Electrodiagnostic subtyping in Guillain-Barré syndrome patients in the International Guillain-Barré Outcome Study.

BACKGROUND AND PURPOSE: Various electrodiagnostic criteria have been developed in Guillain-Barré syndrome (GBS). Their performance in a broad representation of GBS patients has not been evaluated. Motor conduction data from the International GBS Outcome Study (IGOS) cohort were used to compare two widely used criterion sets and relate these to diagnostic amyotrophic lateral sclerosis criteria. METHODS: From the first 1500 patients in IGOS, nerve conduction studies from 1137 (75.8%) were available for the current study. These patients were classified according to nerve conduction studies criteria proposed by Hadden and Rajabally. RESULTS: Of the 1137 studies, 68.3% (N = 777) were classified identically according to criteria by Hadden and Rajabally: 111 (9.8%) axonal, 366 (32.2%) demyelinating, 195 (17.2%) equivocal, 35 (3.1%) inexcitable and 70 (6.2%) normal. Thus, 360 studies (31.7%) were classified differently. The areas of differences were as follows: 155 studies (13.6%) classified as demyelinating by Hadden and axonal by Rajabally; 122 studies (10.7%) classified as demyelinating by Hadden and equivocal by Rajabally; and 75 studies (6.6%) classified as equivocal by Hadden and axonal by Rajabally. Due to more strictly defined cutoffs fewer patients fulfilled demyelinating criteria by Rajabally than by Hadden, making more patients eligible for axonal or equivocal classification by Rajabally. In 234 (68.6%) axonal studies by Rajabally the revised El Escorial (amyotrophic lateral sclerosis) criteria were fulfilled; in axonal cases by Hadden this was 1.8%. CONCLUSIONS AND DISCUSSION: This study shows that electrodiagnosis in GBS is dependent on the criterion set utilized, both of which are based on expert opinion. Reappraisal of electrodiagnostic subtyping in GBS is warranted.

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.

Small and large fiber sensory polyneuropathy in type 2 diabetes: Influence of diagnostic criteria on neuropathy subtypes.

Diabetic polyneuropathy (DPN) can be classified based on fiber diameter into three subtypes: small fiber neuropathy (SFN), large fiber neuropathy (LFN), and mixed fiber neuropathy (MFN). We examined the effect of different diagnostic models on the frequency of polyneuropathy subtypes in type 2 diabetes patients with DPN. This study was based on patients from the Danish Center for Strategic Research in Type 2 Diabetes cohort. We defined DPN as probable or definite DPN according to the Toronto Consensus Criteria. DPN was then subtyped according to four distinct diagnostic models. A total of 277 diabetes patients (214 with DPN and 63 with no DPN) were included in the study. We found a considerable variation in polyneuropathy subtypes by applying different diagnostic models independent of the degree of certainty of DPN diagnosis. For probable and definite DPN, the frequency of subtypes across diagnostic models varied from: 1.4% to 13.1% for SFN, 9.3% to 21.5% for LFN, 51.4% to 83.2% for MFN, and 0.5% to 14.5% for non-classifiable neuropathy (NCN). For the definite DPN group, the frequency of subtypes varied from: 1.6% to 13.5% for SFN, 5.6% to 20.6% for LFN, 61.9% to 89.7% for MFN, and 0.0% to 6.3% for NCN. The frequency of polyneuropathy subtypes depends on the type and number of criteria applied in a diagnostic model. Future consensus criteria should clearly define sensory functions to be tested, methods of testing, and how findings should be interpreted for both clinical practice and research purpose.

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.

Statins and polyneuropathy revisited: case-control study in Denmark, 1999-2013.

AIM: In a previous study, we found a positive association between statin use and polyneuropathy risk. Other studies reported equivocal results. The present study aimed to confirm our findings with a design similar to that used in our previous study but with a larger data set. METHODS: We searched medical registry data to identify patients diagnosed with incident polyneuropathy of no known cause (idiopathic polyneuropathy) between 1999 and 2013; we verified diagnoses through medical records. For each case, we recruited 20 general population controls with no previous history of polyneuropathy. Controls were matched to their respective case for age and gender. We ascertained the prior statin use of cases and controls through a prescription registry. Based on this information, exposure to statins was categorized into 'ever use' or 'never use'. Ever use of statins was classified by how recently they had been used ('current use' or 'past use'); current use was further classified into long-term use (5+ years) and high- or low-intensity use. We used conditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs) to examine associations between polyneuropathy and statin use. RESULTS: We included 370 validated cases and 7400 controls. Ever use of statins was not associated with an elevated risk of polyneuropathy (OR 1.14, 95% CI 0.84, 1.54). Similarly, we found no associations between polyneuropathy risk and current use (OR 1.11, 95% CI 0.79, 1.53), long-term use (OR 1.13, 95% CI 0.66, 1.92) or high-intensity statin use (OR 1.05, 95% CI 0.59, 1.84). CONCLUSION: Statin use was not associated with an increased risk of idiopathic polyneuropathy.

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.

The effect of lacosamide in peripheral neuropathic pain: A randomized, double-blind, placebo-controlled, phenotype-stratified trial.

BACKGROUND: Neuropathic pain is common and difficult to treat. The sodium channel blocker lacosamide is efficacious in animal models of pain, but its effect on neuropathic pain in humans is inconclusive. METHODS: In a multicentre, randomized, double-blinded placebo-controlled phenotype stratified trial, we examined if lacosamide produced better pain relief in patients with the irritable nociceptor phenotype compared to those without. The primary outcome was the change in daily average pain from baseline to last week of 12 weeks of treatment. Secondary and tertiary outcomes included pain relief, patient global impression of change and presence of 30% and 50% pain reduction. RESULTS: The study was prematurely closed with 93 patients included and 63 randomized to lacosamide or placebo in a 2:1 ratio, of which 49 fulfilled the per protocol criteria and was used for the primary objective. We did not find a better effect of lacosamide in patients with the irritable nociceptor phenotype, the 95% CI for the primary objective was 0.41 (-1.2 to 2.0). For all patients randomized, lacosamide had no effect on the primary outcome, but significantly more patients were responders to lacosamide than during placebo, with an NNT of 4.0 (95% CI 2.3-16.1) and 5.0 (95% CI 2.8-24.5) for 30% and 50% pain reduction respectively. We did not identify any predictors for response. Lacosamide was generally well tolerated. CONCLUSION: We could not confirm that lacosamide was more efficacious in patients with the irritable nociceptor type, but the study was prematurely closed, so we cannot exclude a small difference. SIGNIFICANCE: Treatment of neuropathic pain is often a trial and error process. Little is known about which patient benefit from which kind of medication. The sodium channel blocker lacosamide shows variable effect on neuropathic pain. Pain sensory phenotype, as defined by quantitative sensory testing, did not predict response to treatment with lacosamide.

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.

Assessing Corneal Confocal Microscopy and Other Small Fiber Measures in Diabetic Polyneuropathy.

BACKGROUND AND OBJECTIVES: Damage to small nerve fibers is common in diabetic polyneuropathy (DPN), and the diagnosis of DPN relies on subjective symptoms and signs in a combination with objective confirmatory tests, typically electrophysiology or intraepidermal nerve fiber density (IENFD) from skin biopsy. Corneal confocal microscopy (CCM) has been introduced as a tool to detect DPN. However, it is unclear if CCM can reliably be used to diagnose DPN and how the technique compares with other commonly used measures of small fiber damage, such as IENFD, cold detection threshold (CDT), and warm detection threshold (WDT). Therefore, we assessed and compared the use of CCM, IENFD, CDT, and WDT in the diagnosis of DPN in patients with type 2 diabetes. METHODS: In this cohort study, the participants underwent detailed neurologic examination, electrophysiology, quantification of IENFD, CCM, and quantitative sensory testing. Definition of DPN was made in accordance with the Toronto criteria for diabetic neuropathy (without relying on IENFD and thermal thresholds). RESULTS: A total of 214 patients with at least probable DPN, 63 patients without DPN, and 97 controls without diabetes were included. Patients with DPN had lower CCM measures (corneal nerve fiber length [CNFL], nerve fiber density, and branch density), IENFD, CDT, and WDT compared with patients without DPN (p ≤ 0.001, <0.001, 0.002, p < 0.001, p = 0.003, and <0.005, respectively), whereas there was no difference between controls and patients with diabetes without DPN. All 3 CCM measures showed a very low diagnostic sensitivity with CNFL showing the highest (14.4% [95% CI 9.8-18.4]) and a specificity of 95.7% (88.0-99.1). In comparison, the sensitivity of abnormal CDT and/or WDT was 30.5% (24.4-37.0) with a specificity of 84.9% (74.6-92.2). The sensitivity of abnormal IENFD was highest among all measures with a value of 51.1% (43.7-58.5) and a specificity of 90% (79.5-96.2). CCM measures did not correlate with IENFD, CDT/WDT, or neuropathy severity in the group of patients with DPN. DISCUSSION: CCM measures showed the lowest sensitivity compared with other small fiber measures in the diagnosis of DPN. This indicates that CCM is not a sensitive method to detect DPN in recently diagnosed type 2 diabetes. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CCM measures aid in the detection of DPN in recently diagnosed type 2 diabetics but with a low sensitivity when compared with other small fiber measures.

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.

CSF Findings in Relation to Clinical Characteristics, Subtype, and Disease Course in Patients With Guillain-Barré Syndrome.

BACKGROUND AND OBJECTIVES: To investigate CSF findings in relation to clinical and electrodiagnostic subtypes, severity, and outcome of Guillain-Barré syndrome (GBS) based on 1,500 patients in the International GBS Outcome Study. METHODS: Albuminocytologic dissociation (ACD) was defined as an increased protein level (>0.45 g/L) in the absence of elevated white cell count (<50 cells/µL). We excluded 124 (8%) patients because of other diagnoses, protocol violation, or insufficient data. The CSF was examined in 1,231 patients (89%). RESULTS: In 846 (70%) patients, CSF examination showed ACD, which increased with time from weakness onset: ≤4 days 57%, >4 days 84%. High CSF protein levels were associated with a demyelinating subtype, proximal or global muscle weakness, and a reduced likelihood of being able to run at week 2 (odds ratio [OR] 0.42, 95% CI 0.25-0.70; p = 0.001) and week 4 (OR 0.44, 95% CI 0.27-0.72; p = 0.001). Patients with the Miller Fisher syndrome, distal predominant weakness, and normal or equivocal nerve conduction studies were more likely to have lower CSF protein levels. CSF cell count was <5 cells/µL in 1,005 patients (83%), 5-49 cells/µL in 200 patients (16%), and ≥50 cells/µL in 13 patients (1%). DISCUSSION: ACD is a common finding in GBS, but normal protein levels do not exclude this diagnosis. High CSF protein level is associated with an early severe disease course and a demyelinating subtype. Elevated CSF cell count, rarely ≥50 cells/µL, is compatible with GBS after a thorough exclusion of alternative diagnoses. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that CSF ACD (defined by the Brighton Collaboration) is common in patients with GBS.

Association Between Incident Cancer and Guillain-Barré Syndrome Development: A Nationwide Case-Control Study.

BACKGROUND AND OBJECTIVES: Cancer may increase the risk of developing Guillain-Barré syndrome (GBS) due to molecular mimicry or immunosuppression, but the exact relationship is unclear. We aimed to determine the association between incident cancer and the following risk of GBS development. METHODS: We conducted a nationwide population-based case-control study of all patients with first-time hospital-diagnosed GBS in Denmark between 1987 and 2016 and 10 age-, sex-, and index date-matched population controls per case. We identified incident cancer diagnoses between 6 months before and 2 months after the GBS index date. We used conditional logistic regression to compute odds ratios (ORs) as a measure of relative risk and performed stratified analyses to assess the impact of cancer on GBS risk in strata of calendar periods, sex, and age. In sensitivity analyses, to assess any potential risk of survival bias induced by including cancer diagnoses potentially made after GBS diagnosis, we examined incident cancers in both a broader exposure window (1 year before to 3 months after GBS index date) and a narrower window (6 months to 1 month before the GBS index date). RESULTS: Of the 2,414 patients with GBS and 23,909 controls included, 49 cases (2.0%) and 138 controls (0.6%) had a recent cancer diagnosis, yielding a matched OR of 3.6 (95% CI 2.6-5.1) for GBS associated with cancer. Stratification by calendar time, sex, and age showed robust results for the association between cancer and GBS, with no major variations. Broadening and narrowing the exposure window produced slightly weakened associations of OR of 2.4 (95% CI 1.8-3.3) and 2.5 (95% CI 1.5-4.1), respectively. The GBS ORs were highest for cancers of the lymphatic and hematopoietic tissue (OR 7.2, 95% CI 2.9-18.0), respiratory tract (OR 5.6, 95% CI 2.7-11.9), prostate and other male genital organ (OR 5.0, 95% CI 2.1-11.6), and breast (OR 5.0, 95% CI 1.7-14.5) cancer. DISCUSSION: In this large nationwide epidemiologic study, incident cancer was associated with a markedly increased risk of subsequent GBS development. The results suggest that as-yet unidentified factors present in several types of cancer drive this association.