Do you want to buy antibiotics online without prescription? http://buyantibiotics24h.com/ - This is pharmacy online for you!
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 .
of sweating and autonomic cardiovascular reflexes. Muscle Nerve 1992;15:661–665.
Lacomis D. Small-fiber neuropathy. Muscle Nerve 2002; 26:173–188.
Most patients with small fibre neuropathy complain of
Jensen TS, Baron R. Translation of symptoms and signs into mechanisms in
positive sensory disturbances and need symptomatic
neuropathic pain. Pain 2004; 102:1–8.
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.
without neuropathy. Brain 2004; 127:1606 –1615.
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.
34 Mendell JR, Sahenk Z. Painful sensory neuropathy. N Engl J Med 2003;
12 Daousi C, MacFarlane IA, Woodward A, et al. Chronic painful peripheral
neuropathy in an urban community: a controlled comparison of people with
35 Blaes F, Schmitz K, Tschernatsch M, et al. Autoimmune etiology of complex
and without diabetes. Diabet Med 2004; 21:976–982.
regional pain syndrome (M. Sudeck). Neurology 2004; 63:1734–1736.
This immunohistochemical work suggests that an immune-mediated process
13 Lefaucheur JP, Creange A. Neurophysiological testing correlates with clinical
against the sympathetic nervous system may be involved in the pathogenesis
examination according to fibre type involvement and severity in sensory
of this obscure syndrome, and hypothesizes a basis for potential treatments.
neuropathy. J Neurol Neurosurg Psychiatry 2004; 75:417–422.
A study on 45 patients with large, small, and mixed sensory neuropathy examined
36 Dabby R, Weimer LH, Hays AP, et al. Antisulfatide antibodies in neuropathy:
using a comprehensive clinical and neurophysiologic approach with conventional
clinical and lectrophysiologic correlates. Neurology 2000; 54:1448–1452.
and nonconventional tests that provided an objective assessment of presence and
37 Pestronk A, Choksi R, Logigian E, Al-Lozi MT. Sensory neuropathy with
severity of nerve fibre dysfunction.
monoclonal IgM binding to a trisulfated heparin disaccharide. Muscle Nerve
14 Amato AA, Oaklander AL. Case records of the Massachusetts General
Hospital. Weekly clinicopathological exercises. Case 16-2004: a 76-year-
38 Chiang MC, Lin YH, Pan CL, et al. Cutaneous innervation in chronic inflam-
old woman with numbness and pain in the feet and legs. N Engl J Med 2004;
matory demyelinating polyneuropathy. Neurology 2002; 59:1094–1098.
This interesting paper discusses differential diagnosis and management of small
39 Lombardi R, Erne B, Lauria G, et al. Anti-MAG neuropathy patients show
fibre neuropathies starting from a nicely presented case report.
specific IgM deposits in cutaneous nerve fibers. Ann Neurol 2005; 57:180–187.
15 Lauria G, Majorana A, Borgna M, et al. Trigeminal small-fiber sensory neuro-
This study demonstrated the presence of specific IgM deposits in skin small
pathy causes burning mouth syndrome. Pain 2005; 115:332 –337.
myelinated fibres and the loss of unmyelinated fibres in patients with anti-MAG
This paper first correlated the burning mouth syndrome with a loss of epithelial
neuropathy, thus widening the usefulness of skin biopsy to immune-mediated
nerve fibres in the tongue, widening the spectrum of small fibre neuropathies.
16 Hoitsma E, Reulen JP, de Baets M, et al. Small fiber neuropathy: a common
40 Koike H, Mori K, Misu K, et al. Painful alcoholic polyneuropathy with pre-
and important clinical disorder. J Neurol Sci 2004; 227:119 –130.
dominant small-fiber loss and normal thiamine status. Neurology 2001;
A comprehensive review that outlines clinical features, diagnostic tests, and
treatment options of small fibre neuropathies.
41 Koike H, Iijima M, Sugiura M, et al. Alcoholic neuropathy is clinicopatholo-
17 Polydefkis M, Allen RP, Hauer P, et al. Subclinical sensory neuropathy in late-
gically distinct from thiamine-deficiency neuropathy. Ann Neurol 2003;
onset restless legs syndrome. Neurology 2000; 55:1115–1121.
18 Ørstavik K, Mork C, Kvernebo K, Jorum E. Pain in primary erythromelalgia: a
42 Oh SJ, Melo AC, Lee DK, et al. Large-fiber neuropathy in distal sensory
neuropathic component? Pain 2004; 110:531 –538.
neuropathy with normal routine nerve conduction. Neurology 2001;
This paper reports the results of a large clinical and neurophysiologic study.
Patients had significantly higher thermal-detection thresholds than controls, in-dicating the involvement of small fibres in the pathogenesis of painful symptoms.
43 Truini A, Romaniello A, Galeotti F, et al. Laser evoked potentials for assessing
sensory neuropathy in human patients. Neurosci Lett 2004; 361:25–28.
19 Otto M, Bak S, Bach FW, et al. Pain phenomena and possible mechanisms in
This paper outlines the advantages and drawbacks of this technique in assessing
patients with painful polyneuropathy. Pain 2003; 101:187–192.
the dysfunction of small nerve fibres in sensory neuropathies.
20 Holland NR, Crawford TO, Hauer P, et al. Small-fibre sensory neuropathies:
44 Granovsky Y, Matre D, Sokolik A, et al. Thermoreceptive innervation of human
clinical and neuropathology of idiopathic cases. Ann Neurol 1998; 44:47–59.
glabrous and hairy skin: a contact heat evoked potential analysis. Pain 2005;
21 Seneviratne U, Gunasekera S. Acute small fibre sensory neuropathy: another
variant of Guillain–Barre´ syndrome? J Neurol Neurosurg Psychiatry 2002;
This paper describes the newly developed CHEP stimulators, reports normative
data, and emphasizes the potential usefulness of the technique in assessing bothsmall myelinated and unmyelinated fibre function.
22 Sghirlanzoni A, Pareyson D, Lauria G. Sensory neuron diseases. Lancet
45 Osio M, Zampini L, Muscia F, et al. Cutaneous silent period in human
A comprehensive review focused on clinical features, pathogenesis, and diag-
immunodeficiency virus-related peripheral neuropathy. J Periph Nervous Syst
nostic investigations of sensory neuronopathies.
23 Pareyson D. Diagnosis of hereditary neuropathies in adult patients. J Neurol
46 Ørstavik K, Weidner C, Schmidt R, et al. Pathological C-fibres in patients with
a chronic painful condition. Brain 2003; 126:567 –578.
24 Chan CLH, Facer P, Davis JB, et al. Sensory fibres expressing capsaicin
47 Chong PS, Cros DP. Technology literature review: quantitative sensory
receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency.
testing. Muscle Nerve 2004; 29:734–747.
48 Shy ME, Frohman EM, So YT, et al. Quantitative sensory testing. Report of the
25 Fischer G. Management of vulvar pain. Dermatol Ther 2004; 17:134–149.
Therapeutics and Technology Assessment Subcommittee of the AmericanAcademy of Neurology. Neurology 2003; 60:898–904.
26 Houlden H, Blake J, Reilly MM. Hereditary sensory neuropathies. Curr Opin
49 Zinman LH, Bril V, Perkins BA. Cooling detection thresholds in the assess-
An excellent review that summarizes the wide phenotypes of inherited sensory and
ment of diabetic sensory polyneuropathy: comparison of CASE IV and Medoc
instruments. Diabetes Care 2004; 27:1674 –1679.
27 Pestronk A, Florence J, Levine T, et al. Sensory exam with a quantitative tuning
50 Pittenger GL, Ray M, Burcus NI, et al. Intraepidermal nerve fibers are
fork: rapid, sensitive and predictive of SNAP amplitude. Neurology 2004;
indicators of small-fiber neuropathy in both diabetic and nondiabetic patients.
Diabetes Care 2004; 27:1974 –1979.
28 Al-Shekhlee A, Chelimsky TC, Preston DC. Review: small-fiber neuropathy.
51 Shun CT, Chang YC, Wu HP, et al. Skin denervation in type 2 diabetes:
correlations with diabetic duration and functional impairments. Brain 2004;
29 Chin RL, Latov N. Peripheral neuropathy and celiac disease. Curr Treat Opt
An interesting study correlating duration of diabetes and metabolic status with
This paper details the features of peripheral nerve disorders associated with
clinical, neuropathologic, and functional parameters of small fibre impairment.
coeliac disease and outlines the athogenetic mechanisms.
52 Kra¨mer HH, Schmelz M, Birklein F, Bickel A. Electrically stimulated axon
30 Gibbons CH, Freeman R. Autonomic neuropathy and coeliac disease.
reflexes are diminished in diabetic small fiber neuropathies. Diabetes 2004;
J Neurol Neurosurg Psychiatry 2005; 76:579–581.
This paper shows that the size but not the intensity of axon reflex mediated flare,
31 Gondim FAA, Brannagan TH III, Sander HW, et al. Peripheral neuropathy in
which depends on the density and the function of skin C-fibres, is reduced in
patients with inflammatory bowel disease. Brain 2005; 128:867 –879.
A large retrospective study in which the different phenotypes of neuropathies arecharacterized and pathogenesis and treatment options are discussed. It also
53 Said G. Familial amyloid polyneuropathy: mechanisms leading to nerve
reports a wide review of the literature covering the last 30 years.
degeneration. Amyloid 2003; 10:7–12.
54 Seo JH, Ryan HF, Claussen GC, et al. Sensory neuropathy in vasculitis: a
64 Keswani SC, Leitz GJ, Hoke A. Erythropoietin is neuroprotective in models of
clinical, pathologic, and electrophysiologic study. Neurology 2004; 63:874–
HIV sensory neuropathy. Neurosci Lett 2004; 371:102 –105.
An in-vitro study on HIV and neurotoxic models showing that erythropoietin
An interesting paper demonstrating that vasculitis may exclusively present with
prevents sensory axonal degeneration.
symmetric or asymmetric impairment of sensory nerve fibres.
65 Keswani SC, Buldanlioglu U, Fischer A, et al. A novel endogenous erythro-
55 Perretti A, Nolano M, De Joanna G, et al. Is Ross syndrome a dysautonomic
poietin mediated pathway prevents axonal degeneration. Ann Neurol 2004;
disorder only? An electrophysiologic and histologic study. Clin Neurophysiol
An important paper clarifying the mechanisms, mediated by nitric oxide, that
56 Hilz MJ, Axelrod FB, Bickel A, et al. Assessing function and pathology in
underlie the efficacy of erythropoietin in the prevention of axonal degeneration.
familial dysautonomia: assessment of temperature perception, sweating andcutaneous innervation. Brain 2004; 127:2090–2098.
66 Kamiya H, Zhang W, Sima AAF. C-peptide prevents nociceptive sensory
A large study that correlates thermal and sweating assessment with immuno-
neuropathy in type 1 diabetes. Ann Neurol 2004; 56:827–835.
histochemical analysis of somatic and autonomic fibres in the skin.
67 Hahn K, Arendt G, Braun JS, et al. A placebo-controlled trial of gabapentin for
57 Donadio V, Montagna P, Nolano M, et al. Generalised anhidrosis: different
painful HIV-associated sensory neuropathies. J Neurol 2004; 251:1260–
lesion sites demonstrated by microneurography and skin biopsy. J Neurol
Neurosurg Psychiatry 2005; 76:588–591.
This paper shows that combined examination can distinguish between postgan-
68 Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms
glionic autonomic fibre impairment and sweat gland dysfunction in generalized
of painful diabetic neuropathy: a randomized controlled trial. Neurology 2004;
58 Gøransson LG, Mellgren SI, Lindal S, Omdal R. The effect of age and gender
on epidermal nerve fiber density. Neurology 2004; 62:774–777.
69 Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the
A normative reference study reporting the variability of epidermal innervation
treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-
density at the distal leg in a large cohort of healthy individuals.
controlled trial. Pain 2004; 110:628–638.
59 McArthur JC, Stocks EA, Hauer P, et al. Epidermal nerve fiber density:
70 Kochar DK, Rawat N, Agrawal RP, et al. Sodium valproate for painful diabetic
normative reference range and diagnostic efficiency. Arch Neurol 1998;
neuropathy: a randomized double-blind placebo-controlled study. Q J Med
60 Lauria G, Morbin M, Lombardi R, et al. Axonal swellings predict the degen-
71 Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the
eration of epidermal nerve fibers in painful neuropathies. Neurology 2003;
treatment of painful diabetic neuropathy: a double-blind, placebo-controlled
61 Herrmann DN, McDermott MP, Henderson D, et al. Epidermal nerve fiber
density, axonal swellings and QST as predictors of HIV distal sensory
72 Raskin P, Donofrio PD, Rosenthal NR, et al. Topiramate vs placebo in painful
neuropathy. Muscle Nerve 2004; 29:420–427.
diabetic neuropathy: analgesic and metabolic effects. Neurology 2004;
This paper shows that diffuse morphological changes of epidermal unmyelinated
fibres correlated with higher heat-pain threshold and were associated with a fasterprogression of sensory neuropathy.
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.
treatment achieved better analgesia at lower doses of each drug than either as a
A large epidemiological study demonstrating that, beside glycemic control, car-
diovascular risk factors are also associated with an increased incidence ofneuropathy.
74 Cruccu G, Anand P, Attal N, et al. EFNS guidelines on neuropathic pain
63 Bianchi R, Buyukakilli B, Brines M, et al. Erythropoietin both protects from and
assessment. Eur J Neurol 2004; 11:153–162.
reverses experimental diabetic neuropathy. Proc Natl Acad Sci U S A 2004;
The most recent guidelines reporting evidence-based recommendations for the
The study used the quantification of small fibres in the footpad to demonstrate theefficacy of erythropoietin in the treatment of streptozotocin-induced diabetic
75 Masson C, Cisse I, Simon V, et al. Fabry disease: a review. Joint Bone Spine
Präparateübersicht (Stand:1/2009) Effiziente und zugleich sehr wirtschaftlicheTherapieformen – Generika, die Ihnen in jederHinsicht Sicherheit geben. Wir wollen etwas bewegen in der Onkologie! axios Pharma GmbH · Hauptstr. 198 · 33647 BielefeldTel.: 05 21 / 98 83 50 · Fax: 05 21 / 9 71 74 78 · firstname.lastname@example.org · www.axios-pharma.de axitaxel® 6 mg/ml, Ko
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