Maximum axonal following frequency separates classes of cutaneous unmyelinated nociceptors in the pig.

KEY POINTS: C-nociceptors are generally assumed to have a low maximum discharge frequency of 10-30 Hz. However, only mechano-insensitive 'silent' C-nociceptors cannot follow electrical stimulation at 5 Hz (75 pulses) whereas polymodal C-nociceptors in the pig follow stimulation at up to 100 Hz without conduction failure. Sensitization by nerve growth factor increases the maximum following frequency of 'silent' nociceptors in pig skin and might thereby contribute in particular to intense pain sensations in chronic inflammation. A distinct class of C-nociceptors with mechanical thresholds >150 mN resembles 'silent' nociceptors at low stimulation frequencies in pigs and humans, but is capable of 100 Hz discharge and thus is suited to encode painfulness of noxious mechanical stimuli. ABSTRACT: Using extracellular single-fibre recordings from the saphenous nerve in pig in vivo, we investigated peak following frequencies (5-100 Hz) in different classes of C-nociceptors and their modulation by nerve growth factor. Classes were defined by sensory (mechano-sensitivity) and axonal characteristics (activity dependent slowing of conduction, ADS). Mechano-insensitive C-nociceptors (CMi) showed the highest ADS (34% ± 8%), followed only 66% ± 27% of 75 pulses at 5 Hz and increasingly blocked conduction at higher frequencies. Three weeks following intradermal injections of nerve growth factor, peak following frequency increased specifically in the sensitized mechano-insensitive nociceptors (20% ± 16% to 38% ± 23% response rate after 72 pulses at 100 Hz). In contrast, untreated polymodal nociceptors with moderate ADS (15.2% ± 10.2%) followed stimulation frequencies of 100 Hz without conduction failure (98.5% ± 6%). A distinct class of C-nociceptors was exclusively sensitive to strong forces above 150 mN. This class had a high ADS (27.2% ± 7.6%), but displayed almost no propagation failure even at 100 Hz stimulation (84.7% ± 17%). Also, among human mechanosensitive nociceptors (n = 153) those with thresholds above 150 mN (n = 5) showed ADS typical of silent nociceptors. C-fibres with particularly high mechanical thresholds and high following frequency form a distinct nociceptor class ideally suited to encode noxious mechanical stimulation under normal conditions when regular silent nociceptors are inactive. Sensitization by nerve growth factor increases maximum discharge frequency of silent nociceptors, thereby increasing the frequency range beyond their physiological limit, which possibly contributes to excruciating pain under inflammatory conditions.

[Small-fibre neuropathy]. / Tynnfibernevropati.

BACKGROUND: Small-fibre neuropathy is a neuropathy that mainly affects the small nerve fibres. Owing to doctors' inadequate knowledge of the condition and limited diagnostic methods, this type of neuropathy is probably under-diagnosed. Small-fibre neuropathy has many causes, but the symptoms are often relatively similar. This review article is intended to give doctors insight into the clinical expressions and diagnosis of the condition. METHOD: The article is based on literature searches in PubMed and the authors' clinical and scientific experience of the subject. RESULTS: Small-fibre neuropathy generates a characteristic distribution of symptoms, particularly pain, and is associated with a number of common illnesses. Specific tests for small fibre neuropathy, such as skin biopsy and thermal testing, can be used to confirm the diagnosis. The treatment targets the symptoms, but complete pain relief is often difficult to achieve. INTERPRETATION: The clinical neurological examination will not generally be able to detect small-fibre neuropathy, but will contribute primarily to excluding a more general polyneuropathy. Supplementary tests are often necessary to make a final diagnosis.

[Microneurography and research on peripheral neuropathic pain]. / Mikronevrografi og forskning på perifer nevropatisk smerte.

BACKGROUND: Microneurography is a neurophysiological technique which enables recording from single peripheral nerve fibres in persons who are awake. The method is only used in research. We discuss how microneurography has been used to map nerve-fibre functions under normal circumstances and in chronic pain conditions. METHOD: The article is based on a literature search in PubMed and on the authors' own knowledge and experience of the method from their research. RESULTS: Microneurography has contributed to the understanding of pain under physiological conditions and in chronic pain conditions, in particular peripheral neuropathic pain. For example, signs of hyperexcitability have been found in peripheral nerve fibres in connection with neuropathies and peripheral neuropathic pain conditions, and the proportion of hyperexcitable nerve fibres has been shown to be greater in neuropathy patients with chronic pain than in neuropathy patients without pain. Findings indicate that so-called CMi nociceptors play an important role in chronic neuropathic pain. INTERPRETATION: In the longer term we hope that research using microneurography will help to reveal mechanisms of direct importance for the development of targeted treatment of neuropathic pain.

Cold allodynia is correlated to paroxysmal and evoked mechanical pain in complex regional pain syndrome (CRPS).

OBJECTIVES: Mechanisms of complex regional pain syndrome (CRPS) are still debated. Identifying subgroups of patients have been attempted in the hope of linking clinical findings to possible mechanisms. The aim of the present study was to investigate whether subgroups of CRPS (based on quantitative sensory testing (QST)-results) differed with respect to different characteristics of pain like spontaneous ongoing or paroxysmal pain and mechanical dynamic allodynia. METHODS: 61 CRPS-patients (type 1 and 2) were examined clinically and with QST, in affected and contralateral extremity, with assessment of thresholds for warmth, cold and heat-and cold pain. RESULTS: 43 patients (20 men, 23 men) were diagnosed with CRPS 1 (70.5%) and 18 patients (8 women and 10 men) with CRPS 2 (29.5%). Three subgroups were defined based on thermal thresholds; A (thermal allodynia 22.9%), B (thermal hyposensitivity 37.3%), C (thermal allodynia and hyposensitivity 39.3%). Paroxysmal pain was more prevalent in patients with thermal allodynia (merging group A + C, 25/38-65.8%) compared to patients without thermal allodynia (group B, 5/23-21.7%) (p-value=0.00085). CONCLUSIONS: We suggest that cold allodynia is based on hyper-excitability of very superficial skin nociceptors. The correlation between paroxysmal pain, allodynia to light touch and cold allodynia suggests that activity in those peripheral nociceptors can drive both, paroxysmal pain and spinal sensitization leading to stroke evoked allodynia. Mechanistically, the physical cold stimulus can unmask disease-related hyperexcitability by closure of temperature-sensitive potassium channels or induction of resurgent currents. Small fiber degeneration alone may not be the crucial mechanism in CRPS, nor explain pain.

Abstracts from The Cold Weather Operations Conference 2021.

A common effort for both military and civil healthcare is to achieve knowledge-based health care in cold weather injuries and fatal accidents in harsh arctic environment. The Cold Weather Operations Conference in November 2021, having more than 300 participants from 20 countries, was addressing the prevention and treatment of injuries and trauma care in cold weather conditions and the challenges for military prehospital casualty care. The intention of the programme was to stimulate further research and systematic knowledge-based clinical work. The abstracts from the conference present cold weather research and clinical experience relevant for readers of the International Journal of Circumpolar Health.

The challenge of recognizing severe pain and autonomic abnormalities for early diagnosis of CRPS.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a disabling usually post-traumatic pain condition. International guidelines emphasize early diagnosis for treatment and improved outcome. Early intense and persistent pain along with features of autonomic dysfunction in the first week's post-injury are early warning signs for development of CRPS. We have previously reported a delayed diagnosis of CRPS. The main purpose of the present study was to investigate possible causes of a delayed diagnosis, with a special focus of recognition of risk factors. METHODS: A total of 52 CRPS 1 (without detectable nerve damage) and CRPS 2 (with evidence of nerve lesion) patients were included in the study. When examined at OUS-Rikshospitalet, we retrospectively asked the patients on the development of pain and autonomic abnormalities from the time of the eliciting injury, performed a thorough clinical investigation with an emphasis on signs of autonomic failure and compared symptoms and clinical findings with such information in previous medical records. We also evaluated symptoms and signs according to the type of injury they had suffered. RESULTS: Of a total of 52 patients (30 women and 22 men, mean age 39.0 years at the time of injury), 34 patients had CRPS type 1 (65.4%) and 18 CRPS type 2 (34.6%), 25 patients with pain in the upper and 27 in the lower extremity. A total of 35 patients (67.3%) were diagnosed with CRPS (following mean 2.1 years) prior to the investigation at OUS-Rikshospitalet (mean 4.86 years following injury). Mean time from injury to diagnosis was 33.5 months (SD 30.6) (2.8 years) for all patients. In retrospect, all 17 patients first diagnosed at OUS met the CRPS diagnosis at an earlier stage. All patients retrospectively reported intense pain (numeric rating scale > 7) from the time of injury with a large discrepancy to previous medical records which only stated intense pain in 29.4% of patients with CRPS type 1 and 44.4% of patients with CRPS type 2 within the first four months. While the patients reported an early onset of autonomic dysfunction, present in 67.3 and 94.2% of the patients within one week and one month, respectively, reports of autonomic abnormalities within the first four months was far less (maximum in 51.7% of patients with CRPS type 1 and in 60% in CRPS 2). In 10 patients with CRPS type 1, no symptom nor sign of autonomic abnormalities was reported. CONCLUSIONS: We still find a significant delay in the diagnosis of CRPS. There is a large discrepancy between both self-reporting of intense, disproportionate pain, as well as symptoms of autonomic abnormalities from the time of injury, and documentation in previous medical records. Our findings suggest a lack of awareness of risk factors for the development of CRPS, such as early intense pain and autonomic abnormalities without recovery, contributing to delayed diagnosis. The present results suggest causes of delayed CRPS-diagnosis. An increased attention to early warning signs/risk factors may improve diagnosis of CRPS.

[The intern's vein--the patient's nightmare?]. / Kandidatens trøst--pasientens mareritt?

BACKGROUND: Punction of blood vessels is a necessity in modern medicine, but there is a paucity of knowledge about the close relation between vessels and nerves. MATERIAL AND METHODS: We refer to two cases that show possible consequences of cannulation of v. cephalica and a. radialis. RESULTS: Both patients developed clinical symptoms and neurological findings indicating injury of the radial nerve. One of the patients is not likely to develop chronic neuropathic pain, but in the other patient the similar injury of the radial nerve has lead to chronic and disabling pain. INTERPRETATION: We advise against using the distal part of v. cephalica (the intern's vein) as the first choice for training of inexperienced students. The vein should only be used in patients that lack other venous alternatives and in acute situations where quick infusions or blood transfusions are needed.

Slow depolarizing stimuli differentially activate mechanosensitive and silent C nociceptors in human and pig skin.

ABSTRACT: High-threshold mechanosensitive and mechanoinsensitive ("silent") nociceptors have similar electrical thresholds for transcutaneous sine wave stimulation at 4 Hz that selectively activates cutaneous C nociceptors in human skin. Their fundamentally different functions particularly in chronic pain warrant differential stimulation protocols. We used transcutaneously delivered slow depolarizing stimuli (half-sine, 500 ms duration, 0.01-1 mA) in humans to assess intensity-response relations for the induction of pain psychophysically and recorded activation of mechanosensitive and silent nociceptors in healthy volunteers by microneurography. Differential C-fiber activation was confirmed in single-fiber recordings in pig allowing for stimulation amplitudes up to 10 mA. Perception and pain thresholds to half-sine wave pulses were 0.06 ± 0.03 mA and 0.18 ± 0.1 mA, respectively, and caused pain in an amplitude-dependent manner (n = 24). When matched for pain intensity, only sine wave stimulation induced an instant widespread axon reflex erythema (n = 10). In human microneurography, half-sine stimulation activated mechanosensitive nociceptors (n = 13), but only one of 11 silent nociceptors. In pig skin, the amplitude-dependent activation of mechanosensitive nociceptors was confirmed (0.2-1 mA, n = 28), and activation thresholds for most silent nociceptors (n = 13) were found above 10 mA. Non-nociceptive low-threshold mechanosensitive C fibers (n = 14) displayed lower activation thresholds for half-sine wave stimuli with an amplitude-dependent discharge increase between 0.01 and 0.1 mA. We conclude that transcutaneous electrical stimulation with 500-ms half-sine wave pulses between 0.2 and 1 mA causes amplitude-dependent pain by preferential activation of mechanosensitive C nociceptors.

A 4-year follow-up of non-freezing cold injury with cold allodynia and neuropathy in 26 naval soldiers.

Background and aims Non-freezing cold injuries (NFCI), which typically may occur in military personnel, may result from exposure to cold, at temperatures around 0 °C or above, and worsened by wind and moisture. The injury is due to cooling but not freezing of tissue like in frostbite. NFCI may result in in chronic neuropathy and cold hypersensitivity. A recent retrospective study of small-and large fibres has suggested that NFCI results in neuropathic pain due to a sensory neuropathy and question a longitudinal study to verify a possible observation of improvement of NFCI over time. The present study is a 4-year follow-up investigation of large - and small-fibre function in 26 naval cadets and officers who were exposed to cold injury during the same military expedition. Methods The 26 soldiers were investigated clinically (with investigation of motor function, reflexes, sensibility), with nerve conduction studies (NCS) of major nerves in upper- and lower extremity, small fibre testing (QST, measurement of thermal thresholds), measurements of subcutaneous fat tissue and maximal O2 uptake. Investigations found place 2 months following the actual military expedition, with follow-up investigations of affected soldiers at 6-12 months and up to 3-4 years. In order to elucidate possible mechanisms (disinhibition of cold pain by myelinated nerve fibres) of cold allodynia, cold pain thresholds were measured following an ischemic block of conduction of large and small myelinated nerve fibres. Results Of 26 soldiers, 19 complained of numbness in feet and a large majority of 16 of cold hypersensitivity 2 months following injury. There were significant alterations of both large- and small-fibre function, indicating a general large- and small-fibre neuropathy. The most prominent finding was a pronounced cold allodynia, inversely correlated with the amount of subcutaneous fat. During the first year, results of NCS and thermal testing gradually normalized in most. Seven soldiers developed chronic symptoms in the form of cold hypersensitivity and with findings of cold allodynia, which was not further enhanced, but abolished following block of conduction of myelinated nerve fibres. Seven soldiers were free of symptoms from that start of the investigation, probably because they had been more eager to keep their legs moving during the exposure to cold. Conclusions Of a total of 26 soldiers, only seven developed chronic symptoms of cold hypersensitivity, corresponding to the finding of cold allodynia by thermal testing. The cold allodynia may not be explained by disinhibition of cold pain by myelinated fibres as in healthy subjects. A large majority recovered from an initial large-and small fibre neuropathy, demonstrating that recovery from NFCI may occur. Implications Although large-and small fibre neuropathy may be restored following cold injury, there is a risk of a permanent and disabling cold hypersensitivity, corresponding to the findings of cold allodynia. It is of uttermost importance to secure military personnel from the risk of cold injuries. It seems important to avoid immobilisation of extremities during exposure to cold.

Pain and small-fiber affection in hereditary neuropathy with liability to pressure palsies (HNPP).

Background and aims Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal - dominant hereditary neuropathy caused by a deficiency in the peripheral protein PMP-22, due to deletion on chromosome 17p11,2 or in some rare cases point mutations in the PMP-22 gene. The clinical picture is characterized by recurrent mononeuropathies in nerves which frequently may be exposed to pressure, such as the median, ulnar, radial and peroneal nerves or also a more general neuropathy. Although pain is reported to be an unusual clinical symptom, there have been reports of pain in a surprisingly high proportion of these patients. Since pain may be explained by mechanisms in afferent small unmyelinated C- nerve fibers, an assessment of the function of small nerve fibers has been requested. The purpose of the present study was to investigate the presence of pain and the possible affection of afferent small nerve-fibers, A-δ and C-fibers, by quantitative sensory testing (QST)-assessment of thermal thresholds, as well as quantitative sudomotor axon reflex (QSART), a quantitative, validated assessment of efferent postganglionic sumodotor function. QST values were compared to values of age- and sex matched healthy subjects. Methods The 19 patients were investigated clinically, with an emphasis on pain characteristics, with nerve conduction studies (NCS) of major nerves in upper- and lower extremity, small fiber testing (QST, measurement of thermal thresholds) and with QSART. Results A total of 10 patients reported numbness in some extremity, suggesting entrapment of individual nerves as well as a general neuropathy, as verified by NCS in nine patients. A total of 15 patients had findings compatible with a general polyneuropathy. A total of eight patients reported pain, seven patients with pain in the feet, described as burning, aching, shooting and six with severe pathological QST values, mainly cold detection, but also four patients with elevated thresholds to warmth. Four of the patients had signs of a severe sensory neuropathy on NCS, with no sural findings. One patient had only pain in the arms, with only minor changes on NCS and with normal QST-values. Cold detection thresholds (CD) were significantly elevated (reduced sensibility) on the dorsum of the foot (mean of two feet), in patients [26.0 °C (19.7-28.0)] as compared with healthy subjects [28.6 °C (27.4-29.6) p = 0.000]. There were also significantly elevated warmth detection thresholds (WD) in feet in patients 39.5 °C (36.4-42.9) compared to healthy subjects [37.7 °C (36.1-39.4) p = 0.048]. However, there were no significant differences in QST values between patients with and without pain. Conclusions Of a total of 19 patients with verified HNPP, eight patients (42.1%) suffered from neuropathic pain, mainly in both feet. Implications Due to the high percentage of pain in HNPP, it is important not to disregard this diagnosis in a patient presenting with pain. Since there are no significant differences in QST values in patients with and without pain, routine QST studies in HNPP do not seem necessary.

Pain relief in a neuropathy patient by lacosamide: Proof of principle of clinical translation from patient-specific iPS cell-derived nociceptors.

BACKGROUND: Small fiber neuropathy (SFN) is a severe and disabling chronic pain syndrome with no causal and limited symptomatic treatment options. Mechanistically based individual treatment is not available. We report an in-vitro predicted individualized treatment success in one therapy-refractory Caucasian patient suffering from SFN for over ten years. METHODS: Intrinsic excitability of human induced pluripotent stem cell (iPSC) derived nociceptors from this patient and respective controls were recorded on multi-electrode (MEA) arrays, in the presence and absence of lacosamide. The patient's pain ratings were assessed by a visual analogue scale (10: worst pain, 0: no pain) and treatment effect was objectified by microneurography recordings of the patient's single nerve C-fibers. FINDINGS: We identified patient-specific changes in iPSC-derived nociceptor excitability in MEA recordings, which were reverted by the FDA-approved compound lacosamide in vitro. Using this drug for individualized treatment of this patient, the patient's pain ratings decreased from 7.5 to 1.5. Consistent with the pain relief reported by the patient, microneurography recordings of the patient's single nerve fibers mirrored a reduced spontaneous nociceptor (C-fiber) activity in the patient during lacosamide treatment. Microneurography recordings yielded an objective measurement of altered peripheral nociceptor activity following treatment. INTERPRETATION: Thus, we are here presenting one example of successful patient specific precision medicine using iPSC technology and individualized therapeutic treatment based on patient-derived sensory neurons.

The role of Nav1.7 in human nociceptors: insights from human induced pluripotent stem cell-derived sensory neurons of erythromelalgia patients.

The chronic pain syndrome inherited erythromelalgia (IEM) is attributed to mutations in the voltage-gated sodium channel (NaV) 1.7. Still, recent studies targeting NaV1.7 in clinical trials have provided conflicting results. Here, we differentiated induced pluripotent stem cells from IEM patients with the NaV1.7/I848T mutation into sensory nociceptors. Action potentials in these IEM nociceptors displayed a decreased firing threshold, an enhanced upstroke, and afterhyperpolarization, all of which may explain the increased pain experienced by patients. Subsequently, we investigated the voltage dependence of the tetrodotoxin-sensitive NaV activation in these human sensory neurons using a specific prepulse voltage protocol. The IEM mutation induced a hyperpolarizing shift of NaV activation, which leads to activation of NaV1.7 at more negative potentials. Our results indicate that NaV1.7 is not active during subthreshold depolarizations, but that its activity defines the action potential threshold and contributes significantly to the action potential upstroke. Thus, our model system with induced pluripotent stem cell-derived sensory neurons provides a new rationale for NaV1.7 function and promises to be valuable as a translational tool to profile and develop more efficacious clinical analgesics.

Abnormal function of C-fibers in patients with diabetic neuropathy.

The mechanisms underlying the development of painful and nonpainful neuropathy associated with diabetes mellitus are unclear. We have obtained microneurographic recordings from unmyelinated fibers in eight patients with diabetes mellitus, five with painful neuropathy, and three with neuropathy without pain. All eight patients had large-fiber neuropathy, and seven patients had pathological thermal thresholds in their feet, indicating the involvement of small-caliber nerve fibers. A total of 163 C-fibers were recorded at knee level from the common peroneal nerve in the patients (36-67 years old), and these were compared with 77 C-fibers from healthy controls (41-64 years old). The ratio of mechano-responsive to mechano-insensitive nociceptors was approximately 2:1 in the healthy controls, whereas in the patients, it was 1:2. In patients, a fairly large percentage of characterized fibers (12.5% in nonpainful and 18.9% in painful neuropathy) resembled mechano-responsive nociceptors that had lost their mechanical and heat responsiveness. Such fibers were rarely encountered in age-matched controls (3.2%). Afferent fibers with spontaneous activity or mechanical sensitization were found in both patient groups. We conclude that small-fiber neuropathy in diabetes affects receptive properties of nociceptors that leads to an impairment of mechano-responsive nociceptors.

Changes in Ionic Conductance Signature of Nociceptive Neurons Underlying Fabry Disease Phenotype.

The first symptom arising in many Fabry patients is neuropathic pain due to changes in small myelinated and unmyelinated fibers in the periphery, which is subsequently followed by a loss of sensory perception. Here we studied changes in the peripheral nervous system of Fabry patients and a Fabry mouse model induced by deletion of α-galactosidase A (Gla-/0). The skin innervation of Gla-/0 mice resembles that of the human Fabry patients. In Fabry diseased humans and Gla-/0 mice, we observed similar sensory abnormalities, which were also observed in nerve fiber recordings in both patients and mice. Electrophysiological recordings of cultured Gla-/0 nociceptors revealed that the conductance of voltage-gated Na+ and Ca2+ currents was decreased in Gla-/0 nociceptors, whereas the activation of voltage-gated K+ currents was at more depolarized potentials. Conclusively, we have observed that reduced sensory perception due to small-fiber degeneration coincides with altered electrophysiological properties of sensory neurons.

Complex regional pain syndrome following viper-bite.

BACKGROUND: Complex regional pain syndrome (CRPS) may occur following fractures, surgery or different trauma. Development of CRPS following snake-bite has only been published in three reports (from Turkey, Nepal and Korea), although snake bites occur frequently world-wide. There has been no report from Western Europe. Vipera Berus is a common snake in European countries and the only venomous snake in Norway. We here describe the development of CRPS in a young woman as a consequence of a viper bite (Vipera Berus) in the right arm. METHODS: We performed a clinical investigation (inspection, measurement of skin temperatures, sensory and motor evaluation) of the patient six months following the viper-bite, measurement of thermal thresholds (quantitative sensory testing, QST), measurement of resting sweat output (RSO) and quantitative sudomotor axon reflex (QSART) from both arms. RESULTS: The patient fulfilled the Budapest criteria for a CRPS-condition, with continuous pain and symptoms and findings of autonomic dysfunction. In addition, we found elevated thresholds of warmth and cold, evidence of an affection of afferent A-delta and C-fibres as well as an affection of the efferent sympathetic sudomotor C-fibres by QSART. An increased RSO-volume was in inverse relationship to the decreased QSART result. CONCLUSION AND IMPLICATIONS: It is important to be aware of viper-bite as a possible eliciting event for CRPS for early diagnosis and treatment of a patient. As long-lasting pain and oedema are known complications, it is probable that CRPS after viper-bites previously may have been underdiagnosed. As many patients are unaware of being bit, viper bite should be considered in cases of unexplained sudden pain and swelling of a limb.

Delayed diagnosis and worsening of pain following orthopedic surgery in patients with complex regional pain syndrome (CRPS).

BACKGROUND AND AIMS: Complex regional pain syndrome (CRPS) is a serious and disabling chronic pain condition, usually occurring in a limb. There are two main types, CRPS 1 with no definite nerve lesion and CRPS 2 with an identified nerve lesion. CRPS 1 and 2 may occur following an injury (frequently following fractures), surgery or without known cause. An early diagnosis and start of adequate treatment is considered desirable for patients with CRPS. From the clinical experience of the principal investigator, it became apparent that CRPS often remained undiagnosed and that the clinical conditions of many patients seemed to be worsened following orthopedic surgery subsequent to the initial eliciting event. The aim of the present retrospective study of 55 patients, all diagnosed with either CRPS 1 or 2, was to evaluate the time from injury until diagnosis of CRPS and the effect on pain of orthopedic surgical intervention subsequent to the original injury/surgery. METHODS: Clinical symptoms with an emphasis on pain were assessed by going through the patients' records and by information given during the investigation at Oslo University Hospital, where the patients also were examined clinically and with EMG/neurography. Alteration in pain was evaluated in 27 patients who underwent orthopedic surgery subsequent to the eliciting injury. RESULTS: Of a total of 55 patients, 28 women and 27 men (mean age 38.7 (SD 12.3), 38 patients were diagnosed with CRPS type 1, and 17 with CRPS type 2. Mean time before diagnosis was confirmed was 3.9 years (SD1.42, range 6 months-10 years). The eliciting injuries for both CRPS type 1 and type 2 were fractures, squeeze injuries, blunt injuries, stretch accidents and surgery. A total of 27 patients (14 men and 13 women) were operated from one to 12 times at a later stage (from 6 months to several years) following the initial injury or any primary operation because of fracture. A total of 22 patients reported a worsening of pain following secondary surgical events, while four patients found no alteration and one patient experienced an improvement of pain. None of the 22 patients reporting worsening, were diagnosed with CRPS prior to surgery, while retrospectively, a certain or probable diagnosis of CRPS had been present in 17/22 (77%) patients before their first post-injury surgical event. CONCLUSIONS AND IMPLICATIONS: A mean time delay of 3.9 years before diagnosis of CRPS is unacceptable. A lack of attention to more subtle signs of autonomic dysfunction may be an important contributing factor for the missing CRPS diagnosis, in particular serious in patients reporting worsening of pain following subsequent orthopedic surgery. It is strongly recommended to consider the diagnosis of CRPS in all patients with a long-lasting pain condition. We emphasize that the present report is not meant as criticism to orthopedic surgical practice, but as a discussion for a hopefully increased awareness and understanding of this disabling pain condition.

Pathological nociceptors in two patients with erythromelalgia-like symptoms and rare genetic Nav 1.9 variants.

INTRODUCTION: The sodium channel Nav 1.9 is expressed in peripheral nociceptors and has recently been linked to human pain conditions, but the exact role of Nav 1.9 for human nociceptor excitability is still unclear. METHODS: C-nociceptors from two patients with late onset of erythromelalgia-like pain, signs of small fiber neuropathy, and rare genetic variants of Nav 1.9 (N1169S, I1293V) were assessed by microneurography. RESULTS: Compared with patients with comparable pain phenotypes (erythromelalgia-like pain without Nav-mutations and painful polyneuropathy), there was a tendency toward more activity-dependent slowing of conduction velocity in mechanoinsensitive C-nociceptors. Hyperexcitability to heating and electrical stimulation were seen in some nociceptors, and other unspecific signs of increased excitability, including spontaneous activity and mechanical sensitization, were also observed. CONCLUSIONS: Although the functional roles of these genetic variants are still unknown, the microneurography findings may be compatible with increased C-nociceptor excitability based on increased Nav 1.9 function.

Single-Fiber Recordings of Nociceptive Fibers in Patients With HSAN Type V With Congenital Insensitivity to Pain.

OBJECTIVES: Nerve growth factor (NGF) is a protein important for growth and survival, but also for modulation of sensitivity of nociceptors and sympathetic neurons. The purpose of the present study was to investigate the effects of reduced NGF signaling in patients with hereditary sensory and autonomic neuropathies type V, congenital insensitivity to pain, caused by a mutation of the NGFß gene, including a characterization of single nociceptive fibers using microneurography (MNG). MATERIALS AND METHODS: One homozygote and 2 heterozygote patients with this mutation were examined with electromyography/neurography, thermal testing, quantitative sudomotor axon reflex test, and electrically induced axon reflex erythema in addition to MNG. RESULTS: Low quantitative sudomotor axon reflex test measurements of 0.02 (left foot) and 0.03 (right foot) µL/cm and elevated thermal thresholds for warmth and cold detection testing showed clear impairment of small nerve fibers, both sudomotor efferent and somatic afferent fibers, in the patient homozygote for the mutation. MNG from one of the heterozygote patients revealed changes in the small nociceptive fibers in skin, including abnormally low conduction velocity, spontaneous activity in A-δ fibers and C-nociceptors and abnormal or lacking response to heat. DISCUSSION: The findings of grossly intact pain thresholds compared with anamnestic insensitivity of pain in deep somatic tissue such as bone suggest a gradient of impairment dependent on different NGF availability in various tissues. Even though these patients in some aspects report insensitivity to pain, they also report chronic spontaneous pain as their main symptom, strikingly highlighting differential mechanisms of insensitivity to evoked pain versus spontaneous pain.