Exploring neuropathic symptoms in a large cohort of Italian patients with different peripheral nervous system diseases

Neuropathic pain is a disabling symptom frequently reported by patients with neuropathies. Pain-questionnaires are the best way to investigate it. Neuropathic Pain Symptom Inventory (NPSI) questionnaire specifically assesses the different symptoms of neuropathic pain. The objective of this study was to evaluate, through the NPSI, the different neuropathic painful symptoms in a population of neuropathic patients. 277 patients with different neuropathies were evaluated with the NPSI to investigate the prevalence of the different neuropathic symptoms. Neuropathic pain was reported by 94.4% of the patients, resulting to be common not only in diabetic and iatrogenic neuropathies, but also in hereditary, paraproteinemic, and idiopathic neuropathies. The majority of our patients (88.6%) presented paresthesia/dysesthesia. The results of our study point out the difference in the occurrence of the painful symptoms. A scale able to discriminate distinct types of neuropathic pain may provide clinicians with adequate therapeutic choices in the daily practice.     

Traumatic peripheral nerve injuries: epidemiological findings,neuropathic pain and quality of life in 158 patients

The objectives of this study were (1) epidemiological analysis of traumatic peripheral nerve injuries; (2) assessment of neuropathic pain and quality of life in patients affected by traumatic neuropathies. All consecutive patients with a diagnosis of traumatic neuropathies from four Italian centres were enrolled. Electromyography confirmed clinical level and site diagnosis of peripheral nerve injury. All patients were evaluated by disability scales, pain screening tools, and quality of life tests. 158 consecutive patients for a total of 211 traumatic neuropathies were analysed. The brachial plexus was a frequent site of traumatic injury (36%) and the radial, ulnar, and peroneal were the most commonly involved nerves with 15% of iatrogenic injuries. Seventy‐two percent of the traumatic neuropathies were painful. Pain was present in 66% and neuropathic pain in 50% of all patients. Patients had worse quality of life scores than did the healthy Italian population. Moreover, there was a strong correlation between the quality of life and the severity of the pain, particularly neuropathic pain (Short Form‐36 [SF‐36] p < 0.005; Beck Depression Inventory [BDI] p < 0.0001). Traumatic neuropathies were more frequent in young males after road accidents, mainly in the upper limbs. Severe neuropathic pain and not only disability contributed to worsening the quality of life in patients with traumatic neuropathies.     

Myelin protein zero Arg36Gly mutation with very late onset and rapidly progressive painful neuropathy

Mutations in myelin protein zero (MPZ) protein result in a wide spectrum of peripheral neuropathies, from congenital hypomyelinating to late onset sensory and motor axonal forms. In some patients, neuropathic pain can be a prominent symptom, making the diagnosis challenging mainly in those with other risk factors for neuropathy. We describe a 77‐year‐old woman with impaired glucose tolerance presenting with rapidly progressive axonal neuropathy leading to excruciating pain and severe weakness of lower limbs within 2 years from the onset. Her son abruptly complained of similar painful symptoms at the age of 47 years. Molecular analysis revealed a novel heterozygous missense mutation (c.106A>G) in MPZ exon 2, causing the substitution of arginine‐36 with glycine in the extracellular domain. Our observation suggests that MPZ‐related neuropathy should be considered in the diagnostic work up of patients with painful axonal neuropathy even presenting with rapid progression and at a very late age of onset.     

Painful neuropathies: the emerging role of sodium channelopathies

Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (Aδ and C) fibers. Voltage‐gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where Na_V1.7, Na_V1.8, and Na_V1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain‐of‐function SCN9A mutations. Recent studies have expanded this spectrum with gain‐of‐function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia). In addition, painful neuropathies have been recently linked to SCN10A mutations. Patch‐clamp studies have shown that the effect of SCN9A mutations is dependent upon the cell‐type background. The functional effects of a mutation in dorsal root ganglion (DRG) neurons and sympathetic neuron cells may differ per mutation, reflecting the pattern of expression of autonomic symptoms in patients with painful neuropathies who carry the mutation in question. Peripheral neuropathies may not always be length‐dependent, as demonstrated in patients with initial facial and scalp pain symptoms with SCN9A mutations showing hyperexcitability in both trigeminal ganglion and DRG neurons. There is some evidence suggesting that gain‐of‐function SCN9A mutations can lead to degeneration of peripheral axons. This review will focus on the emerging role of sodium channelopathies in painful peripheral neuropathies, which could serve as a basis for novel therapeutic strategies.     

TNF-alpha expression in painful and nonpainful neuropathies

OBJECTIVE: To determine whether the cytokine tumor necrosis factor alpha (TNF-alpha) acts as a pain mediator in neuropathic pain in humans. BACKGROUND: In animal models, inflammatory cytokines such as TNF-alpha have been shown to facilitate neuropathic pain. METHODS: The expression of TNF-alpha was analyzed immunohistochemically in 20 human nerve biopsy specimens of patients with painful (n = 10) and nonpainful (n = 10) neuropathies. Additionally, serum soluble TNF-alpha receptor I (sTNF-RI) levels were determined in 24 patients with neuropathies, 16 of which were painful and 8 that were painless. RESULTS: Colocalization studies by confocal fluorescence microscopy for S-100 and TNF-alpha showed expression of TNF-alpha in human Schwann cells. Patients with painful neuropathies showed a stronger TNF-alpha immunoreactivity in myelinating Schwann cells relative to the epineurial background staining compared with patients with nonpainful neuropathy (0.949 +/- 0.047 vs 1.010 +/- 0.053, p < 0.05). Although there was no difference in sTNF-RI levels between painful (n = 16) and nonpainful (n = 8) neuropathies (sTNF-RI: 1412 +/- 545 pg/mL vs 1,318 +/- 175 pg/mL), patients with a mechanical allodynia (n = 9) had elevated serum sTNF-RI (1627 +/- 645 pg/mL vs 1233 +/- 192 pg/mL, p < 0.05) compared with patients without allodynia (n = 15). CONCLUSIONS: TNF-alpha expression of human Schwann cells may be up-regulated in painful neuropathies. The elevation of sTNF-RI in patients with centrally mediated mechanical allodynia suggests that systemic sTNF-RI levels may influence central pain processing mechanisms.     

Neuropathic pain in post-burn hypertrophic scars: a psychophysical and neurophysiological study

Introduction: Pain complicates hypertrophic post‐burn pathologic scars (PPS) Methods: To investigate the possible neuropathic origin of pain, 13 patients with painful PPS involving at least 1 hand underwent clinical examination, including the Douleur Neuropathique en 4 questions (DN4) questionnaire; median, ulnar, and radial nerve conduction studies (NCS); cold‐ (CDT) and heat‐induced pain threshold evaluation by quantitative sensory testing; and cutaneous silent period (CSP) testing of the abductor pollicis brevis. Controls included 9 patients with non‐painful PPS, 52 healthy subjects, and 28 patients with carpal tunnel syndrome (CTS). Results: All patients with painful PPS had possible neuropathic pain (DN4 score ≥4). NCS signs of CTS were similarly present in PPS subjects with or without pain. Hands with painful PPS had lower CDT and CSP duration, more frequent cold‐ and heat‐pain hypesthesia, and more thermal allodynia than controls. Conclusions: In PPS, possible neuropathic pain is associated with psychophysical and neurophysiological abnormalities suggestive of small‐fiber damage. Muscle Nerve 45: 883–890, 2012     

Diagnosis and management of neuropathic pain: Review of literature and recommendations of the Polish Association for the Study of Pain and the Polish Neurological Society – Part Two

Neuropathic pain may be caused by a variety of lesions or diseases of both the peripheral and central nervous system. The most common and best known syndromes of peripheral neuropathic pain are painful diabetic neuropathy, trigeminal and post-herpetic neuralgia, persistent post-operative and post-traumatic pain, complex regional pain syndrome, cancer-related neuropathic pain, HIV-related neuropathic pain and pain after amputation. The less common central pain comprises primarily central post-stroke pain, pain after spinal cord injury, central pain in Parkinson disease or in other neurodegenerative diseases, pain in syringomyelia and in multiple sclerosis.A multidisciplinary team of Polish experts, commissioned by the Polish Association for the Study of Pain and the Polish Neurological Society, has reviewed the literature on various types of neuropathic pain, with special focus on the available international guidelines, and has formulated recommendations on their diagnosis and treatment, in accordance with the principles of evidence-based medicine (EBM). High quality studies on the efficacy of various medicines and medical procedures in many neuropathic pain syndromes are scarce, which makes the recommendations less robust.     

Painful peripheral neuropathy and its nonsurgical treatment

Treatment of neuropathic pain is the primary focus of management for many patients with painful peripheral neuropathy. Antidepressants and anticonvulsants are the two pharmacological classes most widely studied and represent first-line agents in the management of neuropathic pain. The number of pharmacological agents that have demonstrated effectiveness for neuropathic pain continues to expand. In the current review, we summarize data from randomized, controlled pharmacological trials in painful peripheral neuropathies. Although neuropathic pain management remains challenging because the response to therapy varies considerably between patients, and pain relief is rarely complete, a majority of patients can benefit from monotherapy using a well-chosen agent or polypharmacy that combines medications with different mechanisms of action.     

Pain in Parkinson's disease: facts and uncertainties

Pain is one of the most common and troublesome non‐motor symptoms of Parkinson's disease (PD). It can appear at any time during the disease and is often present before diagnosis. However, there is little or no consensus on its definition. An expert group of clinicians with relevant research experience met to review the existing evidence and to identify gaps in our understanding leading towards AUTHOR: ’understanding towards’ has been changed to ’understanding leading towards‘. Please check and confirm that this is appropriate an optimized therapy of pain in PD. Key findings from epidemiologic, neurophysiologic, neuroimaging and clinical studies are reviewed. In each case, the evidence base is limited by wide variations in the definitions of pain applied, study methodologies and populations evaluated. Disease‐related and medical conditions trigger spontaneous pain in patients with PD, which is then abnormally processed and results in painful manifestations in specific body parts. Dopaminergic medications, such as rotigotine, as well as opiate analgesics, such as oxycodone, have shown positive results but future studies with more detailed pain characterization at inclusion are warranted.     

Pain in Parkinson's disease

Pain and other nonmotor symptoms in PD are increasingly recognized as a major cause of reduced health-related quality of life. Pain in PD may be categorized into a number of different subtypes, including musculoskeletal, dystonic, radicular neuropathic, and central pain. The onset of pain can vary in relation to motor symptoms, and may precede the appearance of motor symptoms by several years, or occur after the diagnosis of PD has been made. Pain in PD is frequently under-recognized and is often inadequately treated. Levodopa-related dystonia may respond to manipulation of dopaminergic medication. Dopaminergic therapy may also improve musculoskeletal pain related to rigidity and akinesia, as well as akathisia in PD. Botulinum toxin injections can be effective for treatment of painful focal dystonia. Pain and dysesthesia have been reported to improve with DBS, in some cases. Increased understanding of basal ganglia pathways has provided further insights into the pathogenesis of pain in PD, but the exact mechanism of pain processing and modulation remains unclear.     

Painful neuropathies

PURPOSE OF REVIEW: To summarize the current understanding of clinical assessment, pathophysiology, and treatment of pain in neuropathies, focusing on selected entities in which the understanding of the mechanisms underlying pain has advanced recently. RECENT FINDINGS: Ongoing studies are classifying the symptoms and signs of painful neuropathies, assuming that this approach may indicate particular pathomechanisms leading to more rational treatment. Nerve injury induces a large number of cellular changes, the relevance of which for the occurrence of pain is still under investigation. In models of diabetic neuropathy, an altered distribution of sodium channels, hyperexcitability of neurons, and changes in spinal connectivity seem to underlie the development of pain. The role of inflammatory mediators has been explored in inflammatory and degenerative neuropathies. Second messenger pathways contributing to hyperalgesia in various neuropathies have been identified, opening up new treatment options. A number of newer and older drugs have been studied for their use in painful neuropathies in clinical trials. Epidemiology has shown that, despite the availability of drugs with moderate efficacy in the treatment of neuropathic pain, a large percentage of patients do not gain access to them. SUMMARY: Advances in the standardization of assessment of patients with painful neuropathies are beginning to have an impact on how clinical studies are designed. Major progress has been made in the understanding of cellular and molecular changes after nerve injury, but their relevance for the pathophysiology of pain in neuropathies has still to be determined.     

Electrically evoked nociceptive potentials for early detection of diabetic small‐fiber neuropathy

Background and purpose: This study investigated the utility of pain‐related evoked potentials (PREP’s) elicited by a nociceptive electrical stimulation of the skin (= electrically evoked nociceptive potentials) in early detection of diabetic small‐fiber neuropathy. Methods: We studied 36 ‘young’ (19–35 years) and 24 ‘older’ (36–65 years) healthy subjects as well as 35 patients (35–64 years) with diabetes and neuropathic symptoms and 22 patients (34–64 years) with diabetes without neuropathic symptoms. Only patients with normal standard nerve conduction testing were included. Results: In patients with neuropathic symptoms, we found a significant increase in PREP latencies and decrease of amplitudes elicited from both, upper and lower limbs. In non‐symptomatic diabetic patients, we observed PREP abnormalities from lower limbs only. Conclusions: These data suggest that the method of pain‐related evoked potentials elicited by a nociceptive electrical stimulation of the skin may contribute to the early detection of diabetic sensory neuropathy.     

Skin biopsy and quantitative sensory testing do not predict response to lidocaine patch in painful neuropathies

Predictors of response to neuropathic pain treatment in patients with painful distal sensory neuropathies are lacking. The 5% lidocaine patch is believed to exert its effects on neuropathic pain via a local stabilizing effect on cutaneous sensory afferents. As such, it provides a model to assess whether the status of epidermal innervation as determined by skin biopsy or quantitative sensory testing (QST) of small- and large-diameter sensory afferents might serve as predictors of response to topical, locally active treatment. In this study we assessed associations between epidermal nerve fiber (ENF) densities, sensory nerve conduction studies (NCS), QST, and response to a 5% lidocaine patch in patients with painful distal sensory neuropathies. We observed no association between distal leg epidermal and subepidermal innervation and response to the lidocaine patch. Several patients with complete loss of distal leg ENF showed a response to the lidocaine patch. Similarly we observed no consistent association between treatment response and QST for vibration, cooling, warm, heat-pain, and cold-pain thresholds, or distal sensory NCS. Thus, distal-leg skin biopsy, QST, and sensory NCS cannot be used to identify patients with painful polyneuropathy likely to respond to a lidocaine patch in clinical practice. Further studies are required to clarify precisely the mechanism and site of action of the lidocaine patch in patients with peripheral neuropathic pain.     

Identifying and treating pain caused by MS

Multiple sclerosis (MS) is a chronic disease that causes disability due to inflammation and demyelination in the central nervous system. Pain is a common symptom in patients with MS but is often inadequately treated, leading to decreased functioning and a low quality of life. Pain associated with MS includes central neuropathic pain due to lesions of the somatosensory system, and nociceptive pain due to spasticity, muscle tightness or contracture, abnormal gait and postures caused by MS, or treatment-related pain. Patient education, physical therapy, and pharmacotherapy can all be helpful in treating the painful symptoms of MS. Tricyclic antidepressants, anticonvulsants, and opioids are first-line options for central neuropathic pain, and spasmolytics, muscle relaxants, benzodiazepines, and anticonvulsants are helpful for nociceptive pain. Pain should be regularly assessed and appropriately treated to improve functioning and quality of life for patients with MS.     

EFNS guidelines on neuropathic pain assessment: revised 2009

Background and purpose: We have revised the previous EFNS guidelines on neuropathic pain (NP) assessment, which aimed to provide recommendations for the diagnostic process, screening tools and questionnaires, quantitative sensory testing (QST), microneurography, pain‐related reflexes and evoked potentials, functional neuroimaging and skin biopsy. Methods: We have checked and rated the literature published in the period 2004–2009, according to the EFNS method of classification for diagnostic procedures. Results: Most of the previous recommendations were reinforced by the new studies. The main revisions relate to: (i) the new definition of NP and a diagnostic grading system; (ii) several new validated clinical screening tools that identify NP components, and questionnaires which assess the different types of NP; (iii) recent high‐quality studies on laser‐evoked potentials (LEPs) and skin biopsy. Conclusions: History and bedside examination are still fundamental to a correct diagnosis, whilst screening tools and questionnaires are useful in indicating probable NP; QST is also useful for indicating the latter, and to assess provoked pains and treatment response. Amongst laboratory tests, LEPs are the best tool for assessing Aδ pathway dysfunction, and skin biopsy for assessing neuropathies with distal loss of unmyelinated nerve fibres.     

Botulinum toxin and painful peripheral neuropathies: what should be expected?

Botulinum toxin type A (BTX-A) is a potent neurotoxin that blocks acetylcholine release from presynaptic nerve terminals by cleaving the SNARE complex. BTX-A has been reported to have analgesic effects independent of its action on muscle tone. The most robust results have been observed in patients with neuropathic pain. Neuropathic pain due to peripheral lesions has been the most widely studied. BTX-A has shown its efficacy on pain and allodynia in various animal models of inflammatory neuropathic pain. The only randomized, double-blind, placebo-controlled trial in patients with focal painful neuropathies due to nerve trauma or postherpetic neuralgia demonstrated significant effects on average pain intensity from 2 weeks after the injections to 14 weeks. Most patients reported pain during the injections, but there were no further local or systemic side effects. The efficacy of BTX-A in painful peripheral neuropathies has been more recently studied. Results were positive in the only study in an animal model of peripheral neuropathy. One study in patients with diabetic painful peripheral neuropathy demonstrated a significant decrease in Visual Analog Scale. In conclusion, one session of multiple intradermal injection of BTX-A produces long-lasting analgesic effects in patients with focal painful neuropathies and diabetic neuropathic pain, and is particularly well tolerated. The findings are consistent with a reduction of peripheral sensitisation, the place of a possible central effect remaining to define. Further studies are needed to assess some important issues, i.e. BTX-A efficacy in patients with small fiber neuropathies and the relevance of early and repeated injections. Future studies could also provide valuable insights into pathophysiology of neuropathic pain.     

Sensory correlates of pain in peripheral neuropathies

ObjectiveTo characterize sensory threshold alterations in peripheral neuropathies and the relationship between these alterations and the presence of pain.MethodsSeventy-four patients with length-dependent sensory axonal neuropathy were enrolled, including 38 patients with painful neuropathy (complaining of chronic, spontaneous neuropathic pain in the feet) and 36 patients with painless neuropathy. They were compared to 28 age-matched normal controls. A standardized quantitative sensory testing protocol was performed in all individuals to assess large and small fiber function at the foot. Large fibers were assessed by measuring mechanical (pressure and vibration) detection thresholds and small fibers by measuring pain and thermal detection thresholds.ResultsBetween patients with neuropathy and controls, significant differences were found for mechanical and thermal detection thresholds but not for pain thresholds. Patients with painful neuropathy and those with painless neuropathy did not differ regarding mechanical or thermal thresholds, but only by a higher incidence of thermal or dynamic mechanical allodynia in case of painful neuropathy. Pain intensity correlated with the alteration of thermal detection and mechanical pain thresholds.ConclusionsQuantitative sensory testing can support the diagnosis of sensory neuropathy when considering detection threshold measurement. Thermal threshold deterioration was not associated with the occurrence of pain but with its intensity.SignificanceThere is a complex relationship between the loss or functional deficit of large and especially small sensory nerve fibers and the development of pain in peripheral neuropathy.     

Immune and inflammatory mechanisms in neuropathic pain

Tissue damage, inflammation or injury of the nervous system may result in chronic neuropathic pain characterised by increased sensitivity to painful stimuli (hyperalgesia), the perception of innocuous stimuli as painful (allodynia) and spontaneous pain. Neuropathic pain has been described in about 1% of the US population, is often severely debilitating and largely resistant to treatment. Animal models of peripheral neuropathic pain are now available in which the mechanisms underlying hyperalgesia and allodynia due to nerve injury or nerve inflammation can be analysed. Recently, it has become clear that inflammatory and immune mechanisms both in the periphery and the central nervous system play an important role in neuropathic pain. Infiltration of inflammatory cells, as well as activation of resident immune cells in response to nervous system damage, leads to subsequent production and secretion of various inflammatory mediators. These mediators promote neuroimmune activation and can sensitise primary afferent neurones and contribute to pain hypersensitivity. Inflammatory cells such as mast cells, neutrophils, macrophages and T lymphocytes have all been implicated, as have immune-like glial cells such as microglia and astrocytes. In addition, the immune response plays an important role in demyelinating neuropathies such as multiple sclerosis (MS), in which pain is a common symptom, and an animal model of MS-related pain has recently been demonstrated. Here, we will briefly review some of the milestones in research that have led to an increased awareness of the contribution of immune and inflammatory systems to neuropathic pain and then review in more detail the role of immune cells and inflammatory mediators.     

Symptomatology and pathogenesis of different types of pain in multiple sclerosis

Multiple sclerosis (MS) is a progressive disease of the central nervous system. It is characterized by disseminated foci of demyelination, which are responsible for the diverse clinical picture of MS. Pain is a frequent but underestimated symptom of multiple sclerosis. It is estimated to affect 29–86% of MS patients in various stages of the disease and severely influences rehabilitation and quality of life. The pain experienced by MS patients is generally caused by nervous system damage during the course of the disease process and can usually be characterized as central neuropathic pain (less frequently as peripheral or nociceptive pain). The most frequent symptoms include dysesthetic extremity pain, painful tonic spasms, Lhermitte's sign, trigeminal neuralgia, headaches and low back pain. This paper discusses the probable mechanisms behind the development of pain in MS, the prevalence, classification, types of pain, as well as the most effective treatment methods.