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Current and Neuroscience Reports (2019) 19:103 https://doi.org/10.1007/s11910-019-1020-1

NERVE AND MUSCLE (L.H. WEIMER, SECTION EDITOR)

Current Diagnosis and Treatment of Painful Small Fiber Neuropathy

Khosro Farhad1,2

# Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract Purpose of Review Small fiber neuropathy (SFN) could cause significant morbidity due to neuropathic and autonomic dysfunction. SFN is underdiagnosed and the knowledge on the condition is limited among general public and health care professionals. This review is intended to enhance the understanding of SFN symptoms, causes, diagnostic tools, and therapeutic options. Recent Findings There is evidence of SFN in up to 40% patients with . The causes of SFN are metabolism defect, dysimmune, sensitivity and celiac disease, monoclonal gammopathy, deficiencies, toxic agents, , and unknown etiology. Auto-antibodies targeting neuronal antigens trisulfated heparin disaccharide (TS-HDS) and fibroblast growth factor 3 (FGFR3) are found in up to 20% of patients with SFN. Treatment of SFN includes treating the etiology and managing symptoms. Summary SFN should be considered in patients with wide-spread body pain. The search for known causes of SFN is a crucial step in disease management.

Keywords Small fiber neuropathy . . Fibromyalgia . TS-HDS . FGFR3 .

Introduction understand the symptoms and learn about the diagnostic tools for early detection. Searching for possible known causes of Small fiber neuropathy (SFN) occurs as a result of to SFN and starting patients on appropriate treatments are impor- the small unmyelinated C or thinly myelinated (Aδ) tant to reduce the burden of the disease. fibers, which have both sensory and autonomic functions [1, 2, 3••]. Patients with SFN present with a variety of subjective symptoms and minimal abnormalities in or conventual neurological testing [3••]. Clinical Features Many of these patients remain undiagnosed for a long pe- riod of time as the condition is not well known to the Symptoms of small fiber neuropathy vary widely. Many indi- healthcare community and general public. SFN could lead to viduals report gradual or abrupt onset of sensory symptoms in disabling symptoms due to and autonomic feet such as numbness and sensory loss, the feeling of a dysfunction. The aim of this review is to provide more infor- wrinkle in a sock that cannot be removed or of small mation on SFN to health care professionals to better pebbles or sand in the shoe. Discomfort and pain are common in SFN and 65–80% of patients experience elec- tric shock–like pain, cold-like pain, itching, burning, tin- This article is part of the Topical Collection on Nerve and Muscle gling, pins, and needles feeling [4]. SFN patients generally present with a symmetric length- * Khosro Farhad dependent: stocking-glove distribution of sensory changes, [email protected] starting in the feet, gradually climbing up the legs and later •• 1 Department of Neurology at Massachusetts General Hospital, affecting the hands [5 ]. This pattern is commonly seen in Harvard Medical School, 55 Fruit Street, WAC 835, patients with . SFN occasionally presents in a non- Boston, MA 02114, USA length dependent pattern with patchy and asymmetric distri- 2 Wentworth Health Partners, 121 Corporate Drive, bution of neuropathic symptoms with involvement of the face, Portsmouth, NH 03801, USA scalp, proximal limbs, and trunk. This phenotype of SFN is 103 Page 2 of 8 Curr Neurol Neurosci Rep (2019) 19:103 primarily caused by sensory ganglionopathy (or sensory cases per 100,000 inhabitants per year. The overall minimum neuronopathy) rather than axonopathy and is thought to be prevalence was 52.95 cases per 100,000. Incidence and prev- mostly caused by dysimmune, toxic or idiopathic etiologies alence rates were higher in male and old compared to female [3••, 5••]. and young population [13]. The severity of symptoms varies in intensity throughout the SFN is under-diagnosed and therefore its incidence and day and they are typically worse during periods of rest and at prevalence are underestimated [3••]. night. In addition to spontaneous pain, many individuals re- There is evidence of SFN in up to 40% of patients with port and hyperesthesia. SFN patients frequently re- widespread body pain who fulfill the American College of port the bed sheets feeling painful to touch their feet, and Rheumatology Criteria for the diagnosis of fibromyalgia therefore, they wear socks or use “foot tents” to keep the [14•, 15–20, 21•, 22]. The prevalence of fibromyalgia in sheets from making physical contact with the feet [4]. general population is between 0.2 and 6.6% in different Some patients with SFN may present with erythromelalgia studies [23]. Considering possibility of small fiber neu- phenotype. They experience erythematous and hot, burning ropathy in up to 40% of these patients, the prevalence of sensation on the skin primarily triggered by heat [6]. SFN could be significantly higher than the Netherlands Small fiber neuropathy may result in autonomic dysfunc- study, possibly more than tens of millions of cases world- tion affecting different body systems and symptoms include wide [3••, 11••]. dry eyes, dry mouth, pupillary and ciliary dysfunction causing photosensitivity and blurry vision, postural orthostatic tachy- cardia syndrome (POTS), neurogenic , Physical Examination presyncope, syncope, abnormal sweating, in male, painful intercourse in female, , , diar- Patients with SFN generally have normal motor, coordination, rhea, , early satiety, urinary frequency, urinary deep tendon , and gait examination. Reduced distal sen- hesitancy or , hot flashes, , and sation to pinprick, temperature, and, in some individuals to other symptoms [6, 7]. vibration, are the abnormal findings [24, 25]. Skin changes Reduced venous contraction in limbs of SFN patients due to with dry, cracked, or shiny skin are not uncommon [4]. , may result in decreased blood return to the heart Physical exam may also include testing pupillary reaction to and cause preload failure and impaired perfusion to tissues. light, orthostatic vital signs, skin examination to look for dys- Among 229 patients with chronic fatigue attributed to preload trophic changes, discoloration, and distal hair loss [3••]. There failure, 31% had evidence of SFN in skin biopsy [3••, 8]. is evidence of early large fiber in some patients with In a subset of patients with SFN, autonomic function is small fiber neuropathy which may explain the finding of distal affected disproportionately relative to sensory function, and large fiber dysfunction in [26]. symptoms may precede sensory symptoms [6]. Somatosensory small nerve fibers also have non-sensory functions such as sweating and small blood vessel tone control Diagnosis [9, 10, 11••]. Most SFN patients with sensory complaints such as neuropathic pain also have autonomic symptoms [3••, Conventional electrodiagnostic testing for the diagnosis of 11••]. (nerve conduction studies and electro- Dr. Levine has proposed a classification for different phe- myography) is normal in patients with pure small fiber neu- notypes of SFN based on skin biopsy results, sodium channel ropathy. These techniques are designed to evaluate large nerve mutation genetic testing, symptoms of widespread body pain fiber function. and predominant autonomic symptoms. The four suggested There is no defined criteria for the diagnosis of SFN. [3••, classes are small fiber sodium channel dysfunction, small 27]. fiber–mediated painful neuropathy, small fiber–mediated Neurological societies including American Academy of widespread pain, and small fiber–mediated autonomic dys- Neurology (AAN) and European Federation of function [12••]. These classification criteria may help with Neurological Societies/Peripheral Nerve Society developing standardized therapeutic guidelines in the future (EFNS/PNS) endorse the use of skin biopsy from the dis- and further research is needed. tal leg and autonomic function testing (AFT), which de- tects autonomic and sudomotor small-fiber activity, for the diagnosis of small fiber neuropathy [28, 29]. Epidemiology Distal leg skin biopsy with quantification of the linear den- sity of intraepidermal nerve fibers (IENF), using generally In one study from the Netherlands on 88 patients with SFN, agreed upon counting rules, is a reliable and efficient tech- the overall minimum incidence over 2010 and 2011 was 11.73 nique for the diagnosis of SFN [29].Theprocedureis Curr Neurol Neurosci Rep (2019) 19:103 Page 3 of 8 103 performed using a 3-mm punch skin biopsy from the distal leg iontophoresis) in response to the electric stimulus. This is a (10 cm above the lateral malleolus). An additional biopsy non-invasive, safe, and quick method for diagnosis of SFN from the proximal thigh may provide information about both [39, 40]. Patients place palms of their hands and soles of their length-dependent and non-length-dependent SFN [29, 30]. feet on metal electrodes for 2–3 min and a low-voltage (< 4 V) The sensitivity of the distal leg skin biopsy in the diagnosis electrical current stimulus will be applied to the electrodes. of small fiber neuropathy has been reported to be higher than Several studies have shown correlation between the findings 80% and specificity of up to 90% [3••, 5••, 27]. and epidermal nerve fiber density [39, 41]. A recent study by AFT is a non-invasive test for evaluation of cardiovagal, Rajan et al. did a systematic review of 37 studies on ESC and sudomotor, and adrenergic autonomic functions. Cardiovagal reported inconsistency in normative values across publica- function is typically evaluated by testing heart rate response to tions and lack of high sensitivity and specificity of the test in deep breathing and to the Valsalva maneuver. Sympathetic large combined data sets. The authors concluded that there is post-ganglionic cholinergic sudomotor fibers are evaluated insufficient evidence that Sudoscan reliably tests sudomotor with the quantitative sudomotor reflex test (QSART). and fiber functions [42]. Adrenergic function is evaluated by the blood pressure and heart rate responses to the Valsalva maneuver and to 70- Etiology A wide range of medical conditions are known to degree head-up tilt [31]. cause peripheral neuropathy including: metabolic abnormali- AFTshould be considered in the evaluation of patients with ties, immune-mediated and inflammatory conditions, vitamin suspected autonomic neuropathy and may be considered in and mineral deficiencies, , celiac disease the evaluation of patients with suspected distal SFN [28]. and gluten sensitivity, monoclonal gammopathies, toxins, ge- QSART has a sensitivity of 80% in the diagnosis of small netic, Ehlers-Danlos Syndrome/joint hypermobility, infec- fiber neuropathy [32]. tions and post-infectious processes, cancer-related/ Quantitative sensory testing (QST) is a method used to paraneoplastic, amyloidosis, and degenerative causes quantify somatosensory function in response to controlled (Table 1). Diabetes and borderline diabetes are the most com- stimuli. It is based on measurements of responses to calibrat- mon causes. The etiology of SFN remains idiopathic in more ed, graded mechanical and thermal stimuli. QST has been than half of the cases [13, 43, 44, 45•, 46••]. used in the research setting and has several limitations, such Metabolic syndrome is considered a risk factor for small as its inability to differentiate between central and peripheral fiber neuropathy. There is evidence of glucose metabolism disease, the requirement for participant coop- eration, and it may be easily confounded by other factors [33]. Table 1 Causes of small fiber neuropathy The sensitivity and specificity of QST as a diagnostic tool has been a variable in different reports. The ability of QST to Metabolic: diabetes, borderline diabetes, untreated thyroid disorder (hyper or hypothyroid), hypertriglyceridemia/dyslipidemia/metabolic detect sensory deficit is complementary to that of standard syndrome clinical examination. QST is not recommended to be used as Autoimmune/inflammatory: Sjögren’s syndrome, erythematosus, thesinglediagnostictool[34]. , , , inflammatory bowel Corneal confocal microscopy (CCM) is a non-invasive test disease, celiac disease/gluten sensitivity Vitamin/micronutrient related: B12, B6, B1, E, and copper to study human corneal in vivo. The sub-basal nerve deficiencies/B6 toxicity plexus has received the most attention in literature for the Toxic: chemotherapeutic agents (taxanes, platinum family, vinca diagnosis of [35, 36]. The cornea is the alkaloids, , , epothilones, and arsenic trioxide), transparent anterior part of the eye, which is the most densely (, oxazolidinones, , , and fluoroquinolones), anti-retroviral , gout medications innervated tissue in human body through ophthalmic division (, ), heavy metal toxicity (lead, arsenic, mercury, (V1) of the trigeminal nerve [36, 37]. The cornea consists of thallium), and excessive alcohol use. the epithelium, stroma, and endothelium layers. The nerve Infectious agents: Lyme, human immunodeficiency virus (HIV), herpes fibers in cornea are distributed 3 different anatomical loca- simplex virus (HSV), varicella zoster virus (VZV), Cytomegalovirus (CMV), -C virus (HCV), hepatitis-B virus (HBV), tions: the sub-basal plexus (under the basal layer of the epi- Post infectious thelium), the subepithelial plexus, and the stromal nerves [35]. Monoclonal gammopathy of undetermined significance (MGUS) This technique is useful for confirmation of the diagnosis of Paraneoplastic and cancer related SFNinpatientswithsymptomsinV1branchoftrigeminal Amyloidosis: transthyretin or familial (TTR), light chain (AL), secondary/autoimmune (AA) nerve territory. Recent study provides further evidence for Genetic: sodium channel mutations (SCN9A, SCN10A, SCN11A), small nerve fiber injury in by use Fabry’s Disease, other genetic of CCM [38]. Ehlers-Danlos syndrome/joint hypermobility syndrome ’ The Sudoscan device (Impeto Medical, Paris, France) mea- Degenerative (associated with Parkinson s disease or multisystem atrophy) sures electrochemical skin conductance (ESC) which is the Idiopathic current produced by sweat chloride ions (reverse 103 Page 4 of 8 Curr Neurol Neurosci Rep (2019) 19:103 defect in many of these patients [47, 48]. Components of (FAP) is an inherited condition that presents metabolic syndrome, including hypertriglyceridemia, are as a progressive polyneuropathy. Symptoms usually present thought to be a risk factor for neuropathy [49]. Neuropathy with painful SFN and could also affect large myelinated fi- prevalence is high in the obese population even in those with bers. dysfunction is common in normoglycemia. Diabetes, pre-diabetes, and obesity are the these patients [61]. FAP affects multiple organs including the most likely risk factors [50]. heart, peripheral nervous system, and kidneys. Most of the SFN could be caused by dysimmune mechanism in patients patient do not survive beyond 10 years of the diagnosis with with known autoimmune diseases such as systemic lupus er- no therapeutic intervention [62]. TTR is a homo-tetrameric ythematosus (SLE), Sjogren’s syndrome, rheumatoid arthritis, plasma protein produced primarily by the liver. Mutations in sarcoidosis, vasculitis, and inflammatory bowel disease. The TTR destabilize the tetramer, enabling monomers to misfold specific mechanism of nerve injury in these patients with and mis-assemble into amyloid, deposited in tissues causing “dysimmune neuropathy” is not well known. Celiac disease neurodegeneration, and other . The identified ab- and gluten sensitivity also may result in SFN [51, 52]. normal amyloid fibril was found to be the result of a substi- , B6, B1, E, and copper deficiencies are tution of methionine for valine at position 30 of the known causes of peripheral neuropathy [45•]. High doses of transthyretin gene (TTR, Val30Met). More than 100 TTR vitamin B6 supplements can cause sensory neuropathy/ mutations have been linked to TTR-FAP, Val30Met neuronopathy. Authorities in the USA set the “non-ob- (V30 M) is the most common pathogenic point mutation that served-adverse-effect” level at 200 mg daily and safe upper causes FAP worldwide [61]. limit of 100 mg per day [45•, 53]. Ehlers-Danlos syndrome (EDS) is a spectrum of ge- Toxic neuropathy is commonly caused by the use of che- netic connective tissue disorders primarily characterized motherapeutic agents; primarily taxanes, platinum family, vin- by joint hypermobility, skin texture abnormalities, and ca alkaloids, thalidomide, bortezomib, epothilones, and arse- visceral/vascular dysfunctions. Most patients with EDS nic trioxide [54, 55•, 56]. Exposure to some antibiotics also suffer from which affects their quality of hasbeenreportedtobeassociatedwithneuropathyincluding life [63]. These patients have both musculoskeletal and isoniazid, oxazolidinones, nitrofurantoin, metronidazole, and neuropathic pain. The musculoskeletal pain is primarily fluoroquinolones [56–58]. Certain antiretroviral medications, causedbyligamentlaxityleadingtojointinstabilitypre- primarily nucleoside reverse transcriptase inhibitors (NRTI) disposing to traumatic injury [64]. Neuropathic pain is a and protease inhibitors (PI), also have potential peripheral common feature in EDS patients caused by entrapment nerve toxicity. Other potentially neurotoxic medications in- neuropathies due to connective tissue disease and SFN clude , long-term use of , tumor necrosis [65]. Recent study has shown high prevalence of signif- factor alpha inhibitors, leflunomide, and triazoles [56]. icant reduction of intraepidermal nerve fiber density in Alcohol and its metabolites have direct neurotoxic effects EDS patients [64]. The mechanism of small nerve fiber on small C fibers. There are other risk factors for neuropathy degeneration in these patients is unclear. Autonomic in alcoholic patients such as deficiency, toxicity with complaints, especially POTS and gastrointestinal and accumulation of impurities (e.g., lead) in certain types of al- bladder dysfunction are common in patients with EDS coholic drinks, and systemic diseases caused by excessive hypermobility type [66–68]. alcohol use. Several clinical studies have shown that the total Parkinson’s disease was traditionally thought to be a neu- lifetime amount of alcohol consumption is significantly corre- rodegenerative disease of the central nervous system. There is lated with the risk of peripheral neuropathy. It has been esti- a substantial body of evidence on peripheral nerve pathology mated that the lifetime consumption of more than 15 kg of in these patients. Phosphorylated alpha-synuclein deposits alcohol per 1 kg of body weight is a risk factor for develop- were seen in cutaneous C fibers, autonomic nerves of the ment of neuropathy [54, 59]. colon and cardiac plexus [5••, 69–74]. Small fiber/ A number of infectious agents are known to injure small autonomic and large fiber neuropathy are common in patients nerve fibers, including Lyme, hepatitis C or B, leprosy, herpes with Parkinson’s disease and Parkinsonism [75–77]. The ad- simplex 1 and 2, varicella zoster, and Cytomegalovirus [45•, ditional role of long-term exposure to levodopa in peripheral 60]. Many patients with SFN report a presumed viral upper neuropathy in these patients has been suggested by some au- respiratory tract or gastrointestinal as the trigger for thors [78–81]. the onset of their symptoms. Dysimmune mechanism is believed to be the underlying The amyloidoses are a group of disorders that may present cause in a subgroup of SFN patients with known or unknown with a diverse spectrum of clinical manifestations. These are [3••]. One of the recently studied anti- characterized by tissue deposition of insoluble, misfolded fi- bodies in SFN patients is IgM binding to IdoA2S-GlcNS-6S, a bril proteins that cause disruption of normal tissue structure trisulfated heparin disaccharide (TS-HDS) by Pestronk et al. and function [61]. Transthyretin (TTR) Familial amyloidosis [82]. They retrospectively compared 58 patients with selective Curr Neurol Neurosci Rep (2019) 19:103 Page 5 of 8 103

IgM binding to TS-HDS to 41 consecutive patients with , , , , sodi- without TS-HDS binding. The authors con- um , , , ), cluded that serum IgM binding to TS-HDS is associated with , topical agents (, , other com- painful, primarily sensory, non-length polyneuropathy with pound medications), , and neuromodulation [3••, 5••]. more common symptoms of hand discomfort, presence of The choice of the is made based on safety profile, IgM M-proteins, and evidence of capillary pathology. concomitant medication use, and other comorbidities. Biopsies showed thickened basal lamina and C5b9 comple- There are several evidence-based guidelines for manage- ment deposition in capillaries. Serum IgM binding to TS-HDS ment of painful neuropathy. Both American Academy of suggests a possible dysimmune etiology as the cause of some Neurology (AAN) and European Federation of Neurological sensory polyneuropathies [22, 82]. Societies (EFNS) have published guidelines on the pharma- The diagnostic accuracy of serum antibodies against the cologic management of painful diabetic peripheral neuropathy intracellular domain of fibroblast growth factor receptor 3 [86, 87]. Both guidelines support the use of tricyclic antide- (FGFR3) was tested to identify a subgroup of patients who pressants, pregabalin, , various , serotonin, have developed a sensory disorder [83]. Anti-FGFR3 and norepinephrine reuptake inhibitors (SNRIs), and topical antibodies (Ab) were detected in 16 out of 106 patients with lidocaine for the treatment of neuropathic pain. The AAN SFN and 1 out of 211 controls. Anti-FGFR3 Ab identifies a guidelines also recommend the use of topical capsaicin, subgroup of patients with SFN in whom an underlying auto- valproate and pregabalin. Medications generally have similar immune disorder is suspected to cause damage to sensory efficacy in treatment of neuropathic pain. [87]. in the dorsal root ganglia and trigeminal nerve gan- Liver transplantation has traditionally been the standard glion. Neuropathy in this group of patients is non-length de- treatment for TTR-FAP despite continued deposition of pendent in 87% of cases [83]. One study on a heterogenous wild-type transthyretin. The US Food and Drug group of 7 patients with neuropathy and positive FGFR3 Administration and the European Commission have approved Ab, repeated testing revealed absence of antibodies in 2 patisiran and inotersen as treatments for TTR-FAP. Patisiran is patients and a significant reduction of the Ab titer in one an RNA interference agent that inhibits hepatic synthesis of patient without any immunotherapy intervention. The au- transthyretin. In a double-blind placebo-controlled phase III thors highlighted the variability and inconsistency in trial, 225 patients were randomized to either intravenous FGFR3AbtitersthroughELISAtestingandadvisedcau- patisiran or placebo every three weeks. Patients receiving tion in interpreting the results [84]. patisiran had a significant improvement in their neuropathy symptoms [53]. In addition, a large phase III randomized double-blind placebo-controlled trial of inotersen, an anti- Treatment sense oligonucleotide that inhibits the hepatic production of transthyretin, has been published. A total of 172 patients (112 Treatment of SFN has two fronts: management of symptoms in the inotersen group and 60 in the placebo group) were given and interventions to address the root cause of the neuropathy. weekly subcutaneous injections for 66 weeks. As in the Peripheral nerves have the capacity to regenerate [85]. patisiran trial, the treatment arm also significantly improved Interfering with the process leading to axonal loss could stop on their neuropathy symptoms [26]. and reverse the process. The treatment options are variable More recently tafamidis was approved by the FDA for treat- based on the underlying cause. Treatment of autonomic symp- ment of cardiomyopathy caused by TTR amyloidosis [53]. toms will not be discussed here. Tafamidis binds to TTR at the thyroxine-binding sites, stabiliz- Addressing the root cause of SFN should be the main strat- ing the tetramer and slowing dissociation into monomers, the egy in management of SFN in patients with known cause. The rate-limiting step in the amyloidogenic process [26]. Diflunisal, intervention is evidently variably based on the etiology a non-steroidal anti-inflammatory drug, strongly inhibits TTR (Table 1) and involves: Correcting metabolic or hormonal de- amyloid fibril formation and has shown promising results in rangement, immunomodulation, replacing deficient vitamin/ large randomized placebo-controlled clinical trials [88]. mineral, eliminating toxic agent, and treating infectious disease. Evidence to support treatment options for dysimmune neu- Symptom management focuses on treating painful sensory ropathies is limited. It is important to consider that there is no symptoms vs. autonomic symptoms. The management options FDA-approved treatment available for SFN. The following for autonomic symptoms are wide and will not be discussed discussion is based on expert opinions, case reports, retrospec- here. The management of neuropathic pain has been a chal- tive studies, small prospective studies, and not based on ran- lenging task for neurologists [46••]. The neuropathic pain med- domized placebo-controlled trials. ications in neurology practice are generally selected among: In a small uncontrolled study for treatment of SFN in the antidepressants (, , , setting of Sjogren’s syndrome, all 5 patients showed a remark- , ), (gabapentin, able improvement in neuropathic pain scores following 0.4 g/kg/ 103 Page 6 of 8 Curr Neurol Neurosci Rep (2019) 19:103 day for 5 days treatment with intravenous immunoglobulin Conclusion (IVIG). The benefit persisted for 2 to 6 months [89]. There was a case report of successful treatment with trial of intravenous SFN is an underdiagnosed neurological condition due to nor- immunoglobulin in patient with Sjogren’s syndrome [90]. mal or near-normal physical examination and electrophysio- A retrospective review of 115 patients with sarcoidosis, the logical testing. The diagnosis is confirmed by skin biopsy, SFN treatment response rates were 76%, 67%, and 71% for autonomic function testing, corneal confocal microscopy, or treatment with intravenous immunoglobulins, anti-TNF-α, other techniques. The etiology of SFN is heterogenous and up and combination therapy with both agents, respectively. The to 50% of patients remain idiopathic. Treatment options focus neuropathic symptoms in patients treated with methotrexate or on addressing the root cause of neuropathy, if one found, and corticosteroids remained the same or worsened [91•]. symptomatic treatment for neuropathic pain or autonomic The effect of IVIG was evaluated on 55 patients with SFN symptoms. The long-term prognosis of the disease has been who were diagnosed based on skin biopsy, autonomic func- promising with close to 5% of long-term disability. Further tion testing (AFT), or nerve biopsy in a recent study. Twenty- studies are needed to prove the role of immunotherapy in seven percent of the patients had known systemic autoimmune management of subgroup of SFN patients with presumed disease and 80% had abnormal lab results suggestive of auto- dysimmune etiology. Despite reports of benefits from immu- immunity. IVIG treatment duration averaged 28 ± 25 months. notherapy in a subgroup of patient with known autoimmune The proportion of AFT results interpreted as indicating SFN causes for SFN, the long-term outcome of these treatments is dropped from 89% at baseline to 55%. Sweat production nor- unknown [3••]. malized and there was improvement in AFT. The neuropathic pain significantly reduced. Overall, 74% of patients consid- Compliance with Ethical Standards ered themselves “improved” on questionnaire and 77% of the patients were considered as “IVIG responders” by their neu- Conflict of Interest Khosro Farhad declares no potential conflicts of rologist. Sixteen percent had sustained remissions after stop- interest. ping IVIG [11••]. Human and Animal Rights and Informed Consent This article does not TS-HDS and FGFR-3 antibodies are detected in up to 20% contain any studies with human or animal subjects performed by any of of idiopathic SFN patients. These antibodies are rare in pa- the authors. tients without SFN. There was a report of favorable results of treatment with IVIG at 2-gram per kilogram of the weight per month for 6 months in 3 patients. Skin biopsies for IENFD References and patient self-reported pain scores at baseline and after 6 months of therapy showed improvement in all patients. Papers of particular interest, published recently, have been The investigators concluded that TS-HDS and FGFR-3 anti- highlighted as: bodies may be markers for a subtype of dysimmune SFN • Of importance patient who may benefit from immunotherapy with IVIG •• Of major importance [92]. A clinical trial on use of IVIG is recruiting patients with SFN and positive TS-HDS or FGFR3 antibodies [93•]. 1. Tavee J, Zhou L. Small fiber neuropathy: a burning problem. Cleve Clin J Med. 2009;76(5):297–305. 2. Hsieh ST. Pathology and functional diagnosis of small-fiber painful neuropathy. Acta Neurol Taiwanica. 2010;19(2):82–9. 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