Transient receptor potential channel polymorphisms are associated with the somatosensory function in neuropathic pain patients.

Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p = 0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p = 0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p = 0.006, p = 0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p = 0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients.

Cortical disinhibition occurs in chronic neuropathic, but not in chronic nociceptive pain.

BACKGROUND: The aim of this study was to examine the relationship between chronic neuropathic pain after incomplete peripheral nerve lesion, chronic nociceptive pain due to osteoarthritis, and the excitability of the motor cortex assessed by transcranial magnetic stimulation (TMS). Hence in 26 patients with neuropathic pain resulting from an isolated incomplete lesion of the median or ulnar nerve (neuralgia), 20 patients with painful osteoarthritis of the hand, and 14 healthy control subjects, the excitability of the motor cortex was tested using paired-pulse TMS to assess intracortical inhibition and facilitation. These excitability parameters were compared between groups, and the relationship between excitability parameters and clinical parameters was examined. RESULTS: We found a significant reduction of intracortical inhibition in the hemisphere contralateral to the lesioned nerve in the neuralgia patients. Intracortical inhibition in the ipsilateral hemisphere of neuralgia patients and in both hemispheres of osteoarthritis patients did not significantly differ from the control group. Disinhibition was significantly more pronounced in neuralgia patients with moderate/severe pain intensity than in patients with mild pain intensity, whereas the relative compound motor action potential as a parameter of nerve injury severity did not correlate with the amount of disinhibition. CONCLUSIONS: Our results suggest a close relationship between motor cortex inhibition and chronic neuropathic pain in the neuralgia patients, which is independent from nerve injury severity. The lack of cortical disinhibition in patients with painful osteoarthritis points at differences in the pathophysiological processes of different chronic pain conditions with respect to the involvement of different brain circuitry.

Sensory changes and loss of intraepidermal nerve fibers in painful unilateral nerve injury.

OBJECTIVES: Dysaesthesias is a common symptom in patients with neuropathic pain after peripheral nerve injury (PNI). In contrast to neuropathies with comparable symptoms there is little knowledge of the underlying mechanisms in PNI patients. METHODS: Quantitative sensory testing according to the German Research Network on Neuropathic Pain protocol, and changes in intraepidermal nerve fiber density were assessed in 15 patients with dysaesthesias after PNI of the lower limb. According to their small-fiber function patients were assigned into 2 subgroups. RESULTS: The sensory profiles of PNI patients were characterized predominantly by minus symptoms (significantly increased thresholds for perception of cold, warm, touch and vibration, and significantly increased thresholds for heat and mechanical pain) on the affected compared with the unaffected side. The only plus symptom reported was a significantly reduced pressure pain threshold. The sensory profile of patients with a severe loss of small-fiber function (n=7) showed a thermal and tactile hypoaesthesia and hypoalgesia; this was in contrast to patients with a moderate loss of small-fiber function, who showed a mild thermal and tactile hypoaesthesia associated with an increased mechanical pain sensitivity. Mean intraepidermal nerve fiber density was significantly decreased in the affected compared with unaffected skin [3.50 (4.00) vs. 11.10 (7.60) fibers/mm] and correlated with warm and mechanical detection thresholds (both r=-0.60). DISCUSSION: In conclusion, even though patients presented with comparable clinical symptoms, their sensory profiles differed, supporting the concept of different underlying mechanisms leading to chronic pain in PNI patients. Skin biopsies support the validity of quantitative sensory testing.

Significant difference between three observers in the assessment of intraepidermal nerve fiber density in skin biopsy.

BACKGROUND: The determination of Intraepidermal Nerve Fiber Density (IENFD) in skin biopsy is a useful method for the evaluation of different types of peripheral neuropathies. To allow a reliable use of the method it is necessary to determine interobserver reliability. Previous studies dealing with this topic used limited suitable statistical methods. METHODS: In the present study three observers determined the IENFD and estimated the staining quality of the basement membrane for an adequate quantity of 120 skin biopsies (stained with indirect immunofluorescence technique) from 68 patients. More adequate statistical methods like intraclass correlation coefficient and Bland Altman Plot were chosen to estimate interobserver reliability. RESULTS: We found an unexpected significant difference in IENFD between the observers (p < 0.05) and so the results of this study are not in line with the high interobserver reliability reported before (intraclass correlation coefficient: 0.73). The Bland Altmann Plot showed a variance growing with rising mean. The difference in IENFD between the observers and the resulting low interobserver reliability is likely caused by different interpretations of the standard counting rules. There was no significant difference in IENFD between observers for biopsies with a well-defined basement membrane. Thus skin biopsies with an inexactly defined basement membrane should not be used diagnostically for the determination of IENFD. CONCLUSION: These results emphasise that standardisation of the method is extremely important and at least two observers should analyse skin biopsies with critical IENFD near the cut-off values.

Habituation and short-term repeatability of thermal testing in healthy human subjects and patients with chronic non-neuropathic pain.

We investigated habituation effects during thermal quantitative sensory testing (tQST) using 8 repetitive measurements for thermal detection and pain thresholds. The same measurements were repeated two days later. 39 healthy subjects and 36 patients with chronic non-neuropathic pain syndromes (migraine, tension-type headache, non-radicular back pain) were enrolled. The pain intensity was assessed using an 11-point (0-10) numerical rating scale. Measurements correlated significantly over the two days in both groups (r=0.41...0.62). Warm detection (WDT) and heat pain threshold (HPT) revealed no significant differences over these days. Cold detection (CDT) and pain thresholds (CPT) showed significant differences but these were small compared to the range of normal variability (CDTDelta -0.28 degrees C; CPTDelta 1.51 degrees C). On both days, WDT showed no habituation during measurements. Although there was a small difference in CDT and CPT between first and second measurement, there was no habituation beyond the second stimuli. In contrast, HPT significantly increased between first and sixth stimuli, indicating pronounced habituation. Average HPT of first to third measurement was significantly lower than HPT of the fourth to sixth assessment (45.9 degrees C; 47.7 degrees C) with a good day-to-day repeatability. Repeatability and habituation was identical in both groups. Ongoing pain intensity in the patient groups correlated significantly with CDT/WDT but not with CPT, HPT, indicating that ongoing pain might suppress the sensitivity to non-painful stimuli. In summary, tQST proved a reliable diagnostic tool for clinical practice. Day-to-day differences were small but without clinical relevance. Habituation was most pronounced for HPT, probably due to peripheral fatigue of the receptors.

Painful or painless lower limb dysesthesias are highly predictive of peripheral neuropathy: comparison of different diagnostic modalities.

Dysesthesias of the lower limbs are a common complaint of patients and may be indicative of peripheral neuropathy. Here we investigated the prevalence and type of neuropathy in patients presenting with this complaint and compared the diagnostic performance of different diagnostic modalities. Forty-two patients were recruited prospectively and underwent a clinical examination, nerve conduction studies, quantitative sensory testing (QST), and skin biopsy at the dorsum of the foot. All patients had a correlate for their dysesthesias in at least one diagnostic modality. Most patients (>90%) had signs of small fiber loss or dysfunction. In about half of all patients large fibers were also affected. Nerve conduction studies were abnormal in 23/42 patients (54.8%). Cold or warm detection thresholds in QST were abnormal in 15/42 (35.7%) patients. Decreased intraepidermal nerve fiber density (IENFD) was found in 37 patients (88.1%), including some patients with normal QST findings. Nearly all patients with pathological QST had a reduced IENFD, indicating a high positive predictive value (93%) of QST in screening for reduced IENFD as correlate for neuropathy. Therefore in all patients with lower limb dysesthesias of unknown origin, the non-invasive methods of NCS and QST should be used and potentially complemented by skin biopsy.

Depression and changed pain perception: hints for a central disinhibition mechanism.

Although patients with a depressive disorder report often of pain, their sensitivity to experimental pain is controversial, probably due to differences in sensory testing methods and to the lack of normal values. Therefore, we used a standardized and validated comprehensive sensory testing paradigm to assess the peripheral and central nervous system performance in depressive patients compared to healthy controls and chronic pain patients with fibromyalgia syndrome (FMS), in which depression is a common comorbidity. Twenty-five depressive psychiatric inpatients (pain-free: n=20), 35 FMS outpatients and 25 healthy controls underwent quantitative sensory testing (QST), including thermal and mechanical detection and pain thresholds, pain sensitivity and responsiveness to repetitive noxious mechanical stimuli (wind-up). In depressive disorder (to a lesser extent also in FMS), significantly decreased cold pain thresholds and an increased wind-up were found, although the mechanical pain thresholds and pain sensitivity were comparable to those of the healthy controls. All the detection thresholds were within the normal range in all the groups. In depressive disorder, there were no significant side differences in the detection and pain thresholds. The results contradict the former assumption of a general insensitivity to experimental pain in depressive disorder. In the mostly pain-free patients signs of an enhanced central hyperexcitability are even more pronounced than usually found in chronic pain patients (e.g. FMS), indicating common mechanisms in depressive disorder and chronic pain in accordance with the assumption of non-pain associated mechanisms in depressive disorder for central hyperexcitability, e.g. by inhibited serotonergic function. Furthermore, this trial demonstrates the feasibility of QST in depressive patients.

Detection of a characteristic painful neuropathy in Fabry disease: a pilot study.

OBJECTIVE: Fabry disease (FD) is an X-linked lipid storage disorder showing a high prevalence and early occurrence of painful neuropathy. Early detection of this likely underdiagnosed disease is an important approach because a causal therapy is available. DESIGN: We used a quantitative sensory testing to determine the detailed somatosensory profile of male Fabry patients and compare this profile with somatosensory profiles of other painful sensory neuropathies (SN). RESULTS: Within this pilot-study, the profile revealed a small-fiber sensory neuropathy selectively affecting C- and A-delta fibers. The comparison with different somatosensory profiles of painful SN, including painful small-fiber sensory neuropathies of other etiologies, showed that the FD profile differs significantly and is characterized by a severe impairment of thermal and preserved vibratory and mechanical discrimination. CONCLUSION: Thus, somatosensory profiling in male patients with painful extremities may be useful in the detection of FD.

NeuroQuick--a novel bedside test for small fiber neuropathy?

BACKGROUND: An appropriate bedside test for small fiber neuropathy does not exist so far. Cold hypaesthesia occurs as an early onset symptom, and the new handheld device NeuroQuick (NQ) was recently claimed to be a valid and reliable screening tool for its quantitative assessment. AIMS: Comparison of the NQ with standardized quantitative sensory testing (QST) in patients suffering from chronic painful dysaesthesia with and without pathological cold detection threshold (CDT). METHODS: Forty-one patients with and without diabetes mellitus displaying chronic painful dysaesthesia were included (18 men, 55.8+/-13 years). According to the German network protocol QST was performed in the body area with the severest symptoms and at the opposite side as control after thorough clinical-neurological examination. The NeuroQuick, developed as quantitative bedside testing of cold thermal perception based on the wind chill, was used subsequently. RESULTS: DT was pathologically increased in 14 and within normal range in 27 patients; NQ values were pathological in 9 and non-pathological in 32 patients. Thus NQ obtained 7.4% false positive and 50% false negative results in detecting cold hypaesthesia, corresponding to 92.6% specificity, 50% sensitivity and a positive and negative predictive value of 78%, respectively. CONCLUSIONS: This study demonstrates that the NeuroQuick is not an adequate screening device for cold hypaesthesia in patients with chronic neuropathic pain. It exhibits a high specificity but only low sensitivity in the identification of such small fiber dysfunction; a reliable and valid screening tool should necessarily provide opposite features.