Analgesic Medication in Fibromyalgia Patients: A Cross-Sectional Study.

There is no approved drug for fibromyalgia syndrome (FMS) in Europe. In the German S3 guideline, amitriptyline, duloxetine, and pregabalin are recommended for temporary use. The aim of this study was to cross-sectionally investigate the current practice of medication in FMS patients in Germany. We systematically interviewed 156 patients with FMS, while they were participating in a larger study. The patients had been stratified into subgroups with and without a decrease in intraepidermal nerve fiber density. The drugs most commonly used to treat FMS pain were nonsteroidal anti-inflammatory drugs (NSAIDs) (41.0% of all patients), metamizole (22.4%), and amitriptyline (12.8%). The most frequent analgesic treatment regimen was "on demand" (53.9%), during pain attacks, while 35.1% of the drugs were administered daily and the remaining in other regimens. Median pain relief as self-rated by the patients on a numerical rating scale (0-10) was 2 points for NSAIDS, 2 for metamizole, and 1 for amitriptyline. Drugs that were discontinued due to lack of efficacy rather than side effects were acetaminophen, flupirtine, and selective serotonin reuptake inhibitors. Reduction in pain severity was best achieved by NSAIDs and metamizole. Our hypothesis that a decrease in intraepidermal nerve fiber density might represent a neuropathic subtype of FMS, which would be associated with better effectiveness of drugs targeting neuropathic pain, could not be confirmed in this cohort. Many FMS patients take "on-demand" medication that is not in line with current guidelines. More randomized clinical trials are needed to assess drug effects in FMS subgroups.

Dorsal Root Ganglion Volumetry by MR Gangliography.

BACKGROUND AND PURPOSE: Dorsal root ganglion MR imaging (MR gangliography) is increasingly gaining clinical-scientific relevance. However, dorsal root ganglion morphometry by MR imaging is typically performed under the assumption of ellipsoid geometry, which remains to be validated. MATERIALS AND METHODS: Sixty-four healthy volunteers (37 [57.8%] men; mean age, 31.5 [SD, 8.3] years) underwent MR gangliography of the bilateral L4-S2 levels (3D-T2WI TSE spectral attenuated inversion recovery-sampling perfection with application-optimized contrasts by using different flip angle evolution, isotropic voxels = 1.1 mm³, TE = 301 ms). Ground truth dorsal root ganglion volumes were bilaterally determined for 96 dorsal root ganglia (derivation cohort) by expert manual 3D segmentation by 3 independent raters. These ground truth dorsal root ganglion volumes were then compared with geometric ellipsoid dorsal root ganglion approximations as commonly practiced for dorsal root ganglion morphometry. On the basis of the deviations from ellipsoid geometry, improved volume estimation could be derived and was finally applied to a large human validation cohort (510 dorsal root ganglia). RESULTS: Commonly used equations of ellipsoid geometry underestimate true dorsal root ganglion volume by large degrees (factor = 0.42-0.63). Ground truth segmentation enabled substantially optimizing dorsal root ganglion geometric approximation using its principal axes lengths by deriving the dorsal root ganglion volume term of [Formula: see text]. Using this optimization, the mean volumes of 510 lumbosacral healthy dorsal root ganglia were as follows: L4: 211.3 (SD, 52.5) mm³, L5: 290.7 (SD, 90.9) mm³, S1: 384.2 (SD, 145.0) mm³, and S2: 192.4 (SD, 52.6) mm³. Dorsal root ganglion volume increased from L4 to S1 and decreased from S1 to S2 (P < .001). Dorsal root ganglion volume correlated with subject height (r = . 22, P < .001) and was higher in men (P < .001). CONCLUSIONS: Dorsal root ganglion volumetry by measuring its principal geometric axes on MR gangliography can be substantially optimized. By means of this optimization, dorsal root ganglion volume distribution was estimated in a large healthy cohort for the clinically most relevant lumbosacral levels, L4-S2.

Stratification of Fabry mutations in clinical practice: a closer look at α-galactosidase A-3D structure.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage and multi-system disorder due to mutations in the α-galactosidase A (α-GalA) gene. We investigated the impact of individual amino acid exchanges in the α-GalA 3D-structure on the clinical phenotype of FD patients. PATIENTS AND METHODS: We enrolled 80 adult FD patients with α-GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α-GalA 3D-structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD-specific treatment. RESULTS: Patients with active site or buried mutations showed a severe phenotype with multi-organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α-GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso-Gb3 levels were higher (P < 0.01 in men; <0.05 in women). CONCLUSIONS: The type of amino acid exchange location in the α-GalA 3D-structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.

Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types.

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene coding for α-galactosidase A (α-GalA). The deleterious mutations lead to accumulation of α-GalA substrates, including globotriaosylceramide (Gb3) and globotriaosylsphingosine. Progressive glycolipid storage results in cellular dysfunction, leading to organ damage and clinical disease, i.e. neuropathic pain, impaired renal function and cardiomyopathy. Many Fabry patients are treated by bi-weekly intravenous infusions of replacement enzyme. While the only available oral therapy is an α-GalA chaperone, which is indicated for a limited number of patients with specific 'amenable' mutations. Lucerastat is an orally bioavailable inhibitor of glucosylceramide synthase (GCS) that is in late stage clinical development for Fabry disease. Here we investigated the ability of lucerastat to lower Gb3, globotriaosylsphingosine and lysosomal staining in cultured fibroblasts from 15 different Fabry patients. Patients' cells included 13 different pathogenic variants, with 13 cell lines harboring GLA mutations associated with the classic disease phenotype. Lucerastat dose dependently reduced Gb3 in all cell lines. For 13 cell lines the Gb3 data could be fit to an IC50 curve, giving a median IC50 [interquartile range (IQR)] = 11 µM (8.2-18); the median percent reduction (IQR) in Gb3 was 77% (70-83). Lucerastat treatment also dose dependently reduced LysoTracker Red staining of acidic compartments. Lucerastat's effects in the cell lines were compared to those with current treatments-agalsidase alfa and migalastat. Consequently, the GCS inhibitor lucerastat provides a viable mechanism to reduce Gb3 accumulation and lysosome volume, suitable for all Fabry patients regardless of genotype.

Detection of blood Gb3 deposits as a new tool for diagnosis and therapy monitoring in patients with classic Fabry disease.

BACKGROUND: The X-linked Fabry disease (FD) is a multiorgan disorder due to alpha-galactosidase A (α-GAL) deficiency with consequent lysosomal accumulation of globotriaosylceramide (Gb3). We established the immunocytochemical detection of Gb3 in blood cells of FD patients as a new method for FD diagnostics, follow-up and treatment control. METHODS: We enrolled 67 FD patients (37 men, 30 women) and 52 healthy controls (26 men, 26 women). PBMC were isolated from whole venous blood and 3x105 cells were immunoreacted with antibodies against CD77 as a marker for Gb3. Using fluorescence microscopy, the mean percentage of Gb3 positive PBMC was determined by an investigator blinded to subject allocation. As a second method, we qualitatively assessed Gb3 positive cells in blood smears. RESULTS: Gb3 deposits were unequivocally visible in PBMC and in blood smears. Men (P < 0.001) and women (P < 0.01) with classical FD had more Gb3-positive PBMC than healthy controls, whose samples only occasionally showed positive cells. The number of Gb3 positive PBMC was negatively correlated with α-GAL activity and positively correlated with plasma lyso-Gb3 levels. Only the PBMC Gb3 load but not plasma lyso-Gb3 reflected short- and long-term effects of enzyme replacement therapy (P < 0.01). CONCLUSIONS: Gb3 can be visualized in PBMC and blood smears and can be used as a novel marker for diagnostics, follow-up and treatment control in FD.

OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency.

Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.

[Etiology and pathophysiology of fibromyalgia syndrome : Updated guidelines 2017, overview of systematic review articles and overview of studies on small fiber neuropathy in FMS subgroups]. / Ätiologie und Pathophysiologie des Fibromyalgiesyndroms : Aktualisierte Leitlinie 2017 und Übersicht von systematischen Übersichtsarbeiten sowie eine Übersicht über Studien zur Kleinfaserpathologie bei Subgruppen des FMS.

BACKGROUND: The regular update of the guidelines on fibromyalgia syndrome, AWMF number 145/004, was planned for April 2017. METHODS: The guidelines were developed by 13 scientific societies and 2 patient self-help organizations coordinated by the German Pain Society. Working groups (n =8) with a total of 42 members were formed balanced with respect to gender, medical expertise, position in the medical or scientific hierarchy and potential conflicts of interest. A systematic search of the literature from December 2010 to May 2016 was performed in the Cochrane library, MEDLINE, PsycINFO and Scopus databases. Prospective population-based studies and systematic reviews with meta-analyses of case control studies were taken into consideration for the statements. Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine version 2009. The statements were generated by multiple step formalized procedures. The guidelines were reviewed and approved by the board of directors of the societies engaged in the development of the guidelines. RESULTS: Current data do not enable identification of distinct factors in the etiology and pathophysiology of fibromyalgia syndrome. Fibromyalgia syndrome can be associated with inflammatory rheumatic diseases, gene polymorphisms, life style factors (e.g. smoking, obesity and lack of physical activity), depressive disorders as well as physical and sexual abuse in childhood and adulthood. CONCLUSION: Fibromyalgia syndrome is most probably the end result of various pathogenetic factors and pathophysiological mechanisms.

[Drug therapy of fibromyalgia syndrome : Updated guidelines 2017 and overview of systematic review articles]. / Medikamentöse Therapie des Fibromyalgiesyndroms : Aktualisierte Leitlinie 2017 und Übersicht von systematischen Übersichtsarbeiten.

BACKGROUND: The regular update of the guidelines on fibromyalgia syndrome, AWMF number 145/004, was scheduled for April 2017. METHODS: The guidelines were developed by 13 scientific societies and 2 patient self-help organizations coordinated by the German Pain Society. Working groups (n =8) with a total of 42 members were formed balanced with respect to gender, medical expertise, position in the medical or scientific hierarchy and potential conflicts of interest. A literature search for systematic reviews of randomized controlled drug trials from December 2010 to May 2016 was performed in the Cochrane library, MEDLINE, PsycINFO and Scopus databases. Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine version 2009. The strength of recommendations was achieved by multiple step formalized procedures to reach a consensus. Efficacy, risks, patient preferences and applicability of available therapies were weighed up against each other. The guidelines were reviewed and approved by the board of directors of the societies engaged in the development of the guidelines. RESULTS AND CONCLUSION: Amitriptyline and duloxetine are recommended in the case of comorbid depressive disorders or generalized anxiety disorder and pregabalin in the case of generalized anxiety disorder. Off-label use of duloxetine and pregabalin can be considered if there are no comorbid mental disorders or no generalized anxiety disorder. Strong opioids are not recommended.

Increased miR-132-3p expression is associated with chronic neuropathic pain.

Alterations in the neuro-immune balance play a major role in the pathophysiology of chronic neuropathic pain. MicroRNAs (miRNA) can regulate both immune and neuronal processes and may function as master switches in chronic pain development and maintenance. We set out to analyze the role of miR-132-3p, first in patients with peripheral neuropathies and second in an animal model of neuropathic pain. We initially determined miR-132-3p expression by measuring its levels in white blood cells (WBC) of 30 patients and 30 healthy controls and next in sural nerve biopsies of 81 patients with painful or painless inflammatory or non-inflammatory neuropathies based on clinical diagnosis. We found a 2.6 fold increase in miR-132-3p expression in WBC of neuropathy patients compared to healthy controls (p<0.001). MiR-132-3p expression was also slightly up-regulated in sural nerve biopsies from neuropathy patients suffering from neuropathic pain compared to those without pain (1.2 fold; p<0.001). These promising findings were investigated further in an animal model of neuropathic pain, the spared nerve injury model (SNI). For this purpose miR-132-3p expression levels were measured in dorsal root ganglia and spinal cord of rats. Subsequently, miR-132-3p expression was pharmacologically modulated with miRNA antagonists or mimetics, and evoked pain and pain aversion were assessed. Spinal miR-132-3p levels were highest 10days after SNI, a time when persistent allodynia was established (p<0.05). Spinal administration of miR-132-3p antagonists via intrathecal (i.t.) catheters dose dependently reversed mechanical allodyina (p<0.001) and eliminated pain behavior in the place escape avoidance paradigm (p<0.001). Intrathecal administration of miR-132-3p mimetic dose-dependently induced pain behavior in naïve rats (p<0.001). Taken together these results indicate a pro-nociceptive effect of miR-132-3p in chronic neuropathic pain.

Severe Epidermal Nerve Fiber Loss in Diabetic Neuropathy Is Not Reversed by Long-Term Normoglycemia After Simultaneous Pancreas and Kidney Transplantation.

Whether nerve fiber loss, a prominent feature of advanced diabetic neuropathy, can be reversed by reestablishment of normal glucose control remains questionable. We present 8-year follow-up data on epidermal nerve fiber (ENF) density and neurological function in patients with type 1 diabetes after simultaneous pancreas and kidney transplantation (SPK) with long-term normoglycemia. Distal thigh skin biopsies with ENF counts, vibration perception thresholds (VPTs), autonomic function testing (AFT) and electrophysiological examinations were performed at time of SPK and 2.5 and 8 years after SPK in 12 patients with type 1 diabetes. In comparison to controls, baseline ENF density, VPT and AFT results of patients indicated severe neuropathy. At follow-up, all SPK recipients were insulin independent with excellent glycemic control and kidney graft function; however, the severe ENF depletion present at baseline had not improved, with total ENF absence in 11 patients at 8-year follow-up. Similarly, no amelioration occurred in the VPT and AFT results. Numerical improvement was seen in some electrophysiological parameters; however, statistical significance was achieved only in median motor nerve conduction velocity. ENF loss and functional deficits in advanced diabetic peripheral neuropathy are rarely reversible, even by long-term normoglycemia, which underscores the importance of neuropathy prevention by early optimal glycemic control.

[Fibromyalgia syndrome: A disease of the small nerve fibers?]. / Fibromyalgiesyndrom : Eine Erkrankung der kleinen Nervenfasern?

Fibromyalgia syndrome (FMS) is characterized by chronic widespread pain and additional associated symptoms, such as fatigue, sleep disturbances and depressive moods. The pathophysiology of pain in FMS is unclear. In recent years, an involvement of the thinly myelinated A-delta and the unmyelinated C-nerve fibers has been reported in FMS patients. Independent research groups published consistent objective and multidimensional findings of damage to these small nerve fibers, such as disturbances of fiber function, electrical properties and morphological changes. All these alterations are not specific for FMS; however, they were described for the first time in subgroups of FMS patients. While the reasons for this small fiber pathology and its contribution to FMS pain are still unclear, a new research field has now been opened that will focus on uncovering the underlying pathophysiology. This review article summarizes these new findings and discusses the significance for the understanding of FMS.

[Pain therapy for Fabry's disease]. / Schmerztherapie bei Morbus Fabry.

Fabry's disease is an X-chromosome linked lysosomal storage disorder with α-galactosidase A deficiency and subsequent multiple organ involvement. An early and common symptom also in later stages of the disease is pain. This pain depends on various precipitating factors and can severely compromise the quality of life. So-called Fabry crises can lead to the necessity for intensive care treatment. The pain can be classified as predominantly neuropathic and is difficult to treat. In addition, medication has to be adjusted to concomitant cardiac and renal involvement in Fabry's disease. This review gives guidance for pain therapy in Fabry's disease based on the available evidence and on experience.

[Fabry disease : diagnosis and treatment]. / Morbus Fabry : diagnostik und therapie.

Fabry disease is an X-linked hereditary lysosomal storage disorder with deficiency of the enzyme α-galactosidase A and lysosomal deposits of the glycosphingolipid globotriaosylceramid-3 (Gb-3). Males are predominantly affected by this multisystem disorder; however, females may develop any grade of disease severity. Cardiac, renal, and cerebral involvement may be life limiting-the latter due to stroke in young age. The peripheral nervous system is affected in terms of small fiber neuropathy with characteristic heat-induced acral pain. Pain is the most frequent first symptom of Fabry disease, but is often misjudged and undertreated. Enzyme replacement therapy is available as a treatment option. Fabry-associated pain is treated following the principles of analgesic treatment in neuropathic pain conditions, but some special features need to be considered and will be discussed.

[Fibromyalgia syndrome. Definition, classification, clinical diagnosis and prognosis]. / Das Fibromyalgiesyndrom. Definition, Klassifikation, klinische Diagnose und Prognose.

BACKGROUND: The scheduled update to the German S3 guidelines on fibromyalgia syndrome (FMS) by the Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF; registration number 041/004) was planned starting in March 2011. MATERIALS AND METHODS: The development of the guidelines was coordinated by the German Interdisciplinary Association for Pain Therapy ("Deutsche Interdisziplinären Vereinigung für Schmerztherapie", DIVS), 9 scientific medical societies and 2 patient self-help organizations. Eight working groups with a total of 50 members were evenly balanced in terms of gender, medical field, potential conflicts of interest and hierarchical position in the medical and scientific fields. Literature searches were performed using the Medline, PsycInfo, Scopus and Cochrane Library databases (until December 2010). The grading of the strength of the evidence followed the scheme of the Oxford Centre for Evidence-Based Medicine. The formulation and grading of recommendations was accomplished using a multi-step, formal consensus process. The guidelines were reviewed by the boards of the participating scientific medical societies. RESULTS AND CONCLUSION: The clinical diagnosis of FMS can be established by the American College of Rheumatology (ACR) 1990 classification criteria (with tender point examination), by the modified preliminary diagnostic ACR 2010 criteria or by the diagnostic criteria of the German interdisciplinary guideline (AWMF) on FMS. The English full-text version of this article is available at SpringerLink (under "Supplemental").

[Etiology and pathophysiology of fibromyalgia syndrome]. / Ätiologie und Pathophysiologie des Fibromyalgiesyndroms.

BACKGROUND: The scheduled update to the German S3 guidelines on fibromyalgia syndrome (FMS) by the Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF; registration number 041/004) was planned starting in March 2011. MATERIALS AND METHODS: The development of the guidelines was coordinated by the German Interdisciplinary Association for Pain Therapy ("Deutsche Interdisziplinären Vereinigung für Schmerztherapie", DIVS), 9 scientific medical societies and 2 patient self-help organizations. Eight working groups with a total of 50 members were evenly balanced in terms of gender, medical field, potential conflicts of interest and hierarchical position in the medical and scientific fields. Literature searches were performed using the Medline, PsycInfo, Scopus and Cochrane Library databases (until December 2010). The grading of the strength of the evidence followed the scheme of the Oxford Centre for Evidence-Based Medicine. RESULTS: Current data do not identify distinct etiologic or pathophysiological factors mediating development of FMS. The development of FMS is associated with inflammatory rheumatic diseases (EL2b), with gene polymorphisms of the 5-hydroxytryptamine (HT)(2) receptor (EL3a), lifestyle factors (smoking, obesity, lack of physical activity; EL2b), physical and sexual abuse in childhood and adulthood (EL3a). CONCLUSION: FMS is most likely the result of various pathogenetic factors and pathophysiological mechanisms. The English full-text version of this article is available at SpringerLink (under "Supplemental").

[Drug therapy of fibromyalgia syndrome. Systematic review, meta-analysis and guideline]. / Medikamentöse Therapie des Fibromyalgiesyndroms. Systematische Übersicht und Metaanalyse.

BACKGROUND: The scheduled update to the German S3 guidelines on fibromyalgia syndrome (FMS) by the Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF; registration number 041/004) was planned starting in March 2011. MATERIALS AND METHODS: The development of the guidelines was coordinated by the German Interdisciplinary Association for Pain Therapy ("Deutsche Interdisziplinären Vereinigung für Schmerztherapie", DIVS), 9 scientific medical societies and 2 patient self-help organizations. Eight working groups with a total of 50 members were evenly balanced in terms of gender, medical field, potential conflicts of interest and hierarchical position in the medical and scientific fields. Literature searches were performed using the Medline, PsycInfo, Scopus and Cochrane Library databases (until December 2010). The grading of the strength of the evidence followed the scheme of the Oxford Centre for Evidence-Based Medicine. The recommendations were based on level of evidence, efficacy (meta-analysis of the outcomes pain, sleep, fatigue and health-related quality of life), acceptability (total dropout rate), risks (adverse events) and applicability of treatment modalities in the German health care system. The formulation and grading of recommendations was accomplished using a multi-step, formal consensus process. The guidelines were reviewed by the boards of the participating scientific medical societies. RESULTS AND CONCLUSION: Amitriptyline and-in case of comorbid depressive disorder or generalized anxiety disorder-duloxetine are recommended. Off-label use of duloxetine and pregabalin can be considered in case of no comorbid mental disorder. Strong opioids are not recommended. The English full-text version of this article is available at SpringerLink (under "Supplemental").

CD8+ T-cell immunity in chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: Chronic inflammatory demyelinating polyradiculopathy (CIDP) is a common, but often misdiagnosed disease of the peripheral nervous system with assumed autoimmune pathogenesis. While current concepts of CIDP postulate a pathogenetic role of B cells and (auto)antibodies, the relevance of CD8 T cells present in the biopsies is still elusive. Thus, we asked whether nervous tissue infiltrating and blood-derived lymphocytes in CIDP are clonally expanded to evaluate the involvement of T cells in the pathogenesis of the disease. METHODS: We characterized the clonal composition of the T-cell receptor repertoire in sural nerve biopsies (n = 25) and matching peripheral blood (n = 12) of patients with CIDP using PCR-based CDR3 spectratyping and subsequent DNA sequencing. As controls we used inflammatory myopathies (dermatomyositis, inclusion body myositis) and nonpathologic control biopsies. Immunohistochemistry was employed to visualize expanded CD8+ T-cell populations in sural nerve biopsies. RESULTS: In contrast to controls, T cells in CIDP biopsies showed strong monoclonal and oligoclonal restrictions in their T-cell receptor repertoire. Strikingly, clonal expansions found in the biopsies were reflected in the CD8+ T-cell pool of patients' peripheral blood. Clones overlapping between blood and biopsy could be confirmed by CDR3 sequencing. Finally, the predominance of expanded nerve-infiltrating CD8+ T-cell clones was visualized by immunohistochemistry. CONCLUSIONS: Together, these data provide strong evidence for an antigen-driven, major histocompatibility complex class I restricted, CD8+ T-cell-mediated attack against peripheral nerve tissue components contributing to the pathogenesis of CIDP.

[Clinical application of pain-related evoked potentials]. / Klinische Anwendung schmerzevozierter Potenziale.

Pain-related evoked potentials (PREPs) represent a novel method for the evaluation of peripheral and central nociceptive pathways, e.g. in the diagnosis of small fiber neuropathy (SFN) or after therapeutic interventions for headache. Compared to contact heat-evoked and laser-evoked potentials, recording of PREPs is less stressful for the subjects and technically less demanding. The clinical usefulness of PREPs has been described for SFN associated with diabetes, HIV and hepatitis C infections as well as in headache and facial pain disorders. They have also been evaluated after interventional methods, such as direct current stimulation (tDCS). The article reviews and discusses the advantages and pitfalls of this technique in the context of recent clinical studies as compared to other paradigms of peripheral electrical stimulation and delineates perspectives and possible indications.

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 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.

Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy.

BACKGROUND: Small fiber neuropathy (SFN) is a subtype of sensory neuropathy with acral pain and normal findings in routine nerve conduction studies. METHODS: Twenty-four patients with SFN and matched controls were prospectively studied in this case-control study. Patients were assessed clinically, with standardized pain and depression questionnaires, by neurophysiologic tests, and by quantitative sensory testing. All patients underwent skin punch biopsy in a clinically affected (distal calf) and a nonaffected area (proximal thigh). Blood samples were collected for systemic cytokine gene expression analysis. RESULTS: Patients with SFN had a 2-fold higher gene expression for interleukin (IL)-2 (p < 0.0001), IL-10 (p = 0.01), and transforming growth factor-beta1 (p = 0.001) in peripheral blood. Skin samples from affected areas showed increased IL-6 (7-fold; p = 0.001) and IL-8 (5-fold; p = 0.002) gene expression when compared to healthy controls. In 10/24 patients, SFN was termed length-dependent (LD) because of a > or =5-fold higher intraepidermal nerve fiber density in the proximal than in the distal skin. Patients with LD-SFN had higher gene expression in the affected distal skin than in nonaffected skin for tumor necrosis factor-alpha (2.6-fold; p = 0.04), IL-1beta (2-fold; p = 0.02), IL-6 (>200-fold; p = 0.01), and IL-8 (>500-fold; p = 0.046). Inflammatory cells were present in most SFN samples but their numbers were not correlated with cytokine levels. CONCLUSIONS: Elevated local proinflammatory cytokines may be involved in the pathophysiology of pain in length-dependent small fiber neuropathy. These findings suggest a potential therapeutic role of locally applied cytokine inhibitors.