Christian Geber

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

&NA; 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 to 18% for mechanical stimuli). Mechanical hyperalgesias occurred more often (blunt pressure: 36%, pinprick: 29%) than thermal hyperalgesias (cold: 19%, heat: 24%), dynamic mechanical allodynia (20%), paradoxical heat sensations (18%) or enhanced wind‐up (13%). Hyperesthesia was less than 5%. Every single sensory abnormality occurred in each neurological syndrome, but with different frequencies: thermal and mechanical hyperalgesias were most frequent in complex regional pain syndrome and peripheral nerve injury, allodynia in postherpetic neuralgia. In postherpetic neuralgia and in central pain, subgroups showed either mechanical hyperalgesia or mechanical hypoalgesia. The most frequent combinations of gain and loss were mixed thermal/mechanical loss without hyperalgesia (central pain and polyneuropathy), mixed loss with mechanical hyperalgesia in peripheral neuropathies, mechanical hyperalgesia without any loss in trigeminal neuralgia. Thus, somatosensory profiles with different combinations of loss and gain are shared across the major neuropathic pain syndromes. The characterization of underlying mechanisms will be needed to make a mechanism‐based classification feasible.

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.

&NA; 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 ± 1.9 years) 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 afternoon session on 2 consecutive days by examiner pairs (4 QSTs/patient). For both, TR‐R and IO‐R, there were high correlations (r = 0.80–0.93) at the affected test area, except for wind‐up ratio (TR‐R: r = 0.67; IO‐R: r = 0.56) and paradoxical heat sensations (TR‐R: r = 0.35; IO‐R: r = 0.44). Mean IO‐R (r = 0.83, 31% unexplained variance) was slightly lower than TR‐R (r = 0.86, 26% unexplained variance, P < .05); the difference in variance amounted to 5%. There were no differences between study centres. In a subgroup with an unaffected control area (n = 43), reliabilities were significantly better in the test area (TR‐R: r = 0.86; IO‐R: r = 0.83) than in the control area (TR‐R: r = 0.79; IO‐R: r = 0.71, each P < .01), suggesting that disease‐related systematic variance enhances reliability of QST. We conclude that standardized QST performed by trained examiners is a valuable diagnostic instrument with good test–retest and interobserver reliability within 2 days. With standardized training, observer bias is much lower than random variance. Quantitative sensory testing performed by trained examiners is a valuable diagnostic instrument with good interobserver and test–retest reliability for use in patients with sensory disturbances of different etiologies to help identify mechanisms of neuropathic and non‐neuropathic pain.

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

Abstract 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 each). Areas of tactile hypaesthesia and mechanical hyperalgesia were assessed. MDT and MPT were quantified adjacent to the stimulation site. Tactile hypaesthesia in pain patients and in experimental pain (MDT‐z‐scores: −0.66 ± 0.30 and −0.42 ± 0.15, respectively, both p < 0.01) was paralleled by mechanical hyperalgesia (MPT‐z‐scores: +0.51 ± 0.27, p < 0.05; and +0.48 ± 0.10, p < 0.001). However, hypaesthesia and hyperalgesia were not correlated. Although 9 patients reported numbness, only 3 of them were able to delineate circumscript areas of tactile hypaesthesia. In experimental pain, the area of tactile hypaesthesia could be mapped in 31/40 experiments (78%). Irrespective of the mode of nociceptive stimulation (phasic vs. tonic) tactile hypaesthesia and hyperalgesia developed with a similar time course and disappeared within approximately 1 day. Hypaesthesia (numbness) often encountered in clinical pain can be reproduced by experimental nociceptive stimulation. The time course of effects suggests a mechanism involving central plasticity.

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

Summary A new set of reference data on the trunk for male and female healthy subjects is presented and applied to patients with postherpetic neuralgia. ABSTRACT 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 significant gender difference. Values outside the 95% confidence interval of healthy subjects (considered abnormal) required temperature changes of >3.3–8.2 °C for thermal detection. For cold pain thresholds, confidence intervals extended mostly beyond safety cutoffs, hence only relative reference data (left‐right differences, hand‐trunk differences) were sufficiently sensitive. For mechanical detection and pain thresholds, left‐right differences were 1.5–2.3 times more sensitive than absolute reference data. The most sensitive parameter was PPT, where already side‐to‐side differences >35% were abnormal. Compared to trunk reference data, patients with postherpetic neuralgia exhibited thermal and tactile deficits and dynamic mechanical allodynia, mostly without reduced mechanical pain thresholds. This pattern deviates from other types of neuropathic pain. QST reference data for the trunk will also be useful for patients with postthoracotomy pain or chronic back pain.

Quantitative Sensory Testing of Neuropathic Pain Patients: Potential Mechanistic and Therapeutic Implications

Quantitative sensory testing (QST) is a widely accepted tool to investigate somatosensory changes in pain patients. Many different protocols have been developed in clinical pain research within recent years. In this review, we provide an overview of QST and tested neuroanatomical pathways, including peripheral and central structures. Based on research studies using animal and human surrogate models of neuropathic pain, possible underlying mechanisms of chronic pain are discussed. Clinically, QST may be useful for 1) the identification of subgroups of patients with different underlying pain mechanisms; 2) prediction of therapeutic outcomes; and 3) quantification of therapeutic interventions in pain therapy. Combined with sensory mapping, QST may provide useful information on the site of neural damage and on mechanisms of positive and negative somatosensory abnormalities. The use of QST in individual patients for diagnostic purposes leading to individualized therapy is an interesting concept, but needs further validation.

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. Transarterial chemoembolization was performed before liver transplantation. During treatment, progressive cachexia and increasing B symptoms occurred. Therefore, DLT was finally considered in this patient. The posttransplant course was uneventful. In 2006, the patient described progressive dysesthesia in the lower extremities. Immunosuppression was switched from a calcineurin inhibitor to a mammalian target of rapamycin inhibitor. Other reasons for neuropathy were excluded. A rectal biopsy specimen at this time was free of amyloid deposition. In 2007, neurological symptoms further deteriorated: burning pain and progressive sensory loss in the lower limbs occurred. In March 2008, amyloid deposition was detected in the gastrointestinal wall, reflecting de novo FAP in this patient. A literature review revealed 2 case reports of symptomatic patients: in the first patient, dysesthesia of the lower limb 8 years after DLT was described, and in the second patient, decreased temperature sensation and pain in the toes and fingertips 7 years after DLT were reported. Interestingly, in our patient and in both previously reported patients, neuropathic symptoms occurred after comparable intervals after DLT (7 and 8 versus 9 years), and the indication for DLT was hepatocellular carcinoma with underlying hepatitis C cirrhosis in the first described patient and our patient. All the patients had received an FAP graft with a transthyretin mutation; the former 2 received grafts with a Val30Met mutation, and our patient received a graft with a Gly47Glu mutation. In individuals with both inherited mutations, neurological symptoms usually occur within the age range of 20 to 35 years. After DLT, the onset of symptoms was thus significantly earlier than the onset in inherited FAP patients. Despite the risk of emerging amyloidosis in recipients, the graft shortage and increasing death rates on the waiting lists prompt alternative approaches to providing grafts. DLT is a feasible technique and may, therefore, be justified in selected patients. Nevertheless, our data reinforce the need for additional caution and meticulous follow-up programs.

Neuropathic pain: is quantitative sensory testing helpful?

Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory system and is characterised by a combination of positive and negative sensory symptoms. Quantitative sensory testing (QST) examines the sensory perception after application of different mechanical and thermal stimuli of controlled intensity and the function of both large (A-beta) and small (A-delta and C) nerve fibres, including the corresponding central pathways. QST can be used to determine detection, pain thresholds and stimulus–response curves and can thus detect both negative and positive sensory signs, the second ones not being assessed by other methods. Similarly to all other psychophysical tests QST requires standardised examination, instructions and data evaluation to receive valid and reliable results. Since normative data are available, QST can contribute also to the individual diagnosis of neuropathy, especially in the case of isolated small-fibre neuropathy, in contrast to the conventional electrophysiology which assesses only large myelinated fibres. For example, detection of early stages of subclinical neuropathy in symptomatic or asymptomatic patients with diabetes mellitus can be helpful to optimise treatment and identify diabetic foot at risk of ulceration. QST assessed the individual’s sensory profile and thus can be valuable to evaluate the underlying pain mechanisms which occur in different frequencies even in the same neuropathic pain syndromes. Furthermore, assessing the exact sensory phenotype by QST might be useful in the future to identify responders to certain treatments in accordance to the underlying pain mechanisms.

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 of the medial longitudinal fasciculus (MLF) and the medial vestibular nucleus are associated with ipsiversive tilt of the SVV, whereas contraversive tilts are associated with lesions affecting the rostral interstitial nucleus of the MLF, the superior cerebellar peduncle, the oculomotor nucleus, and the interstitial nucleus of Cajal. Thus, these structures constitute the anatomical pathway in the brainstem for verticality perception. Present data indicate that graviceptive otolith signals present a predominant role in the multisensory system of verticality perception.

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

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.

Zertifizierungsrichtlinien für QST-Labore

ZusammenfassungDie quantitative sensorische Testung (QST) ist die standardisierte Erweiterung der klinisch-neurologischen Sensibilitätsprüfung. QST erlaubt eine vollständige Erfassung der Funktion aller sensorischer Submodalitäten. Im Gegensatz zur konventionellen Elektrophysiologie können positive und negative sensorische Veränderungen erfasst werden. Im Rahmen des Deutschen Forschungsverbundes Neuropathischer Schmerz (DFNS) wurden eine standardisierte QST-Testbatterie mit 13 Parametern etabliert und Normdaten erhoben. Die QST ist jedoch eine psychophysische Methode, die auch von der Mitarbeit des Patienten bzw. Probanden beeinflusst wird. Daher beinhaltet der standardisierte Untersuchungsablauf die einheitliche Instruktion und Applikation der Testreize, um die laborübergreifende Vergleichbarkeit der QST-Befunde/Messergebnisse zu ermöglichen.Die Deutsche Gesellschaft zum Studium des Schmerzes (DGSS) hat daher in Zusammenarbeit mit dem DFNS Zertifizierungskriterien erarbeitet, um die Verbreitung der QST zu erleichtern. Die QST-Zertifizierung beinhaltet Kriterien zur Bewertung der Struktur-, Prozess- und Ergebnisqualität. Über die festgelegten Qualitätsstandards soll die QST-Zertifizierung nicht nur der Patientenversorgung zu gute kommen, sondern auch zur Verbesserung der Diagnostik in klinischen (Therapie-)Studien neuropathischer Schmerzsyndrome beitragen.AbstractQuantitative sensory testing (QST) is the standardized assessment of the somatosensory system comprising all sensory submodalities. In the German Research Network on Neuropathic Pain (DFNS), a QST-battery consisting of 13 parameters has been established and nationwide normative data have been collected. In contrast to conventional electrophysiology, QST allows detecting negative and positive sensory signs of both large and small fiber systems. However, as a subjective psychophysical method it is critically dependent on patients’ / healthy subjects’ cooperation thus strictly standardized protocols and instructions are needed to allow across laboratory comparisons. To facilitate more widespread use of QST, the German Pain Society (DGSS) and the DFNS have initiated a certification procedure for QST quality standards. Therefore, structural, procedural criteria and outcome parameters were establishd and are hereby presented.By maintaining high quality standards, the certification of QST is intended to contribute to a better understanding of the mechanisms behind neuropathic pain syndromes and thereby improve patient care as well as sensory assessment in clinical studies on the treatment of neuropathic pain syndromes.