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.

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.

An International Perspective on Preceding Infections in Guillain-Barré Syndrome: The IGOS-1000 Cohort.

BACKGROUND AND OBJECTIVES: Infections play a key role in the development of Guillain-Barré syndrome (GBS) and have been associated with specific clinical features and disease severity. The clinical variation of GBS across geographical regions has been suggested to be related to differences in the distribution of preceding infections, but this has not been studied on a large scale. METHODS: We analyzed the first 1,000 patients included in the International GBS Outcome Study with available biosamples (n = 768) for the presence of a recent infection with Campylobacter jejuni, hepatitis E virus, Mycoplasma pneumoniae, cytomegalovirus, and Epstein-Barr virus. RESULTS: Serologic evidence of a recent infection with C. jejuni was found in 228 (30%), M. pneumoniae in 77 (10%), hepatitis E virus in 23 (3%), cytomegalovirus in 30 (4%), and Epstein-Barr virus in 7 (1%) patients. Evidence of more than 1 recent infection was found in 49 (6%) of these patients. Symptoms of antecedent infections were reported in 556 patients (72%), and this proportion did not significantly differ between those testing positive or negative for a recent infection. The proportions of infections were similar across continents. The sensorimotor variant and the demyelinating electrophysiologic subtype were most frequent across all infection groups, although proportions were significantly higher in patients with a cytomegalovirus and significantly lower in those with a C. jejuni infection. C. jejuni-positive patients were more severely affected, indicated by a lower Medical Research Council sum score at nadir (p = 0.004) and a longer time to regain the ability to walk independently (p = 0.005). The pure motor variant and axonal electrophysiologic subtype were more frequent in Asian compared with American or European C. jejuni-positive patients (p < 0.001, resp. p = 0.001). Time to nadir was longer in the cytomegalovirus-positive patients (p = 0.004). DISCUSSION: Across geographical regions, the distribution of infections was similar, but the association between infection and clinical phenotype differed. A mismatch between symptom reporting and serologic results and the high frequency of coinfections demonstrate the importance of broad serologic testing in identifying the most likely infectious trigger. The association between infections and outcome indicates their value for future prognostic models.

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.

A randomized, controlled trial of a ß2-agonist in painful polyneuropathy.

ABSTRACT: Experimental data have suggested that in neuropathic pain, tricyclic antidepressants may work solely through a ß2-agonist action. The aim of this study was to test if the ß2-agonist terbutaline relieves painful polyneuropathy. The study was a randomized, double-blind, placebo-controlled and active-controlled, 3-way, cross-over trial among patients with painful polyneuropathy. The treatment periods were of 5 weeks' duration and were preceded by 1 week for washout and 1 week for baseline observations. The patients received terbutaline (5-15 mg), imipramine (30-150 mg), or placebo in a random order. Drug doses depended on age and metabolizer status. The change in total pain recorded from ratings in diaries (numeric rating scale [NRS] 0-10) was the primary outcome, and the change in rating of specific pain symptoms (NRS 0-10), patient global impression of change, and sleep disturbance were secondary outcomes. Forty-seven patients were randomized. The median score for total pain changed from NRS 6.4 to 6.1 from baseline to week 5 on terbutaline with an average effect during the treatment period as compared with placebo of 0.13 (95% confidence interval -0.12 to 0.38, P = 0.32). The median score for total pain on imipramine changed from NRS 6.6 to 4.8 with an average effect as compared with placebo of -1.17 (95% confidence interval -1.42 to -0.92, P < 0.001). Secondary outcomes were also unaltered by terbutaline but improved by imipramine. The ß2-agonist terbutaline has no effect in painful polyneuropathy. ß2-agonism seems not to be an important mechanism of action of tricyclic antidepressants in neuropathic pain.

Factors with impact on magnitude of the placebo response in randomized, controlled, cross-over trials in peripheral neuropathic pain.

The presence and magnitude of placebo responses is important for the outcome in clinical trials of analgesics. This explorative study aimed at identifying patients and trial-specific factors with impact on this response in randomized, controlled, cross-over trials in peripheral neuropathic pain. Data were derived from 7 trials and included observations on pinprick hyperalgesia, allodynia, and pain on repetitive stimulation. The studies were all performed by the same collaboration group in Denmark. Pain was rated daily using numeric 0 to 10 point rating scales (NRS) and placebo response was calculated as the difference in weekly average or median numeric rating scale from baseline to the last week of treatment. A clinically meaningful placebo response was defined as more than 30% reduction of pain on placebo. In 318 individual observations, the response was on average small (0.17 points, range -4.5 to 6). There was no significant impact on size of placebo response of trial-specific factors such as treatment sequence and chance of having placebo treatment in each period or of the patient-specific factors age, sensory signs, and pain symptoms. The findings were similar in patients having placebo in the first treatment period. There was no marked difference between patients with (n = 43) and without (n = 275) a clinically meaningful placebo response with respect to the patient-specific factors including frequency of sensory signs and symptoms. In conclusion, this study on cross-over trials in peripheral neuropathic pain found no robust impact of trial and patient-specific factors on the placebo response.

Effect of lacosamide in peripheral neuropathic pain: study protocol for a randomized, placebo-controlled, phenotype-stratified trial.

BACKGROUND: Neuropathic pain is a common pain condition that has a major negative impact on health-related quality of life. However, despite decades of research, it remains difficult to treat neuropathic pain. Lacosamide is a sodium-channel blocker that is efficacious in animal models of neuropathic pain. In humans, its effect in neuropathic pain is inconclusive, based on inconsistent results and very large placebo responses. Previous trials have not used patient stratification or looked for predictors for response. METHODS: This study will be conducted as a multicenter, randomized, double-blind, placebo-controlled, parallel, phase 2, proof-of-concept, phenotype-stratified study. The study will enroll 108 patients with peripheral neuropathic pain who will be randomized to a 12-week treatment with lacosamide or placebo up to 400 mg/day in a 2:1 ratio. The primary objective is to compare the change in the mean value of the patients' daily ratings of average pain intensity from baseline to the last week of treatment in patients with and without the irritable nociceptor phenotype in the per-protocol population. A supportive objective is to compare the effect of lacosamide with that of placebo in the two phenotypes. Secondary and tertiary outcomes include the Patient Global Impression of Change, pain relief, presence of 30% and 50% pain reduction, sleep disturbance, depression, and anxiety. DISCUSSION: We will examine the concept of individualized therapy based on phenotyping, and expect that this study will provide important information on the usefulness of lacosamide in the treatment of peripheral neuropathic pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03777956 . Registered on 18 December 2018.

The Impact of Serum Drug Concentration on the Efficacy of Imipramine, Pregabalin, and their Combination in Painful Polyneuropathy.

OBJECTIVE: The aim of this study was to explore the serum concentration-effect relation for first-line drugs in neuropathic pain and to determine if efficacy could be increased. METHODS: Data from a randomized, placebo-controlled, cross-over trial on imipramine, pregabalin, and their combination in painful polyneuropathy were used. Treatment periods were of 4 weeks' duration, outcome was the weekly median of daily pain rated by a 0 to 10 numeric scale, and drug concentrations were determined by high-performance liquid chromatography. RESULTS: In 47 patients, pain was reduced -1.0 (95% confidence interval [CI], -1.5 to -0.6) by imipramine, -0.4 (95% CI, -0.9 to 0.1) by pregabalin, and -1.6 (95% CI, -2.1 to -1.1) by combination therapy. On monotherapy, there was no difference between responders and nonresponders with respect to concentrations of imipramine (mean, 161 vs. 229 nmol/L, P=0.129) and pregabalin (mean, 9.8 vs. 11.7 µmol/L, P=0.178). There was no correlation between drug concentration and pain reduction for imipramine (r=0.17, P=0.247), whereas there was a marginally, positive correlation for pregabalin (r=0.28, P=0.057). There was no interaction between treatment and concentration classes (imipramine < or ≥100 nmol/L, pregabalin < or ≥10 µmol/L) either for monotherapy or for combination therapy (P=0.161 to 0.797). Isobolographic presentations of reponders with imipramine and pregabalin concentrations during combination therapy did not indicate synergistic interaction. DISCUSSION: There were no important relations between drug concentrations and efficacy, or indication of synergistic interaction between the drugs. It was not concluded that treatment can be improved by measurement of drug concentration of pregabalin.

Pain phenotype as a predictor for drug response in painful polyneuropathy-a retrospective analysis of data from controlled clinical trials.

The drugs available for treatment of neuropathic pain have somewhat disappointing efficacy with many patients left with limited or no effect. Individualized treatment based on phenotype according to presumed underlying pain mechanism(s) has been proposed to improve outcomes. We report a retrospective analysis of phenotype-specific effects of several neuropathic pain drugs, which were studied in a series of crossover, placebo-controlled, clinical trials. The data originate from 7 trials with similar design and outcome recordings, which all had a thorough baseline registration of symptoms, signs, and quantitative sensory testing. The latter was used to phenotype patients into subgroups reflecting presumed pain mechanisms. There were a total of 361 patient records distributed over treatments with 4 antidepressants and 4 anticonvulsants. Five of the drugs reduced total pain significantly compared with placebo. Only a few phenotype-specific differences in total pain reduction were found within the investigated drugs. Thus, imipramine reduced total pain 1.84 (CI: 0.02-3.67) and pregabalin 0.81 (CI: -0.67 to 2.29) in patients with than without gain of sensory function. Pregabalin showed a better effect in patients with preserved large fiber function with a mean difference in total pain reduction 1.31 (CI: 0.15-2.47). No phenotype-specific effects were found for venlafaxine, escitalopram, oxcarbazepine, valproic acid, levetiracetam, or St. John's wort. Thus, this post hoc analysis of 8 drugs with mainly nonselective actions on neuropathic pain mechanisms found limited usefulness of sensory phenotyping in pain as the basis for individualized treatment.

Imipramine and pregabalin combination for painful polyneuropathy: a randomized controlled trial.

Monotherapy with first-line drugs for neuropathic pain often fails to provide sufficient pain relief or has unacceptable side effects because of the need for high doses. The aim of this trial was to test whether the combination of imipramine and pregabalin in moderate doses would relieve pain more effectively than monotherapy with either of the drugs. This was a randomized, double-blind, placebo-controlled, crossover, multicenter trial consisting of four 5-week treatment periods in patients with painful polyneuropathy. Treatment arms were imipramine 75 mg/d vs pregabalin 300 mg/d vs combination therapy vs placebo. Patients with polyneuropathy and symptoms for more than 6 months, age 20 to 85 years, pain intensity ≥4 on a 0- to 10-point numeric rating scale (NRS) and pain at least 4 days a week were included in the trial. A total of 262 patients were screened for participation, 73 patients were randomized, and 69 patients were included in the data analysis. The effect on average pain in comparison with placebo was: combination (-1.67 NRS points, P < 0.001), imipramine (-1.08 NRS points, P < 0.001), and pregabalin (-0.48 NRS points, P = 0.03). The combination therapy had significantly lower pain scores than both monotherapies: combination vs imipramine (P = 0.009), combination vs pregabalin (P < 0.001). During combination therapy, the dropout rate was higher and the patients reported a higher rate and severity of side effects. Combination of moderate doses of the tricyclic antidepressant imipramine and pregabalin could be considered as an alternative to high-dosage monotherapy. However, the trial also emphasized that balance between efficacy and safety is an issue.

The anticonvulsant levetiracetam for the treatment of pain in polyneuropathy: a randomized, placebo-controlled, cross-over trial.

UNLABELLED: Levetiracetam is an anticonvulsant which is assumed to act by modulating neurotransmitter release via binding to the vesicle protein SV2A. This could have an impact on signaling in the nociceptive system, and a pilot study indicated relief of neuropathic pain with levetiracetam. OBJECTIVES: The aim of this study was to test the analgesic effect of levetiracetam in painful polyneuropathy. METHODS: This was a randomized, double-blind, placebo-controlled, cross-over trial with levetiracetam 3000 mg/day versus placebo (6-week treatment periods). Patients with diagnosed polyneuropathy and symptoms for more than 6 months, age between 20 and 80 years, pain intensity of more than 4 on a 0-10-point numeric rating scale, and pain at least 4 days a week were included in the study. The primary outcome measure was pain relief at the end of each treatment period as measured on a 6-point verbal scale. RESULTS: Ninety-three patients were screened for participation and 39 patients entered the study. Thirty-five patients were included in the data analysis. There were no differences in the ratings of pain relief (levetiracetam 2.29 versus placebo 2.28, p=0.979), total pain intensity (levetiracetam 5.5 versus placebo 5.3, p=0.293) or any of the other outcome measures (p=0.147-1.00). CONCLUSION: This study indicates that the anticonvulsant levetiracetam has no clinically relevant effect on painful polyneuropathy.