Complex regional pain syndrome: advances in epidemiology, pathophysiology, diagnosis, and treatment.

Complex regional pain syndrome (CRPS) is a rare pain disorder that usually occurs in a limb after trauma. The features of this disorder include severe pain and sensory, autonomic, motor, and trophic abnormalities. Research from the past decade has offered new insights into CRPS epidemiology, pathophysiology, diagnosis, and treatment. Early identification of individuals at high risk of CRPS is improving, with several risk factors established and some others identified in prospective studies during the past 5 years. Better understanding of the pathophysiological mechanisms of CRPS has led to its classification as a chronic primary pain disorder, and subtypes of CRPS have been updated. Procedures for diagnosis have also been clarified. Although effective treatment of CRPS remains a challenge, evidence-based integrated management approaches provide new opportunities to improve patient care. Further advances in diagnosis and treatment of CRPS will require coordinated, international multicentre initiatives.

Cardio-Hepatic Interaction in Cardiac Amyloidosis.

Background: Congestion is associated with poor prognosis in cardiac amyloidosis (CA). The cardio-hepatic interaction and the prognostic impact of secondary liver affection by cardiac congestion in CA are poorly understood and require further characterisation. Methods: Participants of the amyloidosis cohort study AmyKoS at the Interdisciplinary Amyloidosis Centre of Northern Bavaria with proven transthyretin (ATTR-CA) and light chain CA (AL-CA) underwent serial work-up including laboratory tests, echocardiography, and in-depth hepatic assessment by vibration-controlled transient elastography (VCTE) and 13C-methacetin breath test. Results: In total, 74 patients with AL-CA (n = 17), ATTR-CA (n = 26) and the controls (n = 31) were analysed. ATTR-CA patients showed decreased microsomal liver function expressed by maximal percentage of dose rate (PDRpeak) related to hepatic congestion. Reduced PDRpeak in AL-CA could result from altered pharmacokinetics due to changed hepatic blood flow. Liver stiffness as a combined surrogate of chronic liver damage and congestion was identified as a predictor of all-cause mortality. Statistical modelling of the cardio-hepatic interaction revealed septum thickness, NT-proBNP and PDRpeak as predictors of liver stiffness in both CA subtypes; dilatation of liver veins and the fibrosis score FIB-4 were only significant for ATTR-CA. Conclusions: Non-invasive methods allow us to characterise CA-associated hepatic pathophysiology. Liver stiffness might be promising for risk stratification in CA.

[The EAN-NeuPSIG guideline on the diagnosis of neuropathic pain-a summary]. / Die EAN-NeuPSIG-Leitlinie zur Diagnostik bei neuropathischen Schmerzen ­ eine Kurzfassung.

In this joint guideline of the scientific societies and working groups mentioned in the title, evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain were developed. The systematic literature search and meta-analysis yielded the following results: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I­DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, while S­LANSS (self-administered LANSS) and PainDETECT received weak recommendations for their use in the diagnostic workup of patients with possible neuropathic pain. There was a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials. The role of confocal corneal microscopy is still unclear. Functional imaging and peripheral nerve blocks are helpful in elucidating the pathophysiology, but current literature does not support their use in diagnosing neuropathic pain. In selected cases, genetic testing in specialized centers may be considered.

The Effect of Everyday-Life Social Contact on Pain.

Pain is a biopsychosocial phenomenon, resulting from the interplay between physiological and psychological processes and social factors. Given that humans constantly interact with others, the effect of social factors is particularly relevant. Documenting the significance of the social modulation of pain, an increasing number of studies have investigated the effect of social contact on subjective pain intensity and pain-related physiological changes. While evidence suggests that social contact can alleviate pain, contradictory findings indicate an increase in pain intensity and a deterioration of pain coping strategies. This evidence primarily stems from studies examining the effect of social contact on pain within highly controlled laboratory conditions. Moreover, pain assessments often rely on one-time subjective reports of average pain intensity across a predefined period. Ecological momentary assessments (EMAs) can circumvent these problems, as they can capture diverse aspects of behavior and experiences multiple times a day, in real time, with high resolution, and within naturalistic and ecologically valid settings. These multiple measures allow for the examination of fluctuations of pain symptoms throughout the day in relation to affective, cognitive, behavioral, and social factors. In this opinion paper, we review the current state and future relevance of EMA-based social pain research in daily life. Specifically, we examine whether everyday-life social support reduces or enhances pain. The first part of the paper provides a comprehensive overview of the use of EMA in pain research and summarizes the main findings. The review of the relatively limited number of existing EMA studies shows that the association between pain and social contact in everyday life depends on numerous factors, including pain syndromes, temporal dynamics, the nature of social interactions, and characteristics of the interaction partners. In line with laboratory research, there is evidence that everyday-life social contact can alleviate, but also intensify pain, depending on the type of social support. Everyday-life emotional support seems to reduce pain, while extensive solicitous support was found to have opposite effects. Moreover, positive short-term effects of social support can be overshadowed by other symptoms such as fatigue. Overall, gathering and integrating experiences from a patient's social environment can offer valuable insights. These insights can help interpret dynamics in pain intensity and accompanying symptoms such as depression or fatigue. We conclude that factors determining the reducing versus enhancing effects of social contact on pain need to be investigated more thoroughly. We advocate EMA as the assessment method of the future and highlight open questions that should be addressed in future EMA studies on pain and the potential of ecological momentary interventions for pain treatment.

Pain in the Context of Sensory Deafferentation.

Pain that accompanies deafferentation is one of the most mysterious and misunderstood medical conditions. Prevalence rates for the assorted conditions vary considerably but the most reliable estimates are greater than 50% for strokes involving the somatosensory system, brachial plexus avulsions, spinal cord injury, and limb amputation, with controversy surrounding the mechanistic contributions of deafferentation to ensuing neuropathic pain syndromes. Deafferentation pain has also been described for loss of other body parts (e.g., eyes and breasts) and may contribute to between 10% and upwards of 30% of neuropathic symptoms in peripheral neuropathies. There is no pathognomonic test or sign to identify deafferentation pain, and part of the controversy surrounding it stems from the prodigious challenges in differentiating cause and effect. For example, it is unknown whether cortical reorganization causes pain or is a byproduct of pathoanatomical changes accompanying injury, including pain. Similarly, ascertaining whether deafferentation contributes to neuropathic pain, or whether concomitant injury to nerve fibers transmitting pain and touch sensation leads to a deafferentation-like phenotype can be clinically difficult, although a detailed neurologic examination, functional imaging, and psychophysical tests may provide clues. Due in part to the concurrent morbidities, the physical, psychologic, and by extension socioeconomic costs of disorders associated with deafferentation are higher than for other chronic pain conditions. Treatment is symptom-based, with evidence supporting first-line antineuropathic medications such as gabapentinoids and antidepressants. Studies examining noninvasive neuromodulation and virtual reality have yielded mixed results.

Different pain phenotypes are associated with anti-Caspr2 autoantibodies.

Autoantibodies against contactin-associated protein 2 (Caspr2) not only induce limbic autoimmune encephalitis but are also associated with pain conditions. Here, we analyzed clinical data on pain in a large cohort of patients included into the German Network for Research in Autoimmune Encephalitis. Out of 102 patients in our cohort, pain was a frequent symptom (36% of all patients), often severe (63.6% of the patients with pain) and/or even the major symptom (55.6% of the patients with pain). Pain phenotypes differed between patients. Cluster analysis revealed two major phenotypes including mostly distal-symmetric burning pain and widespread pain with myalgia and cramps. Almost all patients had IgG4 autoantibodies and some additional IgG1, 2, and/or 3 autoantibodies, but IgG subclasses, titers, and presence or absence of intrathecal synthesis were not associated with the occurrence of pain. However, certain pre-existing risk factors for chronic pain like diabetes mellitus, peripheral neuropathy, or preexisting chronic back pain tended to occur more frequently in patients with anti-Caspr2 autoantibodies and pain. Our data show that pain is a relevant symptom in patients with anti-Caspr2 autoantibodies and support the idea of decreased algesic thresholds leading to pain. Testing for anti-Caspr2 autoantibodies needs to be considered in patients with various pain phenotypes.

Bilateral deficiency of Meissner corpuscles and papillary microvessels in patients with acute complex regional pain syndrome.

ABSTRACT: Complex regional pain syndrome (CRPS) presents postinjury with disproportionate pain and neuropathic, autonomic, motor symptoms, and skin texture affection. However, the origin of these multiplex changes is unclear. Skin biopsies offer a window to analyze the somatosensory and vascular system as well as skin trophicity with their protecting barriers. In previous studies, barrier-protective exosomal microRNAs were altered in CRPS. We here postulated that tissue architecture and barrier proteins are already altered at the beginning of CRPS. We analyzed ipsilateral and contralateral skin biopsies of 20 fully phenotyped early CRPS patients compared with 20 age- and sex-matched healthy controls. We established several automated unbiased methods to comprehensively analyze microvessels and somatosensory receptors as well as barrier proteins, including claudin-1, claudin-5, and claudin-19. Meissner corpuscles in the skin were bilaterally reduced in acute CRPS patients with some of them lacking these completely. The number of Merkel cells and the intraepidermal nerve fiber density were not different between the groups. Dermal papillary microvessels were bilaterally less abundant in CRPS, especially in patients with allodynia. Barrier proteins in keratinocytes, perineurium of dermal nerves, Schwann cells, and papillary microvessels were not affected in early CRPS. Bilateral changes in the tissue architecture in early CRPS might indicate a predisposition for CRPS that manifests after injury. Further studies should evaluate whether these changes might be used to identify risk patients for CRPS after trauma and as biomarkers for outcome.

Studying serum neurofilament light chain levels as a potential new biomarker for small fiber neuropathy.

BACKGROUND AND PURPOSE: Diagnosing small fiber neuropathies can be challenging. To address this issue, whether serum neurofilament light chain (sNfL) could serve as a potential biomarker of damage to epidermal Aδ- and C-fibers was tested. METHODS: Serum NfL levels were assessed in 30 patients diagnosed with small fiber neuropathy and were compared to a control group of 19 healthy individuals. Electrophysiological studies, quantitative sensory testing and quantification of intraepidermal nerve fiber density after skin biopsy were performed in both the proximal and distal leg. RESULTS: Serum NfL levels were not increased in patients with small fiber neuropathy compared to healthy controls (9.1 ± 3.9 and 9.4 ± 3.8, p = 0.83) and did not correlate with intraepidermal nerve fiber density at the lateral calf or lateral thigh or with other parameters of small fiber impairment. CONCLUSION: Serum NfL levels cannot serve as a biomarker for small fiber damage.

Glycine Receptor ß-Targeting Autoantibodies Contribute to the Pathology of Autoimmune Diseases.

BACKGROUND AND OBJECTIVES: Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα subunit-binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyRß subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRß making it not unlikely that GlyRß-specific autoantibody (aAb) exist and contribute to the disease pathology. METHODS: In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRß. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRß binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyRß aAb binding were resolved by whole-cell patch-clamp recordings. RESULTS: Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRß aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRß colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRß aAb from both patients to its target impair glycine efficacy. DISCUSSION: Our study establishes GlyRß as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRß impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRß aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.

Transient immune activation without loss of intraepidermal innervation and associated Schwann cells in patients with complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) develops after injury and is characterized by disproportionate pain, oedema, and functional loss. CRPS has clinical signs of neuropathy as well as neurogenic inflammation. Here, we asked whether skin biopsies could be used to differentiate the contribution of these two systems to ultimately guide therapy. To this end, the cutaneous sensory system including nerve fibres and the recently described nociceptive Schwann cells as well as the cutaneous immune system were analysed. METHODS: We systematically deep-phenotyped CRPS patients and immunolabelled glabrous skin biopsies from the affected ipsilateral and non-affected contralateral finger of 19 acute (< 12 months) and 6 chronic (> 12 months after trauma) CRPS patients as well as 25 sex- and age-matched healthy controls (HC). Murine foot pads harvested one week after sham or chronic constriction injury were immunolabelled to assess intraepidermal Schwann cells. RESULTS: Intraepidermal Schwann cells were detected in human skin of the finger-but their density was much lower compared to mice. Acute and chronic CRPS patients suffered from moderate to severe CRPS symptoms and corresponding pain. Most patients had CRPS type I in the warm category. Their cutaneous neuroglial complex was completely unaffected despite sensory plus signs, e.g. allodynia and hyperalgesia. Cutaneous innate sentinel immune cells, e.g. mast cells and Langerhans cells, infiltrated or proliferated ipsilaterally independently of each other-but only in acute CRPS. No additional adaptive immune cells, e.g. T cells and plasma cells, infiltrated the skin. CONCLUSIONS: Diagnostic skin punch biopsies could be used to diagnose individual pathophysiology in a very heterogenous disease like acute CRPS to guide tailored treatment in the future. Since numbers of inflammatory cells and pain did not necessarily correlate, more in-depth analysis of individual patients is necessary.

Early Neuroaxonal Damage in Neurologic Disorders Associated With GAD65 Antibodies.

OBJECTIVES: Neurodegeneration is considered a relevant pathophysiologic feature in neurologic disorders associated with antibodies against glutamic acid decarboxylase 65 (GAD65). In this study, we investigate surrogates of neuroaxonal damage in relation to disease duration and clinical presentation. METHODS: In a multicentric cohort of 50 patients, we measured serum neurofilament light chain (sNfL) in relation to disease duration and disease phenotypes, applied automated MRI volumetry, and analyzed clinical characteristics. RESULTS: In patients with neurologic disorders associated with GAD65 antibodies, we detected elevated sNfL levels early in the disease course. By contrast, this elevation of sNfL levels was less pronounced in patients with long-standing disease. Increased sNfL levels were observed in patients presenting with cerebellar ataxia and limbic encephalitis, but not in those with stiff person syndrome. Using MRI volumetry, we identified atrophy predominantly of the cerebellar cortex, cerebellar superior posterior lobe, and cerebral cortex with similar atrophy patterns throughout all clinical phenotypes. DISCUSSION: Together, our data provide evidence for early neuroaxonal damage and support the need for timely therapeutic interventions in GAD65 antibody-associated neurologic disorders.

Future perspectives: the next fifty years of the International Association for the Study of Pain.

ABSTRACT: The International Association for the Study of Pain (IASP) has become the leading professional association dedicated to promoting pain research and management. Through its many activities, including research funding, educational programs, advocacy initiatives, and global collaborations, the Association has significantly contributed to the understanding and treatment of pain. Looking into the future, the IASP is determined to continue its mission of reducing the burden of pain on individuals and societies worldwide. Here, we explore how current and past activities of the IASP will shape the future of pain research, treatment, education, and advocacy as well as provide a valuable service to its members across the world.

Myelin barrier breakdown, mechanical hypersensitivity, and painfulness in polyneuropathy with claudin-12 deficiency.

BACKGROUND: The blood-nerve and myelin barrier shield peripheral neurons and their axons. These barriers are sealed by tight junction proteins, which control the passage of potentially noxious molecules including proinflammatory cytokines via paracellular pathways. Peripheral nerve barrier breakdown occurs in various neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and traumatic neuropathy. Here, we studied the functional role of the tight junction protein claudin-12 in regulating peripheral nerve barrier integrity and CIDP pathogenesis. METHODS: Sections from sural nerve biopsies from 23 patients with CIDP and non-inflammatory idiopathic polyneuropathy (PNP) were analyzed for claudin-12 and -19 immunoreactivity. Cldn12-KO mice were generated and subjected to the chronic constriction injury (CCI) model of neuropathy. These mice were then characterized using a battery of barrier and behavioral tests, histology, immunohistochemistry, and mRNA/protein expression. In phenotype rescue experiments, the proinflammatory cytokine TNFα was neutralized with the anti-TNFα antibody etanercept; the peripheral nerve barrier was stabilized with the sonic hedgehog agonist smoothened (SAG). RESULTS: Compared to those without pain, patients with painful neuropathy exhibited reduced claudin-12 expression independently of fiber loss. Accordingly, global Cldn12-KO in male mice, but not fertile female mice, selectively caused mechanical allodynia associated with a leaky myelin barrier, increased TNFα, decreased sonic hedgehog (SHH), and loss of small axons accompanied by reduced peripheral myelin protein 22 (Pmp22). Other barriers and neurological functions remained intact. The Cldn12-KO phenotype could be rescued either by neutralizing TNFα with etanercept or stabilizing the barrier with SAG, which both also upregulated the Schwann cell barrier proteins Cldn19 and Pmp22. CONCLUSION: These results point to a critical role for claudin-12 in maintaining the myelin barrier presumably via Pmp22 and highlight restoration of the hedgehog pathway as a potential treatment strategy for painful inflammatory neuropathy.