Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Neurotherapeutics
Published in: Neurotherapeutics 1/2016

01-01-2016 | Review

Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies

Author: Anne Louise Oaklander

Published in: Neurotherapeutics | Issue 1/2016

Login to get access

Abstract

The best-known peripheral neuropathies are those affecting the large, myelinated motor and sensory fibers. These have well-established immunological causes and therapies. Far less is known about the somatic and autonomic “small fibers”; the unmyelinated C-fibers, thinly myelinated A-deltas, and postganglionic sympathetics. The small fibers sense pain and itch, innervate internal organs and tissues, and modulate the inflammatory and immune responses. Symptoms of small-fiber neuropathy include chronic pain and itch, sensory impairment, edema, and skin color, temperature, and sweating changes. Small-fiber polyneuropathy (SFPN) also causes cardiovascular, gastrointestinal, and urological symptoms, the neurologic origin of which often remains unrecognized. Routine electrodiagnostic study does not detect SFPN, so skin biopsies immunolabeled to reveal axons are recommended for diagnostic confirmation. Preliminary evidence suggests that dysimmunity causes some cases of small-fiber neuropathy. Several autoimmune diseases, including Sjögren and celiac, are associated with painful small-fiber ganglionopathy and distal axonopathy, and some patients with “idiopathic” SFPN have evidence of organ-specific dysimmunity, including serological markers. Dysimmune SFPN first came into focus in children and teenagers as they lack other risk factors, for example diabetes or toxic exposures. In them, the rudimentary evidence suggests humoral rather than cellular mechanisms and complement consumption. Preliminary evidence supports efficacy of corticosteroids and immunoglobulins in carefully selected children and adult patients. This paper reviews the evidence of immune causality and the limited data regarding immunotherapy for small-fiber-predominant ganglionitis, regional neuropathy (complex regional pain syndrome), and distal SFPN. These demonstrate the need to develop case definitions and outcome metrics to improve diagnosis, enable prospective trials, and dissect the mechanisms of small-fiber neuropathy.
Appendix
Available only for authorised users
Literature
1.
Fukuda T, Takeda S, Xu R, et al. Sema3A regulates bone-mass accrual through sensory innervations. Nature 2013 23;497:490–493.CrossRef
2.
Hsieh ST, Lin WM. Modulation of keratinocyte proliferation by skin innervation. J Invest Dermatol 1999;113:579–586.CrossRefPubMed
3.
Levine J, Dardick SJ, Basbaum AI, Scipio E. Reflex neurogenic inflammation 1. contribution of the peripheral nervous system to spatially remote inflammatory responses that follow injury. J Neurosci 1985;5:1380–1386.PubMed
4.
Egan CL, Viglione-Schneck MJ, Walsh LJ, et al. Characterization of unmyelinated axons uniting epidermal and dermal immune cells in primate and murine skin. J Cutan Pathol 1998;25:20–29.CrossRefPubMed
5.
Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell 2009 16;139:267–284CrossRef
6.
McMahon SB, Russa FL, Bennett DL. Crosstalk between the nociceptive and immune systems in host defence and disease. Nat Rev Neurosci 2015 19;16:389–402.CrossRef
7.
Kuntzer T, Antoine JC, Steck AJ. Clinical features and pathophysiological basis of sensory neuronopathies (ganglionopathies). Muscle Nerve 2004;30:255–268.CrossRefPubMed
8.
Sheikh SI, Amato AA. The dorsal root ganglion under attack: the acquired sensory ganglionopathies. Pract Neurol 2010;10:326–334.CrossRefPubMed
9.
Cole JD, Katifi HA. Evoked potentials in a man with a complete large myelinated fibre sensory neuropathy below the neck. Electroencephalogr Clin Neurophysiol 1991;80:103–107.CrossRefPubMed
10.
Griffin JW, Cornblath DR, Alexander E, et al. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjögren's syndrome. Ann Neurol 1990;27:304–315.CrossRefPubMed
11.
Lauria G, Sghirlanzoni A, Lombardi R, Pareyson D. Epidermal nerve fiber density in sensory ganglionopathies: clinical and neurophysiologic correlations. Muscle Nerve 2001;24:1034–1039.CrossRefPubMed
12.
Hadjivassiliou M, Rao DG, Wharton SB, Sanders DS, Grunewald RA, Davies-Jones AGB. Sensory ganglionopathy due to gluten sensitivity. Neurology 2010 14;75:1003–1008.
13.
Brannagan TH, III, Hays AP, Chin SS, et al. Small-fiber neuropathy/neuronopathy associated with celiac disease: skin biopsy findings. Arch Neurol 2005 1;62:1574–1578.
14.
Sene D, Cacoub P, Authier FJ, et al. Sjögren syndrome-associated small fiber neuropathy: Characterization from a prospective series of 40 cases. Medicine 2013 Aug 26 [Epub ahead of print].
15.
Sene D, Jallouli M, Lefaucheur JP, et al. Peripheral neuropathies associated with primary Sjogren syndrome: immunologic profiles of nonataxic sensory neuropathy and sensorimotor neuropathy. Medicine 2011;90:133–138.CrossRefPubMed
16.
Birnbaum J. Peripheral nervous system manifestations of Sjögren syndrome: clinical patterns, diagnostic paradigms, etiopathogenesis, and therapeutic strategies. Neurologist 2010;16:287–297.CrossRefPubMed
17.
Chai J, Herrmann DN, Stanton M, Barbano RL, Logigian EL. Painful small-fiber neuropathy in Sjögren's syndrome. Neurology 2005 27;65:925–927.
18.
Brito-Zeron P, Ramos-Casals M. Advances in the understanding and treatment of systemic complications in Sjogren's syndrome. Curr Opin Rheumatol 2014;26:520–527.CrossRefPubMed
19.
Gheitasi H, Kostov B, Solans R, et al. How are we treating our systemic patients with primary Sjogren syndrome? Analysis of 1120 patients. Int Immunopharmacol 2015;27:194–199.CrossRefPubMed
20.
Gottenberg JE, Ravaud P, Puechal X, et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjogren syndrome: the JOQUER randomized clinical trial. JAMA 2014;312:249–258.CrossRefPubMed
21.
Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al. Treatment of primary Sjogren syndrome with rituximab: a randomized trial. Ann Intern Med 2014;160:233–242.CrossRefPubMed
22.
Takahashi Y, Takata T, Hoshino M, Sakurai M, Kanazawa I. Benefit of IVIG for long-standing ataxic sensory neuronopathy with Sjögren's syndrome. IV immunoglobulin. Neurology 2003;60:503–505.PubMed
23.
Rist S, Sellam J, Hachulla E, et al. Experience of intravenous immunoglobulin therapy in neuropathy associated with primary Sjögren's syndrome: a national multicentric retrospective study. Arthritis Care Res 2011;63:1339–1344.CrossRef
24.
Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138–1148.CrossRefPubMed
25.
Kalanie H, Harandi AA, Mardani M, et al. Trigeminal neuralgia as the first clinical manifestation of anti-hu paraneoplastic syndrome induced by a borderline ovarian mucinous tumor. Case Rep Neurol 2014;6:7–13.CrossRefPubMedPubMedCentral
26.
Vedeler CA, Antoine JC, Giometto B, et al. Management of paraneoplastic neurological syndromes: report of an EFNS Task Force. Eur J Neurol 2006;13:682–690.CrossRefPubMed
27.
Honnorat J. Therapeutic approaches in antibody-associated central nervous system pathologies. Rev Neurol (Paris) 2014;170:587–594.CrossRef
28.
Honnorat J. Early-onset immunotherapy by intravenous immunoglobulin and corticosteroids in well characterized onconeural-antibody-positive paraneoplastic neurological syndrome. Clin Exp Immunol 2014;178(Suppl. 1):127–129.CrossRefPubMedPubMedCentral
29.
Coret F, Bosca I, Fratalia L, Perez-Griera J, Pascual A, Casanova B. Long-lasting remission after rituximab treatment in a case of anti-Hu-associated sensory neuronopathy and gastric pseudoobstruction. J Neurooncol 2009;93:421–423.CrossRefPubMed
30.
Oaklander AL. The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles. Pain 2001;92:139–145.CrossRefPubMed
31.
Oaklander AL, Fields HL. Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy? Ann Neurol 2009;65:629–638.CrossRefPubMed
32.
de Rooij AM, Perez RSGM, Huygen FJ, et al. Spontaneous onset of complex regional pain syndrome. Eur J Pain 2010;14:510–513.CrossRefPubMed
33.
Förster M, Umnus A, Siebrecht D, Baron R, Wasner G. A case of pain, motor impairment, and swelling of the arm after acute herpes zoster infection. Pain 2012;153:2478–2481.CrossRefPubMed
34.
Merskey H, Bogduk N. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. 2nd ed. IASP Press, Seattle, 1994.
35.
Mitchell SW. Injuries of nerves and their consequences. Dover Publications, American Academy of Neurology Reprint Series (1965 edition), New York, 1864.
36.
Mitchell SW, Morehouse GR, Keen WM. Gunshot wounds and other injuries of nerves. J.B. Lippincott, Philadelphia, PA, 1864.
37.
Sudeck PHM. Über die akute (reflektorische) Knochenatrophie nach Entzündungen und Verletzungen an den Extremitäten und ihre klinischen Erscheinungen. Fortschritte auf dem Gebiete der Röntgenstrahlen 1901;5:277.
38.
Kozin F, McCarty DJ, Sims J, Genant H. The reflex sympathetic dystrophy syndrome. I. Clinical and histologic studies: evidence for bilaterality, response to corticosteroids and articular involvement. Am J Med 1976;60:321–331.CrossRefPubMed
39.
Kozin F, Genant HK, Bekerman C, McCarty DJ. The reflex sympathetic dystrophy syndrome. II. Roentgenographic and scintigraphic evidence of bilaterality and of periarticular accentuation. Am J Med 1976;60:332–338.CrossRefPubMed
40.
Evans JA. Reflex sympathetic dystrophy. Surg Gynecol Obstet 1946;82:36–44.PubMed
41.
Horowitz SH. Peripheral nerve injury and causalgia secondary to routine venipuncture. Neurology 1994;44:962–964.CrossRefPubMed
42.
Oaklander AL, Rissmiller JG, Gelman LB, Zheng L, Chang Y, Gott R. Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy). Pain 2006;120:235–243.CrossRefPubMed
43.
Albrecht PJ, Hines S, Eisenberg E, et al. Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome. Pain 2006;120:244–266.CrossRefPubMed
44.
van der Laan L, ter Laak HJ, Gabreels-Festen A, Gabreels F, Goris RJ. Complex regional pain syndrome type I (RSD): pathology of skeletal muscle and peripheral nerve. Neurology 1998;51:20–25.CrossRefPubMed
45.
de Mos M, Huygen FJ, Dieleman JP, Koopman JS, Stricker BH, Sturkenboom MC. Medical history and the onset of complex regional pain syndrome (CRPS). Pain 2008;139:458–466.CrossRefPubMed
46.
Beerthuizen A, Spijker A, Huygen FJPM, Klein J, de Wit R. Is there an association between psychological factors and the Complex Regional Pain Syndrome type 1 (CRPS1) in adults? A systematic review. Pain 2009;145:52–59.CrossRefPubMed
47.
Sandroni P, Benrud-Larson LM, McClelland RL, Low PA. Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain 2003;103:199–207.CrossRefPubMed
48.
49.
Birklein F, Riedl B, Sieweke N, Weber M, Neundörfer B. Neurological findings in complex regional pain syndromes--analysis of 145 cases. Acta Neurol Scand 2000;101:262–269.CrossRefPubMed
50.
Tilman PBJ, Stadhouders AM, Jap PHK, Goris RJA. Histopathologic findings in skeletal muscle tissue of patients suffering from reflex sympathetic dystrophy. Micron Microscop Acta 1990;21:271–272.CrossRef
51.
Weber M, Birklein F, Neundörfer B, Schmelz M. Facilitated neurogenic inflammation in complex regional pain syndrome. Pain 2001;91:251–257.CrossRefPubMed
52.
Webster GF, Iozzo RV, Schwartzman RJ, Tahmoush AJ, Knobler RL, Jacoby RA. Reflex sympathetic dystrophy: Occurrence of chronic edema and nonimmune bullous skin lesions. J Am Acad Dermatol 1993;28:29–32.CrossRefPubMed
53.
54.
Birklein F, Weber M, Ernst M, Riedl B, Neundörfer B, Handwerker HO. Experimental tissue acidosis leads to increased pain in complex regional pain syndrome (CRPS). Pain 2001;87:227–234.CrossRef
55.
Parkitny L, McAuley JH, Di Pietro F, et al. Inflammation in complex regional pain syndrome: A systematic review and meta-analysis. Neurology 2013 1;80:106–117.
56.
Lenz M, Üçeyler N, Frettloh J, et al. Local cytokine changes in complex regional pain syndrome type I (CRPS I) resolve after 6 months. Pain 2013;154:2142–2149.CrossRefPubMed
57.
58.
Üçeyler N, Rogausch JP, Toyka KV, Sommer C. Differential expression of cytokines in painful and painless neuropathies. Neurology 2007 3;69:42–49.
59.
Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 1997;73:123–139.CrossRefPubMed
60.
Eisenberg E, Sandler I, Treister R, Suzan E, Haddad M. Anti tumor necrosis factor - alpha adalimumab for complex regional pain syndrome type 1 (CRPS-I): A case series. Pain Pract 2013;13:649–656.CrossRefPubMed
61.
Schwartzman RJ, Chevlen E, Bengtson K. Thalidomide has activity in treating complex regional pain syndrome. Arch Intern Med 2003 23;163:1487–1488.
62.
Manning DC, Alexander G, Arezzo JC, et al. Lenalidomide for complex regional pain syndrome type 1: Lack of efficacy in a phase II randomized study. J Pain 2014;15:1366–1376.CrossRefPubMed
63.
Goebel A, Blaes F. Complex regional pain syndrome, prototype of a novel kind of autoimmune disease. Autoimmun Rev 2013;12:682–686.CrossRefPubMed
64.
Kohr D, Tschernatsch M, Schmitz K, et al. Autoantibodies in complex regional pain syndrome bind to a differentiation-dependent neuronal surface autoantigen. Pain 2009;143:246–251.CrossRefPubMed
65.
Kohr D, Singh P, Tschernatsch M, et al. Autoimmunity against the beta(2) adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome. Pain 2011;152:2690–2700.CrossRefPubMed
66.
Tekus V, Hajna Z, Borbely E, et al. A CRPS-IgG-transfer-trauma model reproducing inflammatory and positive sensory signs associated with complex regional pain syndrome. Pain 2014;155:299–308.CrossRefPubMed
67.
Li WW, Guo TZ, Shi X, et al. Autoimmunity contributes to nociceptive sensitization in a mouse model of complex regional pain syndrome. Pain 2014;155:2377–2389.CrossRefPubMed
68.
Staff NP, Engelstad J, Klein CJ, et al. Post-surgical inflammatory neuropathy. Brain 2010;133:2866–2880.CrossRefPubMed
69.
Goebel A, Jones S, Oomman S, Callaghan T, Sprotte G. Treatment of long-standing complex regional pain syndrome with therapeutic plasma exchange: a preliminary case series of patients treated in 2008–2014. Pain Med 2014;15:2163–2164.CrossRefPubMed
70.
Goebel A, Netal S, Schedel R, Sprotte G. Human pooled immunoglobulin in the treatment of chronic pain syndromes. Pain Med 2002;3:119–127.CrossRefPubMed
71.
Goebel A, Baranowski A, Maurer K, Ghiai A, McCabe C, Ambler G. Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann Intern Med 2010 2;152:152–158.
72.
73.
Poda R, Guaraldi P, Solieri L, et al. Standing worsens cognitive functions in patients with neurogenic orthostatic hypotension. Neurol Sci 2012;33:469–473.CrossRefPubMed
74.
Oaklander AL, Klein MM. Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes. Pediatrics 2013;131:e1091-e1100.CrossRefPubMedPubMedCentral
75.
Parkman HP, Yates K, Hasler WL, et al. Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity. Gastroenterology 2011;140:101–115.CrossRefPubMed
76.
Pasricha PJ, Colvin R, Yates K, et al. Characteristics of patients with chronic unexplained nausea and vomiting and normal gastric emptying. Clin Gastroenterol Hepatol 2011;9:567–576.CrossRefPubMedPubMedCentral
77.
England JD, Gronseth GS, Franklin G, et al. Practice Parameter: Evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 2009 13;72:177–184.
78.
Lauria G, Hsieh ST, Johansson O, et al. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol 2010;17:903–909.CrossRefPubMed
79.
Klein MM, Downs H, O'Neil K., Oaklander AL. Skin biopsy of normal children demonstrates inverse correlation between age and epidermal nerve fiber density, meaning age-specific norms are needed. Ann Neurology 2014;76:S69
80.
Bednarik J, Vlckova-Moravcova E, Bursova S, Belobradkova J, Dusek L, Sommer C. Etiology of small-fiber neuropathy. J Peripher Nerv Syst 2009;14:177–183.CrossRefPubMed
81.
Gorson KC, Ropper AH. Positive salivary gland biopsy, Sjögren's syndrome, and neuropathy: clinical implications. Muscle Nerve 2003;28:553–560.CrossRefPubMed
82.
Lang M, Treister R, Oaklander AL. Cost/benefit of blood tests in idiopathic small-fiber polyneuropathy (SFPN). Ann Neurol 2015;78:S19.
83.
Pavlakis PP, Alexopoulos H, Kosmidis ML, et al. Peripheral neuropathies in Sjögren's syndrome: a critical update on clinical features and pathogenetic mechanisms. J Autoimmun 2012;39:27–33.CrossRefPubMed
84.
Thawani SP, Brannagan TH, III, Lebwohl B, Green PH, Ludvigsson JF. Risk of neuropathy among 28232 patients with biopsy-verified celiac disease. JAMA Neurol 2015;72:806–811.CrossRefPubMed
85.
Chin RL, Sander HW, Brannagan TH, et al. Celiac neuropathy. Neurology 2003 27;60:1581–1585.
86.
Martinez AR, Nunes MB, Nucci A, Franca MC, Jr. Sensory neuronopathy and autoimmune diseases. Autoimmune Dis 2012;2012:873587.PubMedPubMedCentral
87.
88.
Souayah N, Chin RL, Brannagan TH, et al. Effect of intravenous immunoglobulin on cerebellar ataxia and neuropathic pain associated with celiac disease. Eur J Neurol 2008;15:1300–1303.CrossRefPubMed
89.
Dabby R, Gilad R, Sadeh M, Lampl Y, Watemberg N. Acute steroid responsive small-fiber sensory neuropathy: a new entity? J Peripher Nerv Syst 2006;11:47–52.CrossRefPubMed
90.
Paticoff J, Valovska A, Nedeljkovic SS, Oaklander AL. Defining a treatable cause of erythromelalgia: acute adolescent autoimmune small-fiber axonopathy. Anesth Analg 2007;104:438–441.CrossRefPubMed
91.
Oaklander AL, Lang M, Treister R, Liu X. First evaluation of immunoglobulin treatment of small-fiber axonal polyneuropathy (SFPN). Ann Neurol 2015;78:S109.
92.
Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain 2013;154:2310–2316.CrossRefPubMed
93.
Üçeyler N, Zeller D, Kahn AK, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013;136:1857–1867.CrossRefPubMed
94.
Serra J, Collado A, Sola R, et al. Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol 2013;75:196–208.CrossRef
95.
Kosmidis ML, Koutsogeorgopoulou L, Alexopoulos H, et al. Reduction of intraepidermal nerve fiber density (IENFD) in the skin biopsies of patients with fibromyalgia: A controlled study. J Neurol Sci 2014;347:143–147.CrossRefPubMed
96.
Harden RN, Bruehl S, Perez RSGM, et al. Validation of proposed diagnostic criteria (the Budapest Criteria) for Complex Regional Pain Syndrome. Pain 2010;150:268–274.CrossRefPubMedPubMedCentral
Metadata
Title
Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies
Author
Anne Louise Oaklander
Publication date
01-01-2016
Publisher
Springer US
Published in
Neurotherapeutics / Issue 1/2016
Print ISSN: 1933-7213
Electronic ISSN: 1878-7479
DOI
https://doi.org/10.1007/s13311-015-0395-1

Other articles of this Issue 1/2016

Neurotherapeutics 1/2016 Go to the issue

Review

Immunotherapies for Immune-Mediated Myopathies: A Current Perspective

News

PROGRAM

Original Article

Improved Treatment Efficacy of Antiangiogenic Therapy when Combined with Picornavirus Vaccination in the GL261 Glioma Model

Review

Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis

Review

Efficacy of Intravenous Immunoglobulin in Neurological Diseases

Review

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders