Sunday, November 28, 2010

Small-Fiber Neuropathy and Hepatitis c

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.

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

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.

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,

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

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 dependentDistalp*
  1. IGT, impaired glucose tolerance; ns, non-significant; SD, standard deviation.
  2. *Fisher's exact test, unless otherwise indicated.
  3. Student's t-test.
No of patients1133
Age at observation, mean ± SD, year53.5 ± 12.266.0 ± 11.30.003
Age at onset, mean ± SD, year50.7 ± 12.963.3 ± 11.90.005
Disease duration, mean ± SD, year2.9 ± 4.52.6 ± 2.8ns
Other: cold-icy/tender-aching/tight2/3/15/1/4ns
Reported touch allodynia890.012
Restless legs syndrome414
Impaired glucose metabolism (diabetes type 2/IGT)1 (0/1)16 (10/6)0.031
Sjögren's syndrome21ns
Hepatitis C virus infection12ns
Rheumatoid arthritis11ns
Crohn's disease11ns
Mixed cryoglobulinaemia02ns
Other (alcohol/drugs)02 (1/1)ns


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.

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