Small fiber neuropathy in sarcoidosis: Something beneath the surface
2010; Elsevier BV; Volume: 105; Issue: 1 Linguagem: Inglês
10.1016/j.rmed.2010.10.005
ISSN1532-3064
Autores Tópico(s)S100 Proteins and Annexins
ResumoUnderwater explorer Jacques Cousteau once said that the more he dove into the sea, the less he understood it. The same could be said about our knowledge of sarcoidosis. Sarcoidosis was originally thought to be a skin disease, as these lesions were readily visible whereas detection of visceral sarcoidosis required the advent of the roentgenogram to submerge beneath the surface. Thanks in large part to William Conrad Roentgen's invention, sarcoidosis was subsequently understood to be a multiorgan granulomatous disease of unknown cause. It became apparent that sarcoid granulomas could deposit anywhere in the body, although most commonly in the lungs, skin, eyes, and liver. However, as we descended into deeper waters, it became obvious that the manifestations of sarcoidosis could not be explained by granuloma deposition alone. Sarcoidosis is associated with elevated levels of circulating immune complexes.1Schoenfeld N. Schmolke B. Schmitt M. et al.Specification and quantitation of circulating immune complexes in the serum of patients with active pulmonary sarcoidosis.Thorax. 1994; 49: 688-691Crossref PubMed Scopus (9) Google Scholar Anergy is commonly seen.2Mathew S. Bauer K.L. Fischoeder A. et al.The anergic state in sarcoidosis is associated with diminished dendritic cell function.J Immunol. 2008; 181: 746-755PubMed Google Scholar Non-granulomatous inflammatory reactions such as erythema nodosum may occur.3Marchell RM, Judson MA. Cutaneous sarcoidosis. Semin Respir Crit Care Med; 31:p. 442–51Google Scholar These three phenomena, which are commonly observed with active sarcoidosis, cannot be easily explained by the granulomatous model. Researchers have pursued genetic, proteomic, and immunological approaches to explain these findings. It is assumed that these sarcoidosis-associated events are related to either a trigger or a consequence of sarcoid granuloma formation. The waters became murkier still upon the realization that several major concerns of sarcoidosis patients include symptoms that cannot be explained by granulomatous involvement of a particular organ. Pain,4Hoitsma E. De Vries J. van Santen-Hoeufft M. et al.Impact of pain in a Dutch sarcoidosis patient population.Sarcoidosis Vasc Diffuse Lung Dis. 2003; 20: 33-39PubMed Google Scholar fatigue,5de Kleijn W.P. De Vries J. Lower E.E. et al.Fatigue in sarcoidosis: a systematic review.Curr Opin Pulm Med. 2009; 15: 499-506Crossref PubMed Scopus (72) Google Scholar and depression6Chang B. Steimel J. Moller D.R. et al.Depression in sarcoidosis.Am J Respir Crit Care Med. 2001; 163: 329-334Crossref PubMed Scopus (100) Google Scholar are common patient complaints that are often debilitating and adversely affect sarcoidosis patients' quality of life. These issues are often troubling to pulmonologists and other sarcoidologists because they do not relate directly to a physiologic abnormality, are problematic to quantify and hence to monitor, and are challenging to treat. Finally, we have reached a depth where the darkness that envelops us has caused complete disorientation. This occurred to my understanding of sarcoidosis when data demonstrated that sarcoidosis is associated with a small fiber neuropathy.7Bakkers M. Merkies I.S. Lauria G. et al.Intraepidermal nerve fiber density and its application in sarcoidosis.Neurology. 2009; 73: 1142-1148Crossref PubMed Scopus (153) Google Scholar, 8Hoitsma E. Drent M. Verstraete E. et al.Abnormal warm and cold sensation thresholds suggestive of small-fibre neuropathy in sarcoidosis.Clin Neurophysiol. 2003; 114: 2326-2333Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar This concept is beyond the event horizon of both pulmonary medicine and the granuloma. The mechanism responsible for the development of small fiber neuropathy in sarcoidosis is unclear. Nevertheless, small fiber neuropathy may occur in more than one quarter of all sarcoidosis patients and lead to significant symptoms.7Bakkers M. Merkies I.S. Lauria G. et al.Intraepidermal nerve fiber density and its application in sarcoidosis.Neurology. 2009; 73: 1142-1148Crossref PubMed Scopus (153) Google Scholar Furthermore, standard sarcoidosis treatments such as corticosteroids and other immunosuppressive agents are often ineffective for this neuropathy. Small fiber neuropathy has been recognized as a specific entity involving the unmyelinated C and thinly myelinated Aδ fibers.9Devigili G. Tugnoli V. Penza P. et al.The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology.Brain. 2008; 131: 1912-1925Crossref PubMed Scopus (509) Google Scholar These fibers encompass thermal and nociceptive sensations and pathology of these nerves may lead to a "painful neuropathy."9Devigili G. Tugnoli V. Penza P. et al.The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology.Brain. 2008; 131: 1912-1925Crossref PubMed Scopus (509) Google Scholar However, these nerves additionally affect the autonomic nervous system, and small fiber neuropathy may also lead to an "autonomic neuropathy."9Devigili G. Tugnoli V. Penza P. et al.The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology.Brain. 2008; 131: 1912-1925Crossref PubMed Scopus (509) Google Scholar Defects in small fibers cannot be detected by routine nerve conduction studies. This may lead to frustration of both the physician and patient from failure to diagnose a neuropathic pain syndrome caused by abnormalities in the small fibers.9Devigili G. Tugnoli V. Penza P. et al.The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology.Brain. 2008; 131: 1912-1925Crossref PubMed Scopus (509) Google Scholar There is no gold standard for the diagnosis of small fiber neuropathy.9Devigili G. Tugnoli V. Penza P. et al.The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology.Brain. 2008; 131: 1912-1925Crossref PubMed Scopus (509) Google Scholar Discordant criteria for the diagnosis include psychophysical tests (temperature sensation thresholds10Reulen J.P. Lansbergen M.D. Verstraete E. et al.Comparison of thermal threshold tests to assess small nerve fiber function: limits vs. levels.Clin Neurophysiol. 2003; 114: 556-563Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar), neurophysiological tests (laser evoked potentials,11Truini A. Galeotti F. Romaniello A. et al.Laser-evoked potentials: normative values.Clin Neurophysiol. 2005; 116: 821-826Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar contact heat evoked potentials,12Atherton D.D. Facer P. Roberts K.M. et al.Use of the novel Contact Heat Evoked Potential Stimulator (CHEPS) for the assessment of small fibre neuropathy: correlations with skin flare responses and intra-epidermal nerve fibre counts.BMC Neurol. 2007; 7: 21Crossref PubMed Scopus (110) Google Scholar and quantitative sudomotor axon testing – QSART13Low P.A. Caskey P.E. Tuck R.R. et al.Quantitative sudomotor axon reflex test in normal and neuropathic subjects.Ann Neurol. 1983; 14: 573-580Crossref PubMed Scopus (408) Google Scholar), and results from skin or nerve biopsies (intraepidermal nerve fiber quantification14Lauria G. Cornblath D.R. Johansson O. et al.EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy.Eur J Neurol. 2005; 12: 747-758Crossref PubMed Scopus (390) Google Scholar, 15Ebenezer G.J. Hauer P. Gibbons C. et al.Assessment of epidermal nerve fibers: a new diagnostic and predictive tool for peripheral neuropathies.J Neuropathol Exp Neurol. 2007; 66: 1059-1073Crossref PubMed Scopus (97) Google Scholar). Two articles published in this issue of Respiratory Medicine may aid the clinician in the detection and treatment of sarcoidosis associated small fiber neuropathy. The paper by Hoistsma and colleagues described a screening instrument for the diagnosis of sarcoidosis associated small fiber neuropathy, the Small Fiber Neuropathy Screening List.16Hoitsma E. De Vries J. Drent M. The small fiber neuropathy screening list: construction and cross-validation in sarcoisdosis.Respir Med. 2010; 105: 95-100Abstract Full Text Full Text PDF Scopus (59) Google Scholar This instrument has actually been previously introduced in a PhD dissertation by the first author17Hoitsma E, De Vries J, Faber CG, et al. The small fiber neuropathy screening list: a novel finding in sarcoidosis. Maastricht, Netherlands, 12; 2005. p. 129–40.Google Scholar but never as a refereed manuscript. This instrument consists of 21 questions and was well constructed to detect sarcoidosis patients who will have an abnormal temperature threshold test. However, the test is not perfectly accurate in detecting sarcoidosis associated small fiber neuropathy since there is no gold standard test for this disorder. Therefore, even if the Small Fiber Neuropathy Screening List accurately identified all sarcoidosis patients with abnormal temperature threshold tests, it may fail to detect symptomatic patients who have a normal temperature threshold test but neurophysiologic or biopsy evidence of the disorder. Nevertheless, I believe that this instrument is an important first step that provides the clinician with a rough screening tool for sarcoidosis associated small fiber neuropathy. The article by Parambil and coworkers18Parambil J.G. Tavee J. Zhou L. et al.Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis.Respir Med. 2010; 105: 101-105Abstract Full Text Full Text PDF Scopus (64) Google Scholar describes the use of intravenous immunoglobulin for sarcoidosis associated small fiber neuropathy in three patients. These patients' neuropathic symptoms failed to respond to corticosteroids (2 patients), methotrexate (2 patients), and infliximab (2 patients), even though the latter agent has been reported to be effective in a previous case report.19Hoitsma E. Faber C.G. van Santen-Hoeufft M. et al.Improvement of small fiber neuropathy in a sarcoidosis patient after treatment with infliximab.Sarcoidosis Vasc Diffuse Lung Dis. 2006; 23: 73-77PubMed Google Scholar Intravenous immunoglobulin has been shown to be effective in previous case series of small fiber neuropathy related to other inflammatory syndromes.20Wakasugi D. Kato T. Gono T. et al.Extreme efficacy of intravenous immunoglobulin therapy for severe burning pain in a patient with small fiber neuropathy associated with primary Sjogren's syndrome.Mod Rheumatol. 2009; 19: 437-440PubMed Google Scholar, 21Souayah N. Chin R.L. Brannagan T.H. et al.Effect of intravenous immunoglobulin on cerebellar ataxia and neuropathic pain associated with celiac disease.Eur J Neurol. 2008; 15: 1300-1303Crossref PubMed Scopus (44) Google Scholar Clearly, this small case series does not prove that intravenous immunoglobulin is effective, much less the superior agent for sarcoidosis associated small fiber neuropathy. However, these data supply the rationale to consider this therapy when faced with a sarcoidosis patient with small fiber neuropathy who has failed standard anti-sarcoidosis treatment. These two papers provide two small flashlights to survey an important clinical issue for sarcoidosis patients that currently remains shrouded in the dark abyss of the sarcoidosis sea. It will require much more work to shine a beacon on this problem. Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosisRespiratory MedicineVol. 105Issue 1PreviewSmall fiber neuropathy (SFN) is commonly associated with sarcoidosis and can cause significant morbidity to afflicted patients. The appropriate treatment of this condition, when associated with sarcoidosis, is not well established. Full-Text PDF Open ArchiveThe small fiber neuropathy screening list: Construction and cross-validation in sarcoidosisRespiratory MedicineVol. 105Issue 1PreviewSmall fiber neuropathy (SFN) appears to be relatively common in sarcoidosis patients. However, there is no golden standard to establish SFN and diagnostic tests for SFN are not widely available. There is a need for an easy to administer SFN screening instrument for clinical assessment, research or therapeutic trials. The aim of the present study was to develop a screening list to identify sarcoidosis patients with SFN in general clinical practice. Full-Text PDF Open Archive
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