The Pathology of Neuropathic Pain
Originally Published in The Transverse Myelitis Association Newsletter
Volume 4 Issue 2
Anne Louise Oaklander, MD, PhD
Massachusetts General Hospital, Boston, Massachusetts
Mary Gabb, MS
Senior Clinical Editor, Champaign, Illinois
Correspondence: Anne Louise Oaklander, MD, PhD, Assistant Professor of Anesthesiology and Neurology, Assistant in Neuropathology, Massachusetts General Hospital, 55 Fruit Street, Clinic 3, Boston, MA 02114.
This article summarizes the clinical presentation and the available information on the neuropathophysiology of neuropathic pain. A review of the somatosensory nervous system anatomy involved in neuropathic pain is also included. The focus is on the peripheral nervous system (PNS) because its mechanisms of pain are better defined than in the central nervous system (CNS). Also, the vast majority of neural damage occurs in the PNS, most likely due to its increased exposure to traumatic injury compared with the CNS. Clinicians who recognize some of the cardinal signs of the most common neuropathies can diagnose and treat their patients earlier, reducing the burden of neuropathic pain. Advances in our understanding of the neural mechanisms of chronic pain will hopefully help to define therapeutic strategies in the future.
Copyright 2001 Galen Publishing, LLC. First published in the September 2001 issue of Advanced Studies in Medicine, New Developments in the Management of Migraine and Neuropathic Pain (Volume 1, Number 6: 237 – 240), www.ASIMCME.com.
There are 2 types of chronic pain: inflammatory nociceptive pain, which is pain associated with tissue damage, and neuropathic pain, which arises from damage to the nerves that carry pain signals from tissue, not damage to the tissue itself. Neuropathic pain is a classic, localizing, neurological sign. It signals damage to the nociceptive neurons that transmit pain signals, just as weakness signals damage to the motor pathways. However, for reasons as yet unknown, neuropathic pain will develop in only a subgroup of patients who have a neurologic lesion. It is important to note that any type of a lesion (e.g., infectious, neoplastic, or vascular) can produce pain if it affects the pain pathways.
Lesions residing anywhere within the central nervous system (CNS) or the peripheral nervous system (PNS) can produce neuropathic pain, and they are highly subject to several modifiers: genetic, environmental, and behavioral.1,2 Genetic differences have been observed in inbred strains of rats, showing that after surgery on peripheral nerves, some strains of rats exhibit striking pain-related behavior, whereas others are seemingly unperturbed by the same procedure.3 Genetic modifiers may help to explain the incomplete expression of neuropathic pain in patients with lesions.
The most common type of neuropathic pain syndromes are the sensory polyneuropathies, the mono-neuropathies, and the central pain syndromes.
Clinical Characteristics of Neuropathic Pain
The most striking sign of neuropathic pain (as opposed to nociceptive pain) is the relative lack of tissue pathology. Most patients do not have obvious tissue injury (although they may have had previous injury) yet complain of pain, and their complaints often seem to be out of proportion to the pain that would be expected to accompany the original injury.
The cardinal features of neuropathic pain include constant pain, which can be superficial or deep, sharp or aching, lancinating pain (i.e., sudden and sharp, severe bursts of pain), and allodynia (i.e., pain experienced after normally nonpainful stimuli, such as light touch). Patients with allodynia can have difficulty wearing clothing. Neurologists often look for motor deficits in neurological disorders, yet many neuropathic pain patients do not have motor damage. If motor deficits are present, they can be helpful in localizing the area of nerve damage, because the technologies available for localizing motor deficits (e.g., electromyography) are better developed than current methods for localizing sensory deficits.
Many polyneuropathies are mixed (i.e., sensory and motor nerves are affected), although some patients can have pure sensory neuropathy and some can have mixed autonomic neuropathy. If the patient complains of pain, it indicates that the neuropathy is affecting their small nociceptive fibers. Some sensory neuropathies affect predominantly the large sensory fibers, producing a pattern of sensory ataxia and loss of proprioception, whereas neuropathies that affect the small fibers produce pain.
Diagnosing Peripheral Neuropathies
Traditional tools such as electromyography and nerve conduction studies are useful primarily if the neuropathy affects the motor fibers or the large sensory fibers. Nerve conduction studies reflect conduction in the large myelinated axons; they do not reflect activity in the small myelinated fibers and unmyelinated C and A-d fibers. Thus, normal nerve conduction study results do not preclude a diagnosis of neuropathy.
Quantitative sensory testing is a helpful adjunct but is not universally available. It involves the application of controlled mechanical, thermal, or chemical stimuli. Patients report their perception of the stimulus and indicate the point at which it becomes painful, which allows an evaluation of the patient’s sensory threshold for various types of stimuli.
Sural nerve biopsy is a technique that is used less frequently because of the resulting scarring, as well as risk for infection, sensory deficits, and, ironically, neuropathic pain syndromes in some patients.4 Skin biopsies are beginning to replace sural nerve biopsies for the diagnosis of peripheral sensory disease in many patients. Skin biopsies require a small sample of the epidermis be taken, using local anesthetic, from anywhere on the body. Skin biopsies can be repeated, which is useful for monitoring response to therapy or disease progression. The biopsy sample is immunolabeled with an antibody against PGP9.5, a panaxonal marker so the small sensory nerve endings in the skin can be seen and counted using a light microscope. Skin biopsies allow quantitative measurement of the sensory nerve endings in the epidermis because they exist as individual nerve endings that can be counted. Measurement of the sensory nerves that end in the dermis (i.e., the large, myelinated Ab fibers that encode touch) cannot be as precise because dermal axons tend to cluster in bundles.5
Normative data are available to show the normal density of cutaneous nerve endings and provide a point of comparison for the test patient.6 However, like sural nerve biopsies, clinical diagnostic skin biopsies are only offered at specialized center such as Johns Hopkins University and the Massachusetts General Hospital.
These epidermal neurites are almost all nociceptors. Many other types of sensory receptors are located in the dermis, so they are not included in epidermal nerve density counts. Skin biopsies therefore are especially useful for patients with disorders of pain neurons. For example, a recent study by Oaklander et. al. showed that there are fewer remaining nerve endings in the skin of patients with posttherpetic neuralgia PHN than in patients without PHN after shingles (dermal innervation is also reduced in PHN after shingles.)7 In fact, all skin biopsy studies of neuropathic pain patients show that epidermal innervation is reduced in neuropathic pain syndromes.8-10 Oaklander recently showed that a minimum innervation level of approximately 650 neurites/mm2 may be necessary to avoid the presence of pain after shingles. Below this threshold, the minimum number of primary nociceptive neurons is not preserved and the result is PHN.11
Pathophysiology of Mononeuropathies
Nerve roots are vulnerable to compression (e.g., compressive radiculopathy, infections, and tumors). If the lesion is proximal to the dorsal root ganglion, there may be abnormality of the central axons but not necessarily of the peripheral axons. Therefore, tests aimed at the peripheral axons will not detect the injury in those situations. Likewise, complete degeneration of the axon is not necessary to produce clinical symptoms: lesions may be in the form of perinodal retraction of myelin or frank demyelination. Demyelination with ephaptic spread of action potentials between adjacent axons is believed to underlie bursts of lancinating pain because the action potentials transmitted along a few fibers can inappropriately spread to many other axons.
Neuropathic pain can also result from the post-injury remodeling of cell membranes of sensory neurons. The remodeled membrane develops new properties that generate action potentials in places where action potentials are not normally generated. Transmission may also be abnormal. When mechanical transducers are present in axonal sprouts located along damaged nerve, a simple tap can produce pain.
Surgery is another cause of painful mononeuropathies. A recent review of surgery- and trauma-induced chronic pain suggests that trauma and surgery should not be considered together as a single categorical cause of chronic pain. Accidental trauma pain patients are more likely to be younger and male than patients with iatrogenic nerve injury. In one study of chronic pain patients, surgery was a cause of pain in up to one fourth of the study population.12
Complex Regional Pain Syndrome
Complex regional pain syndrome (CRPS) is one of the most severe and mysterious neuropathic pain syndromes. CRPS patients are typically in their 30s or 40s, but can be younger. A common cause of nerve injury in CRPS is trauma incurred on the job, or in sports and recreation, which explains the relatively young ages of patients. Interestingly, about 5% to 10% of CRPS patients report no history of trauma. It is important to recognize that there may have been some sort of internal trauma that was not recognized.
The clinical symptoms of CRPS always include pain, hyperalgesia, and allodynia. If there is also motor axon damage, then there may be dystonia, weakness, or atrophy. One common presentation is the patient wearing a single glove over the painful hand to protect it from painful contact, and perhaps to receive some relief from the ongoing soft, mechanical stimulation provided by the glove.
The International Association for the Study of Pain (IASP) classifies CRPS as either CRPS I (pain with no known nerve injury) or CRPS II (pain with known nerve injury).13,14 They are otherwise clinically identical. It is likely that in CRPS II, at least in most cases, patients actually do have an injury that has not yet been detected.
Extraterritorial pain is often seen in CRPSÑ expanding either outside of the area of injury (often proximally), or to the whole limb. Mirror pain, or pain in the other limb or the area immediately opposite the original injury, is also common. It is prudent to refer patients with CRPS to a center experienced in the diagnosis of nerve injury for advanced evaluation.
Lesions Affecting the Neurosensory Ganglion
The sensory ganglia are damaged less frequently than the peripheral nerves because they are fairly well protected by the vertebrae. However, they are vulnerable to bony compression. Several paraneoplastic syndromes and other autoimmune problems (e.g., Sjogren’s syndrome) can attack these ganglia.15
By far, the most common sensory ganglia problem is herpes zoster or shingles, which currently affects 15% of Americans.16 These lesions affect the sensory ganglia themselves: the trigeminal ganglion innervating the face or the dorsal root ganglia innervating the body. Acute shingles can appear on the body or the face. The most important concern with herpes zoster infection is PHN, which occurs in roughly 10% of shingles cases.17 PHN can last long after the shingles has resolved, and in some patients is a lifelong disorder. The risk for PHN is directly proportional to age.18
Shingles causes sensory ganglion cell bodies and their to axons die.19,20 In some patients, these reductions in nerve endings are bilateral and segmental.7,21
CNS-induced neuropathic pain is less common than PNS-induced neuropathic pain. Clinical conditions that affect the lateral spinothalamic tracts are far more likely to produce pain than conditions affecting the dorsal column and medial lemnisci. Not uncommon in clinical practice are syrinxes (abnormal cavities in the spinal cord), which affect sensory fibers as they decussate. When syrinxes enlarge, patients can present with a severe segmental pain syndrome in the absence of motor findings because the motor axons remain laterally located in the spinal cord.
In the CNS, there is no one disease that causes neuropathic pain; it can occur with stroke or multiple sclerosis, or any disease state in which a lesion affects the ascending pain pathways.22-24 Spinal cord injury can combine injuries to both the PNS and CNS.
Functional magnetic resonance imaging (fMRI) has recently shown the presence of widespread cortical plasticity, some of which may account for extraterritorial pain or the spread of pain. Vacant synapses from dying neurons are often filled by neurons in adjacent areas. This plasticity may explain why a patient with phantom pain in an amputated hand can trigger that pain by touching lightly near the corner of his or her mouth. In the cortex homunculus, the mouth region is located adjacent to the hand, so fibers may have sprouted from the mouth area into the hand area.
Neuropathic pain signals damage to nociceptive neurons just as weakness indicates damage to motor nerves. Unfortunately, localization of lesions in nociceptive pathways is not always straightforward. However, understanding the neurophysiology of neuropathic pain can help the physician diagnose and determine the best treatment. In the future, we hope to have better markers or laboratory tests to confirm sensory neural injury.
- Mogil JS, Grisel JE. Transgenic studies of pain. Pain. 1998;77(2):107-28.
- Shir Y, Ratner A, Seltzer Z. Diet can modify autonomy behavior in rats following peripheral neurectomy. Neurosci Lett. 1997;236(2):71-74.
- Mogil JS, Wilson SG, Bon K, et al. Heritability of nonciception I: responses of 11 inbred mouse strains on 12 measures of nociception. Pain. 1999;80(1-2):67-82.
- Gabriel CM, Howard R, Kinsella N, et al. Prospective study of the usefulness of sural nerve biopsy. J Neurol Neurosurg Psychiatry. 2000;69(4):442-446.
- Kruger L, Perl ER, Sedivec MJ. Fine structure of myelinated mechanical nociceptor endings in cat hairy skin. J Comp Neurol. 1981;198(1):137-154.
- McArthur JC, Stocks EA, Hauer P, Cornblath DR, Griffin JW. Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol. 1998;55 (12):1513-1520.
- Oaklander AL, Romans K, Horasek S, Stocks A, Hauer P, Meyer RA. Unilateral postherpetic neuralgia is associated with bilateral sensory neuron damage. Ann Neurol. 1998;44(5):789-795.
- Holland NR, Stocks A, Hauer P, Cornblath DR, Griffin JW, McArthur JC. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology. 1997;48 (3):708-711.
- Periquet MI, Novak V, Collins MP, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 1999;53(8):1641-1647.
- Scott LJ, Griffin JW, Luciano C, et al. Quantitative analysis of epidermal innervation in Fabry disease. Neurology 1999;52(6):1249-1254.
- Oaklander AL. The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles. Pain. 2001;92(1-2):139-145.
- Crombie IK, Davies HT, Macrae WA. Cut and thrust: antecedent surgery and trauma among patients attending a chronic pain clinic. Pain. 1998;76(1-2):167-171.
- Stanton-Hicks M, Janig W, Hassenbusch S, Haddox JD, Boas R, Wilson P. Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain. 1995;63(1):127-133.
- International Association for the Study of Pain Web site. IASP pain terminology. Available at: http://www.halcyon. com/iasp/terms-p.html. Accessed July 13, 2001.
- Griffin JW, Cornblath DR, Alexander E, et al. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjogren’s syndrome. Ann Neurol. 1990;27(3):304-315.
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- Watson CP, Deck JH, Morshead C, Van der Kooy D, Evans RJ. Post-herpetic neuralgia: further post-mortem studies of cases with and without pain. Pain. 1991;44(2):105-117.
- Watson CP, Midha R, Devor M, Nag S, Munro C, Dostrovsky JO. Trigeminal postherpetic neuralgia postmortem: clinically unilateral, pathologically bilateral. In: Proceedings of the 9th World Congress on Pain. Devor M, Rowtham MC, Weisenfeld-Hallin Z, eds. IASP Press: Seattle, WA; 2000:733-739.
- Moulin DE, Foley KM, Ebers GC. Pain syndromes in multiple sclerosis. Neurology. 1988;38(12):1830-1834.
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- Andersen G, Vestergaard K, Ingeman-Nielsen M, Jensen TS. Incidence of central post-stroke pain. Pain. 1995;61 (2):187-193.