What is Operative? Conceptualizing Neuralgia: Neuroma, Compression Neuropathy, Painful Hyperalgesia, and Phantom Nerve Pain

Abstract

Neuralgia, or nerve pain, is a common presenting complaint for the hand surgeon. When the nerve at play is easily localized, and the cause of the pain is clear (eg, carpal tunnel syndrome), the patient may be easily treated with excellent results. However, in more complex cases, the underlying pathophysiology and cause of neuralgia can be more difficult to interpret; if incorrectly managed, this leads to frustration for both the patient and surgeon. Here we offer a way to conceptualize neuralgia into 4 categories—compression neuropathy, neuroma, painful hyperalgesia, and phantom nerve pain—and offer an illustrative clinical vignette and strategies for optimal management of each. Further, we delineate the reasons why compression neuropathy and neuroma are amenable to surgery, while painful hyperalgesia and phantom nerve pain are not. Neuralgia, or nerve pain, is a common presenting complaint for the hand surgeon. When the nerve at play is easily localized, and the cause of the pain is clear (eg, carpal tunnel syndrome), the patient may be easily treated with excellent results. However, in more complex cases, the underlying pathophysiology and cause of neuralgia can be more difficult to interpret; if incorrectly managed, this leads to frustration for both the patient and surgeon. Here we offer a way to conceptualize neuralgia into 4 categories—compression neuropathy, neuroma, painful hyperalgesia, and phantom nerve pain—and offer an illustrative clinical vignette and strategies for optimal management of each. Further, we delineate the reasons why compression neuropathy and neuroma are amenable to surgery, while painful hyperalgesia and phantom nerve pain are not. While research within the fields of surgery, pain management, and anesthesia has continued to further our understanding of neuralgia, there is still much to be understood about the mechanisms, diagnosis, and treatment of pain. The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”1Merskey H. Albe F. Bonica J.J. et al.Pain terms: a list with definitions and notes on usage. Recommended by the IASP subcommittee on taxonomy.Pain. 1979; 6: 249-252Abstract Full Text PDF PubMed Google Scholar By definition, pain is a subjective experience, and for this reason, the treatment of pain must be individualized based on the patient’s unique clinical context, experiences, and anatomy.2Heary KO, Wong AWK, Lau SCL, et al. Quality of life and psychosocial factors as predictors of pain relief following nerve surgery. Hand (N Y). Published online March 19, 2020.https://doi.org/10.1177/1558944720911213Google Scholar, 3Fillingim R.B. Individual differences in pain: understanding the mosaic that makes pain personal.Pain. 2017; 158: S11-S18Crossref PubMed Scopus (162) Google Scholar, 4Swieboda P. Filip R. Prystupa A. Drozd M. Assessment of pain: types, mechanism and treatment.Ann Agric Environ Med. 2013; 1: 2-7Google Scholar The physical and psychologic ramifications of neuralgia to our patients are substantial. Yet, our understanding of pain chronification and its mechanisms remain nascent. Increasingly, research findings indicate that the entire pathway connecting the brain to the periphery is relevant to nerve injury, regeneration, and neuralgia. This corresponds to the upper motor neuron, through the lower motor neuron, through the neuromuscular junction, to muscle; or, if sensory from the peripheral nerve, through the dorsal root ganglion, to the second-order sensory neurons. This new attention to the nerve pathway highlights the importance of Schwann cell senescence and of nonnerve cells in nerve regeneration.5Saheb-Al-Zamani M. Yan Y. Farber S.J. et al.Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence.Exp Neurol. 2013; 247: 165-177Crossref PubMed Scopus (122) Google Scholar,6Pan D. Mackinnon S.E. Wood M.D. Advances in the repair of segmental nerve injuries and trends in reconstruction.Muscle Nerve. 2020; 61: 726-739Crossref PubMed Scopus (34) Google Scholar Cattin et al’s7Cattin A.L. Burden J.J. Van Emmenis L. et al.Macrophage-induced blood vessels guide Schwann cell-mediated regeneration of peripheral nerves.Cell. 2015; 162: 1127-1139Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar key work highlights the mechanism whereby hypoxia triggers macrophage migration and blood vessel formation at nerve injury sites, which guide Schwann-led regeneration. Pain associated with compression neuropathy is reasonably well-understood, with research outlining a pathophysiologic process of ischemia, with ischemia leading to segmental demyelination, diffuse demyelination, and eventually axonal loss.8Bentley F.H. Schlapp W. The effects of pressure on conduction in peripheral nerve.J Physiol. 1943; 102: 72-82Crossref PubMed Scopus (47) Google Scholar,9Dang A.C. Rodner C.M. Unusual compression neuropathies of the forearm, part I: radial nerve.J Hand Surg Am. 2009; 34: 1906-1914Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar This progression corresponds to Sunderland degrees of injury I, II, and III, respectively (Table).10Peters BR, Pripotnev S, Chi D, Mackinnon SE. Complete foot drop with normal electrodiagnostic studies: Sunderland “zero” ischemic conduction block of the common peroneal nerve. Ann Plast Surg. Published online December 3, 2021. https://doi.org/10.1097/SAP.0000000000003053Google Scholar,11Mackinnon S.E. Dellon A.L. Surgery of the Peripheral Nerve. Thieme.1988Google Scholar More recently, we have focused on the preliminary ischemia in this pathway, and noted Sunderland degree 0, ischemic compression, that has normal electrodiagnostic studies and responds to release immediately with resolution of pain. Ischemia is potentially the cause of the majority of compressive pain.10Peters BR, Pripotnev S, Chi D, Mackinnon SE. Complete foot drop with normal electrodiagnostic studies: Sunderland “zero” ischemic conduction block of the common peroneal nerve. Ann Plast Surg. Published online December 3, 2021. https://doi.org/10.1097/SAP.0000000000003053Google Scholar However, injury to another area of the nerve and traction across the nerve can exacerbate damage via disruption of the axonal flow.12Mackinnon S.E. Double and multiple “crush” syndromes. Double and multiple entrapment neuropathies.Hand Clin. 1992; 8: 369-390Abstract Full Text PDF PubMed Google Scholar,13Szabo R.M. Gelberman R.H. The pathophysiology of nerve entrapment syndromes.J Hand Surg Am. 1987; 12: 880-884Abstract Full Text PDF PubMed Scopus (60) Google ScholarTableClassification of Nerve InjurySunderland DegreeMackinnon Classification ModificationsSeddon Classification0∗Recent Pripotnev and Mackinnon modification.10Ischemic conduction blockNeurapraxiaIDemyelination conduction blockNeurapraxiaIIAxonal injury and endoneurial scarring (mild/moderate)AxonotmesisIIIAxonal injury and endoneurial scarring (severe)AxonotmesisIVNerve transection in-continuity with scarNeurotmesisVNerve transectionNeurotmesisVI†Mackinnon modification.11Mixed injuryCopyright Susan Mackinnon (permission to print from Dr. Susan Mackinnon).∗ Recent Pripotnev and Mackinnon modification.10Peters BR, Pripotnev S, Chi D, Mackinnon SE. Complete foot drop with normal electrodiagnostic studies: Sunderland “zero” ischemic conduction block of the common peroneal nerve. Ann Plast Surg. Published online December 3, 2021. https://doi.org/10.1097/SAP.0000000000003053Google Scholar† Mackinnon modification.11Mackinnon S.E. Dellon A.L. Surgery of the Peripheral Nerve. Thieme.1988Google Scholar Open table in a new tab Copyright Susan Mackinnon (permission to print from Dr. Susan Mackinnon). Painful neuromas represent perhaps the best understood neuralgic phenomena.14Domeshek L.F. Krauss E.M. Snyder-Warwick A.K. et al.Surgical treatment of neuromas improves patient-reported pain, depression, and quality of life.Plast Reconstr Surg. 2017; 139: 407-418Crossref PubMed Scopus (46) Google Scholar, 15Meyer R.A. Raja S.N. Campbell J.N. Mackinnon S.E. Dellon A.L. Neural activity originating from a neuroma in the baboon.Brain Res. 1985; 325: 255-260Crossref PubMed Scopus (86) Google Scholar, 16Nath R.K. Mackinnon S.E. Management of neuromas in the hand.Hand Clin. 1996; 12: 745-756Abstract Full Text PDF PubMed Google Scholar, 17Sosin M. Weiner L.A. Robertson B.C. DeJesus R.A. Treatment of a recurrent neuroma within nerve allograft with autologous nerve reconstruction.Hand (N Y). 2016; 11: NP5-NP9Crossref PubMed Scopus (6) Google Scholar, 18Vernadakis A.J. Koch H. Mackinnon S.E. Management of neuromas.Clin Plast Surg. 2003; 30: 247-268Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar Studies led by Campbell et al15Meyer R.A. Raja S.N. Campbell J.N. Mackinnon S.E. Dellon A.L. Neural activity originating from a neuroma in the baboon.Brain Res. 1985; 325: 255-260Crossref PubMed Scopus (86) Google Scholar on neuroma pathophysiology showed ephaptic conduction within the neuroma that was mechanically sensitive but also spontaneously active; this pathophysiologic phenomenon resonates with the clinical narratives given by those with neuroma pain. An injury with Sunderland degree V—complete transection—is a typical neuroma, with degree IV representing a neuroma in continuity (with potential for a degree VI mixed injury in the nerve in this context).15Meyer R.A. Raja S.N. Campbell J.N. Mackinnon S.E. Dellon A.L. Neural activity originating from a neuroma in the baboon.Brain Res. 1985; 325: 255-260Crossref PubMed Scopus (86) Google Scholar Dorsi et al19Dorsi M.J. Chen L. Murinson B.B. Pogatzki-Zahn E.M. Meyer R.A. Belzberg A.J. The tibial neuroma transposition (TNT) model of neuroma pain and hyperalgesia.Pain. 2008; 134: 320-334Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar showed in animal models the possibility of differentiating between hyperalgesia from collateral sprouting of adjacent nerves and the pain from direct mechanical stimulation of a neuroma site.15Meyer R.A. Raja S.N. Campbell J.N. Mackinnon S.E. Dellon A.L. Neural activity originating from a neuroma in the baboon.Brain Res. 1985; 325: 255-260Crossref PubMed Scopus (86) Google Scholar This furthers our understanding of the pain associated with numbness compared to pain from direct stimulation of an injured nerve. Abdo et al’s20Abdo H. Calvo-Enrique L. Lopez J.M. et al.Specialized cutaneous Schwann cells initiate pain sensation.Science. 2019; 365: 695-699Crossref PubMed Scopus (104) Google Scholar recent work with Schwann cells and nociceptive Schwann cells that wrap free nerve endings contributes further to the concept of collateral sprouting nerves and their ability to generate neuralgia. This also potentially explains the mechanism by which the sensory collapse test is useful in examining patients with pain. However, pain from nerve injury is complex and not simply from compression neuropathy (injuries with Sunderland degrees 0, I, II, and III) or neuroma (injuries with Sunderland degrees IV, V, or VI; Table), but is also centrally maintained.3Fillingim R.B. Individual differences in pain: understanding the mosaic that makes pain personal.Pain. 2017; 158: S11-S18Crossref PubMed Scopus (162) Google Scholar,21Kaur A. Guan Y. Phantom limb pain: a literature review.Chin J Traumatol. 2018; 21: 366-368Crossref PubMed Scopus (23) Google Scholar, 22Kumar B. Kalita J. Kumar G. Misra U.K. Central poststroke pain: a review of pathophysiology and treatment.Anesth Analg. 2009; 108: 1645-1657Crossref PubMed Scopus (141) Google Scholar, 23Subedi B. Grossberg G.T. Phantom limb pain: mechanisms and treatment approaches.Pain Res Treat. 2011; 2011: 864605PubMed Google Scholar Extremes such as phantom limb pain or central poststroke pain highlight the importance and complexity of the central nervous system’s contribution to the experience and of A. Guan Y. Phantom limb pain: a literature review.Chin J Traumatol. 2018; 21: 366-368Crossref PubMed Scopus (23) Google Scholar, 22Kumar B. Kalita J. Kumar G. Misra U.K. Central poststroke pain: a review of pathophysiology and treatment.Anesth Analg. 2009; 108: 1645-1657Crossref PubMed Scopus (141) Google Scholar, 23Subedi B. Grossberg G.T. Phantom limb pain: mechanisms and treatment approaches.Pain Res Treat. 2011; 2011: 864605PubMed Google Scholar pain centrally poststroke or is the of the and potential for pain relief are Nerve to be of their in not neuromas but also compression must that hyperalgesia from collateral sprouting or phantom nerve pain or be treated neuralgia, or nerve pain, into 4 with nerve and treatment are amenable to and neuroma By hyperalgesia and phantom nerve to and not by Further, has the potential to pain and neuroma by the by and the of and by A. J.M. The Scholar we to of nerve pain 3, M. E.M. of nerve in Schwann cells PubMed Scopus Google Scholar pain is common and well-understood, with carpal tunnel and tunnel compression by By the entrapment in the are (eg, nerve compression in the M. W. Mackinnon S.E. nerve compression in the a clinical (N Y). 2019; PubMed Scopus Google Scholar compression neuropathy patients may a of pain, numbness and from and with or compression pain is much pain, such as neuroma pain. from compression pain may be on but are to be in to and their and be the compression be a compression that a compression not also or the nerve. to and for a patient may nerve compression at the and the S.E. Double and multiple “crush” syndromes. Double and multiple entrapment neuropathies.Hand Clin. 1992; 8: 369-390Abstract Full Text PDF PubMed Google Scholar compression neuropathy from compression neuropathy, an and with a more and of pain, or for carpal tunnel can also be associated with nerve compression and pain this be with to axonal to the of compression and with and an surgery, the patient has common peroneal nerve and pain in the in the peroneal nerve as the block the patient has resolution in and pain, and are for a potential The patient has peroneal nerve and pain and numbness in the The patient is for and the nerve is to be in continuity but with of in the the patient has resolution of pain and of motor This a of The patient may have of and the was from and across the and this as a Sunderland degree VI injury with degree or III) and also with an of ischemic or Sunderland degree injury, with from ischemia demyelination, the BR, Pripotnev S, Chi D, Mackinnon SE. Complete foot drop with normal electrodiagnostic studies: Sunderland “zero” ischemic conduction block of the common peroneal nerve. Ann Plast Surg. Published online December 3, 2021. https://doi.org/10.1097/SAP.0000000000003053Google Scholar pain is and by injury to the nerve neuroma formation and pain at the of the or mixed pain is in the of the nerve, with with a pain L.F. Krauss E.M. Snyder-Warwick A.K. et al.Surgical treatment of neuromas improves patient-reported pain, depression, and quality of life.Plast Reconstr Surg. 2017; 139: 407-418Crossref PubMed Scopus (46) Google Scholar, 15Meyer R.A. Raja S.N. Campbell J.N. Mackinnon S.E. Dellon A.L. Neural activity originating from a neuroma in the baboon.Brain Res. 1985; 325: 255-260Crossref PubMed Scopus (86) Google Scholar, 16Nath R.K. Mackinnon S.E. Management of neuromas in the hand.Hand Clin. 1996; 12: 745-756Abstract Full Text PDF PubMed Google Scholar, 17Sosin M. Weiner L.A. Robertson B.C. DeJesus R.A. Treatment of a recurrent neuroma within nerve allograft with autologous nerve reconstruction.Hand (N Y). 2016; 11: NP5-NP9Crossref PubMed Scopus (6) Google Scholar, 18Vernadakis A.J. Koch H. Mackinnon S.E. Management of neuromas.Clin Plast Surg. 2003; 30: 247-268Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar While have described to painful the optimal for management and treatment of neuroma patients M.J. et al.Surgical for the treatment of painful a 2018; PubMed Scopus Google Scholar carpal tunnel surgery, and diffuse numbness and but numbness in the radial of the and the of the This is by pain in the into the with hand and by to for a has at the of carpal tunnel into the and numbness in the This patient with a neuroma of the common nerve to the the injured nerve in carpal tunnel A.K. of and carpal tunnel Hand Surg Am. Full Text Full Text PDF PubMed Scopus Google Scholar The patient has a transection to the nerve more painful with across the be to the the carpal the as as to a new and into the in the with an acellular nerve allograft to recurrent neuroma formation if L.F. Krauss E.M. Snyder-Warwick A.K. et al.Surgical treatment of neuromas improves patient-reported pain, depression, and quality of life.Plast Reconstr Surg. 2017; 139: 407-418Crossref PubMed Scopus (46) Google R.K. Mackinnon S.E. Management of neuromas in the hand.Hand Clin. 1996; 12: 745-756Abstract Full Text PDF PubMed Google Scholar we for the and to the of the of the nerve to sensory and collateral sprouting of adjacent J.M. J. Mackinnon S.E. nerve to sensory in (N Y). 2020; PubMed Scopus Google Scholar This transposition is to this as the is a with tissue our in this is based in not by clinical D. L. et of cells within acellular nerve allografts is and for nerve Neurol. 2019; PubMed Scopus Google Scholar if a neuroma degree or neuroma in continuity degree IV is in an area there is tissue and not such a as the we and and an acellular nerve allograft in of L.F. Krauss E.M. Snyder-Warwick A.K. et al.Surgical treatment of neuromas improves patient-reported pain, depression, and quality of life.Plast Reconstr Surg. 2017; 139: 407-418Crossref PubMed Scopus (46) Google R.K. Mackinnon S.E. Management of neuromas in the hand.Hand Clin. 1996; 12: 745-756Abstract Full Text PDF PubMed Google Scholar The for sensory nerves to spontaneously into adjacent of and the of the sensory nerve in this has long J. sensory from collateral nerve PubMed Scopus Google Scholar normal nerves to to a cutaneous This process is by following a nerve This process is for and is collateral sprouting can cause hyperalgesia and pain, from regeneration from nerves into a area of an injured nerve neuralgia that can be hyperalgesia, and unpleasant or can This is by the or from or the The patient be to and or if the This pain is or for neuroma pain. this a neuroma is treated (eg, by transposition into in a of relief and numbness in the cutaneous by of recurrent pain in that a may be to for recurrent neuroma, which not a neuroma treatment has the recurrent pain in the is not a recurrent this painful hyperalgesia can be treatment of a of radial nerve neuroma the cutaneous cutaneous dorsal cutaneous nerves to into the in a the recurrent pain in the may be as a neuroma S.E. Dellon A.L. The of the cutaneous nerve and the of the radial nerve.J Hand Surg Am. 1985; Full Text PDF PubMed Scopus Google Scholar between neuroma and collateral sprouting may be by physical neuroma with pain into a nerve with at the injury into that sprouting pain be a unpleasant painful hyperalgesia with to the not by or at the of injury of the nerve that area at the of a treated However, there may be a at a compression of the adjacent sprouting nerve block can if a block at the of a neuroma not but the adjacent sprouting and cutaneous nerves the this a of collateral sprouting the of a to this collateral a is and collateral the the on and an and This is in nerve the area of numbness with collateral However, in nerve neuroma injury from an or the neuroma can be but pain can be by collateral sprouting of the adjacent peroneal nerve into the nerve This can the injured nerve that the cutaneous area is spontaneously or has the cutaneous neuromas with have of pain from this in collateral sprouting J.M. a to neuroma Res. PubMed Scopus Google Scholar Treatment of painful hyperalgesia from collateral sprouting nerves is not if this pain is as neuroma pain, not neuroma be but pain can also with neuroma The is if there is also compression on the sprouting in which we on the nerve that is this collateral sprouting pain has central in the of the peripheral treatment on motor and pain management as of pain and pain tunnel release by a cutaneous neuroma and with pain into the with of the is from both the and of the into with numbness and pain relief in the for the patient to with the of painful in the as surgery. The pain is unpleasant and and is with or the area or with treatment of the neuroma, this patient has collateral sprouting of adjacent sensory nerves into the painful This is not amenable to surgery. Treatment and pain management, but not on for a repair into the radial with a surgery, a the at the and pain in the that the with numbness in the radial an nerve injury was and treated However, to have pain in the radial and into the associated with unpleasant and that injury, the patient has a and the The patient has pain in the radial sensory the and has a sensory collapse and (with the in and at the entrapment the between the and in the radial A. Mackinnon S.E. in and the collapse Reconstr Surg. 2018; PubMed Scopus Google Scholar This patient has an injury that has with new in the The of painful hyperalgesia from a sprouting is with compression at a compression of the with for pain, pain management, and and focused on both the and A. with improves pain and quality of life for patients with compression of the sensory of the radial Reconstr Surg. Scholar the nerve for pain described by patients to the of numbness is and not phantom nerve pain for patients The painful area is the which as a way to have phantom limb pain in a limb patients with peripheral nerve injury can have phantom nerve pain in the that damage to the peripheral with spontaneously second-order this pain if not treated in a in and centrally pain in phantom limb H. Calvo-Enrique L. Lopez J.M. et al.Specialized cutaneous Schwann cells initiate pain sensation.Science. 2019; 365: 695-699Crossref PubMed Scopus (104) Google M. E.M. of nerve in Schwann cells PubMed Scopus Google R.A. in the pain 2019; 365: PubMed Scopus Google Scholar described as difficult to or pain, is with but is not by or can easily this pain if not understood or, to with neuroma surgery. This is not a peripheral nerve but a more central and is not by we optimal treatment with pain management pain and the a sprouting nerve with a entrapment is pain and can be via compression in sprouting and phantom nerve pain the of collateral sprouting with painful hyperalgesia or phantom nerve pain, there is potential for compression neuropathy of adjacent and this can pain in the of both collateral sprouting and phantom nerve pain. treated an carpal tunnel release by nerve transection with at a nerve has pain in the hand in the nerve with numbness in the radial and at the carpal tunnel not to hand and not to quality of life is to the for neuroma and with nerve surgery, has resolution of the and a the nerve. However, of painful numbness in the hand that and and the hand and the pain is not with but still pain in the nerve This patient has that has treated neuroma pain, but to the of injury has phantom nerve pain that be by surgery. the to the and Schwann cell the nerve not a nerve regeneration across the nerve and not its or the M. Yan Y. Farber S.J. et al.Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence.Exp Neurol. 2013; 247: 165-177Crossref PubMed Scopus (122) Google D. L. et of cells within acellular nerve allografts is and for nerve Neurol. 2019; PubMed Scopus Google Scholar with in pain pain patients may be by their as and this further the patient’s This optimal management of nerve pain. treatment of an pain at the of a at the that and the nerve in continuity but in the The nerve was and but pain surgery, and neuroma and the nerve was into from the a and another and neuroma more at the with transection and transposition into to surgery, neuroma with numbness in nerve that as has in the but an pain. are test findings in the sensory collapse and pressure nerve block for a for this This patient a mixed nerve injury at the neuroma The painful of we phantom nerve pain to neuroma is this our management be pain management, pain and management, with a for a dorsal offer a neuralgia into 4 compression neuropathy, neuroma, painful hyperalgesia, and phantom nerve pain. This can guide to on those that from more for nerve pain that be treated hyperalgesia from collateral sprouting or central and phantom nerve a painful neuroma multiple is not neuroma pain. An of painful hyperalgesia from collateral sprouting with in the or phantom nerve pain with painful numbness in the be and treated surgery. associated nerve entrapment be a pain and on the at in with a patient and physical to pain in the The and sensory collapse test can be as clinical to with H. Calvo-Enrique L. Lopez J.M. et al.Specialized cutaneous Schwann cells initiate pain sensation.Science. 2019; 365: 695-699Crossref PubMed Scopus (104) Google A. Mackinnon S.E. in and the collapse Reconstr Surg. 2018; PubMed Scopus Google R.A. in the pain 2019; 365: PubMed Scopus Google Scholar this we have to a to about neuralgia. we have not pain injury from nerve and neuralgia are the of this the underlying cause of neuralgia through a and physical with the to more patients relief from their

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