Axonal Excitability Does Not Differ between Painful and Painless Diabetic or Chemotherapy-Induced Distal Symmetrical Polyneuropathy in a Multicenter Observational Study.

OBJECTIVE: Axonal excitability reflects ion channel function, and it is proposed that this may be a biomarker in painful (vs painless) polyneuropathy. Our objective was to investigate the relationship between axonal excitability parameters and chronic neuropathic pain in deeply phenotyped cohorts with diabetic or chemotherapy-induced distal symmetrical polyneuropathy. METHODS: Two hundred thirty-nine participants with diabetic polyneuropathy were recruited from sites in the UK and Denmark, and 39 participants who developed chemotherapy-induced polyneuropathy were recruited from Denmark. Participants were separated into those with probable or definite neuropathic pain and those without neuropathic pain. Axonal excitability of large myelinated fibers was measured with the threshold tracking technique. The stimulus site was the median nerve, and the recording sites were the index finger (sensory studies) and abductor pollicis brevis muscle (motor studies). RESULTS: Participants with painless and painful polyneuropathy were well matched across clinical variables. Sensory and motor axonal excitability measures, including recovery cycle, threshold electrotonus, strength-duration time constant, and current-threshold relationship, did not show differences between participants with painful and painless diabetic polyneuropathy, and there were only minor changes for chemotherapy-induced polyneuropathy. INTERPRETATION: Axonal excitability did not significantly differ between painful and painless diabetic or chemotherapy-induced polyneuropathy in a multicenter observational study. Threshold tracking assesses the excitability of myelinated axons; the majority of nociceptors are unmyelinated, and although there is some overlap of the "channelome" between these axonal populations, our results suggest that alternative measures such as microneurography are required to understand the relationship between sensory neuron excitability and neuropathic pain. ANN NEUROL 2022;91:506-520.

Corneal confocal microscopy in small and mixed fiber neuropathy-Comparison with skin biopsy and cold detection in a large prospective cohort.

BACKGROUND AND AIMS: The diagnosis of small fiber neuropathy (SFN) is supported by reduced intraepidermal nerve fiber density (IENFD). The noninvasive method corneal confocal microscopy (CCM) has the potential to be a practical alternative. We aimed to estimate the diagnostic accuracy of CCM compared with IENFD and cold detection thresholds (CDT) in SFN and mixed fiber neuropathy (MFN). METHODS: CCM was performed in an unselected prospective cohort of patients with a clinical suspicion of polyneuropathy. Predefined criteria were used to classify SFN and MFN. Neuropathy scores, including the Utah early neuropathy scale (UENS), were used to describe severity. Patients with established other diagnoses were used for diagnostic specificity calculations. RESULTS: Data were taken from 680 patients, of which 244 had SFN or MFN. There was no significant difference in sensitivities [95%CI] of CCM (0.44 [0.38-0.51]), IEFND (0.43 [0.36-0.49]), and CDT (0.34 [0.29-0.41]). CCM specificity (0.75 [0.69-0.81]) was lower (p = .044) than for IENFD (0.99 [0.96-1.00]) but not than for CDT (0.81 [0.75-0.86]). The AUCs of the ROC curves of 0.63, 0.63 and 0.74 respectively, was lower for corneal nerve fiber density (p = .0012) and corneal nerve fiber length (p = .0015) compared with IENFD. While UENS correlated significantly with IENFD (p = .0016; R2 = .041) and CDT (p = .0002; R2 = .056), it did not correlate with CCM measures. INTERPRETATION: The diagnostic utility of CCM in SNF and MFN is limited by the low specificity compared with skin biopsy. Further, CCM is less suitable than skin biopsy and CDT as a marker for neuropathy severity.

Changes in axonal and clinical function during intravenous and subcutaneous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND AIMS: Intravenous immunoglobulin (IVIg) has a rapid clinical effect which cannot be explained by remyelination during each treatment cycle in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). This study aimed to investigate axonal membrane properties during the IVIg treatment cycle and their potential correlation with clinically relevant functional measurements. METHODS: Motor nerve excitability testing (NET) of the median nerve was performed before and 4 and 18 days after initiation of an IVIg treatment cycle in 13 treatment-naïve (early) CIDP patients and 24 CIDP patients with long term (late) IVIg treatment, 12 CIDP patients treated with subcutaneous immunoglobulin (SCIg) and 55 healthy controls. Clinical function was measured extensively using the Six Spot Step test, 10-Meter Walk test, 9-Hole Peg test, grip strength, MRC sum score, Overall Neuropathy Limitations Score and Patient Global Impression of Change. RESULTS: Superexcitability and S2 accommodation decreased significantly in the early treatment group from baseline to day 4 and returned to baseline levels at day 18, suggesting temporary depolarization of the axonal membrane. A similar trend was observed for the late IVIg group. Substantial clinical improvement was observed in both early and late IVIg groups during the entire treatment cycle. No statistically significant correlation was found between clinical and NET changes. No change was found in NET or clinical function in the SCIg group or controls. INTERPRETATION: NET suggested temporary depolarization of the axonal membrane during IVIg treatment in treatment naïve CIDP patients. The relation to clinical improvement, however, remains speculative.

Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management.

Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in 30-40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential. Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain. Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycaemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one-third of patients with painful DN derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc., which lead to the best therapeutic outcomes.

Original research: Second IVIg course in Guillain-Barré syndrome with poor prognosis: the non-randomised ISID study.

OBJECTIVE: To compare disease course in patients with Guillain-Barré syndrome (GBS) with a poor prognosis who were treated with one or with two intravenous immunoglobulin (IVIg) courses. METHODS: From the International GBS Outcome Study, we selected patients whose modified Erasmus GBS Outcome Score at week 1 predicted a poor prognosis. We compared those treated with one IVIg course to those treated with two IVIg courses. The primary endpoint, the GBS disability scale at 4 weeks, was assessed with multivariable ordinal regression. RESULTS: Of 237 eligible patients, 199 patients received a single IVIg course. Twenty patients received an 'early' second IVIg course (1-2 weeks after start of the first IVIg course) and 18 patients a 'late' second IVIg course (2-4 weeks after start of IVIg). At baseline and 1 week, those receiving two IVIg courses were more disabled than those receiving one course. Compared with the one course group, the adjusted OR for a better GBS disability score at 4 weeks was 0.70 (95%CI 0.16 to 3.04) for the early group and 0.66 (95%CI 0.18 to 2.50) for the late group. The secondary endpoints were not in favour of a second IVIg course. CONCLUSIONS: This observational study did not show better outcomes after a second IVIg course in GBS with poor prognosis. The study was limited by small numbers and baseline imbalances. Lack of improvement was likely an incentive to start a second IVIg course. A prospective randomised trial is needed to evaluate whether a second IVIg course improves outcome in GBS.

A population-based study of long-term outcome in treated chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: The effect of long-lasting immune-modulating therapy was studied in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: A population-based, cross-sectional study of treated patients referred to the Danish health-care system between 1985 and 2006. RESULTS: The 51 participating patients had a median disease duration of 16 (interquartile range, 14-21) years. Twenty-seven patients (53%) had discontinued therapy and 46 walked independently. Disability and isokinetic strength were impaired by 17% and 20%, respectively, as compared with matched control subjects. For a few patients long-term CIDP was associated with severe morbidity (6%) and even mortality (1%). Prolongation of time until start of therapy was associated with an increased burden of long-term disability. DISCUSSION: Long-term prognosis in treated CIDP is characterized by limited disability in the majority of patients. Disability is related to delay of therapy. Therefore, more attention should be given to early treatment start in CIDP.

Quality of life in chronic inflammatory demyelinating polyneuropathy patients treated with subcutaneous immunoglobulin.

BACKGROUND: Subcutaneous immunoglobulin (SCIG) is effective treatment of chronic inflammatory demyelinating polyneuropathy (CIDP). Quality of life (QoL) increases following switch from intravenous administration to SCIG, but its correlation with clinical functioning is sparsely studied. AIMS OF THE STUDY: The aim of this study is to evaluate the correlation between QoL and clinical functioning in CIDP patients treated with SCIG. METHODS: Danish patients with CIDP with a disease duration <10 years and currently treated with SCIG were eligible for inclusion. QoL was assessed with EQ-5D-5L and disability by the Overall Disability Sum Score (ODSS) and Rasch-built Overall Disability Scale (RODS). Gait performance was evaluated by a 40-meter-walk test (40-MWT) and a 6-spot-step test (6-SST) along with assessment of muscle strength (Medical Research Council score [MRC]). Correlations between QoL and the measured scores were calculated. RESULTS: Of 92 eligible patients, 44 were included. QoL on the visual analogue scale (VAS) was 65% (range: 15-90) of the level of healthy controls (P = .03) and correlated to impaired gait function by 40-MWT and 6-SST. QoL correlated to RODS and ODSS, whereas there was no correlation with the MRC score. CONCLUSIONS: In SCIG treated CIDP patients QoL is reduced and correlates to gait performance and disability.

A population-based and cross-sectional study of the long-term prognosis in multifocal motor neuropathy.

A population-based, cross-sectional study of patients referred to the Danish hospital system between 1985 and 2006 was conducted to evaluate the long-term outcome in Danish patients treated for multifocal motor neuropathy (MMN). Thirty-four MMN patients were identified, three had died of unrelated diseases, 10 were excluded, one did not reply to study request and 20 were included. The median disease duration was 24 years (interquartile range: 18.5-31.0). Compared to 24 healthy matched control subjects, the Rasch-built Overall Disability Scale for Multifocal Motor Neuropathy was reduced by 9%, the Neuropathy Impairment Score showed a 3-fold increase, the isokinetic strength was reduced by 29%, the grip strength by 56%, the Timed 25-Foot Walk was prolonged by 13% and the EQ-5D-5 L-Index value was impaired by 20%. The isokinetic strength was significantly more impaired at the wrist and ankle as compared to the elbow and knee, and one patient had lost ambulation because of instability at the ankle. Patients were considerably more fatigued and had substantially impaired hand dexterity, while mood, aerobic capacity, social adjustment, and working capacity were not affected. Regression analysis showed that lag-time until start of initial therapy lead to impaired long-term outcome without any effect of disease duration. Long-term prognosis in treated MMN is characterized by moderate to severe impairment primarily affecting dexterity and stability at the ankle. Our observations support previous observations that the long-term impairment in MMN might be improved following earlier start of therapy and that an effect of disease duration cannot be demonstrated.

Regional variation of Guillain-Barré syndrome.

Guillain-Barré syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barré syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barré Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barré syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barré syndrome was observed in patients from all countries participating in the International Guillain-Barré Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barré syndrome subtypes: 'Europe/Americas', 'Asia' (without Bangladesh), and 'Bangladesh'. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barré overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (n = 33/573, 6%) and other Asian countries (n = 4/65, 6%) (P < 0.001). In all regions, patients with the axonal subtype were younger, had fewer sensory deficits, and showed a trend towards poorer recovery compared to patients with the demyelinating subtype. The proportion of patients able to walk unaided after 1 year varied between Asia (n = 31/34, 91%), Europe/Americas (n = 334/404, 83%) and Bangladesh (n = 67/97, 69%) (P = 0.003). A similar variation was seen for mortality, being higher in Bangladesh (n = 19/114, 17%) than in Europe/Americas (n = 23/486, 5%) and Asia (n = 1/45, 2%) (P < 0.001). This study showed that factors related to geography have a major influence on clinical phenotype, disease severity, electrophysiological subtype, and outcome of Guillain-Barré syndrome.

Resistance training and aerobic training improve muscle strength and aerobic capacity in chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: We investigated the effects of aerobic and resistance exercise in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Eighteen CIDP patients treated with subcutaneous immunoglobulin performed 12 weeks of aerobic exercise and 12 weeks of resistance exercise after a run-in period of 12 weeks without exercise. Three times weekly the participants performed aerobic exercise on an ergometer bike or resistance exercise with unilateral training of knee and elbow flexion/extension. Primary outcomes were maximal oxygen consumption velocity (VO2 -max) and maximal combined isokinetic muscle strength (cIKS) of knee and elbow flexion/extension. RESULTS: VO2 -max and muscle strength were unchanged during run-in (-4.9% ± 10.3%, P = 0.80 and -3.7% ± 10.1%, P = 0.17, respectively). Aerobic exercise increased VO2 -max by 11.0% ± 14.7% (P = 0.02). Resistance exercise resulted in an increase of 13.8% ± 16.0% (P = 0.0004) in cIKS. DISCUSSION: Aerobic exercise training and resistance exercise training improve fitness and strength in CIDP patients. Muscle Nerve 57: 70-76, 2018.

The six-spot-step test - a new method for monitoring walking ability in patients with chronic inflammatory polyneuropathy.

The aim of this study was to evaluate whether the six-spot-step test (SSST) is more suitable for monitoring walking ability in patients with chronic inflammatory polyneuropathy than the timed 25-foot-walking test (T25FW). In the SSST, participants have to walk as quickly as possible across a field measuring 1 × 5 m, while kicking blocks out of five circles on the floor. Sixty-two patients and 61 controls performed the SSST and T25FW. Patients also performed the overall disability sumscore, INCAT sensory sumscore, Medical Research Council sumscore, and 9-hole-peg-test. Twenty-one patients treated with intravenous immunoglobulin (IVIG) every 4-6 weeks were tested prior to and 2-3 weeks after treatment and judged change in their own clinical condition using the patient global impression of change (PGIC) scale. In patients, SSST ranged from 5.7 to 26.8 s and T25FW ranged from 3.6 to 12.9 s. Intra-class correlation between repeated tests was 0.97 for SSST and 0.95 for T25FW. Correlation with the additional tests was stronger for SSST than T25FW. In IVIG-treated patients, the mean change in walking time was -2.3 s for SSST and -0.6 s for T25FW. The SSST showed larger responsiveness in terms of effect size, standardized response means, and relative efficiency. Both ambulation tests correlated moderately to PGIC. The SSST may be superior to the T25FW in terms of dynamic range, floor effect, and responsiveness which makes the SSST a possible alternative for monitoring walking ability in patients with chronic inflammatory polyneuropathy.

Development and Progression of Polyneuropathy Over 5 Years in Patients With Type 2 Diabetes.

BACKGROUND AND OBJECTIVES: There is a need for knowledge regarding the natural course of diabetic polyneuropathy (DPN), a complication in type 2 diabetes (T2D). The aim of this study was to examine the development of DPN over time. METHODS: Patients with newly diagnosed T2D, recruited from a national cohort, and controls without diabetes of similar age and sex, underwent sensory phenotyping in 2016-2018. The Toronto consensus criteria were used to classify patients into possible, probable, and confirmed DPN. For this 5-year, observational, follow-up, cohort study, all participants were invited to a reexamination combining bedside sensory examination, quantitative sensory testing (QST), nerve conduction studies (NCSs), and skin biopsies measuring intraepidermal nerve fiber density (IENFD) in order to compare phenotypic and diagnostic changes over time. RESULTS: Of the baseline 389 patients and 97 controls, 184 patients (median [interquartile range] diabetes duration 5.9 [4.1-7.4] years, mean hemoglobin A1c [HbA1c] 51 ± 11 mmol/mol at baseline) and 43 controls completed follow-up (46.9%). Confirmed DPN was present in 35.8% and 50.3%, probable DPN in 27.2% and 14.6%, possible DPN in 17.2% and 16.6%, and no DPN in 15.2% and 17.9% at baseline and follow-up, respectively. The estimated prevalence (95% CI) of confirmed DPN was 33.5% (24.9-42.1) compared with 22.7% (17.5-28.0) at baseline. During the follow-up period, 43.9% of patients with probable DPN developed confirmed DPN. Progression of neuropathy occurred in 16.5% and 24.7% and regression in 5.9% and 18.6% of patients based on NCS and IENFD, respectively. Progression based on NCS and/or IENFD was associated with higher baseline waist circumference and triglycerides, and regression with lower baseline HbA1c. Patients with at least probable DPN at baseline but neither patients without DPN nor controls developed increased spread of hyposensitivity, more hyposensitivity on QST and lower NCS z-scores at follow-up, and worsening of nerve parameters at follow-up correlated with higher baseline triglycerides. DISCUSSION: In patients with well-regulated T2D, the proportion of patients with confirmed DPN increased over 5 years driven by progression from probable DPN. A large proportion of patients progressed, and a smaller proportion regressed on nerve parameters. Higher triglycerides correlated with this progression and may constitute a risk factor.

Standardized Tapering off Subcutaneous Immunoglobulin in Chronic Inflammatory Demyelinating Polyneuropathy.

BACKGROUND: Attempting discontinuation of treatment in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is recommended. However, there is no evidence based regimen for tapering off subcutaneous immunoglobulin (SCIG). This trial investigated stepwise tapering off SCIG to detect remission and the lowest effective dosage. During tapering off, frequent vs less frequent clinical evaluation was compared. METHODS: Patients with CIDP receiving a stable SCIG dosage followed a standardized tapering off regimen: 90%, 75%, 50%, 25% and 0% of the initial dose every 12th week, pending no deterioration occurred. In case of relapse during tapering off, the lowest effective dose was identified. Treatment with SCIG was registered for two years after participation. Disability score and grip strength were primary parameters. Participants were randomized to clinical evaluation every 6th week (frequent) or 12th week (less frequent). RESULTS: Fifty-five patients were included of which thirty-five relapsed. Twenty patients (36%) were able to discontinue treatment without relapse. In relapsing patients, median dosage could be reduced by 10% (range, 0-75). After two years, 18 of 20 patients were still in remission without treatment. Frequent clinical evaluation did not detect deterioration more frequently than less frequent evaluation; RR 0.5 (95% CI, 0.2-1.2) (p = 0.17). CONCLUSION: In stable CIDP patients, SCIG could be completely tapered off in 36% of the patients and only in 10% of these patients relapse occurred during the following two years. More frequent evaluation was not superior to detect deterioration.

Oral capsules of tetra-hydro-cannabinol (THC), cannabidiol (CBD) and their combination in peripheral neuropathic pain treatment.

BACKGROUND: Cannabinoids are often prescribed for neuropathic pain, but the evidence-based recommendation is 'weak against'. OBJECTIVES: The aim was to examine the effect of two cannabinoids and their combination in peripheral neuropathic pain. METHODS: This was a randomized, double-blind, trial with treatment arms for cannabidiol (CBD), tetra-hydro-cannabinol (THC), CBD and THC combination (CBD/THC), and placebo in a 1:1:1:1 ratio and flexible drug doses (CBD 5-50 mg, THC 2.5-25 mg, and CBD/THC 5 mg/2.5 mg-50 mg/25 mg). Treatment periods of 8-week duration were proceeded by 1 week for baseline observations. Patients with painful polyneuropathy, post-herpetic neuralgia and peripheral nerve injury (traumatic or surgical) failing at least one previous evidence-based pharmacological treatment were eligible for inclusion. The primary outcome was the change in weekly average of daily pain measured with a numeric rating scale (NRS). Trail Making Test (TMT) was used as one of the tests of mental functioning. RESULTS: In all, 145 patients were included in the study of which 118 were randomized and 115 included in the intention-to-treat analysis. None of the treatments reduced pain compared to placebo (p = 0.04-0.60). Effect sizes as estimated in week 8 (positive values worse and negative better than placebo) were CBD mean 1.14 NRS points (95% CI 0.11-2.19), THC 0.38 (CI -0.65 to 1.4) and CBD/THC -0.12 (-1.13 to 0.89). CONCLUSIONS: CBD, THC and their combination did not relieve peripheral neuropathic pain in patients failing at least one previous evidence-based treatment for neuropathic pain.

The additional diagnostic value of motor nerve excitability testing in chronic axonal neuropathy.

OBJECTIVE: To explore potential differences in motor nerve excitability testing (NET) variables at group levels between patients with a clinical diagnosis of polyneuropathy (PNP), which did not fulfil diagnostic criteria of conventional nerve conduction studies (NCS) and patients without polyneuropathy. Such differences could support a role for NET in increasing the diagnostic sensitivity of NCS in chronic axonal PNP. METHODS: Motor NET was performed using the median nerve in patients with a clinical suspicion of PNP in addition to conventional NCS, skin biopsies, corneal confocal microscopy and structured clinical evaluation including scoring of neuropathy symptoms and signs. RESULTS: Of the 57 patients included, 32 had PNP, half of which had NCS, which fulfilled criteria for PNP (NCS+ PNP). There were no significant differences for any of the NET variables between PNP patients with non-diagnostic conventional NCS (NCS- PNP) and patients without PNP. Rheobase was increased, and Ted (undershoot) and subexcitability were decreased in NCS+ PNP. Sural amplitude, peroneal nerve F-wave latency and tibial nerve F-wave-latency were correlated with subexcitability, and tibial nerve motor amplitude was correlated with rheobase. CONCLUSIONS: NET was correlated with conventional NCS and no differences were found between NCS- PNP patients and patients without PNP. SIGNIFICANCE: NET does not seem to offer any additional diagnostic value in chronic mixed etiology neuropathy.

Impact of variability in baseline pain on the placebo response in randomized, placebo-controlled, crossover trials in peripheral neuropathic pain.

ABSTRACT: Large placebo responses often negatively affect randomized controlled trials within the pain area. Understanding different possible factors that influence the placebo response is therefore important. In this retrospective analysis, we hypothesized that a large variability in baseline pain score would predict a greater placebo response and analyzed the impact of the coefficient of variation, SD, and difference between the highest and lowest numeric rating scale (NRS) score at baseline on the placebo response. A total of 160 observations on placebo response from 3 controlled clinical trials with a crossover design were included in this study. In general, the placebo response was low with a mean reduction in pain intensity of 0.5 points (range -5 to 7) measured on a 0 to 10 point NRS, and only 15% were placebo responders as defined by more than 30% reduction in NRS pain score from baseline to the end of the placebo treatment period. We found no significant impact of baseline pain coefficient of variation, SD, or the difference between lowest and highest baseline pain score on the placebo response. Placebo response in one trial did not predict placebo response in another trial. A large placebo response was not associated with a large treatment response. In conclusion, in this retrospective data analysis, there was no impact of baseline pain variability on the placebo response in controlled clinical trials with a crossover design in patients with peripheral neuropathic pain.

Analysis of Macrophages and Peptidergic Fibers in the Skin of Patients With Painful Diabetic Polyneuropathy.

BACKGROUND AND OBJECTIVES: The mechanisms of pain in patients with diabetic polyneuropathy are unknown. Studies have suggested a role of inflammation and increased neuropeptides peripherally in pain generation. This study examined the possible skin markers of painful diabetic polyneuropathy (P-DPN): macrophages, substance P (SP), and calcitonin gene-related peptide (CGRP). METHODS: The participants were included from a large Danish cross-sectional clinical study of type 2 diabetes. We diagnosed definite diabetic polyneuropathy using the Toronto criteria and used the Neuropathic Pain Special Interest Group classification for defining P-DPN. We included 60 skin biopsies from patients with diabetic polyneuropathy-30 with P-DPN and 30 with nonpainful diabetic polyneuropathy (NP-DPN)-and 30 biopsies from healthy controls of similar age and sex. The biopsies were stained using PGP 9.5, IbA1, and SP and CGRP primary markers. RESULTS: There was increased macrophage density in patients with P-DPN (8.0%) compared with that in patients with NP-DPN (5.1%, p < 0.001), and there was increased macrophage density in patients with NP-DPN (5.1%) compared with that in healthy controls (3.1%, p < 0.001). When controlling for neuropathy severity, body mass index, age, and sex, there was still a difference in macrophage density between patients with P-DPN and patients with NP-DPN. Patients with P-DPN had higher median nerve fiber length density (274.5 and 155 mm-2 for SP and CGRP, respectively) compared with patients with NP-DPN (176 and 121 mm-2 for SP and CGRP, respectively, p = 0.009 and 0.04) and healthy controls (185.5 and 121.5 mm-2 for SP and CGRP, respectively), whereas there was no difference between patients with NP-DPN and controls without diabetes (p = 0.64 and 0.49, respectively). The difference between P-DPN and NP-DPN for SP and CGRP was significant only in female patients, although a trend was seen in male patients. DISCUSSION: The findings point to a possible involvement of the innate immune system in the pathogenesis of neuropathic pain in patients with DPN, although markers of activated macrophages were not measured in this study.

Predicting Outcome in Guillain-Barré Syndrome: International Validation of the Modified Erasmus GBS Outcome Score.

BACKGROUND AND OBJECTIVES: The clinical course and outcome of the Guillain-Barré syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with data from Dutch patients, is a clinical model that predicts the risk of walking inability in patients with GBS. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region specificity. METHODS: We used prospective data from the first 1,500 patients included in IGOS, aged ≥6 years and unable to walk independently. We evaluated whether the mEGOS at entry and week 1 could predict the inability to walk unaided at 4 and 26 weeks in the full cohort and in regional subgroups, using 2 measures for model performance: (1) discrimination: area under the receiver operating characteristic curve (AUC) and (2) calibration: observed vs predicted probability of being unable to walk independently. To improve the model predictions, we recalibrated the model containing the overall mEGOS score, without changing the individual predictive factors. Finally, we assessed the predictive ability of the individual factors. RESULTS: For validation of mEGOS at entry, 809 patients were eligible (Europe/North America [n = 677], Asia [n = 76], other [n = 56]), and 671 for validation of mEGOS at week 1 (Europe/North America [n = 563], Asia [n = 65], other [n = 43]). AUC values were >0.7 in all regional subgroups. In the Europe/North America subgroup, observed outcomes were worse than predicted; in Asia, observed outcomes were better than predicted. Recalibration improved model accuracy and enabled the development of a region-specific version for Europe/North America (mEGOS-Eu/NA). Similar to the original mEGOS, severe limb weakness and higher age were the predominant predictors of poor outcome in the IGOS cohort. DISCUSSION: mEGOS is a validated tool to predict the inability to walk unaided at 4 and 26 weeks in patients with GBS, also in countries outside the Netherlands. We developed a region-specific version of mEGOS for patients from Europe/North America. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the mEGOS accurately predicts the inability to walk unaided at 4 and 26 weeks in patients with GBS. TRIAL REGISTRATION INFORMATION: NCT01582763.

A candidate gene study of serotonergic pathway genes and pain relief during treatment with escitalopram in patients with neuropathic pain shows significant association to serotonin receptor2C (HTR2C).

PURPOSE: Previous studies have shown that a small fraction of patients with peripheral neuropathic pain experiences >50% pain relief during treatment with selective serotonin reuptake inhibitors (SSRIs), whereas most patients have no or only slight relief. The aim of this study was to investigate the association between polymorphisms in genes involved in the serotonergic pathway and the effect of escitalopram on peripheral neuropathic pain. METHODS: We genotyped 34 participants from a placebo-controlled trial of escitalopram in peripheral neuropathic pain for polymorphisms in five genes: the serotonin receptor 2A (HTR2A) gene, the serotonin receptor 2C (HTR2C) gene, the ABCB1 gene encoding for the P-glycoprotein, the CYP2C19 gene, and the serotonin transporter gene (SLC6A4). RESULTS: The SNP rs6318 (Cys23Ser) in the HTR2C gene showed significant association with treatment response in men (p = 0.047), with 75% carrying the C allele being responders. The same tendency was seen in women. Similarly, carriership of the C allele at rs6318 was associated with better pain relief during treatment with escitalopram [odds ratio (OR) 15.5, p = 0.014)] Furthermore, there was a tendency of better relief with increasing number of short alleles for the 5-HTTLPR polymorphism of the serotonin transporter (OR 5.7, p = 0.057). None of the other polymorphisms showed a significant association with treatment response to escitalopram. CONCLUSION: This study indicates that variation in the HTR2C gene is associated to the pain-relieving effect of escitalopram in patients with painful polyneuropathy.

Long-term follow-up of facilitated subcutaneous immunoglobulin therapy in multifocal motor neuropathy.

OBJECTIVE: To assess the feasibility, efficacy and patient satisfaction of long-term facilitated subcutaneous immunoglobulin therapy (fSCIG) in multifocal motor neuropathy (MMN). METHODS: Twelve patients previously participating in a randomized trial investigating the short-term efficacy of fSCIG were offered to switch to fSCIG maintenance therapy following a variable interval on conventional subcutaneous immunoglobulin. RESULTS: Eight patients were switched to fSCIG maintenance therapy, seven of whom were invited for a follow-up assessment after 18 months (range 13-23 months) of treatment. The age at follow-up was 57 years (range 45-70 years) and patients received a median weekly dose immunoglobulin G of 32.5 g (range 20.0-50.0 g), the dose being unaltered compared to baseline values following completion of the fSCIG trial. In five patients the infusion was biweekly, whereas two patients were infused weekly. The follow-up mean isometric strength normalized to pre-trial values was 107.7% (95% CI 86.4-129.0%) being non-inferior to baseline values (104.7%, 95% CI 97.6-111.8%, P = 0.015). The mean ODSS was 2.0 (95% CI 0.8-3.2) which is identical to the baseline score following completion of the fSCIG trial, the P-value for non-inferiority being <0.0001. The secondary variables of impairment, function and quality of life at follow-up all were non-inferior to baseline values (P ≤ 0.046). CONCLUSION: fSCIG seems feasible and effective for long-term maintenance treatment in patients with MMN.