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  • Review Article
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Clinical and pathophysiological concepts of neuralgic amyotrophy

Nature Reviews Neurology volume 7, pages 315–322 (2011)Cite this article

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Abstract

Neuralgic amyotrophy—also known as Parsonage–Turner syndrome or brachial plexus neuritis—is a distinct and painful peripheral neuropathy that causes episodes of multifocal paresis and sensory loss in a brachial plexus distribution with concomitant involvement of other PNS structures (such as the lumbosacral plexus or phrenic nerve) in a large number of patients. The phenotype can be limited or extensive and the amount of disability experienced also varies between patients, but many are left with residual disabilities that affect their ability to work and their everyday life. Both idiopathic and hereditary forms exist. The latter form is genetically heterogeneous, but in 55% of affected families, neuralgic amyotrophy is associated with a point mutation or duplication in the SEPT9 gene on chromosome 17q25. The disease is thought to result from an underlying genetic predisposition, a susceptibility to mechanical injury of the brachial plexus (possibly representing disturbance of the epineurial blood–nerve barrier), and an immune or autoimmune trigger for the attacks. The precise pathophysiological mechanisms are still unclear; treatment is empirical, and preventive measures are not yet available. This Review provides an overview of the current clinical and pathophysiological concepts and research topics in neuralgic amyotrophy.

Key Points

  • Neuralgic amyotrophy is an under-recognized but distinctive disorder with prominent features of acute severe pain followed by patchy paresis, atrophy and sensory symptoms that persist for months to years

  • The phenotype is broad and encompasses a spectrum from isolated neuropathies to widespread involvement of both brachial and lumbosacral plexuses with phrenic and other peripheral nerve involvement

  • Neuralgic amyotrophy has a complex and incompletely understood pathophysiology, in which immunologically triggered attacks are thought to affect mechanically vulnerable PNS structures in genetically predisposed individuals

  • Recovery is often incomplete and residual symptoms are common, but no effective pharmacological or rehabilatitive therapy is currently available

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Figure 1: Dorsal views of patients with neuralgic amyotrophy.
Figure 2: A schematic overview of classic neuralgic amyotrophy and its phenotypic variations.

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References

  1. van Alfen, N. & van Engelen, B. G. The clinical spectrum of neuralgic amyotrophy in 246 cases. Brain 129, 438–450 (2006).

    Article  Google Scholar 

  2. Byrne, E. Extended neuralgic amyotrophy syndrome. Aust. N. Z. J. Med. 17, 34–38 (1987).

    Article  CAS  Google Scholar 

  3. England, J. D. The variations of neuralgic amyotrophy. Muscle Nerve 22, 435–436 (1999).

    Article  CAS  Google Scholar 

  4. van Alfen, N. The neuralgic amyotrophy consultation. J. Neurol. 254, 695–704 (2007).

    Article  Google Scholar 

  5. Beghi, E., Kurland, L. T., Mulder, D. W. & Nicolosi, A. Brachial plexus neuropathy in the population of Rochester, Minnesota, 1970–1981. Ann. Neurol. 18, 320–323 (1985).

    Article  CAS  Google Scholar 

  6. MacDonald, B. K., Cockerell, O. C., Sander, J. W. & Shorvon, S. D. The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain 123, 665–676 (2000).

    Article  Google Scholar 

  7. Cruz-Martinez, A., Barrio, M. & Arpa, J. Neuralgic amyotrophy: variable expression in 40 patients. J. Peripher. Nerv. Syst. 7, 198–204 (2002).

    Article  CAS  Google Scholar 

  8. Tonali, P., Uncini, A. & Di Pasqua, P. G. So-called neuralgic amyotrophy: clinical features and long term follow-up. Ital. J. Neurol. Sci. 4, 431–437 (1983).

    Article  CAS  Google Scholar 

  9. Tsairis, P., Dyck, P. J. & Mulder, D. W. Natural history of brachial plexus neuropathy. Report on 99 patients. Arch. Neurol. 27, 109–117 (1972).

    Article  CAS  Google Scholar 

  10. van Alfen, N., van Engelen, B. G, Reinders, J. W., Kremer, H. & Gabreëls, F. J. The natural history of hereditary neuralgic amyotrophy in the Dutch population: two distinct types? Brain 123, 718–723 (2000).

    Article  Google Scholar 

  11. Geertzen, J. H., Groothoff, J. W., Nicolai, J. P. & Rietman, J. S. Brachial plexus neuropathy. A long-term outcome study. J. Hand. Surg. Br. 25, 461–464 (2000).

    CAS  PubMed  Google Scholar 

  12. van Alfen, N., van Engelen, B. G. & Hughes, R. A. Treatment for idiopathic and hereditary neuralgic amyotrophy (brachial neuritis). Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD006976. doi:10.1002/14651858.CD006976.pub2 (2009).

  13. van Alfen, N., van der Werf, S. P. & van Engelen, B. G. Long-term pain, fatigue and impairment in neuralgic amyotrophy. Arch. Phys. Med. Rehab. 90, 435–439 (2009).

    Article  Google Scholar 

  14. Kuhlenbäumer, G. et al. Hereditary neuralgic amyotrophy (HNA) is genetically heterogeneous. J. Neurol. 248, 861–865 (2001).

    Article  Google Scholar 

  15. Collie, A. M. et al. Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy. J. Med. Genet. 47, 601–607 (2010).

    Article  CAS  Google Scholar 

  16. Chance, P. F. et al. Hereditary neuralgic amyotrophy and hereditary neuropathy with liability to pressure palsies: two distinct genetic disorders. Neurology 44, 2253–2257 (1994).

    Article  CAS  Google Scholar 

  17. Gouider, R. et al. Hereditary neuralgic amyotrophy and hereditary neuropathy with liability to pressure palsies: two distinct clinical, electrophysiologic, and genetic entities. Neurology 44, 2250–2252 (1994).

    Article  CAS  Google Scholar 

  18. van Alfen, N. The trouble with neuralgic amyotrophy. Pract. Neurol. 6, 298–307 (2006).

    Article  Google Scholar 

  19. Jensen, M. P., Abresch, R. T., Carter, G. T. & McDonald, C. M. Chronic pain in persons with neuromuscular disease. Arch. Phys. Med. Rehabil. 86, 1155–1163 (2005).

    Article  Google Scholar 

  20. Vanneste, J. A., Bronner, I. M., Laman, D. M. & van Duijn, H. Distal neuralgic amyotrophy. J. Neurol. 246, 399–402 (1999).

    Article  CAS  Google Scholar 

  21. Seror, P. Isolated sensory manifestations in neuralgic amyotrophy: report of eight cases. Muscle Nerve 29, 134–138 (2004).

    Article  CAS  Google Scholar 

  22. van de Ven, A. C., van Alfen, N. & Heijdra, Y. F. An unusual cause of acute dyspnoea: neuralgic amyotrophy [Dutch]. Ned. Tijdschr. Geneeskd. 153, A181 (2009).

    PubMed  Google Scholar 

  23. Lahrmann, H., Grisold, W., Authier, F. J. & Zifko, U. A. Neuralgic amyotrophy with phrenic nerve involvement. Muscle Nerve 22, 437–442 (1999).

    Article  CAS  Google Scholar 

  24. Kumar, N., Folger, W. N. & Bolton, C. F. Dyspnea as the predominant manifestation of bilateral phrenic neuropathy. Mayo Clin. Proc. 79, 1563–1565 (2004).

    Article  Google Scholar 

  25. Tsao, B. E., Ostrovskiy, D. A., Wilbourn, A. J. & Shields R. W. Jr. Phrenic neuropathy due to neuralgic amyotrophy. Neurology 23, 1582–1584 (2006).

    Article  Google Scholar 

  26. Hughes, P. D., Polkey, M. I., Moxham, J. & Green, M. Long-term recovery of diaphragm strength in neuralgic amyotrophy. Eur. Respir. J. 13, 379–384 (1999).

    Article  CAS  Google Scholar 

  27. Hüttl, T. P. et al. Laparoscopic diaphragmatic plication: long-term results of a novel surgical technique for postoperative phrenic nerve palsy. Surg. Endosc. 18, 547–551 (2004).

    Article  Google Scholar 

  28. van Alfen, N. & van Engelen, B. G. Lumbosacral plexus neuropathy: a case report and review of the literature. Clin. Neurol. Neurosurg. 99, 138–141 (1997).

    Article  CAS  Google Scholar 

  29. Dyck, P. J. & Windebank, A. J. Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment. Muscle Nerve 25, 477–491 (2002).

    Article  Google Scholar 

  30. Martin, R. M. & Fish, D. E. Scapular winging: anatomical review, diagnosis, and treatments. Curr. Rev. Musculoskelet. Med. 1, 1–11 (2008).

    Article  Google Scholar 

  31. Friedenberg, S. M., Zimprich, T. & Harper, C. M. The natural history of long thoracic and spinal accessory neuropathies. Muscle Nerve 25, 535–539 (2002).

    Article  Google Scholar 

  32. Schollen, W., Degreef, I. & De Smet, L. Kiloh–Nevin syndrome: a compression neuropathy or brachial plexus neuritis? Acta Orthop. Belg. 73, 315–318 (2007).

    PubMed  Google Scholar 

  33. Stern, M. B. The anterior interosseous nerve syndrome (the Kiloh–Nevin syndrome). Report and follow-up study of three cases. Clin. Orthop. Relat. Res. 187, 223–227 (1984).

    Google Scholar 

  34. Wertsch, J. J. AAEM case report #25: anterior interosseous nerve syndrome. Muscle Nerve 15, 977–983 (1992).

    Article  CAS  Google Scholar 

  35. Dang, A. C. & Rodner, C. M. Unusual compression neuropathies of the forearm, part I: radial nerve. J. Hand Surg. Am. 34, 1906–1914 (2009).

    Article  Google Scholar 

  36. Rosenbaum, R. Disputed radial tunnel syndrome. Muscle Nerve 22, 960–967 (1999).

    Article  CAS  Google Scholar 

  37. Jeannet, P. Y., Watts, G. D., Bird, T. D. & Chance, P. F. Craniofacial and cutaneous findings expand the phenotype of hereditary neuralgic amyotrophy. Neurology 57, 1963–1968 (2001).

    Article  CAS  Google Scholar 

  38. Laccone, F. et al. Dysmorphic syndrome of hereditary neuralgic amyotrophy associated with a SEPT9 gene mutation—a family study. Clin. Genet. 74, 279–283 (2008).

    Article  CAS  Google Scholar 

  39. van Alfen, N., Huisman, W. J., Overeem, S., van Engelen, B. G. & Zwarts, M. J. Sensory nerve conduction studies in neuralgic amyotrophy. Am. J. Phys. Med. Rehab. 88, 941–946 (2009).

    Article  Google Scholar 

  40. Hoque, R., Schwendimann, R. N., Kelley, R. E., Bien-Willner, R. & Sivakumar, K. Painful brachial plexopathies in SEPT9 mutations: adverse outcome related to comorbid states. J. Clin. Neuromuscul. Dis. 9, 379–384 (2008).

    Article  Google Scholar 

  41. Klein, C. J. et al. SEPT9 mutations and a conserved 17q25 sequence in sporadic and hereditary brachial plexus neuropathy. Arch. Neurol. 66, 238–243 (2009).

    PubMed  PubMed Central  Google Scholar 

  42. Pellegrino, J. E., Rebbeck, T. R., Brown, M. J., Bird, T. D. & Chance, P. F. Mapping of hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) to distal chromosome 17q. Neurology 46, 1128–1132 (1996).

    Article  CAS  Google Scholar 

  43. Pellegrino, J. E. et al. Hereditary neuralgic amyotrophy: evidence for genetic homogeneity and mapping to chromosome 17q25. Hum. Genet. 101, 277–283 (1997).

    Article  CAS  Google Scholar 

  44. Stögbauer, F. et al. Refinement of the hereditary neuralgic amyotrophy (HNA) locus to chromosome 17q24-q25. Hum. Genet. 99, 685–687 (1997).

    Article  Google Scholar 

  45. Hünermund, G. et al. Genomic organization and mutation analysis of three candidate genes for hereditary neuralgic amyotrophy. Muscle Nerve 29, 601–604 (2004).

    Article  Google Scholar 

  46. Kalikin, L. M. et al. An integrated physical and gene map of human distal chromosome 17q24–proximal 17q25 encompassing multiple disease loci. Genomics 57, 36–42 (1999).

    Article  CAS  Google Scholar 

  47. Kuhlenbäumer, G. et al. Mutation analysis of a putative sialyltransferase gene, the SFRS2 splicing factor gene and the c-myb ET-locus in two families with hereditary neuralgic amyotrophy (HNA). Ann. Hum. Genet. 62, 397–400 (1998).

    Article  Google Scholar 

  48. Kuhlenbäumer, G. et al. A sequence-ready BAC/PAC contig and partial transcript map of approximately 1.5 Mb in human chromosome 17q25 comprising multiple disease genes. Genomics 62, 242–250 (1999).

    Article  Google Scholar 

  49. Meuleman, J. et al. Hereditary neuralgic amyotrophy: mutation analysis of candidate genes. Ann. NY Acad. Sci. 883, 443–444 (1999).

    Article  CAS  Google Scholar 

  50. Meuleman, J. et al. Mutation analysis of 4 candidate genes for hereditary neuralgic amyotrophy (HNA). Hum. Genet. 108, 390–393 (2001).

    Article  CAS  Google Scholar 

  51. Kuhlenbäumer, G. et al. Mutations in SEPT9 cause hereditary neuralgic amyotrophy. Nat. Genet. 37, 1044–1046 (2005).

    Article  Google Scholar 

  52. Hannibal, M. C. et al. SEPT9 gene sequencing analysis reveals recurrent mutations in hereditary neuralgic amyotrophy. Neurology 72, 1755–1759 (2009).

    Article  CAS  Google Scholar 

  53. Watts, G. D., O'Briant, K. C. & Chance, P. F. Evidence of a founder effect and refinement of the hereditary neuralgic amyotrophy (HNA) locus on 17q25 in American families. Hum. Genet. 110, 166–172 (2002).

    Article  CAS  Google Scholar 

  54. Landsverk, M. L. et al. Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy. Hum. Mol. Genet. 18, 1200–1208 (2009).

    Article  CAS  Google Scholar 

  55. Watts, G. D., O'Briant, K. C., Borreson, T. E., Windebank, A. J. & Chance, P. F. Evidence for genetic heterogeneity in hereditary neuralgic amyotrophy. Neurology 56, 675–678 (2001).

    Article  CAS  Google Scholar 

  56. McIlhatton, M. A. et al. Genomic organization, complex splicing pattern and expression of a human septin gene on chromosome 17q25.3. Oncogene 20, 5930–5939 (2001).

    Article  CAS  Google Scholar 

  57. Peterson, E. A. & Petty, E. M. Conquering the complex world of human septins: implications for health and disease. Clin. Genet. 77, 511–524 (2010).

    Article  CAS  Google Scholar 

  58. Hall, P. A. & Russell, S. E. The pathobiology of the septin gene family. J. Pathol. 204, 489–505 (2004).

    Article  CAS  Google Scholar 

  59. Beausoleil, S. A. et al. Large-scale characterization of HeLa cell nuclear phosphoproteins. Proc. Natl Acad. Sci. USA 101, 12130–12135 (2004).

    Article  CAS  Google Scholar 

  60. Molina, H., Horn, D. M., Tang, N., Mathivanan, S. & Pandey, A. Global proteomic profiling of phosphopeptides using electron transfer dissociation tandem mass spectrometry. Proc. Natl Acad. Sci. USA 104, 2199–2204 (2007).

    Article  CAS  Google Scholar 

  61. Nagata, K., Asano, T., Nozawa, Y. & Inagaki, M. Biochemical and cell biological analyses of a mammalian septin complex, Sept7/9b/11. J. Biol. Chem. 279, 55895–55904 (2004).

    Article  CAS  Google Scholar 

  62. Nagata, K. & Inagaki, M. Cytoskeletal modification of Rho guanine nucleotide exchange factor activity: identification of a Rho guanine nucleotide exchange factor as a binding partner for Sept9b, a mammalian septin. Oncogene 24, 65–76 (2005).

    Article  CAS  Google Scholar 

  63. Scott, M. et al. Multimodality expression profiling shows SEPT9 to be overexpressed in a wide range of human tumours. Oncogene 24, 4688–4700 (2005).

    Article  CAS  Google Scholar 

  64. Sudo, K. et al. SEPT9 sequence alternations causing hereditary neuralgic amyotrophy are associated with altered interactions with SEPT4/SEPT11 and resistance to Rho/Rhotekin-signaling. Hum. Mutat. 28, 1005–1013 (2007).

    Article  CAS  Google Scholar 

  65. Nagata, K. et al. Filament formation of MSF-A, a mammalian septin, in human mammary epithelial cells depends on interactions with microtubules. J. Biol. Chem. 278, 18538–18543 (2003).

    Article  CAS  Google Scholar 

  66. Robertson, C. et al. Properties of SEPT9 isoforms and the requirement for GTP binding. J. Pathol. 203, 519–527 (2004).

    Article  CAS  Google Scholar 

  67. McDade, S. S., Hall, P. A. & Russell, S. E. Translational control of SEPT9 isoforms is perturbed in disease. Hum. Mol. Genet. 16, 742–752 (2007).

    Article  CAS  Google Scholar 

  68. Ueda, M. et al. Phenotypic spectrum of hereditary neuralgic amyotrophy caused by the SEPT9 R88W mutation. J. Neurol. Neurosurg. Psychiatry 8, 94–96 (2010).

    Article  Google Scholar 

  69. Suarez, G. A. in Peripheral Neuropathy Vol. 2 Ch. 104 (eds Dyck, P. J. & Thomas, P. K.) 2299–2308 (Elsevier Saunders, Philadelphia, 2005).

    Book  Google Scholar 

  70. Stek, C. J. et al. Neuralgic amyotrophy associated with Bartonella henselae infection. J. Neurol. Neurosurg. Psychiatry doi:10.1136/jnnp.2009.191940.

    Article  Google Scholar 

  71. Klein, C. J. et al. Inflammation and neuropathic attacks in hereditary brachial plexus neuropathy. J. Neurol. Neurosurg. Psychiatry 73, 45–50 (2002).

    Article  CAS  Google Scholar 

  72. Suarez, G. A. et al. Immune brachial plexus neuropathy: suggestive evidence for an inflammatory-immune pathogenesis. Neurology 46, 559–561 (1996).

    Article  CAS  Google Scholar 

  73. Vriesendorp, F. J., Dmytrenko, G. S., Dietrich, T. & Koski, C. L. Anti-peripheral nerve myelin antibodies and terminal activation products of complement in serum of patients with acute brachial plexus neuropathy. Arch. Neurol. 50, 1301–1303 (1993).

    Article  CAS  Google Scholar 

  74. Sierra, A. et al. Blood lymphocytes are sensitized to brachial plexus nerves in patients with neuralgic amyotrophy. Acta Neurol. Scand. 83, 183–186 (1991).

    Article  CAS  Google Scholar 

  75. Bardos, V. & Somodská, V. Epidemiologic study of a brachial plexus neuritis outbreak in northeast Czechoslovakia. World Neurol. 2, 973–979 (1961).

    CAS  PubMed  Google Scholar 

  76. Jobe, C. M. & Coen, M. J. in The Shoulder Vol. 1 Ch. 2 (eds Rockwood, C. A. et al.) 64–66 (Saunders, Philadelphia, 2004).

    Google Scholar 

  77. van Alfen, N. et al. Histology of hereditary neuralgic amyotrophy. J. Neurol. Neurosurg. Psychiatry 76, 445–447 (2005).

    Article  CAS  Google Scholar 

  78. Windebank, A. J. in Peripheral Neuropathy 3rd edn Vol. 2 Ch. 58 (eds Dyck, P. J. et al.) 1137–1148 (W. B. Saunders, Philadelphia, 1993).

    Google Scholar 

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The author thanks Sigrid Pillen for providing the original artwork and for her critical reading of the manuscript.

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van Alfen, N. Clinical and pathophysiological concepts of neuralgic amyotrophy. Nat Rev Neurol 7, 315–322 (2011). https://doi.org/10.1038/nrneurol.2011.62

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