Small-fiber neuropathy: not a small matter!

<p class="article-intro">The term «small-fiber neuropathy» encompasses a heterogeneous group of diseases characterised by dysfunction of thinly myelinated Aδ- and unmyelinated C-fibers. Clinical presenting features are over-/ underfunction of pain and temperature perception combined with autonomic symptoms. Prevalence is not well established with one study giving a rate of 52.95 cases per 100,000/year. Diagnosis of SFN is graded on the level of certainty of isolated involvement of small nerve fibres. Management relies on ascertainment of etiology and its subsequent treatment in combination with treatment of the sensory symptoms.</p> <p class="article-content"><div id="keypoints"> <h2>Keypoints</h2> <ul> <li>Small-fiber neuropathy (SFN) has a prevalence rate of around 50 cases/100,000/year with higher rates in those over 65 years.</li> <li>SFN is defined by sensory symptoms linked to small nerve fiber dysfunction with findings of small-fiber dysfunction on neurological and laboratory examination.</li> <li>SFN shows two main clinical patterns: length dependent and non-length dependent.</li> <li>Diagnostic criteria of SFN grade diagnosis as possible, probable and definite, regardless of etiology.</li> <li>Numerous etiologies are associated with SFN.</li> <li>Gold standard test for confirming a diagnosis of SFN is low intraepidermal nerve fiber (IENF) density at the ankle.</li> </ul> </div> <p>The expression &laquo;small-fiber neuropathy&raquo; was only coined two decades ago and serves the purpose of providing a framework for defining clinical symptomology with underlying disease of the peripheral nerve&rsquo;s small fibers. The advantage of this approach is that it enables identification of clinical syndromes; the disadvantage, that many disease entities tie into this disease pathway resulting in complex disease identifying algorithms.<br /> The term &laquo;small-fiber neuropathy&rdquo; (SFN) is increasingly accepted as a useful clinical characterisation following its original identification as &laquo;distal small-fiber neuropathy&rdquo; in 1992.¹ Crucial to establishing the concept of SFN was the identification and linking of clinical features of SFN with different types of laboratory confirmation.<br /> In the following is a brief overview of SFN. For a more in-depth analysis the reader is referred to recent articles.^{2, 3} This review highlights the current approach in the clinical classification, laboratory confirmation techniques and brief treatment principles.</p> <h2>Clinical presentation</h2> <p>Small-fiber neuropathy (SFN) is defined by sensory symptoms linked to small nerve fiber dysfunction with findings of small-fiber dysfunction on neurological examination.¹ SFN is represented by dysfunction of thinly myelinated A&delta;- and unmyelinated C-fibers which convey the presenting features of over-/underfunction of pain and temperature perception combined with secondary autonomic symptoms.³ If clinical features are not specifically looked for in the neurological examination, disease recognition is unlikely.</p> <p>SFN shows two main clinical patterns: length dependent and non-length dependant.³ Typical complaints for all types of SFN are painful sensations described as burning, pricking, shooting, painful aching often affected by changes in temperature and exertion.⁴ Cooling of the affected region (mostly toes/feet) often results in amelioration of burning and paroxysmal complaints (personal observation). Additional symptoms include itching and restless legs. Because of the diversity of anatomical involvement, the non-length dependent form of SFN is particularly easy to misdiagnose. Features suggestive of non-length dependent SFN include 1) involvement of the proximal regions of the limbs, face, or trunk, 2) onset of symptoms in the face, scalp, mouth, tongue, trunk, hands, arms or proximal legs before the feet and 3) simultaneous pain of proximal and distal regions of the limbs.³ Length dependant SFN is recognised by sensory symptoms beginning in the toes which over time move proximally and to the fingers.<br /> One should not forget that small nerve fibers drive autonomic function and often show involvement, causing additional symptoms of postural hypotension, hyper-/ hypohidrosis, constipation/diarrhoea and genitourinary dysfunction.<br /> To detect and classify SFN the physical examination focuses on the presence of impaired (increased and or decreased) temperature/pinprick sensation, hyperesthesia and brush allodynia. Although more difficult to elicit in the clinical examination, detection of the wind-up phenomenon, an increase in pain perception with repeated stimulation, can be a useful additional indicator.⁵ It is important to ascertain normality of large-fiber nerve function by documenting normal motor power, deep tendon reflexes, light touch, proprioception and vibration.³</p> <h2>Epidemiology and etiology</h2> <p>Few studies exist regarding the epidemiology of SFN. One study, performed in the Netherlands, gives a minimum incidence of 11.73 cases (15.6 male/8.2 female) per 100,000/year with higher rates in those over 65 years.⁶ Prevalence was 52.95 cases (60.9 male/45.4 female) per 100,000/year. It is likely that causes of SFN vary with geographical location, genetic makeup, and multiple environmental factors. This is reflected by studies highlighting different percentages of etiological factors in the identification of underlying SFN etiology. In a study conducted in the Czech Republic, diabetes mellitus was identified as the most frequent and powerful risk factor for SFN.⁷ A study performed in the USA highlighted idiopathic as the most common etiology of SFN (73 % ), followed by presumed hereditary (18 % ) causation, and diabetes mellitus (10 % ).⁸ A different study from the USA highlighted that up to 40 % of patients with sarcoidosis suffer from SFN.⁹<br /> In clinical practice, the length dependent form initiating with symptoms in the toes is more common than the non-length dependent form.¹⁰ The non-length dependent form is associated with younger age, female gender and immune mediated conditions.<br /> It should be remembered that although most cases associated with diabetes mellitus are thought to be due to the longterm effects of hyperglycemia on the small fibers of the peripheral nerve, there is evidence that a significant proportion of newly diagnosed diabetics develops SFN &ndash; featuring severe pain and autonomic dysfunction &ndash; with initiation of normoglycemia. Data suggests that small nerve fibers are vulnerable to acute dysfunction related to rapid improvement in glucose control.¹¹<br /> Since many differing pathologies can affect the small nerve fibers, it is useful to distinguish between diseases where the target organ is isolated in the form of the small nerve fibers and ones that are part of multiple organ involvement. Isolated SFN is represented by three main groups: sodium channelopathies (inherited), smallfiber sensory Guillain-Barr&eacute; syndrome and idiopathic causes. Diagnosis for hereditary causes is increasingly possible via direct genetic testing.^{12, 13} Table 1 lists the etiological factors associated with SFN.</p> <h2>Diagnosis</h2> <p>The graded diagnostic criteria for use in all forms of SFN regardless of etiology are: 1) possible SFN: the presence of length-dependent symptoms and/or clinical signs of small-fiber damage; 2) probable SFN: the presence of length-dependent symptoms, clinical signs of small-fiber damage, and normal sural nerve conduction study; 3) definite SFN: the presence of length-dependent symptoms, clinical signs of small-fiber damage, normal sural nerve conduction study, and low intra-epidermal nerve fiber (IENF) density at the ankle and/or abnormal quantitative sensory testing thermal thresholds at the foot.¹⁴</p> <p>In patients suspected of SFN, the initial step is to exclude large-fiber nerve involvement using a nerve conduction test. If this is normal, baseline blood tests should be performed and environmental or genetic factors should be considered.³ Which tests to include will depend on the local prevalence of diseases associated with SFN.</p> <h2>Small-fiber tests</h2> <p>The generally accepted gold standard test for confirming a diagnosis of SFN is low intra-epidermal nerve fiber density (IENFD), established using skin punch biopsy, at the ankle. The test requires special expertise and is costly. Age- and sex-adjusted normative reference values of IENFD density are available, allowing the diagnosis of SFN to be made in individual patients.¹⁵</p> <p>Other useful tests include the quantitative sudomotor axon reflex test (QSART), which quantifies sweat secretion based on iontophoresis of acetylcholine at standardised skin regions.²<br /> An ideal test for screening purposes is the stimulated skin wrinkling test with EMLA. It has 81.6 % sensitivity and 74.7 % specificity in detecting abnormal IENFD in patients diagnosed with idiopathic SFN.¹⁶ The process underlying stimulated skin wrinkling has been identified as dependent on digital vasoconstriction mediated via sympathetic nerve fibers.¹⁷ The test has been developed into a semi-quantitative bedside test.¹⁸<br /> Quantitative sensory testing can also be used to determine underlying small nerve fiber functional impairment by measuring temperature thresholds. However, variability of instruments and methodological approaches detract from this technique, and challenge its usefulness in individual diagnosis.¹⁹</p> <h2>Management</h2> <p>The management of SFN is divided into ascertainment of etiology and symptomatic treatment. Being able to identify the underlying causation of SFN allows for potential corrective measures of certain underlying diseases to be taken. When treating SFN due to diabetes mellitus, several factors need to be kept in mind. Induction of normoglycemia should &ndash; if possible &ndash; be gentle and gradual since rapid correction of hyperglycemia is itself associated with painful neuropathy.¹¹ Furthermore, improvement of glycemia on its own is generally not sufficient for significantly reducing pain. Additional symptomatic treatment (see below) is necessary in most patients.²⁰<br /> Inflammatory pathways have been variably successfully targeted using immunomodulatory treatment with IVIg or corticosteroids in patients with sarcoidosis, small-fiber GBS and Sj&ouml;gren&rsquo;s syndrome.^21&ndash;24<br /> The most widely recommended symptomatic treatments for SFN pain, as first line, are the tricyclic antidepressants (e.g. amitriptyline, imipramine), the serotonin norepinephrine reuptake inhibitors (SNRIs, in particular duloxetine²⁵), and the anticonvulsants pregabalin and gabapentin.³ Topical lidocaine and capsaicin have been recommended as first line for localized neuropathic pain but are difficult to use in practice because of issues with application in the presence of footwear. As second line symptomatic treatments, opioids and tramadol have been proposed but need careful consideration because of their frequent side effects.^{26, 27}</p> <p><img src="/custom/img/files/files_datafiles_data_Zeitungen_2017_Leading Opinions_Neuro_1705_Weblinks_lo_neuro_1705_s7_tab.1.jpg" alt="" width="686" height="2437" /></p></p> <p class="article-footer"> <a class="literatur" data-toggle="collapse" href="#collapseLiteratur" aria-expanded="false" aria-controls="collapseLiteratur" >Literatur</a> <div class="collapse" id="collapseLiteratur"> <p><strong>1</strong> Stewart JD et al.: Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes. Muscle Nerve 1992; 15(6): 661-5 <strong>2</strong> Cazzato D and Lauria G: Small fibre neuropathy. Curr Opin Neurol 2017; doi: 10.1097/WCO.0000000000000472. [Epub ahead of print] <strong>3</strong> Chan AC and Wilder-Smith EP: Small fiber neuropathy: Getting bigger! Muscle Nerve 2016; 53(5): 671-82 <strong>4</strong> Lacomis D: Small-fiber neuropathy. Muscle Nerve 2002; 26(2): 173- 88 <strong>5</strong> Lolignier S et al.: Mechanical allodynia. Pflugers Arch 2015; 467(1): 133-9 <strong>6</strong> Peters MJ et al.: Incidence and prevalence of small-fiber neuropathy: a survey in the Netherlands. Neurology 2013: 81(15): 1356-60 <strong>7</strong> Bednarik J et al: Etiology of small-fiber neuropathy. J Peripher Nerv Syst 2009; 14(3): 177-83 <strong>8</strong> Low VA et al: Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve 2006; 34(1): 57-61 <strong>9</strong> Jancin B: Small fiber neuropathy common, vexing in sarcoidosis. Rheumatology News 12th April 2016; http://www.mdedge.com/rheumatologynews ( online article) <strong>10</strong> K han S and Zhou L : Characterization of nonlength- dependent small-fiber sensory neuropathy. Muscle Nerve 2012; 45(1): 86-91 <strong>11</strong> Gibbons CH and Freeman R: Treatment-induced diabetic neuropathy: a reversible painful autonomic neuropathy. Ann Neurol 2010; 67(4): 534-41 <strong>12</strong> Faber CG et al.: Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012; 71(1): 26-39 <strong>13</strong> Faber CG et al.: Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A, 2012; 109(47): 19444-9 <strong>14</strong> Lauria G et al.: Small fibre neuropathy. Curr Opin Neurol 2012; 25(5): 542-9 <strong>15</strong> Lauria G et al.: Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst 2010; 15(3): 202-7 <strong>16</strong> Wilder-Smith EP et al.: Stimulated skin wrinkling for predicting intraepidermal nerve fibre density. Clin Neurophysiol 2009; 120(5): 953-8 <strong>17</strong> Wilder-Smith EP: Stimulated skin wrinkling as an indicator of limb sympathetic function. Clin Neurophysiol 2015; 126(1): 10-6 <strong>18</strong> Ping Ng KW et al.: E MLA-induced s kin wrinkling for the detection of diabetic neuropathy. Front Neurol 2013; 4: 126 <strong>19</strong> Bakkers M et al.: Temperature threshold testing: a systematic review. J Peripher Nerv Syst 2013; 18(1): 7-18 <strong>20</strong> Waldfogel JM et al.: Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review. Neurology 2017; 88(20): 1958-67 <strong>21</strong> Dabby R et al.: A cute s teroid r esponsive s mall-fiber sensory neuropathy: a new entity? J Peripher Nerv Syst 2006; 11(1): 47-52 <strong>22</strong> Parambil JG et al.: Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis. Respir Med 2011; 105(1): 101-5 <strong>23</strong> Seneviratne U and S Gunasekera: Acute small fibre sensory neuropathy: another variant of Guillain-Barr&eacute; syndrome? J Neurol Neurosurg Psychiatry 2002; 72(4): 540-2 <strong>24</strong> Wakasugi D et al.: Extreme efficacy of intravenous immunoglobulin therapy for severe burning pain in a patient with small fiber neuropathy associated with primary Sjogren&rsquo;s syndrome. Mod Rheumatol 2009; 19(4): 437-40 <strong>25</strong> Hossain SM et al.: Duloxetine in painful diabetic neuropathy: A systematic Review. Clin J Pain 2016; 32(11): 1005-10 <strong>26</strong> Bril V et al.: Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM R 2011; 3(4): 345-52, 352 e1-21 <strong>27</strong> Dworkin RH et al.: Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2010; 85(3 Suppl): S3-14</p> </div> </p>