Quantitative Tactile Examination Using Shape Memory Alloy Actuators for the Early Detection of Diabetic Neuropathy

Diabetic neuropathy (DPN) is asymptomatic in its early phases but can cause serious complications as it progresses. Most DPN tests are cumbersome and produce only qualitative assessments, and simpler approaches that yield quantitative results are needed. Techniques that allow patients to perform examinations themselves would be especially valuable. In this study, we focused on quantifying the decline in tactile sensation associated with DPN and developed a measurement device that used a thin shape memory alloy (SMA) wire as the actuator. An ON/OFF pulse current caused the wire to shrink and expand. This vibration was amplified by a round-headed pin, allowing even DPN patients with reduced tactile sensitivity to detect the stimuli generated when lightly touching the pin with their fingertips. The tactile stimuli were ranked into 30 levels of intensity. A key advantage of the device is that it can be used by patients themselves, returning quantified results within minutes. Although developed for DPN, the method can be applied to the detection of peripheral neuropathy in general

Pain and physical functioning in neuropathic pain: a systematic review of psychometric properties of various outcome measures

INTRODUCTION: A range of outcome measures across various domains are used to evaluate change following an intervention in clinical trials on chronic neuropathic pain (NeP). However, to capture a real change in the variable of interest, the psychometric properties of a particular measure should demonstrate appropriate methodological quality. Various outcome measures in the domains of pain and physical functioning have been used in the literature for NeP, for which individual properties (eg, reliability/validity) have been reported. To date, there is no definitive synthesis of evidence on the psychometric properties of those outcome measures; thus, the aim of this systematic review was to evaluate the methodological quality [COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) guidelines] of studies that evaluated psychometric properties of pain and physical functioning outcome measures used for NeP. METHODS: Specific MeSH/keywords related to 3 areas (pain and/or physical functioning, psychometric properties, and NeP) were used to retrieve relevant studies (English language) in key electronic databases (MEDLINE (Ovid), CINAHL (EBSCO), Scopus, AMED, and Web of Science) from database inception-July 2012. Articles retrieval/screening and quality analysis (COSMIN) were carried out by 2 independent reviewers. RESULTS: Twenty-four pain and thirty-seven physical functioning outcome measures were identified, varying in methodological quality from poor-excellent. CONCLUSION: Although a variety of pain and physical functioning outcome measures have been reported in the literature, few have demonstrate methodologically strong psychometric properties. Thus, future research is required to further investigate the psychometric properties of existing pain and physical functioning outcome measures used for clinical and research purposes

Doctor of Philosophy

dissertationCarpal tunnel syndrome (CTS) is the number one cause of disability at work in the United States. Loss of time at work and worker's compensation expenditure caused by CTS is more than that caused by any other condition. However, workplace surveillance is likely to help in detecting CTS at a stage that is treatable at a significantly lower cost. Vibrotactile threshold (VT) testing can be used for this purpose. The VT is the smallest displacement applied (as a sinusoid) to a finger innervated by the median nerve that can be detected by the patient. Vibrotactile threshold evaluation can be a versatile tool for applications involving haptics interfaces, for evaluating peripheral neuropathies, and for studying the effects of chemotherapy induced neuropathies. This dissertation presents the prototype design of a vibrotactile threshold evaluator for the workplace (VTEW), which is portable, and configurable in terms of the probe diameter (1-6 mm), surround diameter (8-10 mm), applied frequency (1-250 Hz), angle of probe (0-1200), and displacement of probe (1-1500 ?m) and is operated with a customizable LabView interface. The VTEW also incorporates a special mount for the probe stimulus to test the subjects in at least two distinctive postures of the hand. Subjects were tested using an existing validated device, Vibrotactile Threshold Tester (VTT) and VTEW. Subjects were tested at 50 Hz with VTT and VTEW for validation. The effect of flexion on VT was observed by testing the subjects on VTEW at 50 Hz with their dominant hand in neutral posture and again with their dominant hand in provocative flexion. Use of low frequency for testing in VT studies is uncommon due to hardware constraints. However, low frequency studies could be potentially useful for investigating the effects of chemotherapy on the perception of pain. Thus, subjects were also tested at 4 Hz using VTEW to obtain preliminary data. Finally, an age regression model was developed to correct for the changes occurring in VT with age

Tools for Assessing Neuropathic Pain

Giorgio Cruccu and Andrea Truini discuss a new pain assessment tool published in PLoS Medicine called Standardized Evaluation of Pain and they review other tools to assess neuropathic pain

The prevalence, characteristics and morbidity of neuropathic pain in AIDS patients, prior to the use of HAART, at the Kalafong Hospital HIV clinic, Pretoria

Includes bibliographical references (leaves 49-56).Neuropathic pain, of which a distal sensory polyneuropathy (DSP) is the most frequent cause, is a common problem in patients with HIV infection and AIDS. The researcher is concerned that neuropathic pain in patients with AIDS tends to be underdiagnosed and under-treated. There are several reasons for this, one of which may be a lack of awareness of the extent of the problem, as well as the impact it has on patients' lives. Several studies around the world have noted the problem of under-diagnosis and undertreatment of pain and more specifically, neuropathic pain, in patients with AIDS. A review of the literature reveals a wide variation in the prevalence of neuropathic pain and peripheral neuropathy in AIDS patients. To determine the prevalence, characteristics, severity and morbidity of neuropathic pain in AIDS patients, attending the Kalafong HIV Clinic, prior to the initiation of HAART.A prospective, cross sectional and descriptive study was done at the Kalafong Hospital HIV Clinic. Data was collected from a systematic sample of 354 AIDS patients, who were referred to this HIV clinic to be initiated on HAART. An interviewer-administered questionnaire and focused neurological examination were used. This included a recently validated instrument, the DN4, for identifying pain which is neuropathic in origin. Selected sections of the Brief Pain Inventory (BPI) were used to determine the severity of the neuropathic pain, as well as pain-related interference on aspects of daily living

(Cost-)effectiveness of lower extremity nerve decompression surgery in subjects with diabetes:the DeCompression (DECO) trial-study protocol for a randomised controlled trial

Introduction The peripheral nerves of patients with diabetes are often pathologically swollen, which results in entrapment at places of anatomical narrowing. This results in nerve dysfunction. Surgical treatment of compression neuropathies in the lower extremities (lower extremity nerve decompression (LEND)) results in relief of symptoms and gain in peripheral nerve function, which may lead to less sensory loss (short term) and less associated detrimental effects including foot ulceration and amputations, and lower costs (long term). The aim of the DeCompression trial is to evaluate the effectiveness and (cost-)effectiveness of surgical decompression of compressed lower extremity nerves (LEND surgery) compared with patients treated with conventional (non-surgical) care. Methods and analysis A stratified randomised (1 to 1) controlled trial comparing LEND surgery (intervention) with conventional non-surgical care (control strategy) in subjects with diabetes with problems of neuropathy due to compression neuropathies in the lower extremity. Randomisation is stratified for participating hospital (n=11) and gender. Patients and controls have the same follow-up at 1.5, 3, 6, 9, 12, 18, 24 and 48 months. Participants (n=344) will be recruited in 12 months and enrolled in all affiliated hospitals in which they receive both the intervention or conventional non-surgical care and follow-up. Outcome assessors are blinded to group assignment. Primary outcome: disease-specific quality of life (Norfolk Quality of Life Questionnaire-Diabetic Neuropathy). Secondary outcomes: health-related quality of life (EuroQoL 5-dimension 5-level (EQ-5D5L), 36-item Short Form (SF-36)), plantar sensation (Rotterdam Diabetic Foot Test Battery), incidence of ulcerations/amputations, resource use and productivity loss (Medical Cost Questionnaire, Productivity Cost Questionnaire) during follow-up. The incremental cost-effectiveness ratio will be estimated on the basis of the collected empirical data and a cost-utility model. Ethics and dissemination Ethics approval has been granted by the Medical Research Ethics Committee of Utrecht University Medical Center (reference: NL68312.041.19v5, protocol number: 19-335/M). Dissemination of results will be via journal articles and presentations at national and international conferences

Neuropathic pain in neuropathy: a combined clinical, neurophysiological and morphological study

Neuropathic pain (NP) is a major symptom which may be intractable in common neurological disorders such as neuropathy, spinal cord injury, multiple sclerosis and stroke. Pain is a complex sensation strongly modulated by cognitive influences, and understanding the underlying pathophysiological mechanisms in patients remains a challenge for pain specialists. The aim of my Phd-research was to show in according with present evidence-based studies the correlation between clinical manifestations of neuropathic pain and the underlying alteration of the different groups of fibers (Aβ, Aδ or C). In the second chapter I revised the previous guidelines about neuropathic pain assessment. History and clinical examination are a requirement to confirm the presence of a NP, and also an important step in reaching an aetiological diagnosis for NP. History and bedside examination are still fundamental to a correct diagnosis, while screening tools and questionnaires are useful in indicating probable NP. I argued in particular a recent technique, skin biopsy; I approached it at the beginning of my Phd during my stage at the I.R.C.S.S. C. Besta in Milan; then, I imported this procedure in our laboratory (Department of Pathological Anatomy, Sapienza University). We are now able to process skin biopsies and immunoassayed them with polyclonal anti-protein-gene-product 9.5 antibodies (specific for nerve fibers) using immunohistochemistry or immunofluorescence, which allowed demonstrating the extensive innervations of the epidermidis. In the following chapters I approached some common conditions of neuropathic pain. The third chapter is dedicated to the post-herpetic neuralgia, an exceptionally drug-resistant neuropathic pain. To investigate the pathophysiological mechanisms underlying postherpetic neuralgia we clinically investigated sensory disturbances, pains and itching, with an 11-point numerical rating scale in 41 patients with ophthalmic postherpetic neuralgia. In all the patients we recorded the blink reflex, mediated by non-nociceptive myelinated Aβ-fibers, and trigeminal laser evoked potentials (LEPs) related to nociceptive myelinated Aδ- and unmyelinated C-fiber activation. We also sought possible correlations between clinical sensory disturbances and neurophysiological data. Neurophysiological testing yielded significantly abnormal responses on the affected side compared with the normal side. The blink reflex delay correlated with the intensity of paroxysmal pain, whereas the Aδ- and C-LEP amplitude reduction correlated with the intensity of constant pain . Allodynia correlated with none of the neurophysiological data. Our study shows that postherpetic neuralgia impairs all sensory fiber groups. The neurophysiological-clinical correlations suggest that constant pain arises from a marked loss of nociceptive afferents, whereas paroxysmal pain is related to Aβ-fiber demyelination. These findings might be useful for a better understanding of pain mechanisms in postherpetic neuralgia. In the fourth chapter I treated the differential involvement of Aδ and Aβ fibers in neuropathic pain related to carpal tunnel syndrome (CTS). We studied 70 patients with a diagnosis of CTS (117 CTS hands). We used the DN4 questionnaire to select patients with neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to assess the intensity of the various qualities of neuropathic pain. All patients underwent a standard nerve conduction study (NCS) to assess the function of non-nociceptive Aβ-fibres, and the cutaneous silent period (CSP) after stimulation of the IIIrd and Vth digits, to assess the function of nociceptive Aδ-fibres. In 40 patients (75 CTS hands) we also recorded LEPs in response to stimuli delivered to the median nerve territory and mediated by nociceptive Aδ-fibres. We sought possible correlations between neurophysiological data and the various qualities of neuropathic pain as assessed by the NPSI. We found that the median nerve sensory conduction velocity correlated with paroxysmal pain and abnormal sensations, whereas LEP amplitude correlated with spontaneous constant pain. Our findings suggest that whereas paroxysmal pain and abnormal sensations reflect demyelination of non-nociceptive Aβ-fibres, spontaneous constant pain arises from damage to nociceptive Aδ-fibres. In the fifth chapter I treated the mechanisms of pain in multiple sclerosis. In this clinical and neurophysiological study we sought information on the clinical characteristics and underlying mechanisms of neuropathic pain related to the disease. A total of 302 consecutive patients with multiple sclerosis were screened for neuropathic pain by clinical examination and the DN4 tool. In patients selected for having ongoing extremity pain or Lhermitte’s phenomenon, we recorded somatosensory evoked potentials, mediated by Aβ non-nociceptive fibres, and LEP, mediated by Aδ nociceptive fibres. Of the 302 patients, 92 had pain (30%), and 42 (14%) neuropathic pain. Patients with neuropathic pain had more severe multiple sclerosis, as assessed by the expanded disability severity score, than those without pain. Whereas in patients with ongoing neuropathic pain laser evoked potentials were more frequently abnormal than somatosensory evoked potentials we found the opposite in patients with Lhermitte’s phenomenon. Our data underline the clinical importance of pain in multiple sclerosis and indicate that a more severe disease is associated with a higher risk of developing neuropathic pain. The prevalence of pain we found, lower than that reported in previous studies, may reflect the lower disease severity in our patients. Neurophysiological data show that whereas ongoing extremity pain is associated with spinothalamic pathway damage, Lhermitte’s phenomenon is related to damage of non-nociceptive pathways. These findings may be useful in designing a new therapeutic approach to neuropathic pain related to multiple sclerosis. The sixth chapter is dedicated to the mechanisms of pain in distal symmetric neuropathy. I and my colleagues performed a clinical, neurophysiological and histomorphological study on patients with neuropathic pain in distal symmetric neuropathy. In patients with distal symmetric polyneuropathy we assessed non-nociceptive Aβ- and nociceptive Aδ- and C-afferents to investigate their role in the development of neuropathic pain. We screened 2240 consecutive patients with sensory disturbances and collected 269 patients with distal symmetric polyneuropathy (57% with pain and 43% without). All patients underwent the Neuropathic Pain Symptom Inventory to rate ongoing, paroxysmal and provoked pains, a standard NCS to assess Aβ-fibre function, LEPs to assess Aδ-fibre function, and skin biopsy to assess the unmyelinated innervations of the epidermidis. Patients with pain had the same age, but a longer delay since symptom onset than those without . Loss of intraepidermal innervation did not correlate with the presence of neuropathic pain. Whereas the LEP amplitude was significantly lower in patients with pain than in those without , NCS and intraepidermal fibre nerves data did not differ between groups. LEPs were more severely affected in patients with ongoing pain than in those with provoked pain. Our findings indicate that the impairment of Aβ-fibres has no role in the development of ongoing or provoked pain. In patients with ongoing pain the severe LEP suppression and the correlation between pain intensity and LEP attenuation may indicate that this type of pain reflects damage to nociceptive axons. The partially preserved LEPs in patients with provoked pain suggest that thistype of pain is related to the abnormal activity arising from partially spared and sensitised nociceptive terminals. Because clinical and neurophysiological abnormalities followed similar patterns regardless of aetiology, pain should be classified and treated on mechanism-based grounds. In the seventh chapter I treated the mechanisms of allodynia in distal symmetric polyneuropathy allodynia. Patients with painful neuropathy frequently complain of allodynia, i.e. pain in response to a normally non-painful stimulus. Many authors consider allodynia to be generated by sensitization of the second-order nociceptive neurons to Aβ-fibre input (central sensitization). With the hypothesis that patients suffering from this type of pain probably have a relative sparing of Aβ-fibres in comparison with patients with ongoing pain only, we sought aimed at seeking information on mechanisms underlying allodynia. In 200 patients with distal symmetric polyneuropathy (114 with pain, 86 without) we assessed non-nociceptive Aβ- and nociceptive Aδ-afferents to investigate their role in the development of allodynia. After a detailed clinical examination and pain questionnaires patients underwent a standard nerve conduction study (NCS) to assess Aβ-fibre function, and LEPs to assess Aδ-fibre function. Forthy-four out of 114 patients with painful neuropathy suffered from allodynia. While NCS data did not differ between patients with and without allodynia, LEP amplitude was higher in patients with allodynia than in those without. Our data argue against a role of Aβ-fibres and central sensitization as the main mechanism for the development of allodynia in distal symmetric polyneuropathy. The partially preserved LEPs in patients with allodynia suggests that this type of pain might be related to the abnormal reduction of mechanical threshold of nociceptive terminals (peripheral sensitization). In the eighth chapter I treated neuropathic pain in patient with crioglobulinemia. The study aimed at gaining information on peripheral neuropathy and neuropathic pain in patients with cryoglobulinaemia. We collected 48 consecutive patients with cryoglobulinaemia. All patients underwent a standard NCS to assess A-fibre function, LEPs to assess A-fibre function, and skin biopsy to assess C-fibre terminals. We used DN4 questionnaire to diagnose neuropathic pain, and the Neuropathic Pain Symptom Inventory to rate the intensity of the different qualities of neuropathic pain. Thirty patients had a peripheral neuropathy. Twenty-three had neuropathic pain as assessed by the DN4 questionnaire. NPSI questionnaire showed that the most frequent type of pain was the burning pain. Patients with peripheral neuropathy had an older age than those without . The duration of the disease correlated with the density of epidermal innervation as assessed by skin biopsy. The severity of the ongoing burning pain correlated with the amplitude of LEPs, but not with the density of epidermal innervation . Our findings showed that an older age is associated with the development of peripheral neuropathy, and a longer duration of disease with a more severe peripheral nerve damage, as assessed by skin biopsy. The correlation between the intensity of ongoing pain and LEP attenuation indicate that neuropathic pain reflects damage to nociceptive axons. In the ninth chapter I discussed the research on a peptide, the kiss-peptine, whose antagonist could be a new analgesic drug. More studies should be perform in the next future about it . Kisspeptin is a neuropeptide known for its role in the hypothalamic regulation of the reproductive axis. Following the recent description of kisspeptin and its 7-TM receptor, GPR54, in the dorsal root ganglia and dorsal horns of the spinal cord, we examined the role of kisspeptin in the regulation of pain sensitivity in mice. Immunofluorescent staining in the mouse skin showed the presence of GPR54 receptors in PGP9.5-positive sensory fibers. Intraplantar injection of kisspeptin (1 or 3 nmol/5 μl) induced a small nocifensive response in naive mice, and lowered thermal pain threshold in the hot plate test. Both intraplantar and intrathecal (0.5 or 1 nmol/3 μl) injection of kisspeptin caused hyperalgesia in the first and second phases of the formalin test, whereas the GPR54 antagonist, p234 (0.1 or 1 nmol), caused a robust analgesia. Intraplantar injection of kisspeptin combined with formalin enhanced TRPV1 phosphorylation at Ser800 at the injection site, and increased ERK1/2 phosphorylation in the ipsilateral dorsal horn as compared to naive mice and mice treated with formalin alone. These data demonstrate for the first time that kisspeptin regulates pain sensitivity in rodents and suggest that peripheral GPR54 receptors could be targeted by novel drugs in the treatment of inflammatory pain. In the tenth last chapter I gathered all the conclusion of the single studies. Here I tried to associate each quality of pain to an underling pathophysiological alteration, since the aim of y studies was to show the correlation between clinical manifestations of neuropathic pain and the underlying alteration of the different groups of fibers (A-β, A-δ or C)

Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity

The skin is equipped with specialized mechanoreceptors that allow the perception of the slightest brush. Indeed, some mechanoreceptors can detect even nanometer-scale movements. Movement is transformed into electrical signals via the gating of mechanically activated ion channels at sensory endings in the skin. The sensitivity of Piezo mechanically gated ion channels is controlled by stomatin-like protein-3 (STOML3), which is required for normal mechanoreceptor function. Here we identify small-molecule inhibitors of STOML3 oligomerization that reversibly reduce the sensitivity of mechanically gated currents in sensory neurons and silence mechanoreceptors $\textit{in vivo}$. STOML3 inhibitors in the skin also reversibly attenuate fine touch perception in normal mice. Under pathophysiological conditions following nerve injury or diabetic neuropathy, the slightest touch can produce pain, and here STOML3 inhibitors can reverse mechanical hypersensitivity. Thus, small molecules applied locally to the skin can be used to modulate touch and may represent peripherally available drugs to treat tactile-driven pain following neuropathy.This study was funded by DFG collaborative research grant SFB958 (projects A09 to K.P. and G.R.L., A01 to V.H. and Z02 to J.S.). Additional support was provided by a senior ERC grant (grant number 294678 to G.R.L.) and by the NeuroCure Cluster of Excellence (to V.H., G.R.L. and J.F.A.P.). K.P. was supported by a Cecile-Vogt Fellowship (MDC). S.P. was supported by a Marie Curie Fellowship from the European Union (grant number 253663 Touch in situ). C.P. received a Ph.D. fellowship from the University of Cagliari. J.F.A.P. was funded by a European Research Council (ERC) starting grant (ERC-2010-StG-260590), the DFG (FOR 1341, FOR 2143), the Berlin Institute of Health (BIH) and the European Union (FP7, 3x3Dimaging 323945). R.K. was supported by an ERC Advanced Investigator grant (294293-PAIN PLASTICITY). D.H. was funded by the Berlin Institute of Health (BIH). E.St.J.S., L.E. and M.M. were supported by an Alexander von Humboldt Fellowship