Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy.
BACKGROUND
Small fiber neuropathy (SFN) is a subtype of sensory neuropathy with acral pain and normal findings in routine nerve conduction studies.


METHODS
Twenty-four patients with SFN and matched controls were prospectively studied in this case-control study. Patients were assessed clinically, with standardized pain and depression questionnaires, by neurophysiologic tests, and by quantitative sensory testing. All patients underwent skin punch biopsy in a clinically affected (distal calf) and a nonaffected area (proximal thigh). Blood samples were collected for systemic cytokine gene expression analysis.


RESULTS
Patients with SFN had a 2-fold higher gene expression for interleukin (IL)-2 (p < 0.0001), IL-10 (p = 0.01), and transforming growth factor-beta1 (p = 0.001) in peripheral blood. Skin samples from affected areas showed increased IL-6 (7-fold; p = 0.001) and IL-8 (5-fold; p = 0.002) gene expression when compared to healthy controls. In 10/24 patients, SFN was termed length-dependent (LD) because of a > or =5-fold higher intraepidermal nerve fiber density in the proximal than in the distal skin. Patients with LD-SFN had higher gene expression in the affected distal skin than in nonaffected skin for tumor necrosis factor-alpha (2.6-fold; p = 0.04), IL-1beta (2-fold; p = 0.02), IL-6 (>200-fold; p = 0.01), and IL-8 (>500-fold; p = 0.046). Inflammatory cells were present in most SFN samples but their numbers were not correlated with cytokine levels.


CONCLUSIONS
Elevated local proinflammatory cytokines may be involved in the pathophysiology of pain in length-dependent small fiber neuropathy. These findings suggest a potential therapeutic role of locally applied cytokine inhibitors.
Uçeyler
N
N
Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany. ueceyler_n@klinik.uni-wuerzburg.de
Kafke
W
W
Riediger
N
N
He
L
L
Necula
G
G
Toyka
K V
KV
Sommer
C
C
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003863:Depression / Q000209:etiology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009412:Nerve Fibers / Q000473:pathology*; D009437:Neuralgia / Q000209:etiology; D010147:Pain Measurement / Q000379:methods; D011115:Polyneuropathies / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D012189:Retrospective Studies; D012867:Skin / Q000276:immunology* / Q000378:metabolism*; D018709:Statistics, Nonparametric; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017252:CD3 Complex; D016207:Cytokines; D043222:Ubiquitin Thiolesterase; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C482860:UCHL1 protein, human