radial tunnel at the elbow that is composed of the radius, the capsule of the radiocapitular joint and the tendons of the biceps brachii and brachialis muscles medially and the brachioradialis, extensor carpi radialis and the extensor carpi ulnaris that form the anterior and lateral walls. A fibrous band around the superficial head of the supinator muscle forms the Arcade of Frohse that is the end of the radial tunnel. The superficial radial nerve travels into the forearm underneath the brachioradialis muscle outside of the radial tunnel. The nerve innervates the extensor surfaces of the hand and fingers (with the exception of the fingertips that are innervated by the median and ulnar nerves) as well as the medial dorsal hand and medial fingers that are innervated by the dorsal ulnar cutaneous nerve. The posterior interosseous nerve courses through the radial tunnel and descends under the Arcade of Frohse. It innervates the supinator, extensor digitorum communis, extensor digiti minimi, extensor carpi ulnaris, abductor pollicis longus, extensor pollicis longus and brevis and the extensor indicis proprius.
The median nerve is composed of spinal nerves C5 - T1 and is formed from the fusion of branches of the medial and lateral cords. Its sensory components are primarily derived from spinal segments C6 and C7. Rarely the C5 spinal segment is a component of the nerve. Sensory fibers arise from the upper and middle trunks to the lateral cord. Motor fibers course through all of the trunks and the medial and lateral cords. The median nerve reaches the antecubital fossa through the anterior compartment of the upper arm. It passes through the two heads of the pronator teres muscle and between the flexor digitorum superficialis and profundus muscles to reach the wrist. It innervates the pronator teres, flexor carpi radialis, palmaris longus, and flexor digitorum superficialis from branches given off in the forearm. It gives of the purely motor anterior interosseous nerve that innervates the flexor digitorum profundus 1 and 2, flexor pollicis longus and the pronator quadrates muscle. Prior to entering the carpal tunnel at the wrist, it gives off the palmar cutaneous nerve that innervates the thenar eminence. The nerve then enters the carpal tunnel that is composed of the carpal bones and a dorsal transverse ligament. It also contains nine flexor tendons to the fingers as well as the median nerve. Either within or just distal to the tunnel the recurrent branch of the nerve arises to innervate the abductor pollicis brevis, opponens pollicis, and the superficial head of the flexor pollicis brevis. The nerve supplies the first and second lumbrical muscles and digital branches to the volar and dorsal tips of the thumb index and long finger as well as the medial one-half of the ring finger.
The ulnar nerve is comprised primarily of spinal nerves C8 and T1, but in over 50% of patients, there is a contribution from the C7 spinal nerve that innervates the flexor carpi ulnaris muscle. This innervation derives from a branch of the lateral cord. The nerve is the termination and then continuation of the medial cord. It descends anteriorly to the teres major and latussimus dorsi muscles to enter the upper arm. It courses down the posterior compartment of the upper arm to the ulnar groove at the elbow. The ulnar groove comprises the medial epicondyle of the humerus and the olecranon process of the ulna. The ulnar collateral ligament bounds it inferiorly. Distal to the ulnar groove (1-2.5 cm), the nerve courses under a fibrous aponeurosis that connects the humeral and ulnar heads of the flexor carpi ulnaris muscle. The ulnar groove and the aponeurosis form the cubital tunnel. There are no branches from the ulnar nerve in the upper arm. The nerve traverses between the flexor carpi ulnaris and flexor digitorum profundus to the wrist. Its forearm branches innervate the flexor carpi ulnaris and the flexor digitorum profundus III and IV. The dorsal ulnar cutaneous nerve innervates the dorsum of the medial hand and fourth and fifth fingers. Prior to entering Guyon’s canal at the wrist, it gives off the palmar branch that gives sensory innervation to the hypothenar eminence and innervates the palmaris brevis muscle. Guyon’s canal is formed radially by the hook of the hamate bone and the pisiform bone on its ulnar side, the pisohamate ligament inferiorly and the transverse carpal ligament superiorly. Either within or immediately distal to Guyon’s canal the ulnar nerve gives off its terminal branches. The superficial sensory branch innervate the volar components of the fifth finger and the ulnar half of the fourth finger as well as the dorsal distal aspects of these digits. The deep motor branch of the ulnar nerve innervates the hypothenar muscles, the third and fourth lumbricals, the interossei, adductor pollicis and the deep head of the flexor pollicis brevis muscle.
1.Supraclavicular lesions present in myotomal and dermatomal distributions
2.Cervical root derived terminal nerves:
a.Phrenic nerve (C3-C5); C4 is the predominant root
b.Dorsal scapular nerve:
i.Arises from the C5 root as it exits the intervertebral foramen
ii.Innervates the major and minor rhomboid muscles and the levator scapuli.
iii.The muscles pull the scapulae medially, rotate it and hold it against the chest wall.
c.Long thoracic nerve:
1.Pulls the scapula forward around the thorax to achieve anteversion of the arm.
2.Compresses the scapula against the wall of the thorax
3.Assists with elevation of the ribs with respiration
4.A component of arm elevation
5.Protraction of the scapula
6.Role in upward rotation of the scapula in synchrony with the trapezius muscle.
a.Arises from the upper trunk immediately after it forms
b.Function:
i.Abducts the arm at the shoulders, it is the main agonist of this movement for the first 10-15 degrees of its arc. Beyond 30 degrees, the deltoid muscle is the primary arm abductor.
ii.Stabilizes the shoulder joint by effecting pressure medially that helps to hold the humeral head in the glenoid fossa.
iii.Provides sensory innervations to the acromiocalvicular and glenohumeral joints.
iv.The infraspinatus muscle:
1.Externally rotates the humerus
2.Stabilizes the shoulder joint
c.Diagnostic points:
i.Lesions at the level of the formation of the trunks:
1.The serratus anterior and the rhomboids are normal
2.Lesions at mid or upper trunk segments:
a.The supra and infraspinatus muscles are normal.
1.Lateral pectoral nerves:
a.Most often arise from the lateral cord. Anatomic variants are its origin from the anterior division of the upper and middle trunks
b.Function:
i.Innervates the pectoralis major muscle that is also innervated from the medial pectoral nerve.
ii.Flexion and adduction of the humerus
iii.Rotates the humerus medially
iv.Sensory innervations of the anterior chest wall
1.Most often is the termination of the lateral cord:
a.Gives off a branch that combines with a branch from the medial cord that forms the median nerve
b.Its major spinal nerves are C5 and C6 although there is a contribution from C7 in greater than 50% of patients.
2.It innervates:
a.Coracobrachialis
b.Biceps brachii
c.Brachialis
d.Forms the lateral cutaneous nerve of the forearm
3.Function:
a.Coracobrachialis:
i.Flexes and adducts the arm
ii.Medial rotation of the humerus
iii.Stabilization of the humeral head within the glenoid fossa
b.Biceps brachii:
i.Supination of the forearm
ii.Flexion of the forearm
iii.Minor functions:
1.Forward flexion of the shoulder
2.Aids abduction of the arm
3.Short head contributes to adduction of the arm
4.Stabilization of the shoulder
iv.Lateral cutaneous nerve of the forearm[HT4]
1.Sensation from the lateral elbow to the wrist (laterally)
1.Medial pectoral nerve:
a.Innervates both the pectoralis major and minor muscles
b.Function:
i.Adduction and medial rotation of the arm
ii.Poland Syndrome (congenital absence of the muscle) may be asymptomatic
2.Medial cutaneous nerve of the arm
a.Provides sensation to the medial upper arm to the elbow
3.Medial cutaneous nerve of the forearm:
a.May arise from the medial cutaneous nerve of the arm
b.Function:
i.Sensory innervation of the medial forearm to the wrist
1.Thoracodorsal nerve:
a.Most often arises from the posterior cord. Rarely its origin is the radial or axillary nerves
b.Its major spinal nerve is C7, but it receives contributions from C5 and C6
c.Function:
i.Extension and adduction of the arm
ii.Horizontal abduction of the arm
iii.Internal rotation
iv.Flexion from an extended position
v.Synergistic for extension and lateral flexion of the lumbar spine
2.Subscapular nerves:
a.The upper subscapular nerve innervates the subscapularis muscle. Derived from C5, C6 spinal nerves
b.Function:
i.Rotates the head of the humerus medially
ii.Draws the humerus forward and downward if the arm is raised
iii.Prevents displacement of the humerus
1.Supplies the lower part of the subscapularis muscle as well as the teres major
2.Its spinal nerves are C5 and C6
3.Function:
a.The subscapularis is the major and most powerful muscle of the rotator cuff
b.Stabilizes the glenohumeral joint
1.One of the terminal branches of the posterior cord. Its spinal nerves are C5 and C6. It innervates the teres minor and deltoid muscles. Its sensory innervation is the lateral proximal arm over the deltoid muscle.
2.Function of the deltoid muscle:
a.Anterior fibers:
i.Shoulder abduction
ii.Medial rotation of the humerus
b.Posterior fibers:
i.Transverse extension
ii.Lateral rotation
c.Lateral fibers:
i.Shoulder abduction
ii.Stabilizes the humeral head
3.Teres minor muscle:
a.Part of the rotator cuff that stabilizes the humeral head in the glenoid fossa
b.Is synergistic with the posterior fibers of the deltoid to laterally rotate the humerus
c.Transverse adduction and extension of the arm
1.The continuation of the posterior cord following branching of the axillary nerve. Its major spinal nerves are C5-C8 although approximately 10% of patients have a contribution from T1
2.Innervates:
a.The long, medial and lateral head of the triceps and the anconeus muscle
b.Brachioradialis, extensor carpi radialis longus and the brachialis (major innervations is from the lateral cord)
c.In the axilla, it gives off the posterior cutaneous nerve that innervates the posterior arm to the elbow. The posterior antebrachial cutaneous nerve innervates the posterior forearm. The superficial radial nerve innervates the extensor surface of the hand and fingers except for the distal fingertips. The dorsal ulnar cutaneous nerve supplies the dorsal medial hand and medial fingers
d.In the forearm, it innervates the extensor carpi radialis brevis, supinator, extensor digitorum communis, extensor digiti quinti, and extensor carpi ulnaris.
e.Above the wrist branches innervate the abductor pollicis longus, extensor pollicis longus and brevis and the extensor indicis
f.In the hand, it gives off dorsal digital nerves
g.At the elbow the motor posterior interosseous nerve arises
1.Primary extensor of the elbow joint
2.Fixates the elbow when the hand is used
3.Long head:
a.Used for sustained force
b.Synergistic for control of the shoulder and elbow
c.Retroversion and adduction
4.Lateral head
a.High-intensity force movements
5.Medial head:
a.Used during low force precise hand movements
1.Assists in elbow extension and supports the elbow in full extension
2.Protects the elbow joint capsule in the olecranon fossa during extension of the elbow
3.Abducts the ulna
1.One of the few muscles that receives innervations directly from the radial nerve (the triceps, anconeus, and extensor carpi radialis are the others). The other radial nerve innervated muscles receive their innervations from a deep branch of the nerve.
2.Function:
a.Flexes the forearm at the elbow
b.Stabilizes the elbow during rapid flexion and extension
c.Synergistic with the brachialis and biceps muscles
1.Curved around the upper 1/3 of the radius and innervated by the deep branch of the radial nerve
2.Function:
a.Supinates the forearm
1.Innervated by the radial nerve. All other major extensor muscles in the superficial layer of the posterior compartment of the forearm are innervated by the posterior interosseus nerve and include:
a.Extensor digitorum
b.Extensor carpi radialis brevis
c.Extensor carpi ulnaris
d.Extensor digiti minimi
2.Function:
a.Extension of the wrist
b.Radial abduction of the hand at the wrist
1.Innervated by the posterior interosseous nerve
2.Function:
a.An extensor and abductor of the hand at the wrist
1.Innervated by the posterior interosseous nerve
2.Function:
a.Principal action is extension of the proximal phalanges, the middle and terminal phalanges are extended by the interrossei and lumbricals
b.Extends the phalanges, the wrist and the elbow (weak).
1.Innervated by a deep branch of the radial nerve (C7, C8 spinal segments)
2.Function:
a.Extends and adducts the wrist
1.Innervated by the posterior interosseous nerve
2.Function:
a.Extension of the thumb (metacarpophalangeal and interphalangeal joints)
b.Extension of the index finger and wrist (extensor indicis) and extension of the little finger at all joints (extensor digiti quinti)
1.Formed by fusion of branches from the medial and lateral cords (spinal segments C6-T1):
a.Motor fibers arise primarily from C6-T1 spinal segments
b.Sensory fibers from C6-C7 spinal segments
c.The sensory fibers transverse the upper and middle trunks to the lateral cord
d.Motor fibers traverse all of the trunks to both the medial and lateral cords
e.In the forearm the median nerve innervates:
i.Pronator teres
ii.Flexor carpi radialis
iii.Palmaris longus
iv.Flexor digitorum supeficialis
2.Pronator Teres:
a.A forearm pronator (C6-C7)
3.Flexor carpi radialis (C6-C7)
a.A radial flexor of the hand
4.Palmaris longus (C7-T1)
5.Flexor digitorum superficialis (C7-T1)
In its descent and after it passes between the two heads of the pronator teres the purely motor anterior osseous nerve takes origin to innervate:
1.Flexor pollicis longus (C7-C8)
2.A flexor of the terminal phalanx of the thumb
3.Flexor digitorum profundus and (C7-C8)
a.A flexor of the terminal phalanges of the second and third fingers
4.Pronator quadrates (C7-C8)
a.A forearm pronator
The median nerve divides into its terminal branches at the distal end of the carpal tunnel. The motor branches innervate the first and second lumbricals and the thenar muscles.
5.First and second lumbricals (C8-T1):
a.Flexors of the proximal and extensors of the two distal phalanges of the second and third fingers
6.Abductor pollicis brevis (C8-T1):
a.An abductor of the metacarpal of the thumb (possibly the best muscle to test for median nerve weakness)
7.Oppenens pollicis (C8-T1)
a.Brings the metacarpal of the thumb into opposition
8.Superficial head of the flexor pollicis brevis (C8-T1)
a.Flexes the proximal phalanx of the thumb
1.Riche-Cannieu Anastomosis:
a.Anastomosis between the motor branch of the median nerve and the deep ulnar nerve branch in the radial aspect of the hand.
2.Adductor pollicus and first dorsal interosseous muscles may be exclusively supplied by the median nerve in 2% of patients.
3.The abductor pollicius brevis and flexor pollicis brevis may be supplied exclusively by the ulnar nerve in 2% of individuals.
The ulnar nerve derives from the C7, C8, and T1 spinal nerves and is the main branch of the medial cord. In its descent into the arm, it traverses the axilla beneath the pectoralis minor muscle and lies medial to the brachial artery in the upper arm. The C7 component arises from a branch of the lateral cord to innervate the flexor carpi ulnaris muscle. It enters a groove in the distal arm between the medial humeral epicondyle and the olecranon process. The dorsal component of this osseous fibrous canal is an aponeurosis between the olecranon and medial epicondyle. It is bound inferiorly by the medial ligament of the elbow joint. This canal is the cubital tunnel. Distal to the elbow joint originate its first two muscular branches.
1.The flexor carpi ulnaris (C7-T1):
a.Flexor of the wrist
2.Flexor digitorum profundus III and IV (C7-C8):
a.A flexor of the terminal phalanges of the fourth and fifth fingers
In the distal forearm, it gives off the palmar cutaneous branch that innervates the skin of the hypothenar eminence. Shortly thereafter, it gives off the dorsal cutaneous branch that innervates the dorsal ulnar hand and the dorsal components of the fifth finger and one-half of the fourth finger. The ulnar nerve proper enters the wrist lateral to the tendon of the flexor carpi ulnaris muscle and gives off the superficial terminal branch. This sensory branch innervates the distal ulnar palm and the volar aspect of the fifth and one-half of the fourth finger. The nerve then traverses Guyon’s canal whose medial component is the piriform carpal bone and the hook of the hamate carpal bone laterally to become the deep muscular branch.
It innervates intrinsic muscles of the hand that includes:
1.Palmaris brevis (C8-T1):
a.Tenses the skin of the palm on the ulnar side of the hand to deepen the hollow of the palm
2.Abductor digiti minimi (C8-T1):
a.An abductor of the fifth finger
3.Opponens digiti minimi (C8-T1):
a.An opposer of the fifth finger
4.Flexor digiti minimi (C8-T1):
a.A flexor of the fifth finger at the metacarpophalangeal joint
5.Lumbricals III and IV (C8-T1):
a.Flexors of the metacarpal phalangeal joints and extensors of the proximal interphalangeal joints of the fourth and fifth fingers
6.Interosseous muscles:
a.Flexors of the metacarpophalangeal joints and extensors of the proximal interphalangeal joints. The four dorsal interossei muscles are finger abductors. The three palmar interossei muscles are finger adductors:
i.Variants are:
1.Innervation of the first dorsal interosseous by the median nerve (1% of individuals)
2.First dorsal interosseous is innervated by the radial nerve (Froment-Rauber nerve)
7.Adductor pollicis (C8-T1):
a.An adductor of the thumb
b.It receives median nerve innervations in approximately 2% of individuals
8.Deep head of the flexor pollicis brevis (C8-T1):
a.A flexor of the first phalanx of the thumb
Most commonly involve the C5 and C6 spinal nerves of the upper trunk of the plexus.
1.Motor signs:
a.C5-C6 spinal nerve innervated muscles are paretic or paralyzed and atrophic. These muscles include:
i.Deltoid
ii.Biceps
iii.Brachioradialis
iv.Brachialis
i.Shoulder abduction: deltoid and supraspinatus
ii.Elbow flexion: biceps brachioradialis and brachialis
iii.External rotation of the arm: infraspinatus
iv.Forearm supination: biceps
b.Very proximal lesions involve the rhomboids, levator scapulae, serratus anterior, and scalene muscles.
3.Sensory signs:
a.Sensation is often intact
b.Sensory loss does occur over the lateral/upper arm and the deltoid muscle in some patients
4.Reflex signs:
a.Depression of the biceps and brachioradialis reflexes
1.Lesions of the middle trunk or the individual anterior primary ramus of C7 are involved
2.Motor signs:
a.Involvement of C7 innervation to the radial nerve is primarily involved which causes weakness or paralysis of extension of the forearm, hand, and fingers
b.The paretic or paralyzed muscles are:
i.Triceps
ii.Anconeus
iii.Extensor carpi radialis and ulnaris
iv.Extensor digitorum
v.Extensor digiti minimi
vi.Extensor policis longus and brevis
vii.Abductor pollicis longus
viii.Extensor indicis
c.Forearm flexion is maintained by the brachioradialis and brachialis (C5-C6 spinal nerves)
3.Sensory signs:
a.Patchy sensory deficit over the extensor surface of the forearm and the dorsum of the hand
a.Triceps reflex is depressed or absent
1.Primary injury involves the C8-T1 spinal nerves or the lower trunk of the plexus
2.Motor signs:
a.Musculature supplied by the C8-T1 spinal nerves is affected. There is weakness of wrist and finger flexion and in the intrinsic hand muscles. There is usually severe hand atrophy leading to the “claw” hand deformity
3.Sensory signs:
a.Decreased sensation of the medial arm and forearm and the ulnar side of the hand.
4.Reflex signs:
a.Loss of finger flexion
5.If T1 is damaged, sympathetic fibers to the superior cervical ganglia are interrupted which causes a Horner’s syndrome. If T2 is damaged, there is an interruption of the sympathetic innervation of the arm.
Usually, result in weakness of the muscles innervated by the musculocutaneous and lateral head of the median nerve.
a.Motor signs:
a.Weakness of the biceps brachii and brachialis:
i.Flexion of the elbow
b.Coracobrachialis:
ii.Supination of the forearm
c.Median nerve innervated muscles:
i.Pronator teres:
1.Pronation of the forearm
ii.Flexor carpi radialis:
1.Radial wrist flexion
iii.Palmaris longus:
1.Flexion of the wrist
iv.Flexor digitorum superficialis:
1.Flexion of the middle phalangeal joints (second through fourth digits)
v.Flexor digitorum profundus I and II:
1.Flexion of the distal phalanges of the second and third fingers
vi.Pronator quadratus:
1.Pronation of the forearm
a.Loss of sensation in the distribution of the lateral cutaneous nerve of the forearm:
i.Sensory loss in the lateral forearm
ii.Branch of the musculocutaneous nerve
a.Depression or absence of the biceps reflex
1.Cause weakness of the muscles innervated by the ulnar nerve and the medial component of the median nerve
2.Ulnar innervated muscles that are weak include:
a.Flexor carpi ulnaris:
i.Ulnar flexion of the wrist
b.Flexor digitorum III and IV:
i.Flexion of the terminal digits of the fourth and fifth fingers
c.All of the ulnar innervated small intrinsic hand muscles
3.Median innervated muscles include:
a.Abductor pollicis brevis
i.Metacarpal abduction of the thumb
b.Opponens pollicis:
i.Opposition of the thumb
c.Superficial head of the flexor pollicis brevis:
i.Flexion of the proximal phalanx of the thumb
d.Lumbricals I and II:
i.Flex the first two metacarpophalangeal joints and extend the digits of the second and third fingers
a.Loss of sensation of the medial arm and forearm due to injury of the medial cutaneous nerves of the arm and forearm.
a.Loss of the finger flexor reflex
1.Injury of the medial anterior thoracic nerve:
a.Weakness of the lower sternocostal portion of the pectoralis major muscle and the pectoralis minor muscle.
Posterior cord lesions cause weakness in the muscles innervated between the subscapular and thoracodorsal, axillary and radial nerves.
1.Motor signs:
a.Subscapular nerve innervated muscles:
i.Weakness of the teres major and subscapularis muscles:
1.Internal rotation of the humerus
b.Thoracodorsal innervated muscles:
i.Latissimus dorsi weakness:
1.Extension, adduction, transverse extension (horizontal abduction), flexion from an extended position and internal rotation of the cap of the shoulder joint
2.Synergistic role (therefore weakness) in extension and lateral flexion of the lumbar spine
c.Axillary nerve innervated muscles:
i.Deltoid:
1.Arm abduction
ii.Teres minor:
1.Lateral rotation of the shoulder joint
iii.Sensory loss:
1.Distribution of the lateral cutaneous nerve of the arm that includes a diminished sensation of the lateral arm.
1.Weakness of elbow extension, wrist extension, supination of the forearm and finger extension. There is a minimal contribution to elbow flexion. Proximal lesions cause triceps reflex loss.
2.Sensory signs: sensory loss in the extensor surface of the arm and forearm, dorsum of the hand and first four fingers distribution
3.Reflexes: depression of triceps and radial reflexes
1.Neuronal dysfunction due to transient conduction block.
2.Compression of a nerve may cause segmental ischemia. If of short duration there may only be a reversible physiologic conduction block that lasts for minutes to hours. There may also be paranodal and then segmental demyelination. In this instance, recovery may take several weeks and is effected by remyelination
In this instance, the axon is interrupted, but the epineurium is preserved. The axon distal to the lesion degenerates over 7-10 days. Regenerating nerve sprouts from the proximal portion of the injured nerve attempt regeneration. The intact epineurium enhances the chance of reinnervation. Axons grow at a rate of 1 mm/day, so this process may require months to over a year.
1.The axon and epineurium are interrupted. The difference between axonotmesis and neurotmesis can only be determined by direct vision (surgery). Scarring from overlying tissue damage often prevents reinnervation.
1.Dependent on the particular process affecting the plexus
1.Primarily high-resolution MRI (microneurography)
2.Ultrasound is useful for focal neuropathies and lesions
1.EMG:
a.The EMG is essential in evaluating radiculopathy, plexopathy, and mononeuropathy.
b.Combined with motor and sensory NCVs, it supports the localization determined by the clinical examination
1.The longitudinal excursion of the brachial plexus is 15.3 mm.
2.The greater the traction on the plexus, the greater the injury (between neuropraxia, axonotmesis to neurotmesis).
3.The primary roots are the most susceptible to traction injury since they are arranged in parallel bundles rather than a lattice structure and therefore have decreased tensile strength.
4.Shoulder depression and lateral head flexion contralaterally injure the upper and middle trunk.
5.Traction on the hyper-abducted arm causes traction on the lower > middle > upper trunk.
6.Preganglionic injuries are usually caused by avulsion of the root.
7.Traction injuries may affect all or a portion of the plexus to a varying degree.
8.C5 and C6 rupture occur close to the exit foramina. C8-T1 rupture is often closer to the spinal cord.
9.The pathology is categorized as neuropraxic axonotmesis and neurotmesis.
10.Treatment (surgical intervention) is dependent on the type and severity of the injury:
a.Most closed injuries are neuropraxic or axonometric that may recover spontaneously:
i.Upper trunk lesions usually demonstrate signs of recovery in 2-3 months
ii.Four to five months are required for recovery in middle and lower trunk lesions
b.High impact injuries and those causing near total paralysis need to be evaluated earlier for possible surgery (3 weeks to 3 months)
c.Injuries that more likely sever nerves such as lacerations or gunshot wounds need to be evaluated for possible surgical repair within 72 hours.
d.Associated conditions that cause neurological worsening after injury:
i.Hematoma
ii.Concomitant bone and vascular injury
iii.Compartment syndromes
1.C5-C6 root lesions after severe trauma:
a.27% avulsions; 33% ruptures
2.Most often are caused by high impact trauma:
a. MVA (motorcycle injuries are the most common)
b.Football, skiing, mountain climbing accidents and falls.
3.C8-T1 root lesions:
a. 98% are avulsion, and 1-2% are ruptures
1.Total plexopathy may occur with high impact trauma:
a. Avulsion is greater in C8-T1 roots > C5, C6 and C7 roots
2.Early severe burning pain in an otherwise anesthetic hand; most severe proprioceptive loss if any sensation is proximal
3.Horner’s syndrome is present in (C8-T1 avulsion)
4.Paralysis of the serratus anterior, rhomboids, infra and supra spinatus muscles
5.Negative supraclavicular Tinel’s sign
6.May have associated spinal cord symptoms and signs
1. Neurotmesis of the roots
1.Traumatic meningocele
2.Fracture of a transverse process
3.Flattening of the root sleeve
4.Extravasation of contrast through the torn root sleeve during myelography
5.High-resolution MRI may demonstrate the lesions and is now more commonly used than myelography
6.Ultrasound is used for focally associated neuropathies
1. EMG:
a. Sensory, motor, and mixed sensorimotor nerve conduction studies
b. SNAP (sensory nerve action potentials) are normal if the lesion is distal to the dorsal root ganglion
i. It requires 7-10 days for SNAPs to disappear with a completely severed nerve
c. Positive sharp-wave and fibrillation potentials in affected muscles and paraspinal muscles:
i. May require one week to appear in paraspinal muscles and three weeks following axonal injury
ii. The Motor Unit Action Potentials (MUAPs) voluntarily recruited are immediately affected
1. Incidence ranges from 0.38 to 2% per 1000 live births
2. Three types of injury occur:
a. Diffuse plexopathy
b. Upper trunk plexopathy (Erb’s)
c. Lower trunk plexopathy (Klumpe’s)
3. Risks for brachial plexus injury during childbirth:
a.Diabetic, multiparous, obese mothers
b.Greater than 4500 gram fetuses
c.Mothers that are short
d.Breech presentation
e.Long and difficult labor
f.Forceful downward traction of the head
1. Erb’s palsy (C5-C6 roots; upper trunk)
2. The most common obstetrical brachial plexus injury:
a.Stretch of the upper trunk
b.Severe traction may avulse the C5 and C6 spinal nerves
c.Occurs with shoulder dystocia in a vertex presentation or the aftercoming head in a breech presentation
d.Upper trunk lesions cause weakness of muscles that include:
i.Supra and infraspinatus
ii.Deltoid
iii.Biceps brachii
iv.Teres minor
v.Brachioradialis
vi.Extensor carpi radialis/longus/brevis
vii.Supinator
e. Weakness of the diaphragm or serratus anterior suggests root avulsion (proximal to the upper trunk)
f. Sensory loss < motor deficit
1. Primarily axonotmesis and neurotmesis (with avulsion)
a.Determines the site and severity of the lesion.
The major components of the thoracic outlet are the sternocostovertebral space that forms the most proximal part of the thoracic outlet tunnel and is bound:
1.Anteriorly by the sternum
2.Posteriorly by the spine
3.Laterally by the first rib
The subclavian artery, subclavian vein, and C4 to T1 spinal nerves traverse this space. Associated structures include the apex of the lung and pleura, sympathetic trunk, jugular vein and lymphatics of the neck. It may be congenitally narrowed.
The usual pathology of the sternocostovertebral space includes:
The scalene triangle is bound by the anterior scalene muscle anteriorly, the middle scalene posteriorly with the first rib forming its base. The origins of the anterior scalene muscle are the transverse processes of C3-C6.
The insertion of the anterior scalene muscles on the scalene tubercle of the first rib varies between the subclavian artery and vein and the pleural dome.
Variants of this insertion include:
1.Behind the artery
2.Between the artery and the brachial plexus
3.The entire base of the scalene triangle (which traps the neurovascular bundle). The anterior insertion may merge with the insertion of the middle scalene muscle in 20% of patients. The C5-C6 spinal nerves may traverse the anterior scalene muscle rather than descend between the anterior and middle scalene muscles.
The origin of the middle scalene muscle is the transverse processes of C2-C7. It inserts on the retro arterial tubercle of the first rib (Chassaignac’s tubercle). It may insert on the fibrous septum of the pleural dome in which case its lateral fibers insert on the second rib. The C8-T1 spinal nerves as the lower trunk of the plexus may be compressed by a more anterior or forward insertion (its sharp anterior edge). Rarely, congenital fibromuscular bands are noted along the anterior edge of the muscle that may also compress the C8-T1 spinal nerves.
The first rib forms the floor of the scalene triangle. The T1 spinal nerve is closest to the rib. Congenital rib anomalies, bony ridges, hypoplasia, or inward curvature may compress the neurovascular bundle. There are congenital variations in the size of the base of the scalene triangle that may cause compression of components of the plexus. Its usual size is approximately 0.77 cm in men and 0.67 cm in women. The C5-C7 spinal nerves emerge from the apex of the triangle in association with interdigitation of the anterior and middle scalene muscles. This anatomical feature is noted in a large percentage of patients with neurogenic thoracic outlet syndrome. Adherence of the C5-C6 spinal nerves to the middle scalene muscle may also irritate these nerves and cause pain. Pathology in the costoclavicular and pectoralis minor space compresses the brachial plexus with various arm positions.
1.Bone defects:
a.Cervical rib
b.Abnormal or rudimentary first rib
2.Congenital bands or ligaments
3.Pectoralis minor insertion variations (hyperabduction syndrome)
4.Large subclavius muscle
5.Tight thoracic inlet
6.Scalene triangle congenital defects:
a.Narrow scalene triangle
b.Proximity of anterior and middle scalene muscles
c.High emergence of spinal nerves from the triangle
d.Interdigitated muscle fibers between the middle and anterior scalene muscles.
e.Adherence of spinal nerves C5-C6 to the anterior scalene muscle
7.Congenital narrowness of the costoclavicular space
8.Clavicle anomalies (acromial head depression compresses the costoclavicular space)
9.A tight pectoralis minor space (below the insertion of the pectoralis minor tendon into the coracoid process); hyper abduction of the arm closes the space.
a.The four anatomical spaces of the thoracic outlet:
i. Sternocostovertebral space
ii.Scalene triangle (most frequently involved)
iii.Costoclavicular space
iv.Pectoralis minor space
b.Congenital bands (12 types)
c.Cervical ribs
d.Long neck droopy shoulders
e.Tight thoracic inlet
f.Abnormal insertions of the anterior, middle or minimus scalene muscle
a.Erb’s point (supraclavicular plexus)
b.Pectoralis minor space (lateral infraclavicular fossa)
c.Compression of the neurovascular bundle (against the proximal humerus)
d.At the cubital tunnel (ulnar nerve)
e.At the Arcade of Frohse (dorsal radial sensory fibers). This Tinel’s sign is invariably misdiagnosed as “tennis elbow”.
f.Pronator canal (median nerve)
g.Occasionally the carpal tunnel and Guyon canal areas are mechanically sensitive.
a.Trapezius ridge, deltoid and medial scapula border (C5-C6 sensory radiations)
b.Pain or tenderness at the tip of the scapula is notalgia and is a C6 sensory nerve radiation, not T6 (most oftern).
a.Medial arm and forearm distributions (brachial and antebrachial cutaneous nerve distributions)
b.Radiation into the complete 4th finger (the ulnar nerve splits the fourth finger and supplies a small triangular area above the wrist). The lower trunk innervates the entire medial forearm and arm. The lower trunk radiations are often misdiagnosed as ulnar nerve lesions.
c.Proximal lesions may be associated with a Horner’s syndrome.
d.Lower trunk lesions are a common cause of chronic regional pain syndrome Type I and II that has severe somatosensory, motor, and autonomic features.
a.Pain or paresthesia in the lateral forearm (lateral antebrachial cutaneous nerve) distribution
b.Thumb, index, and radial side of the third finger have decreased sensation or paresthesias.
a.Medial forearm (territory of the medial antebrachial cutaneous nerve)
i.Rarely the brachial cutaneous nerve territory of the medial proximal upper arm is involved
b.The ulnar side of the third finger and the complete 4th and 5th finger comprise the medial cord sensory topology in the hand
c.There is frequent involvement of the intercostobrachial nerve concomitantly with medial cord injury; this causes pain in the anterior chest wall (T1-T3) and the lateral chest wall (anterior axillary line); paresthesia and pain may radiate under the breast to the middle of the epigastrium at the xiphoid process. These radiations are often misdiagnosed as visceral pain radiations
a.Paresthesias of the triceps muscle and back of the arm
b.Radiations to the dorsal forearm and base of the thumb and parts of the dorsal hand (posterior antebrachial radial cutaneous nerve)
a.Most often, they are normal.
b.They may be increased if CRPS I or II has supervened which is more common with lower trunk lesions (sympathetic hyperactivity induces contraction of the intrafusal muscle fibers of the nuclear bag of the muscle spindle complex).
a.Most patients have suffered trauma with flexion-extension injuries of the neck (“whiplash”)
b.Repetitive movements commonly initiate the process.
i.Falls on the outstretched arms are common.
c.Most often, the process is neuropractic and recovers spontaneously. However, a small percentage of patients become chronic.
d.Secondary concomitant CRPS I and II may be caused by lower trunk trauma most often.
1.Cervical ribs:
a.The incidence of cervical ribs in the population is estimated to be 0.3%.
b.Women are affected two times more frequently than men
c.Approximately 10% of patients with cervical ribs are symptomatic. Usually, symptoms are initiated by trauma.
d.The Gruber classification of cervical ribs:
i.Type I:
1.Protrudes slightly beyond the transverse process and attaches to the first rib by a tight fibrous band.
ii.Type II: 2.5 cm in length:
1.Attaches to the first rib by a tight fibrous band.
2.Rib and band lie within or on the medial border of the middle scalene muscle.
3.This configuration narrows the scalene triangle.
iii.Type III:
1.A complete rib with a fibrous connection to the first rib.
iv.Type IV:
1.A complete rib with a cartilaginous joint at the first rib.
2.The complete rib causes the neurovascular bundle to arch over the rib
3.The neurovascular bundle is compressed when the shoulder girdle is depressed.
2.The most significant ligaments are:
a.Transverse process of C7 to the first rib.
b.Tip of the cervical rib that inserts on the first rib
c.Ligaments that are within the body or on the anterior surface of the middle scalene muscle may affect C8-T1 spinal nerves of the lower trunk.
d.Common anomalies:
i.Incomplete cervical rib on a long transverse process of C7 from which a tight band inserts on the first rib.
1.Type I:
a.Tip of an incomplete cervical rib ligament that inserts posteriorly to the scalene tubercle
2.Type II:
a.The origin of the ligament is from the transverse process of C7 and inserts on the scalene tubercle
3.Type III:
a.A ligament that originates and inserts on the first rib; the origin is posterior and the insertion is anterior.
4.Type IV:
a.The ligament originates within the middle scalene (C2-C7)
b.Courses on the anterior edge of the middle scalene.
c.Inserts with the muscle on the first rib.
d.The ligament is adjacent to C8, T1 spinal nerves
5.Type V:
a.Scalenus minimus muscle is the Vth band.
b.Origin is in the anterior scalene muscle (lower fibers)
c.Courses behind the subclavian artery in front of the plexus to insert on the first rib.
6.Type VI:
a.Scalenus minimus insertion into Sibson’s’ fascia over the cupola of the lung rather than the first rib.
7.Type VII:
a.A fibrous cord that courses on the anterior surface of the anterior scalene muscle.
b.Inserts on the costochondral junction of the sternum.
c.The band lies behind the subclavian vein that it may compress.
8.Type VIII:
a.Origin of the ligament is the middle scalene muscle.
b.Courses under the subclavian artery and vein.
c.Inserts on the costochondral junction
9.Type IX:
a.A web of muscle and fascia that fills the posterior curve of the first rib.
1. Primarily a lower trunk plexopathy.
2. Women are more often affected than men are.
1. Paresthesia of the 4th and 5th fingers, medial forearm to the medial humerus.
2. Atrophy of the thenar is greater than hypothenar muscles of the hand.
1. A sharp fibrous band from the tip of an elongated C7 transverse process of a true cervical rib to the first rib.
2. A neuropraxic injury of the proximal lower trunk.
a.Prominent transverse process at C7
b.Cervical rib
c.The band cannot be appreciated by MRI
2.MRI micrography
3.Ultrasound
1. EMG:
a. The median CMAP and medial antebrachial cutaneous SNAP amplitudes are reduced to a greater extent than the ulnar SNAP and CMAP.
i. Ulnar studies primarily assess C8 fibers
1.Most lesions occur during trans axillary first rib resection; less frequently with scalenectomy and neurolysis of the upper trunk in the supraclavicular fossa.
2.Direct surgical injury as traction (neuropraxis) plexus injury.
3.Phrenic nerve may be involved concomitantly (particularly if the procedure involves the middle scalene muscle).
4.Site of the lesion:
a.Proximal lower trunk
b.C8, T1 spinal nerves
1. Most common procedures are those for:
a.Recurrent anterior shoulder dislocation
b.Shoulder joint replacement
c.Arthroscopy of the shoulder
d.Surgical procedures that compromise the costoclavicular space
e.Direct trauma from arteriography and cannulas
f.Percutaneous cannulation of the subclavian and internal jugular vein
g.Percutaneous brachial plexus block
i.Direct trauma to the musculocutaneous nerve is the most frequent injury
ii.Median, ulnar, radial, and axillary nerves may be inured with clinically expected motor and sensory deficits
i.The bone screw that attaches the coronoid process to the glenoid rim works loose.
ii.Axillary artery may be pierced with pseudo aneurysm formation that compresses the infraclavicular plexus.
1.Direct trauma to the axillary nerve and the supraclavicular plexus.
1.Direct trauma to the infraclavicular nerves:
a.Musculocutaneous
b.Axillary
c.Ulnar
d.Radial
1.Neuropraxis injuries of these nerves
1.Operations to correct Sprengel’s deformity.
2.Midportion of the clavicle surgery (fracture repair or to obtain access to subclavian vessels); regeneration of the lateral clavicle with excess callus formation that compresses the upper trunk.
1.Trauma to the infraclavicular brachial plexus:
a.Cords of the plexus are adjacent to the second segment of the axillary artery; the median nerve is on the surface of the artery
b.Leakage of blood from the puncture site that causes direct compression of the terminal nerves: median > ulnar >radial
c.Most often, there is a combination of median and ulnar nerve trauma.
d.Pain, paresthesia, and arm weakness in characteristic patterns.
i.Onset of symptoms may be delayed for up to two weeks.
e.Nerve lesions may occur from pressure (hematoma) in the medial brachial fascial compartment that:
i.Extends from the axilla to the elbow
ii.Formed by the medial intramuscular septum and the surface of the medial upper arm.
iii.Encloses the neurovascular bundle and fascial axillary sheath.
f.Percutaneous cannulation of the subclavian and internal jugular vein:
i.Direct instrumentation induced trauma.
ii.Hematoma compression.
iii.Rarely axillary mononeuropathy
iv.Rarely upper trunk plexopathy
g.Percutaneous brachial plexus block:
i.Injuries may be caused by:
1.The block itself.
2.Tourniquet-induced ischemia
3.Post-operative casting
4.The surgical procedure
ii.Axillary block approach causes more injuries than interscalene blocks
iii.Usual symptoms are paresthesia in the median and ulnar nerve distributions; usually slight weakness of the involved nerves.
iv.May have delayed onset (up to two days) following the procedure:
1.Bupivacaine at 0.25% may demyelinate nerves.
1. Median sternotomies:
a.Primarily open heart surgeries
b.Thoracotomy
2. Brachial plexus injuries affect up to 5% of patients that undergo the procedure
1.Primarily affects the lower trunk
2.Sensory loss in the medial forearm and hand
3.Weakness of intrinsic hand muscles
1. Neuropraxis injury of the lower trunk; usually recovers in months
1.Ultrasound evaluation of the plexus
2.MRI not effective in visualizing lesions that are neuropractic
1.EMG:
a.Usually, demonstrates a lower trunk lesion
1.Follows surgical procedures usually under general anesthesia
2.Abdominal operation (usually cholecystectomy or hysterectomy; now changing due to minimally invasive surgery)
1.Upper plexus more often involved than lower plexus; usually unilateral.
2.Weakness and paresthesia are the predominant signs and symptoms.
3.Rarely patients complain of pain
4.Rarely a Horner’s syndrome
5.Recovery usually begins 2-3 weeks after onset and may require several months to be complete:
a. Sensory loss recovers first followed in the lower plexus, then in the upper plexus and lastly motor function.
1.A neuropractic injury
2.Positions associated with post-operative paralysis:
a.Supine
b.Trendelenburg (steep and prolonged)
c.Abduction of one or both arms to 90 degrees or greater
d.Extension and external rotation
e.Rotation and lateral flexion of the head to the contralateral side
f.Lower shoulder and arm compressed
g.Flexed and prone position (back procedures)
h.Excessive abduction and arm flexion
1. MRI/MRA:
a.Microneurography to evaluate soft tissue and vascular components in the surgical field.
b.Ultrasonography to evaluate terminal nerves
1. Surgery for neurogenic brachial plexopathy particularly performed without a clear anatomic target such as a cervical rib is fraught with complications
1. First rib trans axillary resection:
a.Weakness and wasting in a lower trunk distribution
b.Paresthesias and burning pain in the 4th and 5th fingers and medial forearm.
c.Less commonly:
i.Flail arm with numbness and pain of the entire upper extremity
ii.This pattern may evolve into a medial cord distribution of weakness.
2. Anterior scalenectomy and neurolysis:
a.Pain across the trapezius ridge and down the medial scapular border.
b.Minimal weakness of the rhomboids, supra and infraspinatus and biceps muscles
c.Occasional paresthesia of the lateral deltoid and the lateral forearm
d.Occasional weakness of the ipsilateral phrenic nerve
1. Neuropractic, axonotmesis, and neurotmesis of components of the brachial plexus
1. MRI:
a. To evaluate the surgical field for hematoma or bone defects (difficult to distinguish brachial plexus components with 1.5 Tesla magnet strength)
2. Ultrasonography to evaluate terminal nerves
1. EMG:
a. After 14-21 days to evaluate the level and extent of the operative injury.
a.85% are in males
b.the average age is 28 years
1.80% of injuries affect the cords or terminal nerves
2.Majority of patients have plexus lesions in continuity
3.Laceration injuries:
a.Knife injury or glass (fall through a glass window); propeller blades; chainsaw
b. Clinical manifestations:
i.Associated damage to blood vessels of the neck, axilla, and upper lung
ii.33% of injuries to the brachial plexus are in continuity
iii.Knife or glass injury tend to be focal
1.MRI/MRA
2.Ultrasonography
1.Noted in military personnel and civilians using improperly positioned heavy backpacks.
2.Males affected more often than females.
3.Related to backpack design and weight; multiple mechanical and time-dependent features.
4.Possible congenital structural or prior trauma as predisposing factors.
5.Hereditary neuropathy with susceptibility to pressure palsies
1.Preceded by transient episodes prior to the fully developed syndrome.
2.Muscle weakness of the shoulder, arm or forearm more than pain
3.Upper trunk > middle plexus innervated muscles are involved; the deltoid may be the most severely involved muscle.
4.Sensory loss and reflex changes are less apparent.
1. Neuropraxic and axonometric injury
1. MRI:
a.To rule out congenital defects and prior traumatic injury (excessive callus formation from a fractured clavicle)
2. Ultrasonography to evaluate the plexus and nerves
1.EMG:
a.To evaluate the location and severity of the injury
1.Brachial plexus involvement is often overlooked in the context of shoulder pathology. Weakness is often ascribed to pain and joint pathology.
2.The usual injuries are:
a.Humeral fracture or dislocation
b.Scapular fracture
c.Rotator cuff tear
1. Rotator cuff tear:
a.Approximately 30% of these injuries are associated with brachial plexopathy.
b.All components of the plexus may be injured.
c.Posterior cord and middle trunk greater than upper trunk and lateral cord.
2. Humeral fractures and dislocation:
a.Ischemic or a vascular compressive lesion
b.Posterior cord and middle and lower trunk may have the greatest deficit
c.Trunks and cords, as well as terminal nerves, may be involved with reductions of shoulder dislocations
1.Excess motion of the clavicle at the fracture site.
2.Exuberant callus formation
3.Tight figure of eight brace
4.Delayed onset (months to years)
1.Anterior division and upper trunk involvement with weakness of the innervated muscles
2.Upper arm pain exaggerated by arm elevation
1. Primarily neuropractic and axonometric injury
1.MRI (local pathology)
2.Ultrasonography (terminal nerves) evaluation
1. Usual contact sports injury (shoulder trauma; face mask injury in football)
1.Neuropractic stretch injury
a.Not necessary unless symptoms persist; if symptoms are persistent then MRI and EMG are required
1.Extremely rare
2.May be seen in individuals that perform repetitive overhead/arm movements (butchers, using saws; pitchers in baseball)
1.Adson’s maneuver less often positive than in patients with true neurogenic thoracic outlet syndrome
2.Ischemia of the hands and fingers rather than specific neurogenic plexopathy is most common; some patients complain of heaviness and weakness of the arm in abduction; primarily upper trunk distribution
3.May have severe ischemic pain
1.Bony abnormalities of the clavicle and first rib cause post stenosis dilatation then aneurysm formation of the subclavian or axillary artery.
2.Distal emboli from thrombi in the artery to the fingers
1.Abrupt presentation
2.Upper extremity swelling cyanosis and livedo reticularis
3.Dilated venous collaterals over the chest and shoulder
4.Brachial plexus is not involved.
1.Prolonged compression of the axillary vein on a hard surface (arm outside of the window and resting on the door of a car); compression of the subclavian vein between the clavicle and the first rib
2.May follow extreme exercise of the arm.
3.Bony, ligamentous and muscular anomalies
1. MRA and MRV to evaluate the circulation to the arm
a.Acute brachial plexitis
b.Neuralgic amyotrophy
c.Parsonage-Turner Syndrome
a.May develop after an infection or vaccination
b.Following bone marrow transplantation
c.During treatment with immunomodulating agents:
i.Interferons
ii.Interleukin 2
iii.Tumor necrosis factor alpha blockers
d.Antibodies against peripheral nerve myelin and soluble terminal complement complexes
e.Response to steroids
f.In association with some autoimmune diseases
i.Suprascapular nerves
ii.Long thoracic nerves
iii.Axillary nerves
b.There may be concomitant involvement of the phrenic and interosseous nerves. These nerves may be involved in isolation
c.Rarely cranial nerves IX, X, XI and XII can be involved
d.Isolated spinal accessory involvement has been described
a.May demonstrate increased T2 weighted signal intensity of the plexus that suggests inflammation with edema
a.Electrodiagnostic studies depend on the component of the plexus that is involved.
b.Nerve damage may be multifocal and is usually axonal
c.The upper trunk is primarily involved:
i.Median and ulnar motor studies are positive in approximately 15% of patients; median and brachial SNAPs may be abnormal.
ii.Decreased CMAP from the deltoid, biceps, and serratus anterior muscles
iii.Decreased SNAPs of the lateral, antebrachial, cutaneous and median sensory nerves
1.Asymmetric form of chronic inflammatory demyelinating neuropathy
2.Multifocal acquired motor and sensory demyelinating neuropathy
3.Multifocal motor neuropathy
a.Encodes the septin-9 protein
1. A history of one or more sudden onset painful attacks that involve the neck, shoulder, or arm
2. Weakness in various affected components of the plexus
3. Associated features:
a. Hypertelorism
b. Occasional cleft palate:
i.Skin folds or creases on the neck or forearm
ii.Short stature
iii.Syndactyly
1.Septins are involved in cytokinesis and cellular trafficking
2.Septin-9 protein localizes with other septins and with septin-intermediate filaments that interact with actin microfilaments and microtubules
1.MRI to rule out other causes of brachial plexopathy; STIR-MRI demonstrates hyperintense signals in the brachial plexus
2.Ultrasonography
3.Magnetic resonance neurography
1.EMG:
a.Similar to idiopathic brachial plexus neuropathy
1.PMP22 gene deletion; AD but gene de novo mutations occur; the gene is on chromosome 17p11.2.
2.The deletion of the 1.5 MB region is the same that is duplicated in CMT1a
3.Prevalence of 7.3/100,000 to 16/100,000 people
1.Age of onset is the second and third decade (but has been described to the 8th decade)
2.60-70% of patients present with a single, focal acute neuropathy
3.Rare cranial nerve involvement that includes V, VII, XII, and components of X.
4.Brachial plexus involvement (12-27%):
a. Possibly causative of backpack neuropathy
5.Painless recurrent plexopathy
6.Scapuloperoneal presentation (Davidenkov phenotype)
7.Muscle weakness and atrophy
8.Numbness in affected plexus distributions
9.Reduced or absent deep tendon reflexes (primarily ankle jerks)
10.Episodes may be preceded by minor compression of the affected nerve or the plexus
11.Rare vocal cord, phrenic nerve and root involvement
1.Nerve biopsy demonstrates segmental demyelination with varying large-fiber loss.
2.Tomacula:
a.Redundant or over folding layers of the myelin sheath of variable thickness are present
3.The 1.5 Mb deletion on chromosome 17p11.2 is found in approximately 85-90% of patients that are clinically affected
4.Mouse model demonstrates focal axonal constriction within tomacula.
1.MRI:
a.CNS white matter lesions occur in isolated patients
2.Ultrasonography:
a.Reveals hypertrophy at entrapment sites
a.Increase in distal motor latencies especially of the median and peroneal nerves
b.Focal motor slowing at entrapment sites
c.NCV may be normal in some segments
d.Sensory nerve conduction velocities may be decreased with decreased SNAP amplitudes
4.DNA testing for the deletion of the PMP22 gene
i.60-80% of brachial plexus tumors are neuronal sheath tumors
a.Schwannoma
b.Neuroma
c.Neurofibroma
1.Present as mass lesions in the supraclavicular fossa or axilla
2.Pain and paresthesia are early symptoms (distortion of nerve fibers without conduction block, demyelination, or destruction of axons)
3.Later motor and sensory loss
1. Approximately 5% of benign and soft tissue neoplasms
2. Approximately 20% of tumors of the brachial plexus
a.Nasal septum
b.Cervical sympathetic chain.
c.Gingiva
d.All cranial nerves; may be plexiform
e.Base of the tongue
f.Cecum and gastric mucosa
g.Sublingual area
1.Benign and well encapsulated
2.Usually, affect the proximal components of the plexus
3.Degenerative changes and variable admixture of spindles (Antoni A), whorls, and hypocellular microcytic (Antoni B) areas with macrophages and collagen fibers; located near vessels and have a well formed collagenous capsule
4.Express S 100 protein and pericellular collagen type IV
5.Plexiform Schwannoma:
a.A subtype that occurs in superficial cutaneous or subcutaneous locations.
b.Intraneural pattern of growth
c.Associated weakly with NF2 and Schwannomatosis (approximately 5% of patients); usually Antoini A pattern and is less encapsulated than classic Schwannomas
1. MRI:
a.Homogeneously isointense on T1 weighted sequences and hyperintense on T2 images
b.Cystic degeneration may be noted in the usual Schwannoma
1.EMG
2.Molecular genetics to evaluate for NFI
i.Localized cutaneous neurofibroma is the most common:
1.May involve a major nerve to cause a fusiform expansion of the nerve trunk (intraneural subtype)
2.Diffuse neurofibromas cause a plaque-like enlargement (usually in the head and neck region)
ii.10% of neurofibromas are seen with neurofibromatosis type I
1.Interdigitate more with nerve fibers within the nerve fascicle
2.In association with neurofibromatosis, they are often multiple and may affect a large portion of the brachial plexus.
3.Demonstrate motor and sensory deficits depending on which component of the plexus is affected
4.Neurofibromas associated with NFI:
a.Occur both supra and infraclavicularly
b.Are frequently multiple and plexiform
c.Present at an earlier age than Schwannomas
d.May extend intraspinally (dumbbell tumor) in the intradural extramedullary compartment
e.Equal male and female incidence
a.Wavy nuclear contours
b.S-100 protein expression
1. Plain films may demonstrate enlargement of an intra foraminal exit canal
2. MRI:
a.Bag of worms appearance from diffuse involvement along a nerve segment
b.Few flow voids within the lesion are seen in T2 weighted images
c.Plexiform neurofibromas may present on imaging with an intermediate signal compared to muscle on T1 weighted images and with a hyperintense signal on T2 weighted sequences
1.EMG
1. Advanced perineural differentiation
2. Two types of tumor have been described:
a. Intraneural
b. Soft tissue
1.A. Localized solitary expansion of peripheral nerve due to involvement of one or more nerve fascicles
2.Remain stable over time or progress slowly
1.Perineurial cell proliferation that extends into the endoneurium that surrounds individual nerve fibers and capillaries that produce “pseudo-onion bulbs”
2.Soft tissue perineuromas lack an associated nerve
3.The most commonly utilized immunohistochemical marker is epithelial membrane antigen (EMA).
1.Neuroimaging and electrodiagnostic features have not been described
1.Localized reactive Schwann cell proliferation (intraneural form)
2.Low-grade fibro myxoid sarcoma (soft tissue form)
1.A solitary painless nodule
2.Equal male to female incidence
3.Approximately 70% arise in the second to fifth decade
4.Wide distribution over the extremities and trunk.
1.Usually well circumscribed; features of Schwannoma and soft tissue perineurioma
2.Encapsulated and composed of spindle cells.
3.EMA and S100 are histological markers
1.Neuroimaging and electrodiagnostic features have not been well delineated.
1. Lipoma
2. Ganglioneuroma
3. Myoblastoma
4. Lymphangioma
5. Dermoid
1.Approximately 15% of neural sheath tumors are malignant
2.They are primarily neurogenic sarcoma and fibrosarcoma
3.Malignant transformation of benign neural sheath tumors:
a.Most common in von Recklinghausen’s disease
b.Late transformation (20-40 years) to sarcoma in patients who have been irradiated for breast cancer or Hodgkin disease
a.Larynx
b.Pancreas
c.Colon
d.Bladder
e.Testes
f.Thyroid
g.Esophagus
h.Lymphoma
i.Melanoma
j.Ewing’s sarcoma
1.Known malignant disease (rare for plexus involvement as a presentation).
2.A long latency from treatment of the primary tumor is not uncommon.
3.Pain in the arm and shoulder is often the first manifestation; weakness and sensory loss occur later
4.Associated extradural spread with cervical cord compression
5.Many breast cancer patients have received X-RT that involved the plexus prior to a metastatic disease presentation
6.Pancoast Syndrome:
a.Direct spread from the apex of the lung (superior sulcus or thoracic inlet tumor)
b.Usually, the syndrome is caused by a squamous cell carcinoma (rarely in the scar of a prior tuberculous infection) or an apical adenocarcinoma
c.Pain in the shoulder, scapula or 4th and 5th finger that is often burning in quality
d.Weakness wasting and sensory loss in the lower trunk distribution.
e.Horner Syndrome
7. Primary lymphoma:
a.Arising from the cervical or axillary lymph nodes may infiltrate the plexus.
1.Metastatic lesions may grow along the components of the plexus.
2.Symptomatology may derive from expression of inflammatory cytokines as well as direct invasion of the tumor
1.Demonstrates thickening of plexus components; often contrast enhancement is noted
2.18-FDG-SPECT:
a. May demonstrate primary and other metastatic sites; useful in following the course of treatment
3. Ultrasonography
1. Electrodiagnosis:
a. Dependent upon the components of the plexus that is affected
2. Dosimetric considerations that induce lesions:
a.Field size
b.Amount of tissue irradiated
c.Time period of the irradiation
d.Number of fractions delivered
e.Dose of each fraction
f.Total dosage
3. Latent period of 0 to 34 years may occur after x-ray treatment
1.Paresthesias in the C5-C6 spinal nerve, lateral cord, and median nerve distributions
2.Pain may develop late and is usually of moderate severity.
3.Weakness of intrinsic hand muscles
4.All parts of the plexus may be involved, but the supraclavicular components of the plexus usually have greater involvement than the infraclavicular
5.Edema of the extremity may develop
6.Most patients have a progressive course although some patients plateau.
7.Rare clinical manifestations:
a.Severe edema (possible compartment syndrome)
b.An acute onset ischemic process:
i.Injury to the subclavian artery
ii.Associated with painless weakness and sensory loss
iii.Segmental occlusion of the subclavian artery
b.Reversible Plexopathy:
i.Develops 2-14 months after X-RT
ii.Hand and forearm paresthesia; shoulder pain; mild hand weakness.
iii.Chemotherapy after X-RT may be causative or associated.
1.Extensive demyelination
2.Proliferative endarteritis of the vasa vasorum
3.Progressive fibrosis in the irradiated field
1.MRI with three Tesla magnet field strength which develops 3D isotropic sequences
2.Gadolinium enhancement is positive for tumor.
1. EMG:
a. Myokymic discharges in affected muscles
1.Tumor:
b.Severe burning pain and intrinsic hand muscle wasting
c.Horner’s Syndrome
d.MRI:
i.May demonstrate thickening or mass in these plexus components
ii.Enhances with gadolinium
a.Occurs primarily in the C5-C6 root or spinal nerve distribution
b.Greater paresthesias than pain and weakness
c.MRI:
i.Fibrosis of the plexus and surrounding tissue
ii.No enhancement with gadolinium
d. EMG:
i.Myokymic discharges