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Abstract
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-β1 (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 ≥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-α (2.6-fold; p = 0.04), IL-1β (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.
Glossary
- ADS=
- Allgemeine Depressionsskala (General Depression Scale, validated for the German population);
- CDT=
- cold detection threshold;
- CPT=
- cold pain threshold;
- Ct=
- threshold cycle;
- DMA=
- dynamic mechanical allodynia;
- GCPS=
- Graded Chronic Pain Scale;
- HPT=
- heat pain threshold;
- IENFD=
- intraepidermal nerve fiber density;
- IL=
- interleukin;
- LD=
- length-dependent;
- MDT=
- mechanical detection threshold;
- MPS=
- mechanical pain sensitivity;
- NLD=
- non-length-dependent;
- NPSI=
- Neuropathic Pain Symptom Inventory;
- NRS=
- numerical rating scale;
- PHS=
- paradoxical heat sensation;
- PPT=
- deep pain sensitivity to blunt pressure;
- qRT-PCR=
- quantitative real-time PCR;
- QST=
- quantitative sensory testing;
- SFN=
- small fiber neuropathy;
- TGFβ1=
- transforming growth factor–β1;
- TNF=
- tumor necrosis factor–α;
- TSL=
- temperature sensory limen;
- VDT=
- vibration detection threshold;
- WDT=
- warm detection threshold;
- WUR=
- wind-up ratio.
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