RSS-Feed abonnieren
DOI: 10.1055/a-2716-1691
Small Fiber Neuropathy in Sarcoidosis
Autor*innen
Abstract
Sarcoidosis is a systemic inflammatory disorder of unknown cause, mainly affecting the lungs and lymph nodes. Symptoms are diverse and range from dyspnea and cough to fatigue, cognitive impairment, and pain. An important cause of pain in patients with sarcoidosis is small fiber neuropathy (SFN), with an estimated prevalence of 33 to 86%. The underlying pathogenesis of SFN in sarcoidosis is not known. In sarcoidosis, symptoms related to SFN can be grouped into general symptoms (e.g., fatigue), sensory symptoms (e.g., pain and numbness), and autonomic symptoms (e.g., gastrointestinal dysmotility, palpitations, or sexual dysfunction). Presentation of SFN in patients with sarcoidosis is heterogeneous and can either be length-dependent or nonlength-dependent. The small fiber neuropathy screening list assesses the frequency and severity of symptoms suggestive of SFN. As a diagnostic gold standard is lacking for SFN, the diagnosis is made on different levels of certainty based on the presence of clinical signs, normal nerve conduction studies, and either abnormal quantitative sensory testing or decreased intraepidermal nerve fiber density on skin biopsy. Autonomic dysfunction in sarcoidosis is even more difficult to diagnose, often under-recognized, and may also have a negative impact on quality of life. At present, only symptomatic relief can sometimes be achieved. While treatment of sarcoidosis usually includes corticosteroids and other immunosuppressants, these drugs are not proven effective in alleviating SFN symptoms related to sarcoidosis. This review provides an overview of symptoms, available diagnostic tools, and treatment options specific to sarcoidosis-associated SFN and autonomic dysfunction.
Publikationsverlauf
Eingereicht: 26. Juni 2025
Angenommen: 02. Oktober 2025
Artikel online veröffentlicht:
11. November 2025
© 2025. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
-
References
- 1 Baughman RP, Valeyre D, Korsten P. et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J 2021; 58 (06) 2004079
- 2 Drent M, Crouser ED, Grunewald J. Challenges of sarcoidosis and its management. N Engl J Med 2021; 385 (11) 1018-1032
- 3 Bakkers M, Merkies IS, Lauria G. et al. Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology 2009; 73 (14) 1142-1148
- 4 Voortman M, Hendriks CMR, Elfferich MDP. et al. The burden of sarcoidosis symptoms from a patient perspective. Lung 2019; 197 (02) 155-161
- 5 Tavee J. Peripheral neuropathy in sarcoidosis. J Neuroimmunol 2022; 368: 577864
- 6 Hovaguimian A, Gibbons CH. Diagnosis and treatment of pain in small-fiber neuropathy. Curr Pain Headache Rep 2011; 15 (03) 193-200
- 7 Nordin M. Low-threshold mechanoreceptive and nociceptive units with unmyelinated (C) fibres in the human supraorbital nerve. J Physiol 1990; 426: 229-240
- 8 Light AR, Perl ER. Unmyelinated afferent fibers are not only for pain anymore. J Comp Neurol 2003; 461 (02) 137-139
- 9 Thio BJ, Titus ND, Pelot NA, Grill WM. Reverse-engineered models reveal differential membrane properties of autonomic and cutaneous unmyelinated fibers. PLOS Comput Biol 2024; 20 (10) e1012475
- 10 Arcilla CK, Tadi P. Neuroanatomy, Unmyelinated Nerve Fibers. StatPearls. StatPearls Publishing Copyright 2025, StatPearls Publishing LLC.; 2025
- 11 Faber CG, Lauria G, Merkies IS. et al. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A 2012; 109 (47) 19444-19449
- 12 Persson AK, Liu S, Faber CG, Merkies IS, Black JA, Waxman SG. Neuropathy-associated Nav1.7 variant I228M impairs integrity of dorsal root ganglion neuron axons. Ann Neurol 2013; 73 (01) 140-145
- 13 Huang J, Han C, Estacion M. et al; PROPANE Study Group. Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy. Brain 2014; 137 (Pt 6): 1627-1642
- 14 Mariotto S, Ferrari S, Monaco S. HCV-related central and peripheral nervous system demyelinating disorders. Inflamm Allergy Drug Targets 2014; 13 (05) 299-304
- 15 Russell JW, Zilliox LA. Diabetic neuropathies. Continuum (Minneap Minn) 2014; 20 (5 peripheral nervous system disorders): 1226-1240
- 16 de Greef BTA, Hoeijmakers JGJ, Gorissen-Brouwers CML, Geerts M, Faber CG, Merkies ISJ. Associated conditions in small fiber neuropathy - a large cohort study and review of the literature. Eur J Neurol 2018; 25 (02) 348-355
- 17 Gavrilova N, Starshinova A, Zinchenko Y. et al. Small fiber neuropathy in sarcoidosis. Pathophysiology 2021; 28 (04) 544-550
- 18 Liampas A, Parperis K, Erotocritou MF. et al. Primary Sjögren syndrome-related peripheral neuropathy: a systematic review and meta-analysis. Eur J Neurol 2023; 30 (01) 255-265
- 19 Sopacua M, Hoeijmakers JGJ, Merkies ISJ, Lauria G, Waxman SG, Faber CG. Small-fiber neuropathy: expanding the clinical pain universe. J Peripher Nerv Syst 2019; 24 (01) 19-33
- 20 Sommer C, Lauria G. Chapter 41 painful small-fiber neuropathies. Handb Clin Neurol 2006; 81: 621-633
- 21 Gemignani F, Bellanova MF, Saccani E, Pavesi G. Non-length-dependent small fiber neuropathy: not a matter of stockings and gloves. Muscle Nerve 2022; 65 (01) 10-28
- 22 Burns TM, Dyck PJ, Aksamit AJ, Dyck PJ. The natural history and long-term outcome of 57 limb sarcoidosis neuropathy cases. J Neurol Sci 2006; 244 (1–2): 77-87
- 23 Prior C, Knight RA, Herold M, Ott G, Spiteri MA. Pulmonary sarcoidosis: patterns of cytokine release in vitro. Eur Respir J 1996; 9 (01) 47-53
- 24 Cunha FQ, Poole S, Lorenzetti BB, Ferreira SH. The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia. Br J Pharmacol 1992; 107 (03) 660-664
- 25 Sommer C, Kress M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 2004; 361 (1–3): 184-187
- 26 Pestronk A, Choksi R, Logigian E, Al-Lozi MT. Sensory neuropathy with monoclonal IgM binding to a trisulfated heparin disaccharide. Muscle Nerve 2003; 27 (02) 188-195
- 27 Pestronk A, Schmidt RE, Choksi RM, Sommerville RB, Al-Lozi MT. Clinical and laboratory features of neuropathies with serum IgM binding to TS-HDS. Muscle Nerve 2012; 45 (06) 866-872
- 28 Antoine JC, Boutahar N, Lassablière F. et al. Antifibroblast growth factor receptor 3 antibodies identify a subgroup of patients with sensory neuropathy. J Neurol Neurosurg Psychiatry 2015; 86 (12) 1347-1355
- 29 Fujii T, Lee EJ, Miyachi Y. et al. Antiplexin D1 antibodies relate to small fiber neuropathy and induce neuropathic pain in animals. Neurol Neuroimmunol Neuroinflamm 2021; 8 (05) e1028
- 30 Darnell RB. Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain. Proc Natl Acad Sci U S A 1996; 93 (10) 4529-4536
- 31 Hoitsma E, Reulen JP, de Baets M, Drent M, Spaans F, Faber CG. Small fiber neuropathy: a common and important clinical disorder. J Neurol Sci 2004; 227 (01) 119-130
- 32 Parikh SM, Diedrich A, Biaggioni I, Robertson D. The nature of the autonomic dysfunction in multiple system atrophy. J Neurol Sci 2002; 200 (1–2): 1-10
- 33 Rocha EA, Mehta N, Távora-Mehta MZP, Roncari CF, Cidrão AAL, Elias Neto J. Dysautonomia: a forgotten condition - part 1. Arq Bras Cardiol 2021; 116 (04) 814-835
- 34 Raasing L, Veltkamp M, Datema M, Korenromp I, Grutters JC, Vogels OJM. Sarcoidosis-related small fiber neuropathy: focus on fatigue, pain, restless legs syndrome, and cognitive function. Sarcoidosis Vasc Diffuse Lung Dis 2025; 42 (01) 16214
- 35 Lacomis D. Small-fiber neuropathy. Muscle Nerve 2002; 26 (02) 173-188
- 36 Tavee J, Zhou L. Small fiber neuropathy: a burning problem. Cleve Clin J Med 2009; 76 (05) 297-305
- 37 Levine TD. Small fiber neuropathy: disease classification beyond pain and burning. J Cent Nerv Syst Dis 2018; 10: 1179573518771703
- 38 Bakkers M, Faber CG, Hoeijmakers JG, Lauria G, Merkies IS. Small fibers, large impact: quality of life in small-fiber neuropathy. Muscle Nerve 2014; 49 (03) 329-336
- 39 Themistocleous AC, Ramirez JD, Shillo PR. et al. The pain in neuropathy study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy. Pain 2016; 157 (05) 1132-1145
- 40 Voortman M, Fritz D, Vogels OJM. et al. Small fiber neuropathy: a disabling and underrecognized syndrome. Curr Opin Pulm Med 2017; 23 (05) 447-457
- 41 Moor CC, Gur-Demirel Y, Koudstaal T, Miedema JR. Sexual dysfunction in patients with sarcoidosis. Chest 2024; 166 (06) 1473-1475
- 42 Raasing LRM, Vogels OJM, Datema M. et al. New phenotyping questionnaire for diagnosing sarcoidosis-associated small fiber neuropathy. Brain Commun 2024; 6 (05) fcae289
- 43 Hoitsma E, De Vries J, Drent M. The small fiber neuropathy screening list: construction and cross-validation in sarcoidosis. Respir Med 2011; 105 (01) 95-100
- 44 Devigili G, Rinaldo S, Lombardi R. et al. Diagnostic criteria for small fibre neuropathy in clinical practice and research. Brain 2019; 142 (12) 3728-3736
- 45 Oudejans LC, Niesters M, Brines M, Dahan A, van Velzen M. Quantification of small fiber pathology in patients with sarcoidosis and chronic pain using cornea confocal microscopy and skin biopsies. J Pain Res 2017; 10: 2057-2065
- 46 Kool D, Hoeijmakers JGJ, Faber CG, Merkies ISJ. The small fiber neuropathy-symptom inventory questionnaire (SFN-SIQ) does not discriminate between patients with or without small fiber neuropathy. J Peripher Nerv Syst 2023; 28 (02) 287-288
- 47 Raasing LRM, Veltkamp M, Datema M, Grutters JC, Vogels OJM. Thermal threshold testing: call for a balance between the number of measurements and abnormalities in the diagnosis of sarcoidosis-associated small fiber neuropathy. Pain Rep 2023; 8 (05) e1095
- 48 Heij L, Niesters M, Swartjes M. et al. Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Mol Med 2012; 18 (01) 1430-1436
- 49 Wells R, Tonkin A. Clinical approach to autonomic dysfunction. Intern Med J 2016; 46 (10) 1134-1139
- 50 Bremner F. Pupil evaluation as a test for autonomic disorders. Clin Auton Res 2009; 19 (02) 88-101
- 51 Casellini CM, Parson HK, Richardson MS, Nevoret ML, Vinik AI. Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Diabetes Technol Ther 2013; 15 (11) 948-953
- 52 Kornum DS, Terkelsen AJ, Bertoli D. et al. Assessment of gastrointestinal autonomic dysfunction: present and future perspectives. J Clin Med 2021; 10 (07) 1392
- 53 Martonosi ÁR, Pázmány P, Kiss S, Zsákai A, Szabó L. Investigating the abnormality of detrusor contractility by uroflowmetry in diabetic children (INTACT trial): protocol of a prospective, observational study. BMJ Open 2022; 12 (11) e062198
- 54 Cheshire Jr WP, Goldstein DS. Autonomic uprising: the tilt table test in autonomic medicine. Clin Auton Res 2019; 29 (02) 215-230
- 55 Goldberger JJ, Arora R, Buckley U, Shivkumar K. Autonomic nervous system dysfunction: JACC focus seminar. J Am Coll Cardiol 2019; 73 (10) 1189-1206
- 56 Teodorovich N, Swissa M. Tilt table test today - state of the art. World J Cardiol 2016; 8 (03) 277-282
- 57 Tiran B, Heller I, Isakov A, Barnea O, Greif J, Topilsky M. Heart rate variability in sarcoidosis: a frequency domain analysis. Eur J Intern Med 2004; 15 (08) 518-522
- 58 Hoitsma E, Faber CG, van Kroonenburgh MJ. et al. Association of small fiber neuropathy with cardiac sympathetic dysfunction in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2005; 22 (01) 43-50
- 59 Kul S, Uyarel H, Guvenc TS. et al. Circadian blood pressure pattern in sarcoidosis patients. Blood Press 2015; 24 (01) 23-29
- 60 Chirumamilla A, Travin MI. Cardiac applications of 123I-mIBG imaging. Semin Nucl Med 2011; 41 (05) 374-387
- 61 Ho TW, Backonja M, Ma J, Leibensperger H, Froman S, Polydefkis M. Efficient assessment of neuropathic pain drugs in patients with small fiber sensory neuropathies. Pain 2009; 141 (1–2): 19-24
- 62 Finnerup NB, Attal N, Haroutounian S. et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015; 14 (02) 162-173
- 63 Dahan A, Dunne A, Swartjes M. et al. ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol Med 2013; 19 (01) 334-345
- 64 Culver DA, Dahan A, Bajorunas D. et al. Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. Invest Ophthalmol Vis Sci 2017; 58 (06) BIO52-BIO60
- 65 Kreß L, Egenolf N, Sommer C, Üçeyler N. Cytokine expression profiles in white blood cells of patients with small fiber neuropathy. BMC Neurosci 2023; 24 (01) 1
- 66 Raasing L, Vogels OJM, Veltkamp M, Grutters JC. Infliximab decreases inflammatory activity but has no effect on small fiber neuropathy related symptoms in Dutch patients with sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2022; 39 (04) e2022033
- 67 Tavee JO, Karwa K, Ahmed Z, Thompson N, Parambil J, Culver DA. Sarcoidosis-associated small fiber neuropathy in a large cohort: Clinical aspects and response to IVIG and anti-TNF alpha treatment. Respir Med 2017; 126: 135-138
- 68 Parambil JG, Tavee JO, Zhou L, Pearson KS, Culver DA. Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis. Respir Med 2011; 105 (01) 101-105
- 69 Chan ACY, Shahana R, Siah KTH. et al. Efficacy of rituximab on antibody-positive small fiber neuropathy: a series of 5 cases. J Neuroimmunol 2025; 401: 578559
- 70 Wright RA, Kaufmann HC, Perera R. et al. A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51 (01) 120-124
- 71 Brailsford B, East EJ, Clayton J, Sathyanarayanan A. Orthostatic hypotension-an approach to work up and management. Br J Hosp Med (Lond) 2025; 86 (05) 1-9
- 72 Pavic NV, Zhang S, Maloof AG. et al. Pyridostigmine in the management of orthostatic hypotension: a systematic review and meta-analysis. Open Heart 2025; 12 (01) e003106
- 73 Smulders NM, Bast A, van Kroonenburgh MJ, Drent M. Improvement of cardiac sympathetic nerve function in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2008; 25 (02) 140-142
- 74 Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig 2013; 4 (01) 4-18
- 75 Mitchell SD, Sidiropoulos C. Therapeutic applications of botulinum neurotoxin for autonomic symptoms in parkinson's disease: an updated review. Toxins (Basel) 2021; 13 (03) 226
- 76 Djouhri L, Lawson SN. Abeta-fiber nociceptive primary afferent neurons: a review of incidence and properties in relation to other afferent: a-fiber neurons in mammals. Brain Res Brain Res Rev 2004; 46 (02) 131-145
- 77 Devigili G, Lombardi R, Lauria G, Cazzato D. The evolving landscape of small fiber neuropathy. Semin Neurol 2025; 45 (01) 132-144