To summarize the recent advances in aetiology, diagnostic Small calibre nerve fibres are distinguished in thinly assessment, and treatment of small fibre neuropathies.
myelinated Ad-fibres and unmyelinated C-fibres. Ad- fibres carry cold sensation, participate in cold and mech- New causes of small fibre neuropathy have been anical nociception, and have preganglionic sympathetic recognized and advances in neurophysiologic and and parasympathetic cholinergic functions. C-fibres con- neuropathologic techniques for investigating small fibres vey warm and nociceptive stimuli, and have postgangli- have been made, increasing the interest in this field. In onic autonomic functions. A subset of C-fibres, known particular, skin biopsy proved to be a sensitive method to as polymodal nociceptors, also responds to chemical diagnose small fibre neuropathy. It allows the detection of and pressure stimuli. C-fibres are differentiated into subclinical abnormalities of peripheral nerve function in mechano-responsive and mechano-insensitive afferents, patients with diabetes and tongue denervation in patients which have different axonal properties and behaviour to with burning mouth syndrome. This technique has also been used to demonstrate the neuroprotective effect oferythropoietin in experimental models of neuropathy.
Although small fibres are frequently involved early in the Among nonconventional neurophysiologic techniques for course of peripheral neuropathies, they cannot be ade- investigating small fibres, laser-evoked potential and quately investigated by routine neurophysiologic exam- contact heat-evoked potential stimulators have been inations. Recently, nonconventional techniques have developed and deserve particular interest. Several trials on been developed and neuropathologic evaluation by skin neuropathic pain that is a typical feature of small fibre biopsy proved to be a reliable diagnostic tool in small fibre neuropathies have been performed and guidelines have No clinical trial has been designed to include specifically Detection of small fibre impairment allows earlier diagnosis patients with small fibre neuropathy; however, several of neuropathy and could be used as an outcome measure in studies demonstrated the usefulness of different pharma- future regenerative neuropathy trials. Standardization of cological treatments in painful neuropathies, in which skin biopsy can have an important impact on clinical pathogenesis small fibres are likely involved.
practice and research. Further studies are needed toassess the reliability of current neurophysiologic techniques for testing small fibre function in peripheral neuropathies Small fibre neuropathies refer to a subtype of peri- and the correlation with well established neuropathologic pheral neuropathies characterized by the impairment of thinly myelinated Ad and unmyelinated C-fibres. Itimplies that both somatic and autonomic fibres may be involved, thus leading to sensory and autonomic neuro- autonomic neuropathy, nerve conduction study, painful pathies. Isolated autonomic neuropathies are rare neuropathy, skin biopsy, small fibre neuropathy Symptoms of somatic nerve fibre dysfunction, such asburning, pain, and hyperaesthesia, frequently prevail Curr Opin Neurol 18:591–597. ß 2005 Lippincott Williams & Wilkins.
over those related to autonomic nerve fibre impairment.
This may explain why the term ‘painful neuropathy’ is Immunology and Muscular Pathology Unit, National Neurological Institute ‘CarloBesta’, Milan, Italy often used as a synonym of small fibre neuropathy, Correspondence to Giuseppe Lauria, Immunology and Muscular Pathology Unit, though it is not correct. In fact, painful symptoms can National Neurological Institute ‘Carlo Besta’, Via Celoria, 11, 20133 Milan, Italy also be a feature of large fibre neuropathies Tel: +39 02 2394 2378; fax: +39 02 7063 3874; e-mail: Current Opinion in Neurology 2005, 18:591–597 Small fibres are currently being explored by reliable neuropathologic and neurophysiologic techniques, but the gold standard for small fibre neuropathy remains primarily based on the clinical ground. There is no consensus yet on whether small fibres should be ex-clusively, or only predominantly, involved in small ß 2005 Lippincott Williams & Wilkins1350-7540 fibre neuropathies. Mild dysfunctions of large nerve fibres, such as reduced Achille’s tendon reflexes or pains frequently occur, can be worse at night and inter- decreased superficial sensation at the distal extremities, fering with sleep. A restless legs syndrome may also with normal routine nerve conduction studies, have coexist When paraesthesias are reported and allo- been generally accepted As previously suggested dynia is found, involvement of large nerve fibres is these criteria were developed for clinical practice expected. Some patients complain of cramps affecting and might not be narrow enough for clinical research the distal legs, which suggest a more widespread mem- purposes assessing the efficacy of neurotrophic or symp- brane hyperexcitability possibly induced by dysfunction tomatic treatments. A better definition of positive sen- of muscle nociceptors. Others also complain of fatigue. A sory symptoms is needed. For instance, paraesthesias, relationship with small fibre neuropathy, however, has which may seldom have a painful component, are com- monly associated with the dysfunction of large nervefibres and should not be included among the Some patients may have cold feet or complain of cold typical symptoms of pure small fibre neuropathy.
and warm hypersensitivity that is likely related to Ad and The limits of routine neurophysiologic examinations C-fibre dysfunction, respectively When patients should be defined. It has recently been demonstrated report attacks of red, hot, and painful extremities, that the conduction of sensory plantar nerves can be induced or aggravated by heating and ameliorated by altered in patients with a clinical picture of small fibre cooling, erythromelalgia should be suspected. This con- neuropathy and normal sural nerve conduction, reflect- dition is associated with small fibre neuropathy and may ing the involvement of very distal branches of large be caused by myeloproliferative diseases, diabetes, infec- nerve fibres Finally, it has been shown that small tions, drugs, and mushroom poisoning Among fibre function is impaired in patients with diabetes stimulus-induced symptoms, allodynia elicited by sheets irrespective of the presence of neuropathy [11Over- or footwear and pain on pressure may be particularly all, these findings suggest the existence of a continuum in distal sensory neuropathies, from pure small to mixed– large and small – fibre dysfunction. Therefore, the Positive sensory symptoms typically have a ‘length- definition of small fibre neuropathy can be restated as ‘a dependent’ distribution and may show a slow progression neuropathy characterised by autonomic abnormalities from feet to knees. Commonly, when symptoms also and/or positive (spontaneous or stimulus-induced) and involve the upper limbs, signs of large fibre dysfunctions negative sensory symptoms, caused by the selective can be observed. Seldom, patients may report a wide- dysfunction of Ad and C-fibres as assessed by specific spread or patchy distribution of symptoms that can be neurophysiologic and neuropathologic tests. Asympto- related to acute idiopathic or immune-mediated small matic impairment of small fibres may occur in certain fibre neuropathy or to sensory neuronopathy  Episodic lancinating pains with acroparaesthesias arereported in Fabry’s disease EpidemiologyThe prevalence of pure small fibre neuropathy is Painful symptoms may be localized, such as in burning unknown because of the lack of focused epidemiologic mouth syndrome, which has recently been associated studies using defined diagnostic criteria It has been with loss of small fibres in the epithelium of the tongue reported that they are relatively rare among sensory Increased density of mucosal small fibres over- neuropathies Nevertheless, impairment of small expressing the capsaicin receptor occurs in rectal hyper- fibres likely occurs early in axonal neuropathies, at least sensitivity and might also be hypothesized in in diabetic neuropathy, as recently shown Impair- vulvodynia though this has never been investigated ment of small fibres is supposed to account for most cases of ‘burning feet’ and, possibly, of burning mouthsyndrome Neurological examination may disclose reduced thermaland pain sensation distally in the feet or at the toe tips.
No longitudinal studies on patients with pure small fibre A pseudosyringomyelic distribution can be found in neuropathy have been specifically designed. Progression patients with Tangier’s disease Early algo-thermal toward a mixed – small and large – fibre neuropathy, anaesthesia involving all the extremities is seen in hereditary sensory and autonomic neuropathies Proprioception and vibratory sensation assessed with the tuning fork should be normal even at the level Positive sensory symptoms, spontaneous or stimulus- of the interphalangeal joint of the large toe, unless a induced, involving the feet commonly dominate the large fibre neuropathy exists. Deep tendon reflexes clinical picture Pain is persisting and described should be retained. There should be no muscle atrophy as burning, prickling, or deep and aching. Lancinating Severe autonomic disturbances are quite rare in pure skin biopsy could be used as an outcome measure in small fibre neuropathies. If present, diabetes, amyloido- sis, immune-mediated or hereditary neuropathy shouldbe considered. Patients may complain of abnormal Pure autonomic neuropathies may have paraneoplastic sweating, flushing, skin decoloration, xerostomia and aetiology. Conversely, pure somatic small fibre neuropa- xerophthalmia, impotence, and, less commonly, of con- thies have never been reported as an isolated feature of stipation or diarrhoea, and orthostatic hypotension paraneoplastic syndromes, though painful neuropathies may be part of them An immune-mediated origin issupposed for several small fibre neuropathies. A patho-genetic link has not been demonstrated yet for several of them, however, including Sjo¨gren’s syndrome, Guillain– Predominant impairment of small fibres can occur in Barre´ syndrome, coeliac disease and inflammatory bowel several types of acquired and hereditary peripheral neu- ropathies Among these, coeliac and inflamma- recently been proposed for the complex regional pain tory bowel diseases and erythromelalgia have recently syndrome a still unknown condition characterized by focal pain and autonomic dysfunctions. Anti-sulfadite ever, particularly in the elderly, their aetiology remains and anti-trisulfated heparin disaccharide antibodies should be assayed in patients with predominant smallfibre neuropathy It has recently been shown that Diabetes is considered one of the most common causes of small fibres are also impaired in typically large fibre small fibre neuropathy because positive sensory symp- immune-mediated neuropathies, such as chronic inflam- toms, including pain, frequently dominate the clinical matory demyelinating polyradiculoneuropathy and picture . In several patients, however, there is also anti-myelin associated glycoprotein neuropathy evidence of large fibre involvement, the contribution ofwhich to the pathogenesis of symptoms should be taken Alcoholic neuropathy may present as a small fibre neuro- into account when designing clinical trials. Pure small pathy, in particular in those patients with normal fibre neuropathy likely represents the early stage of thiamine levels Several other drugs can cause diabetic neuropathy and can be associated with impaired sensorimotor neuropathies and present with an early glucose tolerance . These findings are in keeping with the recent observation that diabetes per se affectssmall fibres, as shown by the slower re-growth rate of Among hereditary sensory and autonomic neuropathies, epidermal nerves following capsaicin denervation types I, IV and V are characterized by predominant loss and suggest that detection of small fibre impairment by of small myelinated and unmyelinated nerve fibres. In Table 1. Causes of small fibre neuropathy Anti-trisulfated heparin disaccharide antibodies Monoclonal gammopathy of undetermined origin Industrial, environmental, and marine toxins Hereditary sensory autonomic neuropathies Faecal urgency and rectal hypersensitivity Complex regional pain syndrome Ross’ syndrome aAutonomic dysfunction may be the only feature (for review, see cMay be also caused by myeloproliferative diseases, diabetes mellitus, infections, drugs, and mushroom poisoning.
dImmune-mediated pathogenesis has been proposed.
eSimilar to hereditary sensory and autonomic neuropathy type I, but motor nerves may be affected.
Fabry’s and Tangier’s diseases, small fibre neuropathy is QST in clinical research, it has some drawbacks that limit the reliability of results in clinical practice, as statedby a Subcommittee of the American Academy of Neu- rology for therapeutics and technology Cooling Routine nerve conduction studies assess large fibre func- detection thresholds have been strongly correlated with tion and are commonly normal in small fibre neuro- clinical indicators of large fibre neuropathy but not with pathies, unless sural nerve is examined. In fact, it has symptoms of small fibre neuropathy . Recent works recently been demonstrated that sensory plantar nerve have shown that warm and heat-pain threshold correlated action potentials were abnormal in about one-third of with quantification of intraepidermal nerve fibre (IENF) patients with normal sural nerve conduction study and density which is the most reliable method to symptoms of small fibre neuropathy confirming diagnose small fibre neuropathy (see below).
previous findings using the near-nerve technique Axon reflex flare induced by intracutaneous electrical A battery of tests, including sural nerve conduction stimulation and analysed by laser Doppler imaging has study, somatosensory-evoked cortical potentials, soleus been used to demonstrate C-fibre dysfunction in diabetic H reflex, laser-evoked potentials (LEPs), and plantar small fibre neuropathy Several other tests of auto- sympathetic skin response, has been successfully used nomic function are available but their sensitivity is to differentiate sensory neuropathies according to fibre variable in small fibre neuropathies and correlation with type involvement LEPs are an accepted method of pathological examination has not been assessed yet investigating nociceptive pathways. Hairy skin stimu- lation with an infrared carbon dioxide laser selectivelyexcites free nerve endings while evoking a pain sen- sation. Late and ultralate LEPs are generated by Ad Sural nerve biopsy should not be part of the diagnostic and C-fibres, respectively, theoretically making them work-up of patients with small fibre neuropathy, unless good tools to assess their function. Ultralate potentials amyloidosis or vasculitis is suspected. Familial amyloid related to C-fibre activation, however, can only be polyneuropathy is typically characterized by early small obtained with dedicated techniques that have not been fibre neuropathy with prominent autonomic disturb- validated for clinical application Contact heat- ances. At the time of the diagnosis, most patients show evoked potential stimulators (CHEPs) with extremely signs of mixed neuropathy and liver and cardiac involve- rapid heat rising time able to evoke Ad and C-fibre related ment may be present Vasculitis may rarely present scalp components, have been developed most recently with an isolated sensory neuropathy, but sural nerve Only a few studies on small fibre neuropathies have conduction is commonly impaired, reflecting the in- been performed with LEPs and CHEPs, however, mak- ing their usefulness for diagnostic purposes in clinicalpractice limited.
Skin biopsy has become part of the diagnostic work-up insmall fibre neuropathies after the extensive innervation The nociceptive reflex known as cutaneous silent period of human epidermis was confirmed by immunostaining (CSP) is a further method to investigate the function of with the neuronal marker protein gene product 9.5, an somatic Ad afferent fibres at the upper limbs. It has been ubiquitin carboxyl-terminal hydrolase. This technique suggested that CSP might be useful in investigating the has the advantage to allow the direct investigation of progression of neuropathy . This technique needs somatic unmyelinated fibres innervating the epidermis validation in larger studies, however. Microneurography and of sweat gland postganglionic autonomic fibres.
is a minimally invasive method that allows single Ad and Moreover, it is minimally invasive, painless, easy to C-fibre activity recording. It has been used to demon- perform in every site of the body, repeatable at the same strate C-fibre dysfunction in erythromelalgia and sites, and cheap. Skin biopsy is usually performed at contribution of skin peripheral nociceptor sensitization the distal site of the leg using a 3 mm punch disposable to secondary hyperalgesia induced by capsaicin dener- device A further biopsy at the proximal thigh can be vation Despite the important contributions to the useful to distinguish the length-dependent denervation knowledge of small fibre functions, microneurography typical of small fibre neuropathies from the non-length- remains unsuitable for routine clinical examinations.
dependent pattern of sensory neuronopathies Thistechnique has recently been used to investigate patients Small fibre functions are most commonly investigated by with Ross’ syndrome familial dysautonomia  quantitative sensory testing (QST) devices for the deter- mination of perception thresholds to warm, cold, andpain. The methodology has recently been reviewed The density of IENF can be reliably quantified, thus . Despite the large diffusion and usefulness of giving an objective measure of small fibre neuropathy.
Normative reference ranges in the leg are available therapy proved to relieve pain, improve quality of life, and slow disease progression in patients with Fabry’s changes of IENF, in particular diffuse swellings, could be predictive as to the progression of neuropathy Most interestingly, a recent study has shown that the re- growth rate of skin nerve fibres is slower in patients with Small fibre neuropathies may have different aetiology diabetes and no evidence of neuropathy This and represent the early stage of sensorimotor neuropa- demonstrates that small fibre functions are impaired early thies. They can also be part of complex hereditary dis- in diabetes, before signs or symptoms of neuropathy eases. A standardized approach using skin biopsy with develop. The possibility of detecting them could be used quantification of IENF density proved to be a reliable to assess the efficacy of neuroprotective agents. Recently, method to diagnose small fibre neuropathy. Psychophysi- a task force set up under the auspices of the European cal assessment of warm and heat–pain thresholds has Federation of Neurological Societies (EFNS) developed been found to correlate with skin biopsy results and can the guidelines on the use of skin biopsy in the diagnosis support the diagnosis. Specific neurophysiologic tests of peripheral neuropathies The paper emphasizes assessing small fibre functions, for example LEPs, that skin biopsy is a safe and reliable technique, with very CHEPs, and axon reflex flare analysis, deserve particular high diagnostic efficiency and predictive values, and attention, but their reliability in diagnosing small fibre that it is more sensitive than sensory nerve conduction neuropathy needs to be assessed in larger studies.
study and sural nerve biopsy in diagnosing small fibreneuropathy.
No controlled trials with neuroregenerative agents,focused on patients with small fibre neuropathy, have been performed thus far. Promising results come from Causative treatment should be given wherever possible.
trials in experimental models. Indications for sympto- There are no specific treatments for diabetic neuropathy matic treatment of small fibre neuropathies can be other than glycemic control. A recent study how- extrapolated by the results of controlled clinical trials ever, showed that cardiovascular diseases are associated on neuropathic pain and recent guidelines.
with double the risk of neuropathy and that hypertrigly-ceridemia, body mass index, smoking, and hypertension are independently associated with the incidence of neu- Papers of particular interest, published within the annual period of review, havebeen highlighted as: ropathy. Since these risk factors are potentially modifi- able, specific treatments and behaviour modifications Weidner C, Schmidt R, Schmelz M, et al. Time course of post-excitatoryeffects separates afferent human C fibre classes. J Physiol 2000; 527:185 – No trials with neuroprotective and neuroregenerative agents have been concluded yet. Experimental trials Serra J, Campero M, Bostock H, Ochoa J. Two types of C-nociceptors in have shown, however, that erythropoietin can both pro- human skin and their behavior in areas of capsaicin-induced secondaryhyperalgesia. J Neurophysiol 2004; 91:2770 –2781.
tect and reverse peripheral nerve damage in streptozo- An interesting paper shedding light on the physiopathology of cutaneous sec- tocin and HIV-induced neuropathy This was ondary hyperalgesia in humans using a model of topical capsaicin denervation.
Lauria G, Cornblath DR, Johansson O, et al. EFNS guidelines on the use of also demonstrated at the pathological level by examin- skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol (in press).
ation of skin small fibres Mechanisms underlying Freeman R. Autonomic peripheral neuropathy. Lancet 2005; 365:1259– the effect of erythropoietin in preventing axonal degener- A comprehensive review on aetiologies, investigations, and treatments of auto- ation have recently been clarified Prevention of C-fibre pathology and nociceptive sensory nerve dysfunc- Sommer C. Painful neuropathies. Curr Opin Neurol 2003; 16:623–628.
tion has been obtained with C-peptide replacement in an Stewart JD, Low PA, Fealey RD. Distal small fiber neuropathy: results of tests experimental model of diabetic neuropathy .
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therapies. Recently, several controlled studies reported This paper discusses the value of a mechanism-based classification and gives apractical guideline for the clinical examination of patients with positive sensory the efficacy of different drugs No study was specifically focused on small fibre neuropathies, however, Cre´ange A. Diagnostic des neuropathies sensitives acquises [The diagnosis and clinical and electrophysiological findings were com- of acquired sensory neuropathies]. Rev Neurol (Paris) 2004; 160:363 –370.
monly poorly detailed. EFNS guidelines for treatment of 10 Herrmann DN, Ferguson ML, Pannoni V, et al. Plantar nerve AP and skin biopsy in sensory neuropathies with normal routine conduction studies.
neuropathic pain, which is a common feature of small fibre neuropathies, have recently been developed This work describes the correlation between neuropathologic examination of smallfibres and routine electrodiagnostic examination, and emphasizes the usefulness Among hereditary neuropathies, enzyme replacement of distal sensory nerve recording in sensory neuropathies.
11 Polydefkis M, Hauer P, Sheth S, et al. The time course of epidermal nerve fibre 32 Sumner CJ, Sheth S, Griffin JW, et al. The spectrum of neuropathy in diabetes regeneration: studies in normal controls and in people with diabetes, with and and impaired glucose tolerance. Neurology 2003; 60:108–111.
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33 Lipton SA. Erythropoietin for neurologic protection and diabetic neuropathy.
This paper first investigated the re-growth rate of skin small fibres in patients with diabetes. It demonstrates at the pathological level that diabetes per se alters thefunction of peripheral nerves, irrespective of the presence of neuropathy.
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Patients had significantly higher thermal-detection thresholds than controls, in-dicating the involvement of small fibres in the pathogenesis of painful symptoms.
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52 Kra¨mer HH, Schmelz M, Birklein F, Bickel A. Electrically stimulated axon 30 Gibbons CH, Freeman R. Autonomic neuropathy and coeliac disease.
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73 Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005; 352:1324–1334.
62 Tesfaye S, Chaturvedi N, Eaton SEM, et al. Vascular risk factors and diabetic This randomized, double-blind, placebo-controlled study showed that combined neuropathy. N Engl J Med 2005; 352:341 –350.
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pTRE-Myc Vector Information GenBank Accession #: Submission in progress. EcoR I BamH I pTRE-Myc ATG GCA TCA ATG CAG AAG CTG ATC TCA GAG GAG GAC CTG CTT ATG GCC ATG GAG GCC CAA GCT TGG TCG ACC GAG ATC TCT CGA GGT ACC GCG GCC GCT CGA CGA TAT CTC TAG A Map and Multiple Cloning Site (MCS) of pTRE-Myc Vector. Unique restriction sites are in bold. Description: pTRE-Myc is a tetracyclin

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