Claudia Sommer

Publications of Claudia Sommer

• The role of antidepressants in the management of fibromyalgia syndrome: a systematic review and meta-analysis.

  Authors: Winfried Häuser, Frederick Wolfe, Thomas Tölle, Nurcan Uçeyler, Claudia Sommer

  CNS drugs. 04/2012; 26(4):297-307.

  Background: The role of antidepressants in the management of fibromyalgia syndrome (FMS) still needs to be determined. Objective: The objective of this study was to provide a quantitative analysisBackground: The role of antidepressants in the management of fibromyalgia syndrome (FMS) still needs to be determined. Objective: The objective of this study was to provide a quantitative analysis (meta-analysis) of the efficacy and harms of antidepressants in the management of adult FMS patients. Data sources: The data sources used were the databases MEDLINE, SCOPUS and the Cochrane Central Register of Controlled Trials (until December 30, 2010), the reference lists of included articles, and the websites of the US National Institutes of Health (NIH) and the Pharmaceutical Research and Manufacturers of America (PhRMA). Study selection: Studies with a randomized controlled trial (RCT) design comparing any types of antidepressants with pharmacological placebo or head-to-head comparisons of different types of antidepressants in FMS patients were included. RCTs in which antidepressants were combined with any other defined treatment or antidepressants were tested against anything but drug placebo were excluded. Patients diagnosed with FMS according to predefined criteria of any age were included. To be included, studies had to assess at least one key domain of FMS (pain, sleep, fatigue, health-related quality of life [HRQOL]) as outcomes of efficacy and report total treatment discontinuation rates and/or dropout rates due to adverse events as outcomes for harms. Data extraction: Data were extracted according to protocols of previous systematic reviews on antidepressants in FMS. Methodology quality was assessed by the van Tulder score. Data synthesis: Standardized mean differences (SMD) were calculated for continuous outcomes by means and standard deviations and relative risks (RR) for 30% pain reduction and total dropout rate for comparisons of antidepressants with placebo. Examination of the combined results was performed by a random effects model. We used Cohen's categories to evaluate the magnitude of the effect size, calculated by SMD. Heterogeneity was tested by the I2 statistic. Thirty-five studies were included in the meta-analysis. The SMDs of serotonin noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) on pain, sleep, fatigue, depression and HRQOL were significant. Based on Cohen's categories, the effect size on pain was small and the ones on sleep, fatigue, depression and HRQOL were not substantial. 1481/3528 (42.0%) patients with SNRIs and 737/2304 (32.0%) patients with placebo reported a 30% pain reduction (number needed to treat [NNT] 10.0; 95% CI 8.00, 13.4; I2 = 4%). The RR of dropouts due to adverse events was 1.83 (95% CI 1.53, 2.18; I2 = 33%). The SMDs of selective serotonin reuptake inhibitors (SSRIs) on pain, sleep, depression and HRQOL were significant. Based on Cohen's categories, the effect sizes on pain, depression and HRQOL were small and the one on sleep not substantial. 72/198 (36.4%) patients with SSRIs and 40/194 (20.6%) patients with placebo reported a 30% pain reduction (NNT 6.3; 95% CI 4.1, 14.1). The RR of dropouts due to adverse events was 1.60 (95% CI 0.84, 3.04; I2 = 0%). The SMDs of tricyclic antidepressants (TCAs) on pain, sleep, fatigue and HRQOL were significant. Based on Cohen's categories, the effect sizes on pain and sleep were moderate and the ones on fatigue and HRQOL were small. 140/290 (48.3%) patients with TCAs and 70/252 (27.8%) patients with placebo reported a 30% pain reduction (NNT 4.9; 95% CI 3.5, 8.0). The RR of dropouts due to adverse events was 0.84 (95% CI 0.46, 1.52; I2 = 0%). Conclusions: The TCA amitriptyline and the SNRIs duloxetine and milnacipran are first-line options for the treatment of FMS patients. Physicians and patients should be realistic about the potential benefits of antidepressants in FMS. A small number of patients experience a substantial symptom relief with no or minor adverse effects. However, a remarkable number of patients dropout of therapy because of intolerable adverse effects or experience only a small relief of symptoms, which does not outweigh the adverse effects.

• Cerebral blood flow in patients with Fabry disease as measured by Doppler sonography is not different from that in healthy individuals and is unaffected by treatment.

  Authors: Nurcan Uçeyler, Lan He, Ann-Kathrin Kahn, Frank Breunig, Wolfgang Müllges, Claudia Sommer

  Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine. 03/2012; 31(3):463-8.

  The purpose of this study was to investigate cervical and cerebral blood flow characteristics in patients with Fabry disease at baseline and under enzyme replacement therapy. In this case-controlThe purpose of this study was to investigate cervical and cerebral blood flow characteristics in patients with Fabry disease at baseline and under enzyme replacement therapy. In this case-control study we prospectively studied 68 patients with Fabry disease with extracranial and transcranial Doppler sonography. We compared extracranial and transcranial cervical and cerebral blood flow properties in all patients with Fabry disease and in subgroups of those with or without enzyme replacement therapy, male and female, and with normal or impaired renal function. Eight male patients were investigated at baseline and 1 year after initiation of enzyme replacement therapy. We show that cervical and cerebral blood flow parameters in patients with Fabry disease are not different from normal values regardless of sex, renal function, or enzyme replacement therapy. Cervical and cerebral blood flow measured with extracranial and transcranial Doppler sonography is not altered in patients with Fabry disease. Enzyme replacement therapy does not change blood flow characteristics.

• Human IgG directed against amphiphysin induces anxiety behavior in a rat model after intrathecal passive transfer.

  Authors: Christian Geis, Benedikt Grünewald, Andreas Weishaupt, Thomas Wultsch, Klaus V Toyka, Andreas Reif, Claudia Sommer

  Journal of neural transmission (Vienna, Austria : 1996). 02/2012;

  Stiff person syndrome with auto-antibodies against amphiphysin is characterized by muscular stiffness, spasms, and anxiety which is a less appreciated core symptom. Here, we report that intrathecalStiff person syndrome with auto-antibodies against amphiphysin is characterized by muscular stiffness, spasms, and anxiety which is a less appreciated core symptom. Here, we report that intrathecal application of purified immunoglobulin G-antibodies against amphiphysin from one patient induce anxiety behavior in rats. Immunostaining demonstrated binding of anti-amphiphysin antibodies to brain structures which are associated with anxiety disorders, such as the amygdala. We propose that antibody-mediated amphiphysin deficiency may account for anxiety behavior in stiff person syndrome via presynaptic dysregulation of GABAergic pathways.

• Analysis of myelinated fibers in human skin biopsies of patients with neuropathies.

  Authors: Kathrin Doppler, Christian Werner, Carsten Henneges, Claudia Sommer

  Journal of neurology. 02/2012;

  Given the availability of effective but costly treatment for acquired demyelinating neuropathies, biomarkers for these disorders are urgently needed. Here we aimed to quantify morphologicalGiven the availability of effective but costly treatment for acquired demyelinating neuropathies, biomarkers for these disorders are urgently needed. Here we aimed to quantify morphological abnormalities of myelinated fibers in skin biopsies from the proximal leg of patients with neuropathies to determine a potential diagnostic role of this method. We used double immunofluorescence to detect myelinated and unmyelinated fibers in thigh skin from 81 patients with polyneuropathy, 19 patients with small fiber neuropathy, and 25 controls. Dermal myelinated fibers were reduced 6.8-fold in patients with polyneuropathy (p < 0.0001). The number of dermal nerve bundles with myelinated fibers was reduced 2.7-fold (p = 0.0025). In small fiber neuropathy, myelinated fibers in dermal nerve bundles were only reduced in the length-dependent type, indicating that this subgroup may represent an early stage of generalized polyneuropathy. Elongated nodes of Ranvier were detectable in demyelinating neuropathies only. Our data suggest that changes in the number and morphology of myelinated fibers in the proximal leg can confirm the diagnosis of neuropathy, and may help to distinguish between demyelinating and axonal neuropathy, and to differentiate pure small fiber neuropathy from early polyneuropathy.

• Small fibers in Fabry disease: baseline and follow-up data under enzyme replacement therapy.

  Authors: Nurcan Üçeyler, Lan He, Dorothee Schönfeld, Ann-Kathrin Kahn, Karlheinz Reiners, Max J Hilz, Frank Breunig, Claudia Sommer

  Journal of the peripheral nervous system : JPNS. 12/2011; 16(4):304-14.

  Fabry disease (FD) is an X-linked lysosomal storage disorder which may lead to impaired peripheral nerve function, mostly affecting small nerve fibers, and to neuropathic pain. Characteristics of theFabry disease (FD) is an X-linked lysosomal storage disorder which may lead to impaired peripheral nerve function, mostly affecting small nerve fibers, and to neuropathic pain. Characteristics of the neuropathy associated with FD and the covariates for its development and temporal course have not been described in a large cohort. We studied small fiber function and morphology in 120 Fabry patients at baseline and in subgroups of these until 4-year follow-up. Baseline neurological (89/120) and electrophysiological (106/120) examination was mostly normal. Quantitative sensory testing revealed impaired cold detection thresholds in 84% of men and 39% of women. Lower leg intraepidermal nerve fiber density (IENFD) was reduced to 46% in Fabry patients compared to controls and to 12.5% in men with impaired renal function. Patients with abnormal IENFD more often had pain. Group means for IENFD did not improve under enzyme replacement therapy (ERT), but IENFD in the back increased under ERT in 4/15 patients with good renal function and clinical improvement. Cutaneous cytokine gene expression did not differ from controls. We conclude that ERT may improve proximal skin innervation in patients with good renal function, but does not protect small fiber function in men with impaired renal function.

• Interdisciplinary approach towards female patients with Fabry disease.

  Authors: Frank Weidemann, Markus Niemann, Claudia Sommer, Meinrad Beer, Frank Breunig, Christoph Wanner

  European journal of clinical investigation. 10/2011;

  Eur J Clin Invest 2011 ABSTRACT: Background  Fabry disease (FD) is a rare X-linked lysosomal storage disorder leading to an accumulation of globotriaosylceramides in the lysosomes of various organs.Eur J Clin Invest 2011 ABSTRACT: Background  Fabry disease (FD) is a rare X-linked lysosomal storage disorder leading to an accumulation of globotriaosylceramides in the lysosomes of various organs. Design  Being X-chromosomal-linked, most studies in the past have focused on involvement in male patients. However, it has been elucidated recently that female patients can present typical organ involvement and thus need to be treated, respectively. Conclusions  This review wants to give a systematical overview of the typical organ involvement in female patients with FD. Moreover, therapy recommendations especially for female patients are discussed.

• Genetic evidence for an essential role of neuronally expressed IL-6 signal transducer gp130 in the induction and maintenance of experimentally induced mechanical hypersensitivity in vivo and in vitro.

  Authors: Serena Quarta, Christian Vogl, Cristina E Constantin, Nurcan Üçeyler, Claudia Sommer, Michaela Kress

  Molecular pain. 09/2011; 7:73.

  Tenderness and mechanical allodynia are key symptoms of malignant tumor, inflammation and neuropathy. The proinflammatory cytokine interleukin-6 (IL-6) is causally involved in all three pathologies.Tenderness and mechanical allodynia are key symptoms of malignant tumor, inflammation and neuropathy. The proinflammatory cytokine interleukin-6 (IL-6) is causally involved in all three pathologies. IL-6 not only regulates innate immunity and inflammation but also causes nociceptor sensitization and hyperalgesia. In general and in most cell types including immune cells and sensory neurons, IL-6 binds soluble μ receptor subunits which heteromerizes with membrane bound IL-6 signal transducer gp130. In the present study, we used a conditional knock-out strategy to investigate the importance of signal transducer gp130 expressed in C nociceptors for the generation and maintenance of mechanical hypersensitivity. Nociceptors were sensitized to mechanical stimuli by experimental tumor and this nociceptor sensitization was preserved at later stages of the pathology in control mice. However, in mice with a conditional deletion of gp130 in Nav1.8 expressing nociceptors mechanical hypersensitivity by experimental tumor, nerve injury or inflammation recovery was not preserved in the maintenance phase and nociceptors exhibited normal mechanical thresholds comparable to untreated mice. Together, the results argue for IL-6 signal transducer gp130 as an essential prerequisite in nociceptors for long-term mechanical hypersensitivity associated with cancer, inflammation and nerve injury.

• A modified score to identify and discriminate neuropathic pain: a study on the German version of the Neuropathic Pain Symptom Inventory (NPSI).

  Authors: Claudia Sommer, Helmut Richter, Jan P Rogausch, Jule Frettlöh, Margitta Lungenhausen, Christoph Maier

  BMC neurology. 08/2011; 11:104.

  Neuropathic pain must be correctly diagnosed for optimal treatment. The questionnaire named Neuropathic Pain Symptom Inventory (NPSI) was developed in its original French version to evaluate theNeuropathic pain must be correctly diagnosed for optimal treatment. The questionnaire named Neuropathic Pain Symptom Inventory (NPSI) was developed in its original French version to evaluate the different symptoms of neuropathic pain. We hypothesized that the NPSI might also be used to differentiate neuropathic from non-neuropathic pain. We translated the NPSI into German using a standard forward-backward translation and administered it in a case-control design to patients with neuropathic (n = 68) and non-neuropathic pain (headache and osteoarthritis, n = 169) to validate it and to analyze its discriminant properties, its sensitivity to change, and to detect neuropathic pain subgroups with distinct profiles. Using a sum score (the NPSI-G score), we found sensitivity to change (r between 0.37 and 0.5 for pain items of the graded chronic pain scale) and could distinguish between neuropathic and other pain on a group basis, but not for individual patients. Post hoc development of a discriminant score with optimized diagnostic properties to distinguish neuropathic pain from non-neuropathic pain resulted in an instrument with high sensitivity (91%) and acceptable specificity (70%). We detected six different pain profiles in the patient group with neuropathic pain; three profiles were found to be distinct. The NPSI-G potentially combines the properties of a diagnostic tool and an instrument to identify subtypes of neuropathic pain.

• Reply to the letter to the editor.

  Authors: Maija Haanpää, Nadine Attal, Miroslav Backonja, Ralf Baron, Didier Bouhassira, Giorgio Cruccu, Per Hansson, Giandomenico Iannetti, Troels S Jensen, Timo Kauppila, Turo J Nurmikko, Andrew S C Rice, Michael Rowbotham, Jordi Serra, Claudia Sommer, Rolf-Detlef Treede

  Pain. 07/2011; 152(7):1683-4.

• Emotional, physical, and sexual abuse in fibromyalgia syndrome: a systematic review with meta-analysis.

  Authors: Winfried Häuser, Maria Kosseva, Nurcan Üceyler, Petra Klose, Claudia Sommer

  Arthritis care & research. 06/2011; 63(6):808-20.

  To systematically assess the potential association of fibromyalgia syndrome (FMS) with emotional, physical, and sexual abuse. The databases EMBase, Google Scholar, Medline, and PsycINFO (throughTo systematically assess the potential association of fibromyalgia syndrome (FMS) with emotional, physical, and sexual abuse. The databases EMBase, Google Scholar, Medline, and PsycINFO (through April 2010) and the reference sections of original studies were searched for eligible studies. Eligible studies were cohort or case--control studies that assessed at least one type of emotional, physical, or sexual abuse in childhood or adulthood in patients with FMS and in controls. Two authors independently extracted descriptive, quality, and outcome data from included studies. Methodologic quality was assessed by the Newcastle-Ottawa Quality Assessment Scale. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were pooled across studies by using the random-effects model. Heterogeneity was assessed by I(2) statistics. The search identified 18 eligible case-control studies with 13,095 subjects. There were significant associations between FMS and self-reported physical abuse in childhood (OR 2.49 [95% CI 1.81-3.42], I(2) = 0%; 9 studies) and adulthood (OR 3.07 [95% CI 1.01-9.39], I(2) = 79%; 3 studies), and sexual abuse in childhood (OR 1.94 [95% CI 1.36-2.75], I(2) = 20%; 10 studies) and adulthood (OR 2.24 [95% CI 1.07-4.70], I(2) = 64%; 4 studies). Study quality was mostly poor. Low study quality was associated with higher effect sizes for sexual abuse in childhood, but not with other effect sizes. The association of FMS with physical and sexual abuse could be confirmed, but is confounded by study quality.

• Nerve biopsy in chronic inflammatory neuropathies: in situ biomarkers.

  Authors: Claudia Sommer, Klaus Toyka

  Journal of the peripheral nervous system : JPNS. 06/2011; 16 Suppl 1:24-9.

  We collected the evidence for potential biomarkers in nerve biopsies that might be of use in diagnosis, assessment, or treatment response in chronic inflammatory demyelinating polyneuropathiesWe collected the evidence for potential biomarkers in nerve biopsies that might be of use in diagnosis, assessment, or treatment response in chronic inflammatory demyelinating polyneuropathies (CIDPs). We performed a literature search in PubMed from 1965 to May 2010 using the key words (["chronic inflammatory polyneuropathy" or "polyradiculoneuritis" or {"chronic and neuritis"}] and "nerve biopsy") and searched manually within these references for relevant publications related to the subject. Twenty references gave information about potential biomarkers for CIDP. Evidence of demyelination alone is not specific for CIDP, but may support the diagnosis in the context of a typical clinical pattern. Although the total numbers of inflammatory cells do not distinguish well between CIDP and non-inflammatory neuropathies, the pattern of macrophage clusters around endoneurial vessels may be a simple marker of inflammation with good sensitivity and specificity. Immunohistochemistry for matrix metalloproteinase-9 may be useful for the distinction of inflammatory and non-inflammatory neuropathies. Microarrays which give a complex pattern of up- and downregulated genes also show promise for developing a biomarker. Immunohistochemistry on sural nerve biopsies has the potential to distinguish inflammatory from non-inflammatory neuropathies. More research is needed to establish the diagnostic validity of specific markers and of gene expression studies and to test whether they can distinguish between subtypes of inflammatory neuropathies.

• Vasculitis-like neuropathy in amyotrophic lateral sclerosis unresponsive to treatment.

  Authors: Grazia Devigili, Nurcan Uçeyler, Marcus Beck, Karlheinz Reiners, Guido Stoll, Klaus V Toyka, Claudia Sommer

  Acta neuropathologica. 05/2011; 122(3):343-52.

  Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with variable involvement of other systems. A pathogenetic role of immune-mediated mechanisms has been suggested. WeAmyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with variable involvement of other systems. A pathogenetic role of immune-mediated mechanisms has been suggested. We retrospectively analyzed sural nerve pathology and the clinical course in 18 patients with ALS. These patients had undergone sural nerve biopsy because of clinical or neurophysiological signs indicating sensory involvement (ALS+). Eleven of the 18 ALS+ patients had inflammatory cell infiltrates (ALS(vasc)) resembling infiltrates seen in patients with vasculitic neuropathy. Data were compared with the 7 patients without vasculitic infiltrates (ALS(nonvasc)) and with those of 16 patients with isolated peripheral nerve vasculitis (NP(vasc)). Biopsy specimens were processed with standard histological stains and with immunohistochemistry for a panel of inflammatory markers, with the hypothesis that the composition of infiltrates should differ between ALS(vasc) and NP(vasc). Immunoreactive cells were quantified in a blinded manner. Unlike patients with NP(vasc), those with ALS(vasc) had only minor neurophysiological abnormalities in the sural nerve and, except for the infiltrates, almost normal nerve morphology on semithin sections. The difference in epineurial T cell count was significant between ALS(vasc) and ALS(nonvasc) (p = 0.031). Surprisingly, the cellular composition of epineurial infiltrates in sural nerve biopsies was indistinguishable between ALS(vasc) and NP(vasc) despite a significant difference in fiber pathology (p < 0.0001). Standard immunosuppressive treatment did not prevent clinical progression of the motor neuron disease in any of the patients with ALS(vasc). ALS(vasc) appears as a neuropathological subtype in ALS+ suggesting immune-mediated disease components but without response to standard immunosuppressive treatment.

• Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel.

  Authors: Alessandro P Burlina, Katherine B Sims, Juan M Politei, Gary J Bennett, Ralf Baron, Claudia Sommer, Anette Torvin Møller, Max J Hilz

  BMC neurology. 05/2011; 11:61.

  Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers areFabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e.g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate.

• Lacosamide has protective disease modifying properties in experimental vincristine neuropathy.

  Authors: Christian Geis, Bettina K Beyreuther, Thomas Stöhr, Claudia Sommer

  Neuropharmacology. 05/2011; 61(4):600-7.

  Pain and paresthesias are the most common symptoms of chemotherapy induced painful neuropathy (CIPN). Current treatment and preventive strategies of CIPN are ineffective, and the neuropathy may leadPain and paresthesias are the most common symptoms of chemotherapy induced painful neuropathy (CIPN). Current treatment and preventive strategies of CIPN are ineffective, and the neuropathy may lead to discontinuation of anti-tumor therapy. Here we used experimental vincristine-induced neuropathy in rats to evaluate the disease modifying potential of lacosamide using a sustained release formulation and the acute treatment effects of a rapid release formulation. Pain behavior was assessed by withdrawal responses to von Frey hairs, acetone drops, the Randall-Selitto device, and to radiant heat. Neuropathy was assessed using electrophysiological recordings. Preventive lacosamide treatment (30 mg/kg subcutaneously b.i.d. for 17 days) was well tolerated, and pharmacokinetic analysis revealed a peak plasma concentration 2 h post-injection with a plasma half-life of approximately 3 h. Rats treated with lacosamide, in contrast to vehicle treated rats, did not develop vincristine-induced cold allodynia. Neurophysiology showed a delayed F-wave latency in vehicle treated rats, which was not present in lacosamide treated animals. We could thus demonstrate a protective disease modifying potency of lacosamide in an animal model of CIPN. Lacosamide may be a promising candidate for preventive treatment of CIPN in patients receiving chemotherapy with vinca alkaloids or platinum drugs.

• Serotonin transporter deficiency protects mice from mechanical allodynia and heat hyperalgesia in vincristine neuropathy.

  Authors: Niels Hansen, Nurcan Uçeyler, Florian Palm, Marek Zelenka, Lydia Biko, Klaus-Peter Lesch, Manfred Gerlach, Claudia Sommer

  Neuroscience letters. 03/2011; 495(2):93-7.

  Painful vincristine (VCR) neuropathy is a frequent and dose-limiting problem in cancer treatment. Here, we investigated how pain behavior is modulated in mice lacking the serotonin transporterPainful vincristine (VCR) neuropathy is a frequent and dose-limiting problem in cancer treatment. Here, we investigated how pain behavior is modulated in mice lacking the serotonin transporter (5-HTT-/- mice) after inducing neuropathy by intraperitoneal injections of VCR. We used standard tests for evoked pain, high performance liquid chromatography to measure serotonin (5-HT), and immunohistochemistry of L4/5 dorsal root ganglia (DRG) to assess neuronal injury and inflammation. After injections of VCR, 5-HTT-/- mice did not develop hypersensitivity to heat, in contrast to their wildtype (wt) littermates (p<0.05). Also, 5-HTT-/- mice recovered faster from mechanical hypersensitivity than wt mice (p<0.05). 5-HT levels were lower in the peripheral and central nervous tissue of vehicle or VCR-treated 5-HTT-/- mice compared to wt mice. VCR-treated mice had higher numbers of injured neurons as identified by immunostaining for activating transcription factor 3, and more immunoreactive macrophages in the L4/5 DRG than vehicle-treated mice. There was no difference between genotypes. Thus the 5-HTT-/- genotype did not protect mice from VCR-induced neuronal injury and macrophage infiltration in the DRG. Our results suggest that the reduced peripheral 5-HT levels of 5-HTT-/- mice in VCR neuropathy underlie the lack of heat hyperalgesia. Conversely, attenuation of mechanical allodynia in 5-HTT-/- mice may indicate reduced 5-HT-mediated facilitation in the central nervous system.

• 5-hydroxyindolacetic acid (5-HIAA), a main metabolite of serotonin, is responsible for complete Freund's adjuvant-induced thermal hyperalgesia in mice.

  Authors: Yong Chen, Florian Palm, Klaus-Peter Lesch, Manfred Gerlach, Rainald Moessner, Claudia Sommer

  Molecular pain. 03/2011; 7:21.

  The role of serotonin (5-hydroxytrptamine, 5-HT) in the modulation of pain has been widely studied. Previous work led to the hypothesis that 5-hydroxyindolacetic acid (5-HIAA), a main metabolite ofThe role of serotonin (5-hydroxytrptamine, 5-HT) in the modulation of pain has been widely studied. Previous work led to the hypothesis that 5-hydroxyindolacetic acid (5-HIAA), a main metabolite of serotonin, might by itself influence pain thresholds. In the present study, we investigated the role of 5-HIAA in inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) into the hind paw of mice. Wild-type mice were compared to mice deficient of the 5-HT transporter (5-HTT-/- mice) using behavioral tests for hyperalgesia and high-performance liquid chromatography (HPLC) to determine tissue levels of 5-HIAA. Wild-type mice reproducibly developed thermal hyperalgesia and paw edema for 5 days after CFA injection. 5-HTT-/- mice treated with CFA had reduced thermal hyperalgesia on day 1 after CFA injection and normal responses to heat thereafter. The 5-HIAA levels in spinal cord and sciatic nerve as measured with HPLC were lower in 5-HTT-/- mice than in wild-type mice after CFA injection. Pretreatment of wild-type mice with intraperitoneal injection of para-chlorophenylalanine (p-CPA), a serotonin synthesis inhibitor, resulted in depletion of the 5-HIAA content in spinal cord and sciatic nerve and decrease in thermal hyperalgesia in CFA injected mice. The application of exogenous 5-HIAA resulted in potentiation of thermal hyperalgesia induced by CFA in 5-HTT-/- mice and in wild-type mice pretreated with p-CPA, but not in wild-type mice without p-CPA pretreatment. Further, methysergide, a broad-spectrum serotonin receptor antagonist, had no effect on 5-HIAA-induced potentiation of thermal hyperalgesia in CFA-treated wild-type mice. Taken together, the present results suggest that 5-HIAA plays an important role in modulating peripheral thermal hyperalgesia in CFA induced inflammation, probably via a non-serotonin receptor mechanism.

• NeuPSIG guidelines on neuropathic pain assessment.

  Authors: Maija Haanpää, Nadine Attal, Miroslav Backonja, Ralf Baron, Michael Bennett, Didier Bouhassira, Giorgio Cruccu, Per Hansson, Jennifer A Haythornthwaite, Gian Domenico Iannetti, Troels S Jensen, Timo Kauppila, Turo J Nurmikko, Andew S C Rice, Michael Rowbotham, Jordi Serra, Claudia Sommer, Blair H Smith, Rolf-Detlef Treede

  Pain. 01/2011; 152(1):14-27.

  This is a revision of guidelines, originally published in 2004, for the assessment of patients with neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesionThis is a revision of guidelines, originally published in 2004, for the assessment of patients with neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at peripheral or central level. Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but further validation of them is needed for epidemiological purposes. Clinical examination, including accurate sensory examination, is the basis of neuropathic pain diagnosis. For more accurate sensory profiling, quantitative sensory testing is recommended for selected cases in clinic, including the diagnosis of small fiber neuropathies and for research purposes. Measurement of trigeminal reflexes mediated by A-beta fibers can be used to differentiate symptomatic trigeminal neuralgia from classical trigeminal neuralgia. Measurement of laser-evoked potentials is useful for assessing function of the A-delta fiber pathways in patients with neuropathic pain. Functional brain imaging is not currently useful for individual patients in clinical practice, but is an interesting research tool. Skin biopsy to measure the intraepidermal nerve fiber density should be performed in patients with clinical signs of small fiber dysfunction. The intensity of pain and treatment effect (both in clinic and trials) should be assessed with numerical rating scale or visual analog scale. For future neuropathic pain trials, pain relief scales, patient and clinician global impression of change, the proportion of responders (50% and 30% pain relief), validated neuropathic pain quality measures and assessment of sleep, mood, functional capacity and quality of life are recommended.

• IL-4 deficiency is associated with mechanical hypersensitivity in mice.

  Authors: Nurcan Üçeyler, Tengü Topuzoğlu, Peter Schiesser, Saskia Hahnenkamp, Claudia Sommer

  PloS one. 01/2011; 6(12):e28205.

  Interleukin-4 (IL-4) is an anti-inflammatory and analgesic cytokine that induces opioid receptor transcription. We investigated IL-4 knockout (ko) mice to characterize their pain behavior before andInterleukin-4 (IL-4) is an anti-inflammatory and analgesic cytokine that induces opioid receptor transcription. We investigated IL-4 knockout (ko) mice to characterize their pain behavior before and after chronic constriction injury (CCI) of the sciatic nerve as a model for neuropathic pain. We investigated opioid responsivity and measured cytokine and opioid receptor gene expression in the peripheral and central nervous system (PNS, CNS) of IL-4 ko mice in comparison with wildtype (wt) mice. Naïve IL-4 ko mice displayed tactile allodynia (wt: 0.45 g; ko: 0.18 g; p<0.001), while responses to heat and cold stimuli and to muscle pressure were not different. No compensatory changes in the gene expression of tumor necrosis factor-alpha (TNF), IL-1β, IL-10, and IL-13 were found in the PNS and CNS of naïve IL-4 ko mice. However, IL-1β gene expression was stronger in the sciatic nerve of IL-4 ko mice (p<0.001) 28 days after CCI and only IL-4 ko mice had elevated IL-10 gene expression (p = 0.014). Remarkably, CCI induced TNF (p<0.01), IL-1β (p<0.05), IL-10 (p<0.05), and IL-13 (p<0.001) gene expression exclusively in the ipsilateral spinal cord of IL-4 ko mice. The compensatory overexpression of the anti-inflammatory and analgesic cytokines IL-10 and IL-13 in the spinal cord of IL-4 ko mice may explain the lack of genotype differences for pain behavior after CCI. Additionally, CCI induced gene expression of μ, κ, and δ opioid receptors in the contralateral cortex and thalamus of IL-4 ko mice, paralleled by fast onset of morphine analgesia, but not in wt mice. We conclude that a lack of IL-4 leads to mechanical sensitivity; the compensatory hyperexpression of analgesic cytokines and opioid receptors after CCI, in turn, protects IL-4 ko mice from enhanced pain behavior after nerve lesion.

• Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features.

  Authors: Franziska Hopfner, Barbara Schormair, Franziska Knauf, Achim Berthele, Thomas R Tölle, Ralf Baron, Christoph Maier, Rolf-Detlef Treede, Andreas Binder, Claudia Sommer [......] Uwe Heemann, Arne Pfeufer, Michael Näbauer, Stefan Kääb, Barbara Nowak, Christian Gieger, Peter Lichtner, Claudia Trenkwalder, Konrad Oexle, Juliane Winkelmann

  BMC neurology. 01/2011; 11:134.

  Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related toAction myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features. In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons. A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA). Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features.

• Systematic review with meta-analysis: cytokines in fibromyalgia syndrome.

  Authors: Nurcan Uçeyler, Winfried Häuser, Claudia Sommer

  BMC musculoskeletal disorders. 01/2011; 12:245.

  To perform a systematic review and meta-analysis on cytokine levels in patients with fibromyalgia syndrome (FMS). Through December 2010 we systematically reviewed the databases PubMed, MEDLINE, andTo perform a systematic review and meta-analysis on cytokine levels in patients with fibromyalgia syndrome (FMS). Through December 2010 we systematically reviewed the databases PubMed, MEDLINE, and PsycINFO and screened the reference lists of 22 review articles for suitable original articles. Original articles investigating cytokines in patients with FMS were included. Data were extracted by two independent authors. Differences of the cytokine levels of FMS patients and controls were summarized by standardized mean differences (SMD) using a random effects model. Study quality was assessed applying methodological scores: modified Center of Evidence Based Medicine, Newcastle-Ottawa-Scale, and Würzburg Methodological Quality Score. Twenty-five articles were included investigating 1255 FMS patients and 800 healthy controls. Data of 13/25 studies entered meta-analysis. The overall methodological quality of studies was low. The results of the majority of studies were not comparable because methods, investigated material, and investigated target cytokines differed. Systematic review of the selected 25 articles revealed that FMS patients had higher serum levels of interleukin (IL)-1 receptor antagonist, IL-6, and IL-8, and higher plasma levels of IL-8. Meta-analysis of eligible studies showed that FMS patients had higher plasma IL-6 levels compared to controls (SMD = -0.34 [-0.64, -0.03] 95% CI; p = 0.03). The majority of investigated cytokines were not different between patients and controls. The pathophysiological role of cytokines in FMS is still unclear. Studies of higher quality and with higher numbers of subjects are needed.