Heidrun H. Krämer

MRI and neurophysiology in vestibular paroxysmia: contradiction and correlation

Background Vestibular paroxysmia (VP) is defined as neurovascular compression (NVC) syndrome of the eighth cranial nerve (N.VIII). The aim was to assess the sensitivity and specificity of MRI and the significance of audiovestibular testing in the diagnosis of VP. Methods 20 VP patients and, for control, 20 subjects with trigeminal neuralgia (TN) were included and underwent MRI (constructive interference in steady-state, time-of-flight MR angiography) for detection of a NVC between N.VIII and vessels. All VP patients received detailed audiovestibular testing. Results A NVC of N.VIII could be detected in all VP patients rendering a sensitivity of 100% and a specificity of 65% for the diagnosis of VP by MRI. Distance between brain stem and compressing vessels varied between 0.0 and 10.2u2005mm. In 15 cases, the compressing vessel was the anterior inferior cerebellar artery (75%, AICA), the posterior inferior cerebellar artery in one (5%, posterior inferior cerebellar artery (PICA)), a vein in two (10%) and the vertebral artery (10%, VA) in another two cases. Audiovestibular testing revealed normal results in five patients (25%), a clear unilateral loss of audiovestibular function in nine patients (45%) and audiovestibular results with coinstantaneous signs of reduced and increased function within the same nerve in six patients (30%). From the 20 TN patients 7, (35%) showed a NVC of the N.VIII (5 AICA, 1 PICA, 1 vein). Conclusions Only the combination of clinical examination, neurophysiological and imaging techniques is capable of (1) defining the affected side of a NVC and to (2) differentiate between a deficit syndrome and increased excitability in VP.

Cardiac Troponin I elevation after epileptic seizure

BackgroundCardiac troponin-I (cTNI) is highly specific biomarker to prove myocardial damage, e.g. in acute coronary syndrome (ACS). However, it occurs in other conditions as well. We therefore analysed cTNI increase in patients after generalized convulsive seizure.MethodsConsecutive patients admitted with acute generalized convulsive seizure were included in case of cTNI measurement on admission. Among 898 selected cases, 53 patients were referred secondary to our department; in 845 cases cTNI measurements on admission were available. In case of multiple admissions (81 cases), only the first admission entered our analysis. In 17 patients elevated cTNI was determined due to ACS; in one patient a myocarditis was found. 5 patients suffered of relevant renal insufficiency. Finally 741 patients were included in the analysis. A cTNI cut-off level ofu2009≥u20090.1 ng/ml was considered. Factors associated with a cTNI increase were analysed subsequently.ResultsThe mean age of the study population (nu2009=u2009741) was 47.8 years (SDu2009±u200918.6), 40.9% were female. In 50 patients (6.7%) a cTNI elevation of unknown origin was found; no obvious cardiac involvement could be detected in these patients who all remained asymptomatic. A vascular risk profile (including at least hypertension, hypercholesterolemia or diabetes) (ORu2009=u20093.62; CI: 1.59 to 8.21; pu2009=u20090.001) and elevated creatine kinase on admission (ORu2009=u20092.36; CI: 1.26 to 4.39; pu2009=u20090.002) were independent factors associated with cTNI release.ConclusioncTNI release occurs in patients with generalized convulsive seizure with predominance in patients with vascular risk profile.

Osteoprotegerin: A new biomarker for impaired bone metabolism in complex regional pain syndrome?

Summary We provide evidence that elevated serum osteoprotegerin reflects pathophysiological processes of complex regional pain syndrome. ABSTRACT Osteoprotegerin (OPG) is important for bone remodeling and may contribute to complex regional pain syndrome (CRPS) pathophysiology. We aimed to assess the value of OPG as a biomarker for CRPS and a possible correlation with radiotracer uptake in 3‐phase bone scintigraphy (TPBS). OPG levels were analyzed in 23 CRPS patients (17 women; mean age 50 ± 9.0 years; disease duration: 12 weeks [IQR 8–24]), 10 controls (6 women; mean age 58 ± 9.6 years) and 21 patients after uncomplicated fractures (12 women; mean age: 43 ± 15 years; time after fracture: 15 weeks [IQR: 6–22]). The CRPS and control patients also underwent TPBS. OPG in CRPS patients was significantly increased by comparison with both control groups (P = 0.001; Kruskal‐Wallis test; CRPS patients: 74.1 pg/mL [IQR: 47.1–100.7]; controls: 46.7 pg/mL [IQR: 35.5–55.0]; P = 0.004; fracture patients: 45.9 pg/mL [IQR: 37.5–56.7]; P = 0.001). As a diagnostic test for CRPS, OPG had a sensitivity of 0.74, specificity of 0.80, positive predictive value of 68% and negative predictive value of 84%. Receiver operating characteristic curve analysis showed an area under the curve of 0.80 (CI: 0.68–0.91). For the CRPS‐affected hand, a significant correlation between OPG and TPBS region of interest analysis in phase III was detected (carpal bones; r = 0.391; P = 0.03). The persistent OPG increase in CRPS indicates enhanced osteoblastic activity shown by increased radiotracer uptake in TPBS phase III. A contribution of bone turnover to CRPS pathophysiology is likely. OPG might be useful as a biomarker for CRPS.

Excellent interrater agreement for the differentiation of fasciculations and artefacts - a dynamic myosonography study.

OBJECTIVEnThe aim of the study was to confirm the diagnostic performance of dynamic myosonography with regard to its reliability to correctly identify fasciculations and to distinguish them from artefacts. Furthermore, interrater agreement regarding the identification of different muscle movements was investigated.nnnMETHODSnA total of 11 observers analysed 25 muscle ultrasound videos acquired using a standardized protocol. The video files illustrated fasciculations and artefacts (voluntary probe movements, voluntary contractions or swallowing and pulsating vessels) in different muscle groups.nnnRESULTSnFasciculations could be distinguished from artefacts with a sensitivity of 90.9% and specificity of 98.5%. Interrater agreement regarding the presence or absence of fasciculations showed an overall median of 100% (interquartile range, IQR: 96-100%). In every investigated muscle group, the median of the interpreter agreement was found to be 100% (correct ratings of all observers: submental muscles: 43 of 44; biceps muscles: 22 of 22; forearm flexors: 31 of 33; rectus abdominis muscles: 33 of 33; quadriceps muscles: 19 of 22; tibialis anterior muscles: 51 of 55; undefinable muscles: 65 of 66).nnnCONCLUSIONnDynamic myosonography is an extremely reliable tool with excellent interrater agreement to correctly identify fasciculations and to distinguish them from artefacts.nnnSIGNIFICANCEnMyosonography should be further incorporated in clinical routine diagnostic work-up.

Slow brushing reduces heat pain in humans

C‐tactile (CT) afferents are unmyelinated low‐threshold mechanoreceptors optimized for signalling affective, gentle touch. In three separate psychophysical experiments, we examined the contribution of CT afferents to pain modulation.

Identification of KRT16 as a target of an autoantibody response in complex regional pain syndrome

Objective: Using a mouse model of complex regional pain syndrome (CRPS), our goal was to identify autoantigens in the skin of the affected limb. Methods: A CRPS‐like state was induced using the tibia fracture/cast immobilization model. Three weeks after fracture, hindpaw skin was homogenized, run on 2‐d gels, and probed by sera from fracture and control mice. Spots of interest were analyzed by liquid chromatography‐mass spectroscopy (LC‐MS) and the list of targets validated by examining their abundance and subcellular localization. In order to measure the autoantigenicity of selected protein targets, we quantified the binding of IgM in control and fracture mice sera, as well as in control and CRPS human sera, to the recombinant protein. Results: We show unique binding between fracture skin extracts and fracture sera, suggesting the presence of auto‐antigens. LC‐MS analysis provided us a list of potential targets, some of which were upregulated after fracture (KRT16, eEF1a1, and PRPH), while others showed subcellular‐redistribution and increased membrane localization (ANXA2 and ENO3). No changes in protein citrullination or carbamylation were observed. In addition to increased abundance, KRT16 demonstrated autoantigenicity, since sera from both fracture mice and CRPS patients showed increased autoantibody binding to recombinant kRT16 protein. Conclusions: Pursuing autoimmune contributions to CRPS provides a novel approach to understanding the condition and may allow the development of mechanism‐based therapies. The identification of autoantibodies against KRT16 as a biomarker in mice and in humans is a critical step towards these goals, and towards redefining CRPS as having an autoimmune etiology. HighlightsAn autoimmune mechanism of pain in a murine model of CRPS is proposed.Multiple potential target antigens are identified by LC‐MS.Keratin16 is a validated target both in the mouse model and in CRPS patients.

Central correlation of muscle sympathetic nerve activation during baroreflex unloading – a microneurography–positron emission tomography study

The baroreceptor reflex controls spontaneous fluctuations in blood pressure. One major control variable of the baroreflex is the sympathetic vasoconstrictor activity to muscles [MSNA; burst frequency (BF) and burst incidence (BI)], which can be quantitatively assessed by microneurography. We aimed to investigate the central regions involved in baroreflex regulation of MSNA. Healthy men (mean age 25 years) participated in three experimental sessions. (i) Microneurography recordings of MSNA from the left peroneal nerve during rest and baroreflex unloading, induced by lower body negative pressure (LBNP; −40 mmHg). If MSNA could be reliably recorded throughout this procedure (n = 15), the subjects entered the positron emission tomography (PET) experiments. The two PET sessions took place in a randomised order. Cerebral glucose metabolism (18‐fluorodeoxyglucose) was analysed after: (ii) baroreflex unloading (LBNP); and (iii) control condition (lying in the LBNP chamber without suction). The PET data were analysed employing SPM8. LBNP elicited a significant increase in MSNA in all successfully recorded subjects (BI: P = 0.001; F = 5.54; BF: P < 0.001; F = 36.59). As compared with the control condition, LBNP was associated with increased PET regional glucose metabolism bilaterally in the orbitofrontal cortex (OFC; BA 11, 47). Related to the rise of BF, there was increased activation of the left OFC (BA 11); related to the rise of BI there was increased activation of the brainstem corresponding to the rostral ventrolateral medulla. Our data support a role for the ventrolateral medulla and the OFC in baroreflex‐mediated control of MSNA in humans.

Low threshold unmyelinated mechanoafferents can modulate pain

BackgroundHuman, hairy skin contains a subgroup of C-fibers, the C-low threshold mechanoreceptive afferents ((C-LTMR) C-tactile or C-touch (CT) fibers) that are linked with the signaling of affective aspects of human touch. Recent studies suggest an involvement of these afferents in the modulation of pain in healthy volunteers. Small fiber neuropathy (SFN) is associated with a damage of C-fibers. Therefore, an impairment of C-LTMRs can be assumed. We aimed to elaborate a possible role of CT-afferents in pain modulation by investigating healthy volunteers and SFN-patients.MethodsExperiment I: 20 SFN-patients (12 women, median age 52.0xa0years) and 20 healthy controls (14 women, median age 43.0xa0years) participated in this prospective fMRI and psychophysical study. Heat-pain (HP), CT-targeted touch (slow brushing) and HP combined with CT-targeted touch were applied in randomized order to the left shank in a block design. The participants rated pain intensity on a visual analogue scale. Experiment II: We investigated a possible impact of pain intensity on CT induced pain modulation (10 healthy participants). The intensity of HP stimulation was chosen to induce pain intensity 50/100 (NRS). HP stimulation was applied with and without CT-targeted touch.ResultsExperiment I: CT-stimulation was sufficient to reduce heat pain in healthy participants (pxa0=xa00.016), but not in SFN-patients. HP induced pain intensity was significantly higher (32,2 vs 52,6) in SFN-patients. During HP, bold responses in pain associated areas were observed in both groups. Additional CT-stimulation elicited no significant difference of bold responses compared to HP. Experiment II: In healthy volunteers, we reproduced a significant reduction of HP intensity by CT-stimulation (pxa0=xa00.038).ConclusionsCT input seems to be sufficient to modulate pain, independent of intensity of the pain stimulus. As a prerequisite, the CT fibers have to be intact as in healthy volunteers. If CT fibers are impaired – as in SFN -, CT-targeted touch does not modulate pain intensity. The location of CT-induced pain modulation might be attributed to the level of the dorsal horn since the cortical activation pattern of heat pain with and without CT-targeted touch did not differ in healthy subjects and in SFN-patients.

Zolmitriptan inhibits neurogenic inflammation and pain during electrical stimulation in human skin

Triptans are agonists to 5‐HT 1B/D/F receptors, which are present on nociceptive neurons not only within but also beyond the trigeminal system. The aim of this study was to investigate whether zolmitriptan interacts with peptidergic nociceptive afferents in human skin.

The impact of baroreflex function on endogenous pain control: a microneurography study.

The interaction between sympathetic vasoconstrictor activity to muscles [muscle sympathetic nerve activity (MSNA), burst frequency (BF) and burst incidence (BI)] and different stress and somatosensory stimuli is still unclear. Eighteen healthy men (median age 28 years) underwent microneurography recordings from the peroneal nerve. MSNA was recorded during heat pain (HP) and cold pain (CP) alone as well as combined with different stress tasks (mental arithmetic, singing, giving a speech). An additional nine healthy men (median age 26 years) underwent the stimulation protocol with an additional control task (thermal pain combined with listening to music) to evaluate possible attentional confounders. MSNA was significantly increased by CP and HP. CP‐evoked responses were smaller. The diastolic blood pressure followed the time course of MSNA while heart rate remained unchanged. The mental stress tasks further increased MSNA and were sufficient to reduce pain while the control task had no effect. MSNA activity correlated negatively with pain intensity and positively with analgesia. High blood pressure values were associated with lower pain intensity. Our study indicates an impact of central sympathetic drive on pain and pain control.