Pain in chemotherapy-induced neuropathy – More than neuropathic?

Chemotherapy-induced neuropathy (CIN) is an adverse effect of chemotherapy. Pain in CIN might comprise neuropathic and nonneuropathic (ie, musculoskeletal) pain components, which might be characterized by pain patterns, electrophysiology, and somatosensory profiling. Included were 146 patients (100 female, 46 male; aged 56 ± 0.8 years) with CIN arising from different chemotherapy regimens. Patients were characterized clinically through nerve conduction studies (NCS) and quantitative sensory testing (QST). Questionnaires for pain (McGill) and anxiety/depression (Hospital Anxiety and Depression Scale) were supplied. Patients were followed-up after 17 days. Large- (61%) and mixed- (35%) fibre …

Revised Definition of Neuropathic Pain and Its Grading System: An Open Case Series Illustrating Its Use in Clinical Practice

The definition of neuropathic pain has recently been revised by an expert committee of the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) as "pain arising as direct consequence of a lesion or disease affecting the somatosensory system," and a grading system of "definite," "probable," and "possible" neuropathic pain has been introduced. This open case series of 5 outpatients (3 men, 2 women; mean age 48 +/- 12 years) demonstrates how the grading system can be applied, in combination with appropriate confirmatory testing, to diagnosis neuropathic conditions in clinical practice. The proposed grading system includes a dynamic algorithm …

"Symptom vs sensory profiling"-taking one step after the other.

Insula and sensory insular cortex and somatosensory control in patients with insular stroke

Background In functional imaging studies, the insular cortex (IC) has been identified as an essential part of the processing of a whole spectrum of multimodal sensory input. However, there are no lesion studies including a sufficient number of patients, which would reinforce the functional imaging data obtained from healthy subjects. Such lesion studies should examine how damage to the IC affects sensory perception. We chose acute stroke patients with lesions affecting the IC in order to fill this gap. Methods A comprehensive sensory profiling by applying a quantitative sensory testing protocol was performed and a voxel-lesion behaviour mapping analysis in 24 patients with acute unilateral …

Clinical symptomatic de novo systemic transthyretin amyloidosis 9 years after domino liver transplantation

Four years ago, Stangou et al. reported a patient who developed clinical symptoms of amyloidosis 8 years after domino liver transplantation (DLT). In order to alleviate the graft shortage, livers from patients with familial amyloidotic polyneuropathy (FAP) are used as domino grafts for other patients under the assumption that several decades will pass before clinical symptoms due to amyloid accumulation emerge. We now report on another case, the third reported case in the literature, of de novo systemic amyloidosis in a 75-year-old woman 9 years after DLT. The patient underwent DLT at 65 years of age for hepatocellular carcinoma exceeding the Milan criteria in hepatitis C cirrhosis. Transar…

A Pathway in the Brainstem for Roll-Tilt of the Subjective Visual Vertical: Evidence from a Lesion–Behavior Mapping Study

The perceived subjective visual vertical (SVV) is an important sign of a vestibular otolith tone imbalance in the roll plane. Previous studies suggested that unilateral pontomedullary brainstem lesions cause ipsiversive roll-tilt of SVV, whereas pontomesencephalic lesions cause contraversive roll-tilts of SVV. However, previous data were of limited quality and lacked a statistical approach. We therefore tested roll-tilt of the SVV in 79 human patients with acute unilateral brainstem lesions due to stroke by applying modern statistical lesion–behavior mapping analysis. Roll-tilt of the SVV was verified to be a brainstem sign, and for the first time it was confirmed statistically that lesions…

Stress and thermoregulation: different sympathetic responses and different effects on experimental pain.

Stress and thermoregulation both activate the sympathetic nervous system (SNS) but might differently affect pain. Studies investigating possible interactions in patients are problematic because of the high prevalence of SNS disturbances in patients. We therefore analyzed the influence of these different sympathetic challenges on experimentally-induced pain in healthy subjects. SNS was activated in two different ways: by mental stress (Stroop task, mental arithmetic task), and by thermoregulatory stimulation using a water-perfused thermal suit (7 degrees C, 32 degrees C, or 50 degrees C). Attentional effects of the mental stress tasks were controlled by using easy control tasks. Both, stress…

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): reference data for the trunk and application in patients with chronic postherpetic neuralgia.

Age- and gender-matched reference values are essential for the clinical use of quantitative sensory testing (QST). To extend the standard test sites for QST-according to the German Research Network on Neuropathic Pain-to the trunk, we collected QST profiles on the back in 162 healthy subjects. Sensory profiles for standard test sites were within normal interlaboratory differences. QST revealed lower sensitivity on the upper back than the hand, and higher sensitivity on the lower back than the foot, but no systematic differences between these trunk sites. Age effects were significant for most parameters. Females exhibited lower pressure pain thresholds (PPT) than males, which was the only si…

Naloxone inhibits not only stress-induced analgesia but also sympathetic activation and baroreceptor-reflex sensitivity

Interactions between the sympathetic nervous system and pain are manifold and still have not been sufficiently characterized. Accordingly, several possible neuronal pathways have been described as being involved in mental stress-induced analgesia. We studied the role of the endogenous opioidergic system in stress-induced analgesia in 14 healthy participants in a double-blind cross-over trial. Naloxone or placebo was applied while electrical pain stimulation was started and electrical current increased. After reaching a constant stimulation at 30 mA, a color word interference test (Stroop task) was performed in a stressful and a non-stressful version. Blood pressure, heart rate and barorefle…

Explicit episodic memory for sensory-discriminative components of capsaicin-induced pain: Immediate and delayed ratings

Pain memory is thought to affect future pain sensitivity and thus contribute to clinical pain conditions. Systematic investigations of the human capacity to remember sensory features of experimental pain are sparse. In order to address long-term pain memory, nine healthy male volunteers received intrader- mal injections of three doses of capsaicin (0.05, 1 and 20 lg, separated by 15 min breaks), each given three times in a balanced design across three sessions at one week intervals. Pain rating was performed using a computerized visual analogue scale (0-100) digitized at 1/s, either immediately online or one hour or one day after injection. Subjects also recalled their pains one week later.…

Psychophysics, flare, and neurosecretory function in human pain models: capsaicin versus electrically evoked pain.

Intradermal capsaicin injection (CAP) and electrical current stimulation (ES) are analyzed in respect to patterns and test-retest reliability of pain as well as sensory and neurosecretory changes. In 10 healthy subjects, 2 CAP (50 g) and 2 ES (5 to 30 mA) were applied to the volar forearm. The time period between 2 identical stimulations was about 4 months. Pain ratings, areas of mechanical hyperalgesia, and allodynia were assessed. The intensity of sensory changes was quantified by using quantitative sensory testing. Neurogenic flare was assessed by using laser Doppler imaging. Calcito- nin gene-related peptide (CGRP) release was quantified by dermal microdialysis in combination with an en…

Spotting the pain in Fibromyalgia syndrome - Widespread effects of local pain therapy

Test–retest and interobserver reliability of quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain (DFNS): A multi-centre study

Quantitative sensory testing (QST) is an instrument to assess positive and negative sensory signs, helping to identify mechanisms underlying pathologic pain conditions. In this study, we evaluated the test-retest reliability (TR-R) and the interobserver reliability (IO-R) of QST in patients with sensory disturbances of different etiologies. In 4 centres, 60 patients (37 male and 23 female, 56.4±1.9years) with lesions or diseases of the somatosensory system were included. QST comprised 13 parameters including detection and pain thresholds for thermal and mechanical stimuli. QST was performed in the clinically most affected test area and a less or unaffected control area in a morning and an a…

Heterogeneous presentation of caspr2 antibody‐associated peripheral neuropathy – A case series

Contactin-associated protein 2-like (caspr2) antibodies have been discovered recently. Since then a multitude of patients with caspr2 antibodies presenting with different neurological symptoms have been reported. Here, we describe three patients with caspr2 antibodies with different types of pain/no pain in combination with peripheral neuropathy. The first patient, a 33-year-old woman, presented with erythromelalgia-like pain and autonomic symptoms; the second patient, a 58-year-old man, with paresthesia and pain while walking together with signs of peripheral motor neuron hyperexcitability in combination with optic neuritis, and the third patient, a 74-year-old man, without any pain but wi…

Follow-up in transthyretin familial amyloid polyneuropathy: Useful investigations

Patients with transthyretin amyloid polyneuropathy (TTR-FAP) and asymptomatic mutation-carriers have to be regularly followed-up in order to identify disease progression and the time point for starting or modifying therapy. In this case series we describe the potential suitability of different variables as progression markers. We retrospectively analyzed the follow-up charts of 10 TTR-FAP patients. Clinical examination included the Neuropathy Impairment Score of Lower Limb (NIS-LL), temperature perception thresholds, nerve conduction and autonomic function tests. The NIS-LL had the greatest value for a sensitive and correct follow-up for all TTR-FAP stages. All other examinations provided u…

Hand-arm vibration syndrome: clinical characteristics, conventional electrophysiology and quantitative sensory testing.

Abstract Objective Workers exposed to vibrating tools may develop hand-arm vibration syndrome (HAVS). We assessed the somatosensory phenotype using quantitative sensory testing (QST) in comparison to electrophysiology to characterize (1) the most sensitive QST parameter for detecting sensory loss, (2) the correlation of QST and electrophysiology, and (3) the frequency of a carpal tunnel syndrome (CTS) in HAVS. Methods QST, cold provocation tests, fine motor skills, and median nerve neurography were used. QST included thermal and mechanical detection and pain thresholds. Results Thirty-two patients were examined (54 ± 11 years, 91% men) at the more affected hand compared to 16 matched contro…

Response to letter by Werner et al.

Severe Tremor After Cotrimoxazole-Induced Elevation of Venlafaxine Serum Concentrations in a Patient With Major Depressive Disorder

: We describe a female patient who was an extensive metabolizer of cytochrome P450 isoenzyme (CYP) 2D6 and an intermediate metabolizer of CYP2C19 (genotype: CYP2C19 *1/*2). She exhibited high serum concentrations of venlafaxine and O-desmethylvenlafaxine and developed severe tremor after comedication with cotrimoxazole (sulfamethazole/trimethoprim). Venlafaxine is mainly metabolized by O- and N-demethylation. O-demethylation is catalyzed by the highly polymorphic CYP2D6 and N-demethylation by several enzymes, CYP2C19, CYP2C9, and CYP3A4. The observed overall pharmacokinetic effect was most probably the result of decreased N-demethylation of venlafaxine by (1) reduced expression of CYP2C19 d…

Interaction of calcitonin gene related peptide (CGRP) and substance P (SP) in human skin.

Calcitonin gene related peptide (CGRP) and substance P (SP) are neuropeptides that are simultaneously released from nociceptive C-fibers. CGRP is a potent vasodilator, inducing a long-lasting increase in superficial skin blood flow, whereas SP induces only a brief vasodilation but a significant plasma extravasation. CGRP and SP may play important roles in the pathophysiology of various pain states but little is known about their interaction. Different concentrations of SP (ranging from 10-5M to 10-9M) were applied to the volar forearm of 24 healthy subjects via dermal microdialysis. SP was applied either alone or in combination with CGRP10-9M and CGRP 10-6M. As expected, SP induced a transi…

Progression of transthyretin (TTR) amyloidosis in donors and recipients after domino liver transplantation-a prospective single-center cohort study

Liver transplantation (LT) is the first-line therapy in patients with transthyretin (TTR) amyloidosis and progressive familial amyloid polyneuropathy (FAP). Explanted organs from these patients can be used for domino liver transplantation (DLT). After DLT, de novo amyloidosis may develop in domino recipients (DR). Data were collected prospectively in a transplant database. Electroneurography by nerve conduction velocity (NCV), quantitative sensory testing, heart rate variability (HRV), sympathetic skin response, orthostatic reaction (tilt table test), transthoracic echocardiography, cardiac MRI and organ biopsy results were evaluated. The cohort included 24 FAP- (11 Val30Met, 13 nonVal30Met…

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes

Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non-nociceptive stimuli. Data distributions showed a systematic shift to hyperalgesia for nociceptive, and to hypoesthesia for non-nociceptive parameters. Across all parameters, 92% of the patients presented at least one abnormality. Thermosensory or mechanical hypoesthesia (up to 41%) was more frequent than hypoalgesia (up…

Anosognosia for hemiparesis after left-sided stroke

In patients with left-sided lesions, anosognosia for hemiparesis (AHP) seems to be a rare phenomenon. It has been discussed whether this rareness might be due to an inevitable bias due to language dysfunction and whether the left hemisphere's role for our self-awareness of motor actions thus is underestimated. By applying functional magnetic resonance imaging (fMRI) we examined whether patients with AHP following a left hemisphere stroke show a regular, left-sided or a reversed, right-sided lateralization of language functions. Only the former observation would argue for an original role of the left hemisphere in self-awareness about limb function. In a consecutive series of 44 acute left-s…

200 TEST/RETEST- AND INTEROBSERVER-RELIABILITIY IN QUANTITATIVE SENSORY TESTING ACCORDING TO THE PROTOCOL OF THE GERMAN NETWORK ON NEUROPATHIC PAIN (DFNS)

Posterior insular cortex - a site of vestibular-somatosensory interaction?

Background In previous imaging studies the insular cortex (IC) has been identified as an essential part of the processing of a wide spectrum of perception and sensorimotor integration. Yet, there are no systematic lesion studies in a sufficient number of patients examining whether processing of vestibular and the interaction of somatosensory and vestibular signals take place in the IC. Methods We investigated acute stroke patients with lesions affecting the IC in order to fill this gap. In detail, we explored signs of a vestibular tone imbalance such as the deviation of the subjective visual vertical (SVV). We applied voxel-lesion behaviour mapping analysis in 27 patients with acute unilate…

Numbness in clinical and experimental pain – A cross-sectional study exploring the mechanisms of reduced tactile function

Pain patients often report distinct numbness of the painful skin although no structural peripheral or central nerve lesion is obvious. In this cross-sectional study we assessed the reduction of tactile function and studied underlying mechanisms in patients with chronic pain and in healthy participants exposed to phasic and tonic experimental nociceptive stimulation. Mechanical detection (MDT) and pain thresholds (MPT) were assessed in the painful area and the non-painful contralateral side in 10 patients with unilateral musculoskeletal pain. Additionally, 10 healthy participants were exposed to nociceptive stimulation applied to the volar forearms (capsaicin; electrical stimulation, twice e…

Differential effect of Incobotulinumtoxin A on pain, neurogenic flare and hyperalgesia in human surrogate models of neurogenic pain

Background: The effectiveness of Botulinum-neurotoxin A (BoNT/A) to treat pain in human pain models is very divergent. This study was conducted to clarify if the pain models or the route of BoNT/A application might be responsible for these divergent findings. Methods: Sixteen healthy subjects (8 males, mean age 27 ± 5 years) were included in a first set of experiments consisting of three visits: (1) Visit: Quantitative sensory testing (QST) was performed before and after intradermal capsaicin injection (CAPS, 15 μg) on one thigh and electrical current stimulation (ES, 1 Hz) on the contralateral thigh. During stimulation pain and the neurogenic flare response (laser-Doppler imaging) were ass…

Patterns of sympathetic responses induced by different stress tasks.

Stress tasks are used to induce sympathetic nervous system (SNS) arousal. However, the efficacy and the patterns of SNS activation have not been systematically compared between different tasks. Therefore, we analyzed SNS activation during the following stress tasks: Presentation of negative, positive, and – as a control – neutral affective pictures, Color-Word interference test (CWT), mental arithmetic under time limit, singing a song aloud, and giving a spontaneous talk. We examined 11 healthy subjects and recorded the following SNS parameters: Activation of emotional sweating by quantitative sudometry, skin vasoconstriction by laser-Doppler flowmetry, heart rate by ECG, blood pressure by …

Dissecting post-herniotomy pain – Scratching the surface?

Do Intensity Ratings and Skin Conductance Responses Reliably Discriminate Between Different Stimulus Intensities in Experimentally Induced Pain?

Abstract The present study addresses the question whether pain-intensity ratings and skin conductance responses (SCRs) are able to detect different intensities of phasic painful stimuli and to determine the reliability of this discrimination. For this purpose, 42 healthy participants of both genders were assigned to either electrical, mechanical, or laser heat-pain stimulation (each n = 14). A whole range of single brief painful stimuli were delivered on the right volar forearm of the dominant hand in a randomized order. Pain-intensity ratings and SCRs were analyzed. Using generalizability theory, individual and gender differences were the main contributors to the variability of both intens…

Transthyretin familial amyloid polyneuropathy (TTR‐FAP): Parameters for early diagnosis

Abstract Background Familial transthyretin amyloidosis is a life‐threatening disease presenting with sensorimotor and autonomic polyneuropathy. Delayed diagnosis has a detrimental effect on treatment and prognosis. To facilitate diagnosis, we analyzed data patterns of patients with transthyretin familial amyloid polyneuropathy (TTR‐FAP) and compared them to polyneuropathies of different etiology for clinical and electrophysiological discriminators. Methods Twenty‐four patients with TTR‐FAP and 48 patients with diabetic polyneuropathy (dPNP) were investigated (neurological impairment score NIS; neurological disability score NDS) in a cross‐sectional design. Both groups were matched for gende…

Warm and cold complex regional pain syndromes: Differences beyond skin temperature?

Objective: To investigate clinical differences in warm and cold complex regional pain syndrome (CRPS) phenotypes. Background: CRPS represents inhomogeneous chronic pain conditions; approximately 70% patients with CRPS have “warm” affected limbs and 30% have “cold” affected limbs. Methods: We examined 50 patients with “cold” and “warm” CRPS (n 25 in each group). Both groups were matched regarding age, sex, affected limb, duration of CRPS, and CRPS I and II to assure comparability. Detailed medical history and neurologic status were assessed. Moreover, quantitative sensory testing (QST) was performed on the affected ipsilateral and clinically unaffected contralateral limbs. Results: Compared …

Transthyretin-Amyloidose (ATTR-Amyloidose): Empfehlungen zum Management in Deutschland und Österreich

ZusammenfassungDie Transthyretin-Amyloidose (ATTR-Amyloidose) ist eine seltene, rasch verlaufende neurodegenerative Erkrankung, verursacht durch Mutationen im Transthyretin-Gen. Aufgrund der Seltenheit ist sie wenig bekannt mit der Folge, dass die Diagnose in vielen Fällen nicht oder für eine effektive Therapie zu spät gestellt wird. Therapeutisch steht seit Anfang der 1990er-Jahre die Lebertransplantation zur Verfügung, seit 2011 der oral einzunehmende Transthyretinstabilisator Tafamidis. Weitere Substanzen sind in der klinischen Prüfung oder stehen vor der Zulassung. Hierzu zählen die gentherapeutischen Substanzen Inotersen und Patisiran, die auf dem Boden der RNA-Interferenz wirken, für …

251 SENSORY PROFILES IN PAINFUL VS. NON-PAINFUL CHEMOTHERAPY-INDUCED POLYNEUROPATHY

Skin innervation at different depths correlates with small fibre function but not with pain in neuropathic pain patients

Background: Neuropathy can lead not only to impaired function but also to sensory sensitization. We aimed to link reduced skin nerve fibre density in different levels to layer-specific functional impairment in neuropathic pain patients and tried to identify pain-specific functional and structural markers. Methods: In 12 healthy controls and 36 patients with neuropathic pain, we assessed clinical characteristics, thermal thresholds (quantitative sensory testing) and electrically induced pain and axon reflex erythema. At the most painful sites and at intra-individual control sites, skin biopsies were taken and innervation densities in the different skin layers were assessed. Moreover, neurona…