Painful neuroma pathophysiology review: double crush syndrome due to coexistent proximal neural lesion?
Autoři:
V. Mačionis
Působiště autorů:
Independent researcher, Vilnius, Lithuania
Vyšlo v časopise:
ACTA CHIRURGIAE PLASTICAE, 68, 1-2, 2026, pp. 26-33
doi:
https://doi.org/10.48095/ccachp202626
...
Zdroje
1. Oliveira KMC., Pindur L., Han Z., et al. Time course of traumatic neuroma development. PLoS One. 2018, 13 (7): e0200548.
2. Dahlin E., Gudinge H., Dahlin LB., et al. Neuromas cause severe residual problems at long-term despite surgery. Sci Rep. 2023, 13 (1): 15693.
3. Hwang CD., Hoftiezer YAJ., Raasveld FV., et al. Biology and pathophysiology of symptomatic neuromas. Pain. 2024, 165 (3): 550–564.
4. Krauss EM., Mackinnon SE. Definition, etiology, and epidemiology of symptomatic neuroma. In: Eberlin KR., Ducic I., Moore A., et al. (eds). Contemporary neuroma management. Springer International Publishing. 2024, 3–15.
5. Scott BB., Winograd JM. Peripheral sensitization: peripheral mechanisms of neuroma and neuropathic pain. In: Eberlin KR., Ducic I., Moore A., et al. (eds). Contemporary neuroma management. Springer International Publishing. 2024, 17–25.
6. Macionis V. Chronic pain and local pain in usually painless conditions including neuroma may be due to compressive proximal neural lesion. Front Pain Res (Lausanne). 2023, 4 : 1037376.
7. Bove GM., Dilley A. The conundrum of sensitization when recording from nociceptors. J Neurosci Methods. 2010, 188 (2): 213–218.
8. Satkeviciute I., Goodwin G., Bove GM., et al. Time course of ongoing activity during neuritis and following axonal transport disruption. J Neurophysiol. 2018, 119 (5): 1993–2000.
9. Bove GM., Ransil BJ., Lin HC., et al. Inflammation induces ectopic mechanical sensitivity in axons of nociceptors innervating deep tissues. J Neurophysiol. 2003, 90 (3): 1949–1955.
10. Deininger S., Schumacher J., Blechschmidt A., et al. Nerve injury converts Schwann cells in a long-term repair-like state in human neuroma tissue. Exp Neurol. 2024, 382 : 114981.
11. Burchiel KJ., Russell LC. Has the amount of spontaneous electrical activity in experimental neuromas been overestimated? Somatosens Res. 1987, 5 (1): 63–75.
12. Gorodetskaya N., Grossmann L., Constantin C., et al. Functional properties of cutaneous A - and C-fibers 1–15 months after a nerve lesion. J Neurophysiol. 2009, 102 (6): 3129–3141.
13. Meyer RA., Raja SN., Campbell JN., et al. Neural activity originating from a neuroma in the baboon. Brain Res. 1985, 325 (1–2): 255–260.
14. Ding YQ., Qi JG. Sensory root demyelination: transforming touch into pain. Glia. 2022, 70 (3): 397–413.
15. Dellon AL., Mackinnon SE. Chronic nerve compression model for the double crush hypothesis. Ann Plast Surg. 1991, 26 (3): 259–264.
16. Foltán R., Klíma K., Spacková J., et al. Mechanism of traumatic neuroma development. Med Hypotheses. 2008, 71 (4): 572–576.
17. Weigel DT., Raasveld FV., Liu WC., et al. Neuroma-to-nerve ratio: does size matter? Neurosurgery. 2025, 96 (3): 545–554.
18. Hayashi A., Pannucci C., Moradzadeh A., et al. Axotomy or compression is required for axonal sprouting following end-to-side neurorrhaphy. Exp Neurol. 2008, 211 (2): 539–550.
19. Hagg T. Collateral sprouting as a target for improved function after spinal cord injury. J Neurotrauma. 2006, 23 (3–4): 281–294.
20. Lemaitre D., Court FA. New insights on the molecular mechanisms of collateral sprouting after peripheral nerve injury. Neural Regen Res. 2021, 16 (9): 1760–1761.
21. Xu QG., Midha R., Martinez JA., et al. Facilitated sprouting in a peripheral nerve injury. Neuroscience. 2008, 152 (4): 877–887.
22. Wolvetang NHA., Lans J., Verhiel SHWL., et al. Surgery for symptomatic neuroma: anatomic distribution and predictors of secondary surgery. Plast Reconstr Surg. 2019, 143 (6): 1762–1771.
23. Pet MA., Ko JH., Friedly JL., et al. Traction neurectomy for treatment of painful residual limb neuroma in lower extremity amputees. J Orthop Trauma. 2015, 29 (9): e321–325.
24. Guse DM., Moran SL. Outcomes of the surgical treatment of peripheral neuromas of the hand and forearm: a 25-year comparative outcome study. Ann Plast Surg. 2013, 71 (6): 654–658.
25. Tupper JW., Booth DM. Treatment of painful neuromas of sensory nerves in the hand: a comparison of traditional and newer methods. J Hand Surg Am. 1976, 1 (2): 144–151.
26. Raasveld FV., Nieuwdorp NJ., Der Avoort DJJCV., et al. Long-term outcomes of symptomatic neuromas in the wrist, hand, and digits: a prospective cohort study. J Plast Reconstr Aesthet Surg. 2026, 116 : 34–45.
27. Langeveld M., Hundepool CA., Duraku LS., et al. Surgical treatment of peripheral nerve neuromas: a systematic review and meta-analysis. Plast Reconstr Surg. 2022, 150 (4): 823e–834e.
28. Gottlieb RW., Westenberg RF., Chen NC., et al. Long-term outcomes after surgical treatment of radial sensory nerve neuromas: patient-reported outcomes and rate of secondary surgery. Plast Reconstr Surg. 2021, 147 (1): 101–111.
29. Anantavorasakul N., Lans J., Macken AA., et al. Surgery for lower extremity symptomatic neuroma: long-term outcomes. J Plast Reconstr Aesthet Surg. 2020, 73 (8): 1456–1464.
30. Dahlin E., Zimmerman M., Nyman E. Patient reported symptoms and disabilities before and after neuroma surgery: a register-based study. Sci Rep. 2023, 13 (1): 17226.
31. Stokvis A., Coert JH., van Neck JW. Insufficient pain relief after surgical neuroma treatment: prognostic factors and central sensitisation. J Plast Reconstr Aesthet Surg. 2010, 63 (9): 1538–1543.
32. Cohen BH., Gaspar MP., Daniels AH., et al. Multifocal neuropathy: expanding the scope of double crush syndrome. J Hand Surg Am. 2016, 41 (12): 1171–1175.
33. Guerrero-Moreno A., Fakih D., Parsadaniantz SM., et al. How does chronic dry eye shape peripheral and central nociceptive systems? Neural Regen Res. 2021, 16 (2): 306–307.
34. Devor M., Tal M. Nerve resection for the treatment of chronic neuropathic pain. Pain. 2014, 155 (6): 1053–1054.
35. van Vliet E., Raasveld FV., Liu WC., et al. Evaluation of MRI features of neuromas in oncological amputees, and the relation to pain. Skeletal Radiol. 2025, 54 (5): 979–991.
36. Yoon SY., Oh J. Neuropathic cancer pain: prevalence, pathophysiology, and management. Korean J Intern Med. 2018, 33 (6): 1058–1069.
37. Chaker SC., Hung YC., Saad M., et al. Systematic review and meta-analysis of global neuroma incidence in upper extremity amputees. Ann Plast Surg. 2024, 92 (1): 80–85.
38. List EB., Krijgh DD., Martin E., et al. Prevalence of residual limb pain and symptomatic neuromas after lower extremity amputation: a systematic review and meta-analysis. Pain. 2021, 162 (7): 1906–1913.
39. Huang YJ., Assi PE., Drolet BC., et al. A systematic review and meta-analysis on the incidence of patients with lower-limb amputations who developed symptomatic neuromata in the residual limb. Ann Plast Surg. 2022, 88 (5): 574–580.
40. Tasmuth T., von Smitten K., Hietanen P., et al. Pain and other symptoms after different treatment modalities of breast cancer. Ann Oncol. 1995, 6 (5): 453–459.
41. Alves Nogueira Fabro E., Bergmann A., do Amaral E Silva B., et al. Post-mastectomy pain syndrome: incidence and risks. Breast. 2012, 21 (3): 321–325.
42. Broyles JM., Tuffaha SH., Williams EH., et al. Pain after breast surgery: etiology, diagnosis, and definitive management. Microsurgery. 2016, 36 (7): 535–538.
43. Kerr AJ., Dodwell D., McGale P., et al. Adjuvant and neoadjuvant breast cancer treatments: a systematic review of their effects on mortality. Cancer Treat Rev. 2022, 105 : 102375.
44. Dellon AL., Mackinnon SE. Susceptibility of the superficial sensory branch of the radial nerve to form painful neuromas. J Hand Surg Br. 1984, 9 (1): 42–45.
45. Dellon AL., Mackinnon SE. Radial sensory nerve entrapment in the forearm. J Hand Surg Am. 1986, 11 (2): 199–205.
46. Dobyns JH. Digital nerve compression. Hand Clin. 1992, 8 (2): 359–367.
47. Dunlop RLE., Wormald JCR., Jain A. Outcome of surgical repair of adult digital nerve injury: a systematic review. BMJ Open. 2019, 9 (3): e025443.
48. Ray WZ., Mackinnon SE. Nerve problems in the lower extremity. Foot Ankle Clin. 2011, 16 (2): 243–254.
49. Mackinnon SE. Evaluation and treatment of the painful neuroma. Tech Hand Up Extrem Surg. 1997, 1 (3): 195–212.
50. Ko JH., Kim PS., O’Shaughnessy KD., et al. A quantitative evaluation of gross versus histologic neuroma formation in a rabbit forelimb amputation model: potential implications for the operative treatment and study of neuromas. J Brachial Plex Peripher Nerve Inj. 2011, 6 : 8.
51. Remy K., Raasveld FV., Saqr H., et al. The neuroma map: a systematic review of the anatomic distribution, etiologies, and surgical treatment of painful traumatic neuromas. Surgery. 2024, 176 (4): 1239–1246.
52. Latinovic R., Gulliford MC., Hughes RAC. Incidence of common compressive neuropathies in primary care. J Neurol Neurosurg Psychiatry. 2006, 77 (2): 263–265.
53. Hulkkonen S., Lampainen K., Auvinen J., et al. Incidence and operations of median, ulnar and radial entrapment neuropathies in Finland: a nationwide register study. J Hand Surg Eur Vol. 2020, 45 (3): 226–230.
54. Mansfield M., Smith T., Spahr N., et al. Cervical spine radiculopathy epidemiology: a systematic review. Musculoskeletal Care. 2020, 18 (4): 555–567.
55. Fournier-Farley C., Boudier-Revéret M., Gagnon DH. Residual limb neuropathic pain association with neuroma, prosthetic, function, and participation outcomes in individuals living with a transtibial amputation: an exploratory study. J Rehabil Med. 2025, 57: jrm40551.
56. Mackinnon SE., Dellon AL., Hudson AR., et al. Alteration of neuroma formation by manipulation of its microenvironment. Plast Reconstr Surg. 1985, 76 (3): 345–353.
57. Vlot MA., Wilkens SC., Chen NC., et al. Symptomatic neuroma following initial amputation for traumatic digital amputation. J Hand Surg Am. 2018, 43 (1): 86.e1–86.e8.
58. Koch H., Haas F., Hubmer M., et al. Treatment of painful neuroma by resection and nerve stump transplantation into a vein. Ann Plast Surg. 2003, 51 (1): 45–50.
59. Lemaire-Petit A., Milaire A., Amar S., et al. Surgical treatment of painful neuroma in amputated and non-amputated patients: does the level of neurotomy affect clinical outcomes? Eur J Trauma Emerg Surg. 2024, 50 (4): 1799–1806.
60. Soroush M., Modirian E., Soroush M., et al. Neuroma in bilateral upper limb amputation. Orthopedics. 2008, 31 (12): orthosupersite.com/view.asp?rID=32929.
61. Poppler LH., Parikh RP., Bichanich MJ., et al. Surgical interventions for the treatment of painful neuroma: a comparative meta-analysis. Pain. 2018, 159 (2): 214–223.
62. Aguayo A., Nair CP., Midgley R. Experimental progressive compression neuropathy in the rabbit. Histologic and electrophysiologic studies. Arch Neurol. 1971, 24 (4): 358–364.
63. Mackinnon SE., Dellon AL., Hudson AR., et al. Chronic human nerve compression – a histological assessment. Neuropathol Appl Neurobiol. 1986, 12 (6): 547–565.
64. Gomes I., Becker J., Ehlers JA., et al. Prediction of the neurophysiological diagnosis of carpal tunnel syndrome from the demographic and clinical data. Clin Neurophysiol. 2006, 117 (5): 964–971.
65. Penna A., Konstantatos AH., Cranwell W., et al. Incidence and associations of painful neuroma in a contemporary cohort of lower-limb amputees. ANZ J Surg. 2018, 88 (5): 491–496.
66. Buch NS., Qerama E., Brix Finnerup N., et al. Neuromas and postamputation pain. Pain. 2020, 161 (1): 147–155.
67. Modirian E., Shojaei H., Soroush MR., et al. Phantom pain in bilateral upper limb amputation. Disabil Rehabil. 2009, 31 (22): 1878–1881.
68. Van der Avoort DJJC., Hovius SER., Selles RW., et al. The incidence of symptomatic neuroma in amputation and neurorrhaphy patients. J Plast Reconstr Aesthet Surg. 2013, 66 (10): 1330–1334.
69. Nigam M., Webb A., Harbour P., et al. Symptomatic neuromas in lower extremity amputees: implications for pre-emptive-targeted muscle reinnervation. Plast Reconstr Surg Glob Open. 2019, 7 (8 Suppl): 80–81.
70. Örücü Atar M., Demir Y., Kılınç Kamacı G., et al. Neuroma prevalence and neuroma-associated factors in patients with traumatic lower extremity amputation. GMJ. 2022, 64 (1): 54–59.
71. Holmes A., Williamson O., Hogg M., et al. Predictors of pain 12 months after serious injury. Pain Med. 2010, 11 (11): 1599–1611.
72. Lans J., Groot OQ., Hazewinkel MHJ., et al. Factors related to neuropathic pain following lower extremity amputation. Plast Reconstr Surg. 2022, 150 (2): 446–455.
73. Mackinnon SE., Novak CB. Clinical commentary: pathogenesis of cumulative trauma disorder. J Hand Surg Am. 1994, 19 (5): 873–883.
74. Levine NA., Rigby BR. Thoracic outlet syndrome: biomechanical and exercise considerations. Healthcare. 2018, 6 (2): 68.
75. Chung BM., Lee GY., Kim WT., et al. MRI features of symptomatic amputation neuromas. Eur Radiol. 2021, 31 (10): 7684–7695.
76. O’Reilly MAR., O’Reilly PMR., Sheahan JN., et al. Neuromas as the cause of pain in the residual limbs of amputees. An ultrasound study. Clin Radiol. 2016, 71 (10): 1068.e1–1068.e6.
77. Pardo LA., Thomas C., Schilling AF., et al. Preserved fascicular architecture predicts neuroma pain: a morphometric study. Acta Neuropathol Commun. 2025, 13 (1): 248.
78. Kretschmer T., Happel LT., England JD., et al. Accumulation of PN1 and PN3 sodium channels in painful human neuroma-evidence from immunocytochemistry. Acta Neurochir. 2002, 144 (8): 803–810.
79. Bird EV., Christmas CR., Loescher AR., et al. Correlation of Nav1.8 and Nav1.9 sodium channel expression with neuropathic pain in human subjects with lingual nerve neuromas. Mol Pain. 2013, 9 : 52.
80. Gold MS., Weinreich D., Kim CS., et al. Redistribution of Na (V) 1.8 in uninjured axons enables neuropathic pain. J Neurosci. 2003, 23 (1): 158–166.
81. Kretschmer T., Nguyen DH., Beuerman RW., et al. Painful neuromas: a potential role for a structural transmembrane protein, ankyrin G. J Neurosurg. 2002, 97 (6): 1424–1431.
82. Barry J., Gu Y., Jukkola P., et al. Ankyrin-G directly binds to kinesin-1 to transport voltage-gated Na+ channels into axons. Dev Cell. 2014, 28 (2): 117–131.
83. Atherton DD., Taherzadeh O., Facer P., et al. The potential role of nerve growth factor (NGF) in painful neuromas and the mechanism of pain relief by their relocation to muscle. J Hand Surg Br. 2006, 31 (6): 652–656.
84. Brain SD. Sensory neuropeptides: their role in inflammation and wound healing. Immunopharmacology. 1997, 37 (2–3): 133–152.
85. Reis C., Chambel S., Ferreira A., et al. Involvement of nerve growth factor (NGF) in chronic neuropathic pain – a systematic review. Rev Neurosci. 2023, 34 (1): 75–84.
86. Crowe R., Parkhouse N., McGrouther D., et al. Neuropeptide-containing nerves in painful hypertrophic human scar tissue. Br J Dermatol. 1994, 130 (4): 444–452.
87. Lebonvallet N., Laverdet B., Misery L., et al. New insights into the roles of myofibroblasts and innervation during skin healing and innovative therapies to improve scar innervation. Exp Dermatol. 2018, 27 (9): 950–958.
88. Hinz B., Celetta G., Tomasek JJ., et al. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell. 2001, 12 (9): 2730–2741.
89. Yan H., Gao W., Pan Z., et al. The expression of a-SMA in the painful traumatic neuroma: potential role in the pathobiology of neuropathic pain. J Neurotrauma. 2012, 29 (18): 2791–2797.
90. Weng W., Zhao B., Lin D., et al. Significance of alpha smooth muscle actin expression in traumatic painful neuromas: a pilot study in rats. Sci Rep. 2016, 6 : 23828.
91. Badalamente MA., Hurst LC., Ellstein J., et al. The pathobiology of human neuromas: an electron microscopic and biochemical study. J Hand Surg Br. 1985, 10 (1): 49–53.
92. Merkt W., Zhou Y., Han H., et al. Myofibroblast fate plasticity in tissue repair and fibrosis: deactivation, apoptosis, senescence and reprogramming. Wound Repair Regen. 2021, 29 (4): 678–691.
93. Fujiwara T., Kubo T., Kanazawa S., et al. Direct contact of fibroblasts with neuronal processes promotes differentiation to myofibroblasts and induces contraction of collagen matrix in vitro. Wound Repair Regen. 2013, 21 (4): 588–594.
94. Anand U., Otto WR., Sanchez-Herrera D., et al. Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons. Pain. 2008, 138 (3): 667–680.
95. Maccarrone M., Bab I., Bíró T., et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015, 36 (5): 277–296.
96. Atwood BK., Mackie K. CB2: a cannabinoid receptor with an identity crisis. Br J Pharmacol. 2010, 160 (3): 467–479.
97. Bie B., Wu J., Foss JF., et al. An overview of the cannabinoid type 2 receptor system and its therapeutic potential. Curr Opin Anaesthesiol. 2018, 31 (4): 407–414.
98. Wotherspoon G., Fox A., McIntyre P., et al. Peripheral nerve injury induces cannabinoid receptor 2 protein expression in rat sensory neurons. Neuroscience. 2005, 135 (1): 235–245.
99. Cravioto H., Battista A. Clinical and ultrastructural study of painful neuroma. Neurosurgery. 1981, 8 (2): 181–190.
100. Fried K., Govrin-Lippmann R., Rosenthal F., et al. Ultrastructure of afferent axon endings in a neuroma. J Neurocytol. 1991, 20 (8): 682–701.
101. Gupta R., Rowshan K., Chao T., et al. Chronic nerve compression induces local demyelination and remyelination in a rat model of carpal tunnel syndrome. Exp Neurol. 2004, 187 (2): 500–508.
102. Nath RK., Mackinnon SE. Management of neuromas in the hand. Hand Clin. 1996, 12 (4): 745–756.
103. Novak CB., Collins ED., Mackinnon SE. Outcome following conservative management of thoracic outlet syndrome. J Hand Surg Am. 1995, 20 (4): 542–548.
104. Fisher GT., Boswick JA. Neuroma formation following digital amputations. J Trauma. 1983, 23 (2): 136–142.
105. Luu D., Seto R., Deoraj K. Exercise rehabilitation for neurogenic thoracic outlet syndrome: a scoping review. J Can Chiropr Assoc. 2022, 66 (1): 43–60.
106. Mauch JT., Kao DS., Friedly JL., et al. Targeted muscle reinnervation and regenerative peripheral nerve interfaces for pain prophylaxis and treatment: a systematic review. PM R. 2023, 15 (11): 1457–1465.
107. Dumanian GA., Potter BK., Mioton LM., et al. Targeted muscle reinnervation treats neuroma and phantom pain in major limb amputees: a randomized clinical trial. Ann Surg. 2019, 270 (2): 238–246.
108. Hendler N. Why chronic pain patients are misdiagnosed 40 to 80% of the time? J Rec Adv Pain. 2016, 2 (3): 94–98.
Štítky
Chirurgie plastická Ortopedie Popáleninová medicína TraumatologieČlánek vyšel v časopise
Acta chirurgiae plasticae
2026 Číslo 1-2
- Potenciál vinpocetinu v léčbě kardiovaskulárních onemocnění
- Aktuální evropská doporučení pro léčbu renální koliky v důsledku urolitiázy
- Hybridní kooperující komplexy v léčbě osteoartrózy
-
Všechny články tohoto čísla
- Cutting-edge biotechnological strategies to enhance autologous fat graft survival
- A systematic review of sensory outcomes in nipple reinnervation after implant-based breast reconstruction
- Painful neuroma pathophysiology review: double crush syndrome due to coexistent proximal neural lesion?
- Principles of nasal framework reconstruction for complex nasal defects: review
- Transverse spinal cord lesion after embolization of a vascular lesion at the Th11 level: a case report of a severe complication of interventional treatment
- Reconstruction of traumatic nasal tip defect using a composite graft: a case report
- Editorial
- Cylindroma – an “untreatable” condition with a simple surgical solution: a case report
- Reconstructive challenges following Fournier’s gangrene: a case report
- Self-esteem and quality of sexual life in women undergoing breast reconstruction due to mastectomy: a cross-sectional study in a non-European setting
- The rationale for early diagnosis and management of benign soft tissue masses: a case report
- Labial adhesion in an adult – clinical manifestation and treatment: a case report
- Unseen and overlooked: barriers to oncologic and reconstructive breast surgery for homeless women in the Czech Republic
- Antegrade posterior interosseous artery flap for coverage of full-thickness elbow defects when radial forearm flap is not feasible
- Patient-controlled analgesia in burn care in the Czech Republic and Slovakia
- Acta chirurgiae plasticae
- Archiv čísel
- Aktuální číslo
- Informace o časopisu
Nejčtenější v tomto čísle
- A systematic review of sensory outcomes in nipple reinnervation after implant-based breast reconstruction
- Principles of nasal framework reconstruction for complex nasal defects: review
- Self-esteem and quality of sexual life in women undergoing breast reconstruction due to mastectomy: a cross-sectional study in a non-European setting
- Cutting-edge biotechnological strategies to enhance autologous fat graft survival