Development of a prototype toe sensor for detection of diabetic peripheral small fiber neuropathy.

Diabetic peripheral neuropathy (DPN) affects a large proportion of people with diabetes, and early detection is essential to prevent further progression. Widespread clinical testing relies on simplicity and cost-effectiveness of examination. Early signs of DPN may be detected by assessing the sudomotor nerves, and sudomotor activity can be measured by bioimpedance. We present a prototype toe probe for DPN detection including sensors for measuring skin AC conductance, skin temperature and humidity. The prototype was tested on five participants with DPN and five healthy age-matched controls in a pilot study. Sudomotor sensor responses to a simple deep breathing test were very weak or absent in the DPN group, with all controls having larger responses than the DPN group. Evaporation was lower for the DPN group, and skin temperature was higher on average. For the same foot, the results for sudomotor responses were in agreement with sensory neurography amplitudes from the sural nerve whereas the monofilament test gave normal results for two of the DPN participants. If sufficient detection accuracy is confirmed in larger studies, the method may provide a simple and cost-effective tool to support clinical examination. Clinical Relevance- We present the early realization and testing of a simple device to support early detection of diabetic peripheral neuropathy.

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.

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.