Small fiber neuropathy: A burning problem

Also See

2018 - Neurological manifestation in chronic hepatitis C: Peripheral neuropathy

2010 - Small-Fiber Neuropathy and Hepatitis c

Of Interest - Updates
Link to current articles - Other Conditions Related To HCV

Small fiber neuropathy: A burning problem .

JINNY TAVEE, MD

Neuromuscular Disease Center, Neurological Institute, Cleveland Clinic

LAN ZHOU, MD, PhD

Director, Cleveland Clinic Cutaneous Nerve Laboratory, Neuromuscular Disease Center, Neurological Institute, Cleveland Clinic

Abstract

Small fiber neuropathy is increasingly being recognized as a major cause of painful burning sensations in the feet, especially in the elderly. Although strength remains preserved throughout the course of the disease, the pain and paresthesias are often disabling. Diabetes mellitus is the most common identifiable cause of small fiber neuropathy, and impaired oral glucose tolerance and individual components of the metabolic syndrome are often associated with it. Some cases, however, are idiopathic. Skin biopsy (with an evaluation of the density of intraepidermal nerve fibers) and tests of autonomic nerve function are useful for the diagnosis. Management involves controlling pain and identifying and aggressively treating the underlying cause.

An estimated 15 to 20 million people in the United States over age 40 have some type of peripheral neuropathy.1 In many, the impairment is purely or predominantly in small nerve fibers, and the clinical presentation consists of pain, burning, tingling, and numbness in a length-dependent or stocking-glove distribution. (“Length” refers to distance from the trunk; distal fibers are affected first.) Symptoms typically begin in the feet and slowly ascend to the distal legs, at which point the hands may also be affected

.

FIGURE 1 Below

In many of these patients, the findings on neurologic examination, nerve conduction studies, and electromyography are normal, although some may show signs of mild distal sensory loss on physical examination. The lack of objective findings on routine nerve conduction studies and electromyography may lead many physicians to attribute the symptoms to other disorders such as plantar fasciitis, vascular insufficiency, or degenerative lumbosacral spine disease.

The past 2 decades have seen the development of specialized tests that have greatly facilitated the diagnosis of small fiber neuropathy; these include skin biopsy to evaluate the density of nerve fibers in the epidermis and studies of autonomic nerve function. Common etiologies have been identified for small fiber neuropathy and can be specifically treated, which is critical for controlling progression of the disease. Pain management is becoming easier with more available options but is still quite challenging

.

WHAT IS SMALL FIBER NEUROPATHY?

Small fiber neuropathy is a disorder of the peripheral nerves that primarily or exclusively affects small somatic fibers, autonomic fibers, or both, resulting in sensory changes and autonomic dysfunction when both types are involved .

(FIGURE 1)

.

Symptoms are pain, burning, numbness, and autonomic dysfunction (lack of sweating) in the hands and feet in a stocking-glove distribution. Strength is not affected. Tendon reflexes are normal, as are nerve conduction studies

Peripheral nerve fibers can be classified according to size, which correlates with the degree of myelination.

Large nerve fibers are heavily myelinated and include A-alpha fibers, which mediate motor strength, and A-beta fibers, which mediate vibratory and touch sensation.

Medium-sized fibers, known as A-gamma fibers, are also myelinated and carry information to muscle spindles.

Small fibers include myelinated A-delta fibers and unmyelinated C fibers, which innervate skin (somatic fibers) and involuntary muscles, including cardiac and smooth muscles (autonomic fibers). Together, they mediate pain, thermal sensation, and autonomic function.

Small fiber neuropathy results from selective impairment of small myelinated A-delta and unmyelinated C fibers.

Sensory symptoms:

Pain, burning, tingling, numbness

Damage to or loss of small somatic nerve fibers results in pain, burning, tingling, or numbness that typically affects the limbs in a distal-toproximal gradient. In rare cases, small fiber neuropathy follows a non-length-dependent distribution in which symptoms may be manifested predominantly in the arms, face, or trunk.

Symptoms may be mild initially, with some patients complaining of vague discomfort in one or both feet similar to the sensation of a sock gathering at the end of a shoe. Others report a wooden quality in their feet, numbness in their toes, or a feeling as if they are walking on pebbles, sand, or golf balls. The most bothersome and fairly typical symptom is burning pain in the feet that extends proximally in a stocking-glove distribution and is often accompanied by stabbing or aching pains, electric shock-like or pins-and-needles sensations, or cramping of the feet and calves.

Symptoms are usually worse at night and often affect sleep. Some patients say that their feet have become so exquisitely tender that they cannot bear having the bed sheets touch them, and so they sleep with their feet uncovered. A small number of patients do not have pain but report a feeling of tightness and swelling in their feet (even though the feet appear normal).

Examination often reveals allodynia (perception of nonpainful stimuli as being painful), hyperalgesia (perception of painful stimuli as being more painful than expected), or reduced pinprick and thermal sensation in the affected area. Vibratory sensation can be mildly reduced at the toes. Motor strength, tendon reflexes, and proprioception, however, are preserved because they are functions of large nerve fibers.

Autonomic symptoms

When autonomic fibers are affected, patients may experience dry eyes, dry mouth, orthostatic dizziness, constipation, bladder incontinence, sexual dysfunction, trouble sweating, or red or white skin discoloration.2 Examination may show orthostatic hypotension and skin changes. The skin over the affected area may appear atrophic, dry, shiny, discolored, or mildly edematous as the result of sudomotor and vasomotor abnormalities.

FIGURE 2 Click To Enlarge

WHAT CAUSES SMALL FIBER NEUROPATHY?

Small fiber neuropathy has been associated with many medical conditions, including glucose dysmetabolism,3 connective tissue disease,4,5 dysthyroidism,6 vitamin B12 deficiency, paraproteinemia, human immunodeficiency virus (HIV) infection,7 hepatitis C virus infection, celiac disease,8 restless legs syndrome,9 neurotoxic drug exposure, hereditary diseases, and paraneoplastic syndrome. While most of these conditions cause a length-dependent small fiber neuropathy, others (Sjögren disease, celiac disease, and paraneoplastic syndrome) can cause a form of small fiber neuropathy that is not length-dependent.4,8,10

Diabetes and prediabetes

Glucose dysmetabolism, including diabetes and prediabetes with impaired oral glucose tolerance (a glucose level 140–199 mg/dL 2 hours after a 75-g oral dextrose load), is the most common identifiable associated condition, present in about one-third of patients with painful sensory neuropathy11 and in nearly half of those with otherwise idiopathic small fiber neuropathy.12–14

Research findings strongly suggest that even prediabetes is a risk factor for small fiber neuropathy, and that so-called “impaired glucose tolerance neuropathy” may represent the earliest stage of diabetic neuropathy. Several recent studies have found a high prevalence of impaired glucose tolerance in patients with sensory peripheral neuropathy,12–14 with a rate of up to 42% in cases initially thought to be idiopathic14 compared with 14% in the general population.15 Also, a dose-response relationship between the severity of hyperglycemia and the degree of neuropathy was demonstrated in one study, in which patients with impaired glucose tolerance more often had small fiber neuropathy, whereas those with diabetes more often had polyneuropathy involving both small and large fibers.14 And studies in animals and cell cultures have shown that intermittent hyperglycemia, which can be seen in patients with impaired glucose tolerance, caused sensory neuron and nerve fiber damage and increased spontaneous C-fiber firing, resulting in neuropathic pain.8,16,17

.Metabolic syndrome

Insulin resistance with prediabetes and diabetes is a part of the metabolic syndrome, which also consists of hypertension, hyperlipidemia, and obesity. The individual components of the metabolic syndrome have been implicated as risk factors not only for cardiovascular and cerebrovascular disease but also for small fiber neuropathy.

One study in 548 patients with type 2 diabetes showed that those with the metabolic syndrome were twice as likely to have neuropathy as those without.18 Another study showed that in 1,200 patients with type 1 diabetes without neuropathy at baseline, hypertension, hyperlipidemia, and increased body mass index were each independently associated with a higher risk of developing neuropathy.19

A recent study of 219 patients with idiopathic distal symmetrical peripheral neuropathy and 175 diabetic patients without neuropathy found a higher prevalence of metabolic syndrome in patients with neuropathy than in normal populations. The prevalence of dyslipidemia (high levels of total and low-density lipoprotein cholesterol and triglycerides and low levels of high-density lipoprotein cholesterol), but not hypertension or obesity, was higher in patients with neuropathy than in patients with diabetes but no neuropathy.20 The findings linked dyslipidemia to neuropathy and showed the need for further studies of the potential pathogenic role of dyslipidemia in neuropathy.

Hereditary causes

Hereditary causes of small fiber neuropathy are rare and include Fabry disease, Tangier disease, hereditary sensory autonomic neuropathy, and hereditary amyloidosis.

/

HOW DO YOU EVALUATE PATIENTS WITH SUSPECTED SMALL FIBER NEUROPATHY?

A thorough history should be taken to obtain details regarding onset and features of neuropathy symptoms, exacerbating factors, and progression. It is also important to ascertain whether the patient has any associated conditions as mentioned above, a family history of neuropathy, risk factors for HIV or hepatitis C virus infection, or a history of neurotoxic drug exposure.

Clinical suspicion of small fiber neuropathy should be high if a patient presents with predominant small fiber symptoms and signs with preserved large fiber functions.

.Nerve conduction studies and electromyography

For diagnostic testing, routine nerve conduction studies and electromyography assess the function of large nerve fibers only and are thus normal in small fiber neuropathy. These tests should still be ordered to rule out subclinical involvement of large fibers, which may affect the diagnostic evaluation, prognosis, and treatment plan. However, if the results of these tests are normal, specialized studies are needed to evaluate small fibers.

Although several tests are available to evaluate somatic and autonomic small fibers, the two that have the highest diagnostic efficiency for small fiber neuropathy and that are used most often are skin biopsy, to evaluate intraepidermal nerve fiber density, and quantitative sudomotor axon reflex testing (QSART), to assess sudomotor autonomic function.21–23

.

Skin biopsy

Skin biopsy is a minimally invasive procedure in which 3-mm-diameter punch biopsy specimens are taken from the distal leg, distal thigh, and proximal thigh of one lower limb. The procedure takes only 10 to 15 minutes.

Biopsy specimens are immunostained using an antibody against protein gene product 9.5, which is a panaxonal marker. Small nerve fibers in the epidermis are counted under a microscope, and intraepithelial nerve fiber densities are calculated and compared with established normative values. The diagnosis of small fiber neuropathy can be established if the intraepidermal nerve fiber density is lower than normal (FIGURE 1). Nerve fiber density may be normal in the early stage of small fiber neuropathy, but in this setting skin biopsy often shows abnormal morphologic changes in the small fibers, especially large swellings,24 and repeat biopsy in 6 to 12 months may be considered.

The diagnostic efficiency of skin biopsy is about 88%.21,23 For diagnosing small fiber neuropathy, it is more sensitive than quantitative sensory testing21,25 and more sensitive and less invasive than sural nerve biopsy.26 Intraepidermal nerve fiber density also correlates well with a variety of measures of severity of HIV distal sensory neuropathy and thus may be used to measure the severity and treatment response of small fiber neuropathy.27

Quantitative sudomotor axon reflex testing

QSART is an autonomic study that measures sweat output in response to acetylcholine, which reflects the function of postganglionic sympathetic unmyelinated sudomotor nerve fibers. Electrodes are placed on the arms and legs to record the volume of sweat produced by acetylcholine iontophoresis, in which a mild electrical stimulation on the skin allows acetylcholine to stimulate the sweat glands. The output is compared with normative values.

One prospective study showed that 67 (72.8%) of 92 patients with painful feet had abnormal results on QSART, ie, low sweat output.28 A retrospective study found that 77 (62%) of 125 patients with clinical features of distal small fiber neuropathy had a length-dependent pattern of QSART abnormalities.22 QSART abnormalities were detected in some patients without autonomic symptoms.

If these tests are not available

Skin biopsy and QSART are objective, reproducible, sensitive, and complementary in diagnosing small fiber neuropathy. One or both can be ordered, depending on whether the patient has somatic symptoms, autonomic symptoms, or both. However, these two tests are not widely available. Only a few laboratories in the country can process skin biopsy specimens to evaluate intraepidermal nerve fiber density. Nevertheless, it is easy to learn the skin punch biopsy procedure, and primary care physicians and neurologists can perform it after appropriate training. (A concern is avoiding damage to the epidermis.) They can then send specimens to one of the cutaneous nerve laboratories (but not to a routine reference laboratory).

View this table:

In a new window

TABLE 1

Drugs for pain control in small fiber neuropathy

A special technique, including unique fixative and cryoprotectant, is used to fix and process the biopsy specimens, because routine techniques for processing dermatologic punch biopsy specimens often result in lower intraepidermal nerve fiber densities. Therefore, it is very important to contact the laboratory regarding fixative and processing before performing a biopsy.

QSART requires specialized equipment and must be performed on site. In addition, the test is very sensitive to drugs that can affect sweating, such as antihistamines and antidepressants, and such drugs must be discontinued 48 hours before the study.

Basic laboratory tests to find the cause

Once the diagnosis of small fiber neuropathy is established, the next important step is to order a battery of laboratory tests to search for an underlying cause.

The tests should include the following:

Complete blood cell count

Comprehensive metabolic panel

Lipid panel

Erythrocyte sedimentation rate

Thyroid-stimulating hormone level

Free thyroxine (T4) level

Antinuclear antibody

Extractable nuclear antigens

Angiotensin-converting enzyme (ACE) level

Serum and urine immunofixation tests

Vitamin B12 level

2-hour oral glucose tolerance test.

Oral glucose tolerance testing is much more sensitive than measuring the hemoglobin A1c and fasting glucose levels in detecting diabetes and prediabetes. These two conditions were detected by oral glucose tolerance testing in more than 50% of patients with otherwise idiopathic sensory-predominant peripheral neuropathy and normal hemoglobin A1c and fasting glucose levels.13,14 Therefore, every patient with small fiber neuropathy without a known history of diabetes or prediabetes should have an oral glucose tolerance test.

.

Special laboratory tests in special cases

If there is a history of gastrointestinal symptoms or herpetiform-like rash, then testing for gliadin antibody and tissue transglutaminase antibodies as well as small-bowel biopsy may be pursued to evaluate for celiac sprue.

Serologic tests for HIV or hepatitis C should be ordered if the patient has risk factors.

If there is a significant family history, further genetic testing should be considered.

Lip biopsy or bone marrow biopsy should be considered if clinical suspicion is high for Sjögren disease, seronegative sicca syndrome, or amyloidosis.

The serum ACE level has a low sensitivity and specificity; therefore, if sarcoid is suspected clinically, additional confirmatory testing, such as computed tomography of the chest, should be ordered despite a normal ACE value.

.

HOW DO YOU TREAT SMALL FIBER NEUROPATHY?

Treatment of small fiber neuropathy should target the underlying cause and neuropathic pain. Cause-specific treatment is a key in preventing small fiber neuropathy or slowing its progression.

Glucose control, weight control, and regular exercise

As glucose dysmetabolism is the condition most often associated with small fiber neuropathy (and since individual components of the metabolic syndrome are potential risk factors for it), tight glycemic control and lifestyle modification with diet control, weight control, and regular exercise are of paramount importance in patients with these conditions.

The Diabetic Prevention Program,29 a study in 3,234 people with prediabetes, found that diet and exercise were more effective than metformin (Glucophage) in preventing full-blown diabetes. At an average of 2.8 years of follow-up, the incidence of diabetes was 11.0 cases per 100 patient-years in a group assigned to receive placebo, compared with 7.8 in those assigned to receive metformin (31% lower), and 4.8 (58% lower) in those who were assigned to undergo a lifestyle intervention that included at least 150 minutes of physical activity per week with a weight-loss goal of 7%. Put another way, to prevent one case of diabetes over 3 years, 6.9 patients would have to undergo the lifestyle intervention program, or 13.9 would have to receive metformin. Since impaired glucose tolerance neuropathy may represent the earliest stage of diabetic neuropathy, the neuropathy at this stage may be reversible with lifestyle intervention and improvement of impaired glucose tolerance

.This concept is supported by a 3-year study in 31 people, which showed that lifestyle intervention significantly improved impaired glucose tolerance, reduced the body mass index, and lowered total serum cholesterol levels.30 Changes in these metabolic variables were accompanied by significant improvement of neuropathy as evidenced by significantly increased intraepidermal nerve fiber density, increased foot sweat volume, and decreased neuropathic pain.30

Treatment of other diseases

It has also been reported that treatment of sarcoidosis, autoimmune diseases, and celiac disease improved the symptoms of small fiber neuropathy resulting from these conditions.8,31 Therefore, it is important to identify the cause and treat it to prevent and slow the progression of small fiber neuropathy, and doing so may improve the disease in some mild cases.

.

Pain management

Pain management is crucial in the treatment of small fiber neuropathy, as neuropathic pain can be debilitating and can cause depression. Pain management often requires a multidisciplinary team, including a primary care physician, a neurologist, a pain specialist, and a psychiatrist. Medications include antidepressants, anticonvulsants, and topical anesthetics (TABLE 1) as well as narcotic and non-narcotic analgesics and antiarrhythmics. Nonpharmacologic management includes transcutaneous electrical nerve stimulation (TENS), heat, ice, and massage of painful areas (reviewed by Chen et al32 and Galluzzi33).

First-line choices of pain medications are the anticonvulsants gabapentin (Neurontin) and pregabalin (Lyrica), the tricyclic antidepressants amitriptyline (Elavil) and nortriptyline (Aventyl), a 5% lidocaine patch (Lidoderm), and the semisynthetic opioid analgesic tramadol (Ultram). These can be used alone or in combination.

Gabapentin is relatively well tolerated, but drowsiness can occur, especially with high starting doses. We usually start with 300 mg daily and increase it by 300 mg every week up to 1,200 mg three times a day as tolerated. Most patients need 600 to 900 mg three times a day.

Pregabalin is a newer antiepileptic drug, similar to gabapentin but less sedating. It can be started at 75 mg twice a day and gradually increased to 300 mg twice a day as needed. Weight gain and, rarely, swelling of the lower extremities may limit the use of both of these drugs.

Tricyclic antidepressants, such as amitriptyline, nortriptyline, and desipramine (Norpramin), are proven effective in controlling neuropathic pain, although no response with amitriptyline was seen in patients with painful HIV distal sensory neuropathy.34

Lidocaine patch is preferred if the painful area is small. Patients should be instructed to use the patch to cover the painful area 12 hours on and 12 hours off. If it does not provide relief within 1 week, it should be discontinued.

Tramadol is also helpful in treating neuropathic pain. It can be started at 50 mg two to four times a day as needed.

Nonsteroidal anti-inflammatory drugs and selective serotonin reuptake inhibitors are typically less effective than the other drugs mentioned.

Opioids should be reserved for refractory cases, given the potential for addiction, but they are sometimes necessary in patients with disabling pain that does not respond to other drugs.

TENS may be of benefit. The patient controls a pocket-size device that sends electrical signals to leads placed on affected areas.

Alternative therapies for small fiber neuropathy, such as meditation, yoga, and acupuncture, have yet to be studied.

It is also important to explain to patients that the typical course of small fiber neuropathy is relatively benign, as many patients worry about developing weakness and eventually not being able to walk. These concerns and fears can aggravate pain and depression, which can make treatment difficult.

WHAT IS THE PROGNOSIS OF SMALL FIBER NEUROPATHY?

Most patients with small fiber neuropathy experience a slowly progressive course, with symptoms and signs spreading proximally over time.

In one study, only 13% of 124 patients with small fiber neuropathy showed evidence of large-fiber involvement over a 2-year period. 21 None went on to develop Charcot joints, foot ulcers, weakness, or sensory ataxia, as is often seen in patients with long-standing or severe large fiber neuropathy. Neuropathic pain worsened in 30% and resolved spontaneously in 11%.21

Most patients with small fiber neuropathy require chronic pain management. Again, treatment of the underlying cause is important and can improve the prognosis.

We believe that the overall progression of small fiber neuropathy is slow. A longitudinal study with a follow-up longer than 2 years would be useful to confirm this.

TAKE-HOME POINTS

As the population continues to age and as more patients develop diabetes and the metabolic syndrome, the prevalence of small fiber neuropathy will rise. Patients who present to their primary care physicians with painful, burning feet require a thorough diagnostic evaluation, which may include referral for specialized neurodiagnostic testing. Aggressive cause-specific treatment, lifestyle modification, and pain control are key elements of a team approach to managing small fiber neuropathy.

Small-Fiber Neuropathy and Hepatitis c

Also See
2018 - Neurological manifestation in chronic hepatitis C: Peripheral neuropathy

Small Fiber Neuropathy A Burning Problem

What Causes Small-Fiber Neuropathy?

Ezekiel Fink and Anne Louise Oaklander, authors of "Small-Fiber Neuropathy:Answering the Burning Questions," explain that as you get older, you become more susceptible to getting small fiber neuropathy.

Several conditions may cause small fiber neuropathy. 

Viruses, such as the hepatitis C virus and the human immunodeficiency virus, can cause small fiber neuropathy. The treatment for HIV, antiretroviral therapy, may also cause this type of neuropathy, notes Marc M. Treihaft, M.D., FAAN, author of "Painful Feet: The Small Fiber Neuropathies."

If you have glucose problems, such as with prediabetes or diabetes, you may develop small fiber neuropathy. A deficiency in vitamin B-12 or celiac disease, in which your body cannot handle gluten, may also cause small fiber neuropathy. Other causes include restless leg syndrome, exposure to neurotoxic drugs, Fabry disease and hereditary amyloidosis.

Source

Non-length dependent small fiber neuropathy. A prospective case series

Franco Gemignani1,*,Michela Giovanelli1,Francesca Vitetta1, Daniele Santilli2,
Maria F. Bellanova1, Francesca Brindani1, Adriana Marbini1

Article first published online: 1 MAR 2010
DOI: 10.1111/j.1529-8027.2010.00252.x
© 2010 Peripheral Nerve Society

SFN= small fiber neuropathy

Abstract

We report the features of non-length dependent small fiber neuropathy (SFN) and compare them to those with distal length-dependent SFN. In a series of 224 consecutive neuropathy patients, we evaluated 44 patients with SFN diagnosed in the presence of both symptoms and signs. Eleven were classified as non-length dependent SFN.

Disease associations were Sjögren's syndrome (two patients), impaired glucose tolerance, rheumatoid arthritis, hepatitis C virus, Crohn's disease, and idiopathic (five patients).

,

In the 33 patients with distal SFN, the age of onset was significantly older and more had impaired glucose metabolism (16/33). In both groups, pain was mainly characterized as burning, but patients with non-length dependent SFN more often reported an “itchy” quality and allodynia to light touch.

Introduction

Small fiber neuropathy (SFN) is a form of polyneuropathy restricted to A-delta and C fibers, representing a frequent cause of neuropathic pain (Gorson and Ropper, 1995; Lacomis, 2002; Devigili et al., 2008).

Recently, SFN with an atypical topographic pattern different from distal symmetric polyneuropathy has been reported in a small series (Holland et al., 1998; Mori et al., 2003; Moghekar et al., 2004; Brannagan et al., 2005; Chai et al., 2005) and better characterized in a multi-center retrospective study (Gorson et al., 2008) as “non-length dependent” SFN. The etiopathogenesis of this condition remains elusive; however, it has been suggested that the main site of lesion may reside in the dorsal root ganglia (DRG), hence the term “small fiber neuronopathy-ganglionopathy” has been also proposed (Brannagan et al., 2005; Gorson et al., 2008). Gorson et al.(2008) showed impaired glucose metabolism in a fair proportion of their cases.

We evaluated the occurrence of non-length dependent SFN in a cohort of patients with peripheral neuropathy, assessing its features in comparison with the distal form of SFN.We prospectively evaluated all consecutive patients referred to the Neuromuscular Center between January 2007 and December 2008 with main symptoms of pain or dysesthesia and a clinical suspicion of SFN. The patients were evaluated with a standard clinical protocol to define whether minimal criteria for the diagnosis of SFN, according to Lacomis (2002), were met. This required the presence of

(1) symptoms of neuropathic pain and/or dysesthesia

(2) abnormal sensory findings pertinent to small fibers on neurological examination.

In addition, conventional electroneurographic study had to be negative, to exclude large fiber involvement. Sensory and motor symptoms and signs likely related to large fiber involvement were also ruled out. When appropriate, neuroimaging studies were performed to exclude a central nature of sensory symptoms.

The topographic pattern of SFN was classified as “distal,” in the presence of a “stocking and glove” distribution of sensory symptoms and signs; otherwise, SFN was classified as “non-length dependent,” when the sensory disturbance was restricted to, or predominant in, different body sites, with involvement of face, trunk, and proximal limbs, either sparing the acral extremities or with simultaneous involvement of proximal and distal areas (Gorson et al., 2008).
A semi-structured interview was conducted to assess the features of pain or dysesthesia (International Association for the Study of Pain-IASP, http://www.iasp-pain.org/).

The neuropathic type of symptoms was established by consensus (FG and FB), by obtaining a detailed history of the nature of the pain and after exclusion of relevant sources of nociceptive pain. Patients were asked to describe the features and quality of pain/dysesthesia, using volunteered descriptors, and to report whether they experienced pain, discomfort or oversensibility to light touch (clothing, sheets), pressure, or thermal stimuli, that is, symptoms suggesting allodynia.

A diagnostic work-up for potential causes of polyneuropathy, and in particular for SFN, was performed in keeping with recommendations for investigation of peripheral neuropathies (Léger, 1999). Besides standard biochemical tests, most patients underwent additional investigations, including oral glucose tolerance test and auto-immunity tests. In eight patients with non-length dependent SFN, the diagnosis was further confirmed by a skin biopsy from the distal leg and proximal thigh, analyzed according to standardized procedures (Devigili et al., 2008).
For continuous variables, statistical analysis was conducted using Student's t-test (two-tailed). For categorical variables, analysis was conducted using the Fisher's exact test (two-tailed).

We evaluated 44 patients with SFN (35 women), diagnosed on clinical grounds, in a series of 224 consecutive patients with polyneuropathy or multiple mononeuropathy seen during the considered period.

Eleven patients (nine women and two men) were classified as non-length dependent SFN (Fig. 1).

The clinical features of the patients with non-length dependent SFN are shown in

Table 1. (see Below )

Patients 1–6 have been previously reported in a study focused on the changes in the corneal small fibers demonstrated with in vivo confocal microscopy (Gemignani et al., in press)

.

Most patients were idiopathic (five patients) or had a previously diagnosed autoimmune disease (Sjögren's syndrome in two, rheumatoid arthritis and Crohn's disease in one each); one patient (Patient 7) with hepatitis C virus infection had been treated with pegylated interferon and ribavirine for 1 year, until 1 month before onset of symptoms.

,

Click To Enlarge

Table 1.

,

An alteration of glycemic metabolism was found in only one patient, who had impaired glucose tolerance, besides a previous chemotherapy 2 years before the onset of neuropathic symptoms. Onset was over days in three patients (Patients 1, 5, and 7), and indolent in the remainder, evolving over months.

The pain was mainly characterized as burning (n = 8) and itchy (n = 4). Most patients (except Patients 4, 5, and 6) reported discomfort or pain to light touch (contact with sheets or clothes), although in only one patient (Patient 9) dynamic mechanic allodynia could be demonstrated during examination by sensory testing using a brush. Symptoms of restless legs syndrome were reported by Patients 1, 4, 6, and 8.

Skin biopsy showed reduced intraepidermal nerve fiber density both proximal and distal in all examined patients, with reduction in the thigh equal to or more prominent than in the leg in some patients

All patients were treated with neuropathic pain medications, with a symptomatic improvement to some degree (Table 1). VAS score was 6.5–10 (median 9) at first evaluation, and 2–6.5 (median 4) on follow-up, after 5–33 months (median 9). In addition, current treatment included steroids (Patients 1, 3 and 8), hydroxychloroquine (Patient 3), and leflunomide (Patient 8); Patients 7 and 9 had been previously treated with pegylated interferon and ribavirine.

In the remaining 33 patients (27 women), distal SFN was more often associated with diabetes and pre-diabetes (Table 2). The age of onset and at observation were significantly older than in patients with non-length dependent SFN, whereas the average duration of symptoms at the time of the initial evaluation was similar. In both groups, quality of pain or dysesthesia was more often characterized as burning (72.7% and 69.7%, respectively), but in patients with non-length dependent SFN an “itchy” quality was more frequent, whereas in patients with distal SFN the descriptor “pricking” was often used (27.3%). Reported allodynia to touch was significantly more common in patients with non-length dependent SFN (Table 2).

Table 2. Comparison of subgroups of patients with small fiber neuropathy.

	Non-length dependent	Distal	p*
IGT, impaired glucose tolerance; ns, non-significant; SD, standard deviation. *Fisher's exact test, unless otherwise indicated. †Student's t-test.
No of patients	11	33
Males/females	2/9	7/26	ns
Age at observation, mean ± SD, year	53.5 ± 12.2	66.0 ± 11.3	0.003†
Age at onset, mean ± SD, year	50.7 ± 12.9	63.3 ± 11.9	0.005†
Disease duration, mean ± SD, year	2.9 ± 4.5	2.6 ± 2.8	ns†
Symptoms
Pain/dysesthesia	7/4	18/15	ns
Descriptors
Burning	8	23	ns
Itchy	4	1	0.010
Pricking	1	9	ns
Other: cold-icy/tender-aching/tight	2/3/1	5/1/4	ns
Reported touch allodynia	8	9	0.012
Restless legs syndrome	4	14
Causes
Idiopathic	5	8	ns
Impaired glucose metabolism (diabetes type 2/IGT)	1 (0/1)	16 (10/6)	0.031
Sjögren's syndrome	2	1	ns
Hepatitis C virus infection	1	2	ns
Rheumatoid arthritis	1	1	ns
Crohn's disease	1	1	ns
Mixed cryoglobulinaemia	0	2	ns
Other (alcohol/drugs)	0	2 (1/1)	ns

Discussion

The entity of non-length dependent SFN has been described in a recent multi-center retrospective study (Gorson et al., 2008) and previously (Holland et al., 1998; Periquet et al., 1999; Mori et al., 2003, 2005; Moghekar et al., 2004; Brannagan et al., 2005; Chai et al., 2005; Oki et al., 2007). It is likely that non-length dependent SFN is under recognized in the general population, as a consequence of its unusual presentation, sometimes reminiscent of somatoform disorders. The frequency of non-length dependent SFN in our polyneuropathy population, approaching 5%, is clearly influenced by a referral bias of diagnostically puzzling cases but it may reflect the recurrence of this problem in selected neuropathy series. Although the diagnosis of SFN was based upon clinical criteria, the clinical diagnosis was validated by skin biopsy findings in the majority of non-length dependent SFN patients.

The main scope of our study was to evaluate the general features of non-length dependent SFN, with regard to possible disease associations, in comparison with distal SFN. Within the limits of this series, we confirmed a predominance of auto-immune or undetermined causes, as previously noted by others (Holland et al., 1998; Mori et al., 2003; Gorson et al., 2008). A high frequency (24%) of patients with impaired glucose metabolism was reported by Gorson et al.(2008), but this was less common in our patients, whereas it was common in the distal form of SFN. The series of Gorson et al. was composed of selected patients from different centers, referred for undiagnosed non-length dependent neuropathy, whereas we evaluated consecutive patients. It is also possible that the prevalence and impact of impaired glucose metabolism varies depending on different geographical areas and/or populations, as previously suggested for distal diabetic neuropathy (Gemignani, 2008; Nebuchennykh et al., 2008).

The peculiar pattern of non-length dependent distribution is suggestive of a ganglionopathy with selective involvement of the small DRG neurons (Brannagan et al., 2005; Gorson et al., 2008; Koike and Sobue, 2008), however, this requires pathologic confirmation. Our data showed significant differences in clinical manifestations, range of age, and disease associations between distal SFN and non-length dependent SFN. Patients with non-length dependent SFN complained more often of allodynic symptoms, which are ascribed to central sensitization induced by ongoing afferent inputs (Baron, 2006). Assuming that the pathology of non-length dependent SFN is actually localized to DRG, it may be that sensitization in the dorsal horns is more efficiently elicited by abnormal inputs originating in the DRG, rather than in distal nerves. Indeed, allodynia is far more frequent in postherpetic neuralgia, a ganglionopathy in distal polyneuropathy, such as diabetic neuropathy (Baron et al., 2009).

Most patients reported benefit with symptomatic treatment. In the series of Gorson et al. (2008) only 13 of 23 patients had symptomatic improvement, but two patients responded to immune therapies. Controlled clinical trials are needed in this specific neuropathic pain syndrome.