We performed responsiveness comparison between the patient-reported Inflammatory Rasch-built Overall Disability Scale (I-RODS) and the widely used clinician-reported Inflammatory Neuropathy Cause and Treatment-Overall Neuropathy Limitation Scale (INCAT-ONLS) in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and immunoglobulin M-monoclonal gammopathy of undetermined significance related polyneuropathy (IgM-MGUSP).
Human studies have firmly implicated voltage-gated sodium channels in human pain disorders, and targeted and massively parallel genomic sequencing is beginning to be used in clinical practice to determine which sodium channel variants are involved. Missense substitutions of SCN9A, the gene encoding sodium channel NaV1.7, SCN10A, the gene encoding sodium channel NaV1.8, and SCN11A, the gene encoding sodium channel NaV1.9, produce gain-of-function changes that contribute to pain in many human painful disorders. Genomic sequencing might help to establish a diagnosis, and in the future might support individualisation of therapeutic approaches. However, in many cases, and especially in sodium channelopathies, the results from genomic sequencing can only be appropriately interpreted in the context of an extensive functional assessment, or family segregation analysis of phenotype and genotype.
Peripheral neuropathy is a frequently occurring side-effect of chemotherapy as a cancer treatment. The incidence of chemotherapy-induced peripheral neuropathy (CIPN) is increasing as a consequence of better treatment of cancer becoming available and increasing use of chemotherapy, and because CIPN occurs more frequently with use of new chemotherapeutics. The diagnosis 'CIPN' is made principally on clinical grounds, and it is characterized by predominantly sensory symptoms. The National Cancer Institute Common Toxicity Criteria (NCI-CTC) are commonly used to grade CIPN, but the reliability of these criteria is debated. If CIPN occurs, the only effective strategies are dose reduction or discontinuation of chemotherapy. CIPN impairs quality of life. It is important to evaluate the symptoms of CIPN, as well as the impact on daily living.
Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (A? and C) fibers. Voltage-gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where NaV 1.7, NaV 1.8, and NaV 1.9 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.
Painful diabetic peripheral neuropathy (PDPN) is a common complication of diabetes mellitus. Unfortunately, pharmacological treatment is often partially effective or accompanied by unacceptable side effects, and new treatments are urgently needed. Small observational studies suggested that spinal cord stimulation (SCS) may have positive effects.
Painful neuropathies are frequently encountered in clinical practice as an early or late complication of several systemic disorders. Among them, diabetes is one of the most important due to its epidemiology and the relevance for regulatory agencies in the assessment of efficacy of new analgesics. However, the presentation and course of painful neuropathies, as well as the response to available drugs, are highly variable and unpredictable, posing significant challenges in the management of patients. Experimental and clinical studies have suggested that polymorphisms and mutations in pain-related genes are involved in the facilitation or inhibition of nociception, and might modulate neuropathic pain and the response to analgesics in patients. Voltage-gated sodium channel genes are among the most relevant, due to the key role of these membrane proteins in the physiology of nociception and their involvement in the pathogenesis of idiopathic painful small fiber neuropathies. These compelling features make sodium channel candidate targets for a novel approach to painful diabetic and idiopathic neuropathies, which will hopefully allow a new classification of patients and more effective targeted treatments.
Diabetes mellitus, a major global health problem, is commonly associated with painful peripheral neuropathy, which can substantially erode quality of life. Despite its clinical importance, the pathophysiology of painful diabetic neuropathy is incompletely understood. It has traditionally been thought that diabetes may cause neuropathy in patients with appropriate genetic makeup. Here, we propose a hypothesis whereby painful neuropathy is not a complication of diabetes, but rather occurs as a result of mutations that, in parallel, confer vulnerability to injury in pancreatic ? cells and pain-signaling dorsal root ganglion (DRG) neurons. We suggest that mutations of sodium channel NaV1.7, which is present in both cell types, may increase susceptibility for development of diabetes via ? cell injury and produce painful neuropathy via a distinct effect on DRG neurons.
Sodium channel Nav1.9 is expressed in peripheral nociceptive neurons, as well as visceral afferents, and has been shown to act as a threshold channel. Painful peripheral neuropathy represents a significant public health challenge and may involve gain-of-function variants in sodium channels that are preferentially expressed in peripheral sensory neurons. Although gain-of-function variants of peripheral sodium channels Nav1.7 and Nav1.8 have recently been found in painful small fibre neuropathy, the aetiology of peripheral neuropathy in many cases remains unknown. We evaluated 459 patients who were referred for possible painful peripheral neuropathy, and confirmed the diagnosis of small fibre neuropathy in a cohort of 393 patients (369 patients with pure small fibre neuropathy, and small fibre neuropathy together with large fibre involvement in an additional 24 patients). From this cohort of 393 patients with peripheral neuropathy, we sequenced SCN11A in 345 patients without mutations in SCN9A and SCN10A, and found eight variants in 12 patients. Functional profiling by electrophysiological recordings showed that these Nav1.9 mutations confer gain-of-function attributes to the channel, depolarize resting membrane potential of dorsal root ganglion neurons, enhance spontaneous firing, and increase evoked firing of these neurons. Our data show, for the first time, missense mutations of Nav1.9 in individuals with painful peripheral neuropathy. These genetic and functional observations identify missense mutations of Nav1.9 as a cause of painful peripheral neuropathy.
This study describes the swallowing function of patients with myotonic dystrophy type 1 (DM1) and the effect of bolus consistency on swallowing in this group. The aim of the study is twofold: (a) to identify which (and to what extent) swallowing variables change for DM1 patients relative to healthy control subjects and (b) to examine whether the degree of oropharyngeal dysphagia is associated with disease severity. Forty-five consecutive DM1 patients and ten healthy subjects underwent a swallowing assessment, at Maastricht University medical Center in the Netherlands. The assessment included a standardized fiberoptic endoscopic evaluation of swallowing (FEES) protocol using different bolus consistencies. Clinical severity of the disease was assessed using the muscular impairment rating scale (MIRS). Significant differences were found between patients and controls for all FEES variables. The magnitude of these differences depended on the bolus consistency. The odds of a more pathological swallowing outcome increased significantly with higher MIRS levels. In conclusion, swallowing function is found to be significantly altered in DM1 patients. The results emphasize the importance of conducting a detailed swallowing assessment in all patients, even those with mild muscle weakness.
Itch is a common experience. It can occur in the course of systemic diseases and can be a manifestation of allergies or a consequence of diseases affecting the somatosensory pathway. We describe a kindred characterized by paroxysmal itch caused by a variant in SCN9A gene encoding for the Nav1.7 sodium channel. Patients underwent clinical and somatosensory profile assessment by quantitative sensory testing, nerve conduction study, autonomic cardiovascular reflex, and sympathetic skin response examination, skin biopsy with quantification of intraepidermal nerve fiber density, and SCN9A mutational analysis. The index patient, her mother, and a sister presented with a stereotypical clinical picture characterized by paroxysmal itch attacks involving the shoulders, upper back, and upper limbs, followed by transient burning pain, and triggered by environmental warmth, hot drinks, and spicy food. Somatosensory profile assessment demonstrated a remarkably identical pattern of increased cold and pain thresholds and paradoxical heat sensation. Autonomic tests were negative, whereas skin biopsy revealed decreased intraepidermal nerve fiber density in 2 of the 3 patients. All affected members harbored the 2215A>G I739V substitution in exon 13 of SCN9A gene. Pregabalin treatment reduced itch intensity and attack frequency in all patients. The co-segregation of the I739V variant in the affected members of the family provides evidence, for the first time, that paroxysmal itch can be related to a mutation in sodium channel gene.
Chemotherapy-induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI-PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28-6.07), 3.49 (95%CI: 1.61-7.55), and 4.42 (95%CI: 1.35-14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81-41.42), 2.54 (95%CI: 1.19-5.41), and 7.47 (95%CI: 2.49-22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN.
Painful small fibre neuropathy (SFN) represents a significant public health problem, with no cause apparent in one-half of cases (termed idiopathic, I-SFN). Gain-of-function mutations of sodium channel NaV1.7 have recently been identified in nearly 30% of patients with biopsy-confirmed I-SFN. More recently, gain-of-function mutations of NaV1.8 have been found in patients with I-SFN. These NaV1.8 mutations accelerate recovery from inactivation, enhance the response to slow depolarisations, and enhance activation at the channel level, thereby producing hyperexcitability of small dorsal root ganglion (DRG) neurons, which include nociceptors, at the cellular level. Identification and functional profiling of additional NaV1.8 variants are necessary to determine the spectrum of changes in channel properties that underlie DRG neuron hyperexcitability in these patients.
Idiopathic small-fiber neuropathy (I-SFN), clinically characterized by burning pain in distal extremities and autonomic dysfunction, is a disorder of small-caliber nerve fibers of unknown etiology with limited treatment options. Functional variants of voltage-gated sodium channel Nav1.7, encoded by SCN9A, have been identified in approximately one-third of I-SFN patients. These variants render dorsal root ganglion (DRG) neurons hyperexcitable. Sodium channel Nav1.8, encoded by SCN10A, is preferentially expressed in small-diameter DRG neurons, and produces most of the current underlying the upstroke of action potentials in these neurons. We previously demonstrated two functional variants of Nav1.8 that either enhance ramp current or shift activation in a hyperpolarizing direction, and render DRG neurons hyperexcitable, in I-SFN patients with no mutations of SCN9A. We have now evaluated additional I-SFN patients with no mutations in SCN9A, and report a novel I-SFN-related Nav1.8 mutation I1706V in a patient with painful I-SFN. Whole-cell voltage-clamp recordings in small DRG neurons demonstrate that the mutation hyperpolarizes activation and the response to slow ramp depolarizations. However, it decreases fractional channels resistant to fast inactivation and reduces persistent currents. Current-clamp studies reveal that mutant channels decrease current threshold and increase the firing frequency of evoked action potentials within small DRG neurons. These observations suggest that the effects of this mutation on activation and ramp current are dominant over the reduced persistent current, and show that these pro-excitatory gating changes confer hyperexcitability on peripheral sensory neurons, which may contribute to pain in this individual with I-SFN.
NaV1.7 is preferentially expressed, at relatively high levels, in peripheral neurons, and is often referred to as a "peripheral" sodium channel, and NaV1.7-specific blockers are under study as potential pain therapeutics which might be expected to have minimal CNS side effects. However, occasional reports of patients with NaV1.7 gain-of-function mutations and apparent hypothalamic dysfunction have appeared. The two sodium channels previously studied within the rat hypothalamic supraoptic nucleus, NaV1.2 and NaV1.6, display up-regulated expression in response to osmotic stress.
Sodium channel NaV1.7 is preferentially expressed in dorsal root ganglion (DRG) and sympathetic ganglion neurons. Gain-of-function NaV1.7 mutations/variants have been identified in the painful disorders inherited erythromelalgia and small-fiber neuropathy (SFN). DRG neurons transfected with these channel variants display depolarized resting potential, reduced current-threshold, increased firing-frequency and spontaneous firing. Whether the depolarizing shift in resting potential and enhanced spontaneous firing are due to persistent activity of variant channels, or to compensatory changes in other conductance(s) in response to expression of the variant channel, as shown in model systems, has not been studied. We examined the effect of wild-type NaV1.7 and a NaV1.7 mutant channel, D623N, associated with SFN, on resting potential and membrane potential during interspike intervals in DRG neurons. Resting potential in DRG neurons expressing D623N was depolarized compared to neurons expressing WT-NaV1.7. Exposure to TTX hyperpolarized resting potential by 7mV, increased current-threshold, decreased firing-frequency, and reduced NMDG-induced-hyperpolarization in DRG neurons expressing D623N. To assess the contribution of depolarized resting potential to DRG neuron excitability, we mimicked the mutant channels depolarizing effect by current injection to produce equivalent depolarization; the depolarization decreased current threshold and increased firing-frequency. Voltage-clamp using ramp or repetitive action potentials as commands showed that D623N channels enhance the TTX-sensitive inward current, persistent at subthreshold membrane voltages, as predicted by a Hodgkin-Huxley model. Our results demonstrate that a variant of NaV1.7 associated with painful neuropathy depolarizes resting membrane potential and produces an enhanced inward current during interspike intervals, thereby contributing to DRG neuron hyperexcitability.
Introduction: The impact of small-fiber neuropathy (SFN) on patients quality of life (QOL) has not been studied extensively. Our aim was to determine the impact of SFN on QOL and examine possible determinants. Methods: We examined a total of 265 patients diagnosed with SFN. The SFN Symptoms Inventory Questionnaire (SFN-SIQ), the pain Visual Analog Scale (VAS), and the generic SF-36 Health Survey were assessed. Regression studies were undertaken to evaluate determinants of functioning. Results: SFN patients demonstrated a severe overall reduction in QOL. The biggest deficits were in Role Functioning-Physical, Body Pain, and Physical Component Summary (PCS) scores. VAS scores, changed sweating pattern, dry mouth, and age were the strongest predictors for PCS, explaining 32% of the QOL decrease. Conclusions: SFN leads to a reduction in overall QOL. The presence of pain and some autonomic symptoms explained only a small portion of the findings. Muscle Nerve, 2013.
Neuropathic pain (NP) is a pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. A variety of factors associated with the development of persistent NP have been suggested. The goal of the present article is to provide an overview of current knowledge about prognostic factors for persistent NP. The International Classification of Functioning, Disability and Health model is used as a framework to categorize these predictors. Most reported predictors in the literature were found in the International Classification of Functioning, Disability and Health-category of personal factors, especially age and psychological factors, functions and structure, including sensory signs and symptoms. Predictors in the category of environmental factors, activities and participation were less frequently described.
The diagnosis of small fiber neuropathy (SFN) has been recently defined as typical symptoms due to small nerve fiber dysfunction accompanied by reduced intra-epidermal nerve fiber density (IENFD) or abnormal temperature threshold testing (TTT). Guidelines have been published for the assessment of IENFD. However, international guidelines for TTT are lacking. This paper presents a systematic literature review on reported TTT methods and provides recommendations for its future use in studies evaluating patients. A total of 164 papers fulfilled pre-defined requirements and were selected for review. Over 15 types of instruments are currently being used with a variety of methodological approaches for location, stimulus application, and sensation qualities examined. Consensus is needed to standardize the use of TTT as a diagnostic and follow-up tool in patients.
Small-fiber neuropathy (SFN) is characterized by injury to small-diameter peripheral nerve axons and intraepidermal nerve fibers (IENF). Although mechanisms underlying loss of IENF in SFN are poorly understood, available data suggest that it results from axonal degeneration and reduced regenerative capacity. Gain-of-function variants in sodium channel Na(V)1.7 that increase firing frequency and spontaneous firing of dorsal root ganglion (DRG) neurons have recently been identified in ?30% of patients with idiopathic SFN. In the present study, to determine whether these channel variants can impair axonal integrity, we developed an in vitro assay of DRG neurite length, and examined the effect of 3 SFN-associated variant Na(V)1.7 channels, I228M, M932L/V991L (ML/VL), and I720K, on DRG neurites in vitro. At 3 days after culturing, DRG neurons transfected with I228M channels exhibited ?20% reduced neurite length compared to wild-type channels; DRG neurons transfected with ML/VL and I720K variants displayed a trend toward reduced neurite length. I228M-induced reduction in neurite length was ameliorated by the use-dependent sodium channel blocker carbamazepine and by a blocker of reverse Na-Ca exchange. These in vitro observations provide evidence supporting a contribution of the I228M variant Na(V)1.7 channel to impaired regeneration and/or degeneration of sensory axons in idiopathic SFN, and suggest that enhanced sodium channel activity and reverse Na-Ca exchange can contribute to a decrease in length of peripheral sensory axons.
The Medical Research Council grading system has served through decades for the evaluation of muscle strength and has been recognized as a cardinal feature of daily neurological, rehabilitation and general medicine examination of patients, despite being respectfully criticized due to the unequal width of its response options. No study has systematically examined, through modern psychometric approach, whether physicians are able to properly use the Medical Research Council grades. The objectives of this study were: (i) to investigate physicians ability to discriminate among the Medical Research Council categories in patients with different neuromuscular disorders and with various degrees of weakness through thresholds examination using Rasch analysis as a modern psychometric method; (ii) to examine possible factors influencing physicians ability to apply the Medical Research Council categories through differential item function analyses; and (iii) to examine whether the widely used Medical Research Council 12 muscles sum score in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy would meet Rasch models expectations. A total of 1065 patients were included from nine cohorts with the following diseases: Guillain-Barré syndrome (n?=?480); myotonic dystrophy type-1 (n?=?169); chronic inflammatory demyelinating polyradiculoneuropathy (n?=?139); limb-girdle muscular dystrophy (n?=?105); multifocal motor neuropathy (n?=?102); Pompes disease (n?=?62) and monoclonal gammopathy of undetermined related polyneuropathy (n?=?8). Medical Research Council data of 72 muscles were collected. Rasch analyses were performed on Medical Research Council data for each cohort separately and after pooling data at the muscle level to increase category frequencies, and on the Medical Research Council sum score in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Disordered thresholds were demonstrated in 74-79% of the muscles examined, indicating physicians inability to discriminate between most Medical Research Council categories. Factors such as physicians experience or illness type did not influence these findings. Thresholds were restored after rescoring the Medical Research Council grades from six to four options (0, paralysis; 1, severe weakness; 2, slight weakness; 3, normal strength). The Medical Research Council sum score acceptably fulfilled Rasch model expectations after rescoring the response options and creating subsets to resolve local dependency and item bias on diagnosis. In conclusion, a modified, Rasch-built four response category Medical Research Council grading system is proposed, resolving clinicians inability to differentiate among its original response categories and improving clinical applicability. A modified Medical Research Council sum score at the interval level is presented and is recommended for future studies in Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.
Chronic neuropathic pain has a major effect on quality of life. In order to prevent neuropathic pain from becoming chronic and improve neuropathic pain care, it is important to identify predictors associated with the persistence of neuropathic pain.
Sodium channel NaV1.7 is preferentially expressed within dorsal root ganglia (DRG), trigeminal ganglia and sympathetic ganglion neurons and their fine-diamter axons, where it acts as a threshold channel, amplifying stimuli such as generator potentials in nociceptors. Gain-of-function mutations and variants (single amino acid substitutions) of NaV1.7 have been linked to three pain syndromes: Inherited Erythromelalgia (IEM), Paroxysmal Extreme Pain Disorder (PEPD), and Small Fiber Neuropathy (SFN). IEM is characterized clinically by burning pain and redness that is usually focused on the distal extremities, precipitated by mild warmth and relieved by cooling, and is caused by mutations that hyperpolarize activation, slow deactivation, and enhance the channel ramp response. PEPD is characterized by perirectal, periocular or perimandibular pain, often triggered by defecation or lower body stimulation, and is caused by mutations that severely impair fast-inactivation. SFN presents a clinical picture dominated by neuropathic pain and autonomic symptoms; gain-of-function variants have been reported to be present in approximately 30% of patients with biopsy-confirmed idiopathic SFN, and functional testing has shown altered fast-inactivation, slow-inactivation or resurgent current. In this paper we describe three patients who house the NaV1.7/I228M variant.
Small nerve fiber neuropathy (SFN) often occurs without apparent cause, but no systematic genetic studies have been performed in patients with idiopathic SFN (I-SFN). We sought to identify a genetic basis for I-SFN by screening patients with biopsy-confirmed idiopathic SFN for mutations in the SCN9A gene, encoding voltage-gated sodium channel Na(V)1.7, which is preferentially expressed in small diameter peripheral axons.
The Jamar dynamometer has been widely used in various chronic illnesses and has demonstrated its strength as a potential prognostic indicator. Various stratified normative values have been published using different methodologies, leading to conflicting results. No study used statistical techniques considering the non-Gaussian distribution of the obtained grip strength (GS) values. Jamar GS was assessed in 720 healthy participants, subdivided into seven age decade groups consisting of at least 50 men and 50 women each. Normative values (median and fifth values) were calculated using quantile regressions with restricted cubic spline functions on age. Possible confounding personal factors (hand dominance, length, weight, hobby, and job categorization) were examined. Clinically applicable revised normative values for the Jamar dynamometer, stratified for age and gender, are presented. Hand dominance had no influence. Other personal factors only minimally influenced final values. This study provides revised normative GS values for the Jamar dynamometer.
Myotonic dystrophy 1 (DM1) is characterized by a wide range of clinical features. We aimed to verify the presence of peripheral nerve involvement in a large cohort of DM1 patients and to determine clinical consequences. A total of 93 patients underwent detailed neurological examination and nerve conduction studies. Additionally, balance impairment was assessed with the Berg Balance Scale and health status was evaluated with the SF-36 health survey. Sensory symptoms were not reported and mild sensory signs were found in six patients. Electrophysiological abnormalities consistent with a diagnosis of neuropathy were found in 16 patients (17%). Peripheral nerve involvement was significantly associated with decreased muscle strength (p = 0.001) and absence of Achilles-tendon reflexes (p = 0.003), but not with age or duration of neuromuscular symptoms. It had no significant effect on balance, mental or physical health. In conclusion, peripheral nerve involvement may be one of the multisystemic manifestations of DM1, but is usually subclinical. Other causes should be excluded when sensory symptoms or signs are severe.
Painful diabetic polyneuropathy is a common complication of diabetes mellitus. Drug therapies are ineffective in many patients. Therefore other treatment modalities should be considered, including spinal cord stimulation. We performed a systematic review to evaluate treatment efficacy and safety of spinal cord stimulation in painful diabetic polyneuropathy. SEARCH STRATEGY AND SELECTION CRITERIA: A systematic search with reference tracing was conducted in Pubmed and Embase from January 1980 to March 2010 to determine possible eligible articles. Reports were identified using the following keywords: (1) "diabetic neuropathies" AND "electric stimulation"; (2) "diabetic neuropathies" AND "spinal cord" and (3) "pain" AND "electric stimulation" AND "spinal cord". Subsequently, data were recruited on the efficacy and safety of spinal cord stimulation in this disorder.
This article evaluates the concept of minimal clinically important difference (MCID) through the results of two studies. The first study was a randomised trial in patients with Parkinsons disease claiming a positive effect of treatment with rasagiline over placebo, based on statistical differences in ordinal outcome measures. However, the clinical relevance of the findings according to the concept of MCID was not taken into consideration. In the second study, MCIDs were defined by several methods in a large trial in patients with chronic inflammatory demyelinating polyneuropathy receiving intravenous immunoglobulin (IGIV) or placebo. In that study, the differences in outcomes between the intervention group and the placebo group were not only statistically significant, but also clinically relevant, in favour of the intervention group. This was demonstrated using various MCID cut-off values.
The diagnostic reliability of skin biopsy in small fiber neuropathy depends on the availability of normative reference values. We performed a multicenter study to assess the normative values of intraepidermal nerve fiber (IENF) density at distal leg stratified by age deciles. Eight skin biopsy laboratories from Europe, USA, and Asia submitted eligible data. Inclusion criteria of raw data were healthy subjects 18 years or older; known age and gender; 3-mm skin biopsy performed 10-cm above the lateral malleolus; bright-field immunohistochemistry protocol, and quantification of linear IENF density in three 50-µm sections according to published guidelines. Data on height and weight were recorded, and body mass index (BMI) was calculated in subjects with both available data. Normative IENF density reference values were calculated through quantile regression analysis; influence of height, weight, or BMI was determined by regression analyses. IENF densities from 550 participants (285 women, 265 men) were pooled. We found a significant age-dependent decrease of IENF density in both genders (women p < 0.001; men p = 0.002). Height, weight, or BMI did not influence the calculated 5th percentile IENF normative densities in both genders. Our study provides IENF density normative reference values at the distal leg to be used in clinical practice.
Complex regional pain syndrome (CRPS), formerly known as reflex sympathetic dystrophy is a pain syndrome with an unclear pathophysiology and unpredictable clinical course. The disease is often therapy resistant, the natural course not always favorable. The diagnosis of CRPS is based on signs and symptoms derived from medical history and physical examination. Pharmacological pain management and physical rehabilitation of limb function are the main pillars of therapy and should be started as early as possible. If, however, there is no improvement of limb function and persistent severe pain, interventional pain management techniques may be considered. Intravenous regional blocks with guanethidine did not prove superior to placebo but frequent side effects occurred.Therefore this technique receives a negative recommendation (2 A-). Sympathetic block is the interventional treatment of first choice and has a 2 B+ rating. Ganglion stellatum (stellate ganglion) block with repeated local anesthetic injections or by radiofrequency denervation after positive diagnostic block is documented in prospective and retrospective trials in patients suffering from upper limb CRPS. Lumbar sympathetic blocks can be performed with repeated local anesthetic injections. For a more prolonged lumbar sympathetic block radiofrequency treatment is preferred over phenol neurolysis because effects are comparable whereas the risk for side effects is lower (2 B+). For patients suffering from CRPS refractory to conventional treatment and sympathetic blocks, plexus brachialis block or continuous epidural infusion analgesia coupled with exercise therapy may be tried (2 C+). Spinal cord stimulation is recommended if other treatments fail to improve pain and dysfunction (2 B+). Alternatively peripheral nerve stimulation can be considered, preferentially in study conditions (2 C+).
We describe the development of an outcome measure of activity and participation for patients with myotonic dystrophy type 1 using the Rasch measurement model. A 49-item questionnaire was completed by 163 DM1 patients. Data were subsequently analyzed with Rasch software to design the item set to fit model expectations. Through systematic investigation of response category ordering, model fit, item bias, and local response dependency, we succeeded in constructing a 20-item unidimensional scale of activity and participation (DM1-Activ). High internal consistency (PSI=0.95) and good test-retest reliability values of item difficulty hierarchy and patient location were demonstrated. Patient measures had acceptable correlations with MRC sum scores and MIRS grades (ICC=0.69 and 0.71, respectively), indicating good external construct validity. DM1-Activ is a practical, reliable and valid outcome measure that fulfils all clinimetric requirements. Further evaluation of this scale is needed to provide a nomogram for clinical use.
Pulsed high-dose dexamethasone induced long-lasting remission in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in a pilot study. The PREDICT study aimed to compare remission rates in patients with CIDP treated with high-dose dexamethasone with rates in patients treated with standard oral prednisolone.
Myotonic dystrophy type 1 (DM1) is one of the most variable inherited human disorders. It is characterized by the involvement of multiple tissues and is caused by the expansion of a highly unstable CTG repeat. Variation in disease severity is partially accounted for by the number of CTG repeats inherited. However, the basis of the variable tissue-specific symptoms is unknown. We have determined that an unusual Dutch family co-segregating DM1, Charcot-Marie-Tooth neuropathy, encephalopathic attacks and early hearing loss, carries a complex variant repeat at the DM1 locus. The mutation comprises an expanded CTG tract at the 5-end and a complex array of CTG repeats interspersed with multiple GGC and CCG repeats at the 3-end. The complex variant repeat tract at the 3-end of the array is relatively stable in both blood DNA and the maternal germ line, although the 5-CTG tract remains genetically unstable and prone to expansion. Surprisingly though, even the pure 5-CTG tract is more stable in blood DNA and the maternal germ line than archetypal DM1 alleles of a similar size. Complex variant repeats were also identified at the 3-end of the CTG array of approximately 3-4% of unrelated DM1 patients. The observed polarity and the stabilizing effect of the variant repeats implicate a cis-acting modifier of mutational dynamics in the 3-flanking DNA. The presence of such variant repeats very likely contributes toward the unusual symptoms in the Dutch family and additional symptomatic variation in DM1 via affects on both RNA toxicity and somatic instability.
Fatigue is a major disabling complaint in patients with immune-mediated neuropathies (IN). The 9-item fatigue severity scale (FSS) has been used to assess fatigue in these conditions, despite having limitations due to its classic ordinal construct. The aim was to improve fatigue assessment in IN through evaluation of the FSS using a modern clinimetric approach [Rasch unidimensional measurement model (RUMM2020)]. Included were 192 stable patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUSP). The obtained FSS data were exposed to RUMM2020 model to investigate whether this scale would meet its expectations. Also, reliability and validity studies were performed. The original FSS did not meet the Rasch model expectations, primarily based on two misfitting items, one of these also showing bias towards the factor walking independent. After removing these two items and collapsing the original 7-point Likert options to 4-point response categories for the remaining items, we succeeded in constructing a 7-item Rasch-built scale that fulfilled all requirements of unidimensionality, linearity, and rating scale model. Good reliability and validity were also obtained for the modified FSS scale. In conclusion, a 7-item linearly weighted Rasch-built modified FSS is presented for more proper assessment of fatigue in future studies in patients with immune-mediated neuropathies.
Spinal cord stimulation (SCS) has proven to be an effective however an invasive and relatively expensive treatment of chronic Complex Regional Pain Syndrome type 1(CRPS-1). Furthermore, in one third of CRPS-1 patients, SCS treatment fails to give significant pain relief and 32-38% of treated patients experience complications. The aim of the current study was to develop effective prognostic factors for prediction of successful outcome of SCS.
Anti-myelin associated glycoprotein (MAG) neuropathy is a chronic disorder in which IgM antibodies react with Schwann cell glycoproteins, including MAG and peripheral myelin protein 22 (PMP22). Nerve conduction studies show features of axon loss and predominantly distal slowing consistent with demyelination. Because a genetic loss of PMP22 function yields hereditary neuropathy with liability to pressure palsies (HNPP), loss of PMP22 function due to anti- MAG antibodies may result in increased sensitivity to entrapment. We investigated this by performing standardized electrophysiological studies in 16 patients with anti-MAG neuropathy and 16 disease controls with genetically confirmed HNPP. Disproportionate slowing relative to adjacent segments occurred in similar proportions of patients with anti-MAG neuropathy and HNPP, and was of the same magnitude in each group. Affected were the elbow, carpal tunnel and the wrist-hand segments of the median and ulnar nerves. However, in anti-MAG neuropathy as compared to HNPP, absolute values of distal motor latencies and conduction velocities outside entrapment sites were slower and amplitudes were lower. In conclusion, increased sensitivity for entrapment may occur in anti-MAG neuropathy and contribute to part of the nerve damage.
Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) epsilon-subunit gene underlying congenital myasthenic syndromes in nine patients (seven kinships) of Dutch origin. Previously reported mutations epsilon1369delG and epsilonR311Q were found to be common; epsilon1369delG was present on at least one allele in seven of the nine patients, and epsilonR311Q in six. Phenotypes ranged from relatively mild ptosis and external ophthalmoplegia to generalized myasthenia. The common occurrence of epsilonR311Q and epsilon1369delG suggests a possible founder for each of these mutations originating in North Western Europe, possibly in Holland. Knowledge of the ethnic or geographic origin within Europe of AChR deficiency patients can help in targeting genetic screening and it may be possible to provide a rapid genetic diagnosis for patients of Dutch origin by screening first for epsilonR311Q and epsilon1369delG.
Neuropathic pain complicates many diseases of the peripheral and central nervous system and is frequently encountered in clinical practice. The mechanisms underlying its occurrence and chronification remain poorly understood. As a consequence, symptomatic treatment is frequently the only available therapeutic option. An appropriate diagnostic workup is an important prelude to treatment. Moreover, identification of the site of damage in the somatosensory pathway represents a mandatory step in the process of deciding on a disease-modifying therapy for any given patient. The recent revision of the definition of neuropathic pain has introduced the concept of a nosologic-based approach to the diagnosis, which is expected to be supported by the demonstration of a relationship between the clinical picture and a lesion or disease. This underscores the need for precise diagnostic assessment of the patient. In the last decade, a number of tools including validated scales, psychophysical tests and morphometric analysis of small nerve fibers carrying thermal and nociceptive sensation have been developed; these can provide important information about the quality and intensity of the multiple features that characterize neuropathic pain. More recently, advances on the recognition of a molecular substrate for neuropathic pain, both in terms of susceptibility and novel gene mutations, have provided the potential for new diagnostic perspectives and a path toward a better comprehension of the pathogenetic mechanisms. This editorial addresses briefly the impact of these developments on the diagnosis of neuropathic pain in clinical practice.
Fatigue, a highly debilitating symptom, is reported in most patients with immune-mediated neuropathies, particularly in Guillain-Barré syndrome, chronic immune-mediated demyelinating polyradiculoneuropathy, monoclonal gammopathy of undetermined significance related polyneuropathy, and multifocal motor neuropathy. Aspects like the degree of known fatigue in these disorders, its impact on daily functioning and quality of life, the suggested underlying mechanisms, and possible therapeutic interventions for fatigue will be addressed in this review.
Painful peripheral neuropathy often occurs without apparent underlying cause. Gain-of-function variants of sodium channel Na(v)1.7 have recently been found in ?30% of cases of idiopathic painful small-fiber neuropathy. Here, we describe mutations in Na(v)1.8, another sodium channel that is specifically expressed in dorsal root ganglion (DRG) neurons and peripheral nerve axons, in patients with painful neuropathy. Seven Na(v)1.8 mutations were identified in 9 subjects within a series of 104 patients with painful predominantly small-fiber neuropathy. Three mutations met criteria for potential pathogenicity based on predictive algorithms and were assessed by voltage and current clamp. Functional profiling showed that two of these three Na(v)1.8 mutations enhance the channels response to depolarization and produce hyperexcitability in DRG neurons. These observations suggest that mutations of Na(v)1.8 contribute to painful peripheral neuropathy.
Fatigue and excessive daytime sleepiness are frequent complaints in myotonic dystrophy type 1 (DM1) that often overlap. We aimed to construct a combined fatigue and daytime sleepiness rating scale for DM1 using the Rasch measurement model.
Enzyme replacement therapy (ERT) in adults with Pompe disease, a progressive neuromuscular disorder, is of promising but variable efficacy. We investigated whether it alters the course of disease, and also identified potential prognostic factors.
Myotonic dystrophy type 1 (MD1) is a neuromuscular disorder with potential involvement of the heart and increased risk of sudden death. Considering the importance of cardiomyopathy as a predictor of prognosis, we aimed to systematically evaluate and describe structural and functional cardiac alterations in patients with MD1.
Patients with small fibre neuropathy typically manifest pain in distal extremities and severe autonomic dysfunction. However, occasionally patients present with minimal autonomic symptoms. The basis for this phenotypic difference is not understood. Sodium channel Na(v)1.7, encoded by the SCN9A gene, is preferentially expressed in the peripheral nervous system within sensory dorsal root ganglion and sympathetic ganglion neurons and their small diameter peripheral axons. We recently reported missense substitutions in SCN9A that encode functional Na(v)1.7 variants in 28% of patients with biopsy-confirmed small fibre neuropathy. Two patients with biopsy-confirmed small fibre neuropathy manifested minimal autonomic dysfunction unlike the other six patients in this series, and both of these patients carry the Na(v)1.7/R185H variant, presenting the opportunity to compare variants associated with extreme ends of a spectrum from minimal to severe autonomic dysfunction. Herein, we show by voltage-clamp that R185H variant channels enhance resurgent currents within dorsal root ganglion neurons and show by current-clamp that R185H renders dorsal root ganglion neurons hyperexcitable. We also show that in contrast, R185H variant channels do not produce detectable changes when studied by voltage-clamp within sympathetic neurons of the superior cervical ganglion, and have no effect on the excitability of these cells. As a comparator, we studied the Na(v)1.7 variant I739V, identified in three patients with small fibre neuropathy characterized by severe autonomic dysfunction as well as neuropathic pain, and show that this variant impairs channel slow inactivation within both dorsal root ganglion and superior cervical ganglion neurons, and renders dorsal root ganglion neurons hyperexcitable and superior cervical ganglion neurons hypoexcitable. Thus, we show that R185H, from patients with minimal autonomic dysfunction, does not produce detectable changes in the properties of sympathetic ganglion neurons, while I739V, from patients with severe autonomic dysfunction, has a profound effect on excitability of sympathetic ganglion neurons.
Small-fibre neuropathy (SFN), a disorder of thinly myelinated A?-fibres and unmyelinated C-fibres, is clinically characterized by neuropathic pain symptoms and autonomic complaints. Diagnosis of SFN is challenging as the clinical picture can be difficult to interpret and results from nerve conduction studies are often normal. In cases of suspected SFN, measurement of intraepidermal nerve fibre density and/or analysis of quantitative sensory testing can enable diagnosis. New diagnostic techniques (including measurement of nerve fibre density using corneal confocal microscopy, and nociceptive evoked potentials) may contribute to the diagnostic work-up. SFN can be associated with systemic diseases such as immune-mediated disorders, but remains idiopathic in a substantial proportion of patients. Gain-of-function variants in the Na(v)1.7 sodium channel have recently been found in nearly 30% of patients with idiopathic SFN, but the mechanisms of axonal degeneration in the disorder remain under investigation. Identification of the systemic diseases underlying SFN will enable development of drugs that target affected pathways to improve the management of neuropathic pain and autonomic dysfunction. In this Review, we discuss recent advances in the diagnosis and pathophysiology of SFN, highlighting how improved understanding of these aspects of the disorder will contribute to better patient management.
Previous studies have explicitly shown that small nerve fibers are affected in Fabry disease which is assumed to cause the severe neuropathic pain that patients may have from childhood on. Neuropathic pain and small fiber neuropathy characteristics have therefore been considered as appropriate study endpoints in studies on the efficacy of enzyme replacement therapy. However, the relationship between small fiber neuropathy characteristics and pain, as well as the course of small fiber neuropathy in Fabry disease is still uncertain. In this article a comprehensive overview of the existing literature on small nerve fiber function and structure and the relationship with pain, age and disease severity is presented supplemented with data from the Dutch Fabry cohort, with the aim to identify consensus as well as controversies and to propose a hypothesis on the evolution of neuropathy in Fabry disease.
Small fibre neuropathy is a neuropathy of the small non-myelinated C-fibres and myelinated A?-fibres. Clinically, an isolated small fibre neuropathy is distinguished by sensory and autonomic symptoms, with practically no abnormalities on neurological examination other than possible distorted pain and temperature sensation. Specific diagnostic tests for small fibre neuropathy are skin biopsy, including a count of the intra-epidermal small nerve fibres that cross the basal membrane, and quantitative sensory and autonomic testing. Diabetes mellitus is the most frequent underlying cause of small fibre neuropathy. Other causes can be classified into the following categories: toxic (e.g. alcohol), metabolic, immune-mediated, infectious and hereditary. Recently, in a substantial proportion (29%) of a group of patients with idiopathic small fibre neuropathy, a SCN9A gene mutation was demonstrated, which leads to hyperexcitability of the dorsal root ganglion neurons. Treatment of small fibre neuropathy consists of symptomatic pain relief and, if possible, treatment of the underlying cause of the condition.
Complex regional pain syndrome type 1 (CRPS-1) has a 31% probability of becoming chronic. The early use of spinal cord stimulation (SCS) has been recommended as a strategy to prevent chronicity and functional impairment.
The Na(V)1.7 sodium channel is preferentially expressed within dorsal root ganglion and sympathetic ganglion neurons and their small-diameter peripheral axons. Gain-of-function variants of Na(V)1.7 have recently been described in patients with painful small fibre neuropathy and no other apparent cause. Here, we describe a novel syndrome of pain, dysautonomia, small hands and small feet in a kindred carrying a novel Na(V)1.7 mutation. A 35-year-old male presented with erythema and burning pain in the hands since early childhood, later disseminating to the feet, cheeks and ears. He also experienced progressive muscle cramps, profound sweating, bowel disturbances (diarrhoea or constipation), episodic dry eyes and mouth, hot flashes, and erectile dysfunction. Neurological examination was normal. Physical examination was remarkable in revealing small hands and feet (acromesomelia). Blood examination and nerve conduction studies were unremarkable. Intra-epidermal nerve fibre density was significantly reduced compared to age- and sex-matched normative values. The patients brother and father reported similar complaints including distal extremity redness and pain, and demonstrated comparable distal limb under-development. Quantitative sensory testing revealed impaired warmth sensation in the proband, father and brother. Genetic analysis revealed a novel missense mutation in the SCN9A gene encoding sodium channel Na(V)1.7 (G856D; c.2567G?>?A) in all three affected subjects, but not in unaffected family members. Functional analysis demonstrated that the mutation hyperpolarizes (-9.3?mV) channel activation, depolarizes (+6.2?mV) steady-state fast-inactivation, slows deactivation and enhances persistent current and the response to slow ramp stimuli by 10- to 11-fold compared with wild-type Na(V)1.7 channels. Current-clamp analysis of dorsal root ganglion neurons transfected with G856D mutant channels demonstrated depolarized resting potential, reduced current threshold, increased repetitive firing in response to suprathreshold stimulation and increased spontaneous firing. Our results demonstrate that the G856D mutation produces DRG neuron hyperexcitability which underlies pain in this kindred, and suggest that small peripheral nerve fibre dysfunction due to this mutation may have contributed to distal limb under-development in this novel syndrome.
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