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Pompe disease is an inherited metabolic myopathy caused by deficiency of acid α-glucosidase (GAA), resulting in lysosomal glycogen accumulation. Residual GAA enzyme activity affects disease onset and severity, although other factors, including dysregulation of cytoplasmic glycogen metabolism, are suspected to modulate the disease course. In this study, performed in mice and patient biopsies, we found elevated protein levels of enzymes involved in glucose uptake and cytoplasmic glycogen synthesis in skeletal muscle from mice with Pompe disease, including glycogenin (GYG1), glycogen synthase (GS), glucose transporter 4 (GLUT4), glycogen branching enzyme (GBE1), and UDP-glucose pyrophosphorylase (UGP2). Expression levels were elevated before the loss of muscle mass and function. For first time, quantitative mass spectrometry in skeletal muscle biopsies from five adult patients with Pompe disease showed increased expression of glycogen branching enzyme protein relative to healthy controls at the group level. Paired analysis of individual patients who responded well to treatment with enzyme replacement therapy (ERT) showed reduction of glycogen synthase, glycogenin, and glycogen branching enzyme 1 in all patients after start of ERT compared to baseline. These results indicate that metabolic changes precede muscle wasting in Pompe disease, and imply a positive feedforward loop in Pompe disease, in which lysosomal glycogen accumulation promotes cytoplasmic glycogen synthesis and glucose uptake, resulting in aggravation of the disease phenotype.

Our objective was to investigate brain structure, cerebral vasculature, and cognitive function in a cohort of patients with late-onset Pompe disease, with particular reference to the differences from those with the classic infantile phenotype, where extensive white-matter abnormalities (WMA) and impaired cognition on long-term enzyme treatment are reported in a subset of patients. Brain imaging (T1, T2, T2 fluid-attenuated inversion recovery, susceptibility-weighted images, and magnetic resonance angiography-time of flight) was combined with extensive cognitive testing of general intelligence (Wechsler IQ Test, Montreal Cognitive Assessment [MoCA]) and specific neuropsychological domains (verbal fluency, cognitive flexibility, attention, memory, and visuospatial abilities). We included 19 patients with late-onset Pompe disease (age range 11-56 years). Two patients showed mild punctate WMA within normal range for age, with a Fazekas score (FS) of 1 to 2. Magnetic resonance angiography revealed a slight vertebrobasilar dolichoectasia in two patients yet did not show any aneurysms or vascular dissections. Most patients had age-adjusted scores within the normal range for the Wechsler index scores (verbal comprehension, perceptual reasoning, working memory, and processing speed) and combined total intelligence (IQ) score (median 101, interquartile range 91-111; one patient had a below-average score for total IQ) as well as for the specific domains verbal fluency, attention, and memory. A subset of patients performed suboptimally on the Rey Complex Figure Test (9/14 patients) or cube-copying/clock-drawing test of the MoCA (8/10 patients). We therefore concluded that our study showed no brain abnormalities, other than minor microvascular lesions considered within normal range for age, nor general cognitive impairment in late-onset Pompe patients. These findings are in sharp contrast with the widespread WMA and cognitive problems found in some classic infantile patients.

Objective: To revise the 2010 consensus guideline on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods: Seventeen disease experts, a patient representative, and two Cochrane methodologists constructed 12 Population/Intervention/Comparison/Outcome (PICO) questions regarding diagnosis and treatment to guide the literature search. Data were extracted and summarized in GRADE summary of findings (for treatment PICOs) or evidence tables (for diagnostic PICOs). Results: Statements were prepared according to the GRADE Evidence-to-Decision frameworks. Typical CIDP and CIDP variants were distinguished. The previous term “atypical CIDP” was replaced by “CIDP variants” because these are well characterized entities (multifocal, focal, distal, motor, or sensory CIDP). The levels of diagnostic certainty were reduced from three (definite, probable, possible CIDP) to only two (CIDP and possible CIDP), because the diagnostic accuracy of criteria for probable and definite CIDP did not significantly differ. Good Practice Points were formulated for supportive criteria and investigations to be considered to diagnose CIDP. The principal treatment recommendations were: (a) intravenous immunoglobulin (IVIg) or corticosteroids are strongly recommended as initial treatment in typical CIDP and CIDP variants; (b) plasma exchange is strongly recommended if IVIg and corticosteroids are ineffective; (c) IVIg should be considered as first-line treatment in motor CIDP (Good Practice Point); (d) for maintenance treatment, IVIg, subcutaneous immunoglobulin or corticosteroids are recommended; (e) if the maintenance dose of any of these is high, consider either combination treatments or adding an immunosuppressant or immunomodulatory drug (Good Practice Point); and (f) if pain is present, consider drugs against neuropathic pain and multidisciplinary management (Good Practice Point).

High peak levels of serum IgG may not be needed for maintenance treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with intravenous immunoglobulin (IVIg). More frequent dosing of IVIg leads to more stable IgG levels and higher trough levels which may be related with improved clinical efficacy. More frequent lower dosing leads to lower peak levels and may induce less systemic side-effects. The DRIP study is a double-blind randomized controlled cross-over intervention study. CIDP patients ≥18 years old, proven IVIg dependent and receiving an individually established but stable maintenance dose and interval of IVIg (Kiovig) can be included. One group (A) will be treated with their normal dosage and interval of IVIg and receive a placebo (albumin 0.5%) infusion in between their regular IVIg infusions, for a total of four infusions. The other group (B) will be treated with half their normal IVIg dosage (with the same volume of placebo to maintain the total volume) at half their interval (double their frequency) for four infusions. After a wash-out phase (2 infusions), patients will cross-over to the other treatment group. During the study the total dose of IVIg administered will remain unchanged as before start of the trial. The main objective is to investigate whether high frequent low dosage IVIg treatment is more effective than low frequent high dosage IVIg treatment as maintenance treatment for CIDP. Hand grip strength, as measured by the Martin Vigorimeter, will be used as the primary outcome measure. Secondary objective is to investigate whether high frequent low dosage of IVIg results in less adverse events compared to low frequent high dosage treatment. The DRIP study is currently ongoing and the protocol is presented.

Patients with Miller Fisher syndrome (MFS) may have a relatively mild clinical course or progress to Guillain-Barre syndrome (GBS) with limb weakness (MFS-GBS overlap syndrome). Other variants in this spectrum are GBS with ophthalmoparesis and Bickerstaff's Brainstem encephalitis (BBE). To compare the clinical course of MFS and overlap syndromes and to identify predictors of disease progression. In a prospective study of 170 patients with GBS and variant forms, 37 (22%) had a MFS, MFS-GBS overlap syndrome, ophthalmoplegic GBS or BBE. The clinical, serological, and electrophysiological features were compared. Twenty-three patients presented with MFS, of which 10 (43%) developed limb weakness (MFS-GBS overlap syndrome). All these transitions occurred in the first week after onset of symptoms. There were no differences in the clinical, electrophysiological and serological features at entry between MFS and MFS-GBS. Twelve patients had ophthalmoplegic GBS and the disease severity at nadir and outcome was worse than in the patients with a MFS-GBS overlap syndrome. No early predictors for progression from MFS to MFS-GBS overlap syndrome were found. All transitions occurred in the first week. This finding implicates that all patients with MFS need careful monitoring for at least 1 week.

Skin biopsies from patients with neuropathic pain often show changes in epidermal innervation, although it remains to be elucidated to what extent such changes can be linked to a particular subgroup of nerve fibers and how these changes are correlated with pain intensity. Here, we investigated to what extent behavioral signs of hyperalgesia are correlated with immunohistochemical changes of peptidergic and non-peptidergic epidermal nerve fibers in a rat model of nerve injury-induced pain. Rats subjected to unilateral partial ligation of the sciatic nerve developed significant mechanical and thermal hyperalgesia as tested by the withdrawal responses of the ipsilateral footpad to von Frey hairs and hotplate stimulation. At day 14, epidermal nerve fiber density (IENFD) and total epidermal nerve fiber length/mm(2) (ENFL) were significantly and consistently reduced compared to the contralateral side, following testing and re-testing by two blinded observers. The expression of calcitonin gene-related peptide (CGRP), a marker for peptidergic nerve fibers, was not significantly changed on the ipsilateral side. In contrast, the expression of the P2X3 receptor, a marker for non-peptidergic nerve fibers, was not only significantly reduced but could also be correlated with behavioral hyperalgesia. When labeling both peptidergic and non-peptidergic nerve fibers with the pan-neuronal marker PGP9.5, the expression was significantly reduced, albeit without a significant correlation with behavioral hyperalgesia. In conjunction, our data suggest that the pathology of the P2X3 epidermal nerve fibers can be selectively linked to neuropathy, highlighting the possibility that it is the degeneration of these fibers that drives hyperalgesia. This article is protected by copyright. All rights reserved.

Polyneuropathy is a prevalent and disabling disorder. Despite extensive evaluation, the cause often remains unknown. Factors that predispose for the development of polyneuropathy need to be identified. We investigated the effect of anthropometric and metabolic factors on peripheral nerve function in 908 participants of the population-based Rotterdam Study without any symptoms or signs of polyneuropathy. Participants underwent nerve conduction studies of the sural and peroneal nerve. Data on age, height, weight, waist circumference, diabetes, lipid levels, hypertension, and kidney function were collected. Regression analyses were used to investigate determinants of nerve action potential amplitudes. The frequency of abnormal sural sensory nerve action potential (SNAP) amplitudes increased with age from 1% under 60 years to 23% over 80 years. Similarly, the frequency of abnormal peroneal nerve compound motor action potential (CMAP) amplitudes increased from 4% to 13%. High weight and body mass index were independently associated with reduced sural SNAP amplitudes and peroneal CMAP amplitudes. Participants with hypertension and kidney dysfunction were more likely to have abnormal sural SNAP amplitudes. Older age, high weight, hypertension, and moderate kidney dysfunction might thus lead to peripheral nerve dysfunction in persons yet without symptoms or signs of polyneuropathy.

Epidemiological studies that investigate the occurrence and determinants of chronic length-dependent polyneuropathy are scarce. Population-based studies on polyneuropathy require a valid and reliable screening protocol with both good sensitivity and specificity. Several questionnaires and scoring scales have been developed for the detection of polyneuropathy, grading the severity of the disease, or evaluating the clinical course during follow-up. This review summarizes the aims and content of existing diagnostic polyneuropathy screening tools in order to help future studies decide which scale to use for screening in specific situations. We searched the PubMed database and identified 27 scales, 13 are based on symptoms alone, 8 on neurological signs alone, and 6 on a combination of symptoms and signs. Scales that combine questions concerning symptoms and a neurological examination with a focus on sensory alterations seem to have the best discriminatory power. However, all scoring scales were developed for and investigated in prespecified patient populations. Therefore, the generalizability of specific findings to the general population may be limited. We also discuss other limitations of existing scales. Future studies are required to determine which clinimetrically well-developed scales are preferred for use in population-based studies.

_Introduction:_ The aim of this study was to determine whether electrically evoked multiplet discharges (MDs) are related to severity of clinical deterioration in motor neuron disease (MND). _Methods:_ Stimulated high-density surface electromyographic (HDsEMG) recordings were performed in thenar muscles. Data were collected from 31 MND patients. MDs from the HDsEMG recordings were determined at baseline. ALSFRS-R scores were obtained at baseline and at a maximum of 16 weeks follow-up. _Results:_ The presence of MDs was associated with progressive deterioration of ALSFRS-R score (P = 0.02) and fine motor function (FMF) (P < 0.001). Patients who had a higher number of motor units that generated MDs (r = 0.61, P < 0.001) and patients who had a higher number of MDs (as percentage of applied stimuli) (r = 0.59, P = 0.001) had a more severe decline in FMF. _Conclusions:_ Electrically evoked MDs are associated with more marked clinical deterioration in patients with MND.

Introduction: Fasciculations, the spontaneous activity of single motor units (MUs) are characteristic, but nonspecific for motor neuron disease (MND). We aimed to identify MU discharge properties to optimally differentiate MND patients from healthy controls. Methods: High-density surface electromyography recordings were performed in the thenar muscles during 10 min of rest. MU discharges were classified as “isolated” when the interspike intervals (ISIs) before and after were > 250 ms, “continual” when both ISIs were ≤ 250 ms, or as “other”. Results: In patients (n = 30) compared with controls (n = 14), more MUs were active (9 vs. 3, P < 0.001) and generated relatively more isolated discharges (35% vs. 10%, P = 0.01). Two or more MUs with isolated discharges occurred more frequently in patients compared with controls (24% vs.

This study aimed to 'define responder' through the concept of minimum clinically important differences using the individually obtained standard errors (MCID-SE) and a heuristic 'external criterion' responsiveness method in patients with Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). One hundred and fourteen newly diagnosed or relapsing patients (GBS: 55, CIDP: 59) were serially examined (1-year follow-up). The inflammatory Rasch-built overall disability scale (I-RODS), Rasch-transformed MRC sum score (RT-MRC), and Rasch-transformed modified-INCAT-sensory scale (RT-mISS) were assessed. Being-a-responder was defined as having a MCID-SE cut-off ≥1.96. Also, the correlations between patients' scores on each scale and the EuroQoL health-status 'thermometer' (external criterion) were determined (higher correlation indicated better responsiveness). In both diseases, the SEs showed a characteristic 'U'-shaped dynamic pattern across each scales' continuum. The number of patients showing a meaningful change were higher for the I-RODS > RT-MRC > RT-mISS and were in GBS higher than CIDP patients. The MCID-SE concept using Rasch-transformed data demonstrated an individual pattern of 'being-a-responder' in patients with immune-mediated neuropathies, and the findings were validated by the external criterion responsiveness method. The I-RODS showed greater responsiveness compared with the MRC and INCAT-sensory scales, and its use is therefore recommended in future trials in GBS and CIDP.

The Jamar dynamometer and Vigorimeter have been used to assess grip strength in immune-mediated neuropathies, but have never been compared to each other. Therefore, we performed a comparison study between these two devices in patients with immune-mediated neuropathies. Grip strength data were collected in 102 cross-sectional stable and 163 longitudinal (new diagnoses or changing condition) patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), gammopathy-related polyneuropathy (MGUSP), and multifocal motor neuropathy (MMN). Stable patients were assessed twice (validity/reliability studies). Longitudinal patients were assessed 3-5 times during 1 year. Responsiveness comparison between the two tools was examined using combined anchor-/distribution-based minimum clinically important difference (MCID) techniques. Patients were asked to indicate their preference for the Jamar or Vigorimeter. Both tools correlated highly with each other (ρ = 0.86, p < 0.0001) and showed good intra-class correlation coefficients (Jamar [Right/Left hands]: ICC 0.997/0.96; Vigori: ICC 0.95/0.98). Meaningful changes were comparable between the two instruments, being higher in GBS compared to CIDP patients. In MGUSP/MMN poor responsiveness was seen. Significant more patients preferred the Vigorimeter. In conclusion, validity, reliability, and responsiveness aspects were comparable between the Jamar dynamometer and Vigorimeter. However, based on patients' preference, the Vigorimeter is recommended in future studies in immune-mediated neuropathies.

Clinical trials in multifocal motor neuropathy (MMN) have often used ordinal-based measures that may not accurately capture changes. We aimed to construct a disability interval outcome measure specifically for MMN using the Rasch model and to examine its clinimetric properties. A total of 146 preliminary activity and participation items were assessed twice (reliability studies) in 96 clinically stable MMN patients. These patients also assessed the ordinal-based overall disability sum score (construct, sample-dependent validity). The final Rasch-built overall disability scale for MMN (MMN-RODS(©) ) was serially applied in 26 patients with newly diagnosed or relapsing MMN, treated with intravenous immunoglobulin (IVIg) (1-year follow-up; responsiveness study). The magnitude of change for each patient was calculated using the minimum clinically important difference technique related to the individually obtained standard errors. A total of 121 items not fulfilling Rasch requirements were removed. The final 25-item MMN-RODS(©) fulfilled all Rasch model's expectations and showed acceptable reliability and validity including good discriminatory capacity. Most serially examined patients improved, but its magnitude was low, reflecting poor responsiveness. The constructed MMN-RODS(©) is a disease-specific, interval measure to detect activity limitations in patients with MMN and overcomes the shortcomings of ordinal scales. However, future clinimetric studies are needed to improve the MMN-RODS(©) 's responsiveness by longer observations and/or more rigorous treatment regimens.

We performed a comparison between Neuropathy Impairment Scale-sensory (NISs) vs. the modified Inflammatory Neuropathy Cause and Treatment sensory scale (mISS), and NIS-motor vs. the Medical Research Council sum score in patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and IgM monoclonal gammopathy of undetermined significance-related polyneuropathy (MGUSP). The ordinal data were subjected to Rasch analyses, creating Rasch-transformed (RT)-intervals for all measures. Comparison between measures was based on validity/reliability with an emphasis on responsiveness (using the patient's level of change related to the individually obtained varying SE for minimum clinically important difference). Eighty stable patients (GBS: 30, CIDP: 30, and MGUSP: 20) were assessed twice (entry: two observers; 2-4 weeks later: one observer), and 137 newly diagnosed or relapsing patients (GBS: 55, CIDP: 59, and IgM-MGUSP: 23) were serially examined with 12 months follow-up. Data modifications were needed to improve model fit for all measures. The sensory and motor scales demonstrated approximately equal and acceptable validity and reliability scores. Responsiveness scores were poor but slightly higher in RT-mISS compared to RT-NISs. Responsiveness was equal for the RT-motor scales, but higher in GBS compared to CIDP; responsiveness was poor in patients with MGUSP, suggesting a longer duration of follow-up in the latter group of patients.

Introduction: Electrodiagnostic studies (EDX) are not performed routinely before treatment suspension in CIDP, and no data exist regarding their value in predicting clinical relapse. Methods: Serial EDX (baseline and after IGIV-C therapy) were analyzed from subjects in the ICE clinical trial who responded to IGIV-C treatment and were subsequently re-randomized to placebo in an extension phase. Comparisons were made between subjects who relapsed and those who did not. Results: A total of 55% (6/11) of the Relapse group had an increase in total number of demyelinating findings (DF) versus 8% (1/13) in the No Relapse group (P = 0.023). In the Relapse group, 100% had ≥1 new DF and 73% (8/11) had ≥4 new DF versus 60% (8/13) and 8% (1/13), respectively, in the No Relapse group. Conclusions: An increased total number of DF or the occurrence of ≥4 new DF may indicate a higher risk of clinical relapse after treatment cessation in IGIV-C-responsive patients. Muscle Nerve 52: 498–502, 2015

Objective: Guillain-Barre syndrome (GBS) is a postinfectious neuropathy most frequently caused by Campylobacter jejuni. Lipo-oligosaccharides (LOS), expressed by C. jejuni induce antibodies that cross-react with self-glycolipids in peripheral nerves, causing neuropathy. Less than 1 in 1,000 persons infected with C. jejuni develop GBS, and the factors that determine GBS susceptibility are poorly understood. We hypothesized that these persons have a high intrinsic dendritic cell (DC) response to C. jejuni LOS through Toll-like receptor 4 (TLR4) activation. Methods: Intrinsic DC responsiveness to C. jejuni LOS was investigated first in 20 healthy controls at three time points with a 3-month interval, and second in patients, who previously developed GBS after a C. jejuni infection (n = 27) and controls (n = 26). Results: The DC response to C. jejuni LOS was highly variable between, but not within, healthy individuals, suggesting that intrinsic factors determine the magnitude of TLR4-mediated innate response. High responsiveness to C. jejuni LOS by former GBS patients was evidenced by increased expression of CD38 and CD40. Frequency of CD38, CD40 and type I interferon high responders was significantly increased in the GBS group. Interpretation: These results suggest that a strong response to TLR4 stimulation is a critical host condition for the development of GBS after an infection with C. jejuni.

Dynamics of structures within the carpal tunnel may alter in carpal tunnel syndrome (CTS) due to fibrotic changes and increased carpal tunnel pressure. Ultrasound can visualize these potential changes, making ultrasound potentially an accurate diagnostic tool. To study this, we imaged the carpal tunnel of 113 patients and 42 controls. CTS severity was classified according to validated clinical and nerve conduction study (NCS) classifications. Transversal and longitudinal displacement and shape (changes) were calculated for the median nerve, tendons and surrounding tissue. To predict diagnostic value binary logistic regression modeling was applied. Reduced longitudinal nerve displacement (p≤0.019), increased nerve cross-sectional area (p≤0.006) and perimeter (p≤0.007), and a trend of relatively changed tendon displacements were seen in patients. Changes were more convincing when CTS was classified as more severe. Binary logistic modeling to diagnose CTS using ultrasound showed a sensitivity of 70-71% and specificity of 80-84%. In conclusion, CTS patients have altered dynamics of structures within the carpal tunnel.

Typical Miller Fisher syndrome (MFS) lacks limb muscle weakness, but some patients may unpredictably progress to severe Guillain-Barre syndrome. The compound muscle action potential (CMAP) scan is a recently developed non-invasive, painless, and reproducible method for detecting early changes in motor nerve excitability. This technique was used to monitor subclinical limb motor nerve dysfunction during disease course in typical MFS. Three Miller Fisher patients with preserved limb muscle strength and normal routine nerve conduction studies were included. Frequent serial CMAP scanning of the median nerve was performed during acute phase and follow-up and was related to clinical course and outcome. All patients showed an abnormal increase in the range of stimulus intensities at the day of hospital admission, indicating reduced motor nerve excitability already at the earliest stage of disease. Median nerve dysfunction progressed in parallel or even before clinical deterioration, and improved with clinical recovery. Our study shows that typical MFS is a more general neuropathy, affecting peripheral motor nerves even in patients with preserved limb strength and conduction velocity. CMAP scanning is a sensitive technique for early detection of subclinical motor nerve dysfunction and for monitoring disease activity in immune-mediated neuropathies.

Background Guillain-Barre syndrome is an acute, paralysing, inflammatory peripheral nerve disease. Intravenous immunoglobulin is beneficial in other autoimmune diseases. Objectives We aimed to determine the efficacy of intravenous immunoglobulin for Guillain-Barre syndrome. Search strategy We updated the searches of the Cochrane Neuromuscular Disease Group Trials Specialized Register, MEDLINE and EMBASE in June 2009 using the terms 'Guillain-Barre syndrome' and 'acute polyradiculoneuritis' combined with 'intravenous immunoglobulin'. Selection criteria We included randomised and quasi-randomised trials. Data collection and analysis Two authors independently selected papers, extracted data and assessed quality. Main results Another Cochrane systematic review has shown that plasma exchange significantly hastens recovery. In this review, five trials compared intravenous immunoglobulin with plasma exchange in 536 severely affected, mostly adult participants. The mean difference of change in a seven-grade disability scale after four weeks was not significantly different between the two treatments: 0.02 (95% CI 0.25 to -0.20) of a grade more improvement in the intravenous immunoglobulin than the plasma exchange group. There were also no statistically significant differences in the other measures considered. Three studies including a total of 75 children suggested that intravenous immunoglobulin significantly hastens recovery compared with supportive care. In one trial involving 249 participants comparing plasma exchange followed by intravenous immunoglobulin with plasma exchange alone, the mean grade improvement was 0.2 (95% CI -0.14 to 0.54) more in the combined treatment group than in the plasma exchange alone group, not significantly different but not excluding the possibility of significant extra benefit. Another trial with 37 participants comparing immunoabsorption followed by intravenous immunoglobulin with immunoabsorption alone did not reveal significant extra benefit from the combined treatment. Small trials in children showed a trend towards more improvement with high-dose compared with low-dose intravenous immunoglobulin and no significant difference when the standard dose was given over two days rather than five days. Authors' conclusions A previous Cochrane review has shown that plasma exchange hastens recovery compared with supportive treatment alone. There are no adequate comparisons of intravenous immunoglobulin with placebo in adults but this review provides moderate quality evidence that, in severe disease, intravenous immunoglobulin started within two weeks from onset hastens recovery as much as plasma exchange. Adverse events were not significantly more frequent with either treatment but intravenous immunoglobulin is significantly much more likely to be completed than plasma exchange. Also according to moderate quality evidence, giving intravenous immunoglobulin after plasma exchange did not confer significant extra benefit. In children, according to low quality evidence, intravenous immunoglobulin probably hastens recovery compared with supportive care alone. More research is needed in mild disease and in patients whose treatment starts more than two weeks after onset. Dose-ranging studies are also needed. Plain Language Summary Intravenous immunoglobulin for Guillain-Barre syndrome Guillain-Barre syndrome is an uncommon disease of the peripheral nerves. It causes weakness, numbness and breathing difficulty. Another Cochrane review has shown that plasma exchange (taking blood from one vein, separating the plasma from the blood cells and then returning the blood cells with a plasma substitute into another vein) is more effective than supportive care alone. In adults, moderate quality evidence shows that receiving intravenous immunoglobulin (antibodies that have been purified from donated blood) speeds recovery from severe Guillain-Barre syndrome as much as plasma exchange. Intravenous immunoglobulin is slightly safer and much easier to give than plasma exchange. According to moderate quality evidence, intravenous immunoglobulin added to plasma exchange is not significantly more effective than either alone. A small amount of evidence suggests that intravenous immunoglobulin is also beneficial in children. More research is needed to determine the best dose in adults and children.

A European Federation of Neurological Societies/Peripheral Nerve Society consensus guideline on the definition, investigation, and treatment of multifocal motor neuropathy (MMN) was published in 2006. The aim is to revise this guideline. Disease experts considered references retrieved from MEDLINE and Cochrane Systematic Reviews published between August 2004 and July 2009 and prepared statements that were agreed to in an iterative fashion. The Task Force agreed on Good Practice Points to define clinical and electrophysiological diagnostic criteria for MMN, investigations to be considered, and principal recommendations for treatment.

Data are lacking on correlations between changes in nerve conduction (NC) studies and treatment response in chronic inflammatory demyelinating polyneuropathy (CIDP). This report examined data from a randomized, double-blind trial of immune globulin intravenous, 10% caprylate/chromatography purified (IGIV-C [Gamunex]; n = 59) versus placebo (n = 58) every 3 weeks for up to 24 weeks in CIDP. Motor NC results and clinical measures were assessed at baseline and endpoint/week 24. Improvement from baseline in adjusted inflammatory neuropathy cause and treatment score correlated with improvement in proximally evoked compound muscle action potential (CMAP) amplitudes (r = -0.53; P < 0.001) of all nerves tested and with improvement in CMAP amplitude of the most severely affected motor nerve (r = -0.36; P < 0.001). Correlations were observed between improvement in averaged CMAP amplitudes and dominant-hand grip strength (r = 0.44; P < 0.001) and Medical Research Council sum score (r = 0.38; P < 0.001). Overall, the change in electrophysiologic measures of NC in CIDP correlated with clinical response to treatment.

Many patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) suffer from excessive fatigue. To assess whether this fatigue might be related to changes in slow-conducting nerve fibers, we determined the conduction velocity distribution (CVD) in the median nerve. Thirteen fatigued but neurologically well-recovered GBS patients, 2 fatigued and stable CIDP patients, and 19 healthy controls participated in this study. Conventional maximal nerve conduction velocities (NCVs) did not show differences between GBS patients and healthy controls. However, in both GBS and CIDP patients the CVD was altered, showing significant narrowing of the velocity distribution with loss of the fastest- and slowest-conducting fibers. These changes were most pronounced in the subgroup of patients with the lowest fatigue scores. We therefore conclude that the observed CVD changes in patients are not likely to contribute to persisting complaints of fatigue after GBS.

In this prospective study of 73 relapsing remitting multiple sclerosis patients followed up for a mean of 1.7 years, the relation was tested between serologically defined Chlamydia pneumoniae (CP) infection periods and exacerbation rate. Episodes of serologically defined CP infections were observed in a subgroup, and these episodes were associated with increased risk for exacerbation. CP polymerase chain reaction was positive in most of the CP seropositive patients. No correlation was found between the anti-CP antibody increase and titers of control antibodies.

The ability of a scale to detect clinical relevant changes over time, i.e., its "responsiveness," may help clinicians to choose among valid and reliable measures. Therefore, we investigated the responsiveness' rank ordering (best to worse) of six selected valid and reliable scales, namely the Medical Research Council (MRC)-sumscore, sensory-sumscore, grip-strength (Vigorimeter), nine-hole peg, ten-meters walking, and a disability-sumscore, in immune-mediated polyneuropathies. Patients with newly diagnosed Guillain-Barre syndrome (n = 7) or chronic inflammatory demyelinating polyneuropathy (n = 13) were examined over 52 weeks. Responsiveness of each scale was measured using different methods (effect-size, standardized response mean score, Wilcoxon matched-pairs signed-rank, and a newly devised Schmitz's distribution-free responsiveness score), and the obtained scores in each method were plotted against the follow-up period, thus allowing area-under-the-curve calculations (higher area-under-the-curve indicating better responsiveness). Also, longitudinal correlations were performed between the scales' values and patients' own clinical judgments (deteriorated, unchanged, improved) (higher correlation = better responsiveness). A consistent rank ordering was observed in each technique with the disability-sumscore, MRC-sumscore, and Vigorimeter being among the best responsive scales. Hence, the primary use of these measures is suggested in studies of immune-mediated polyneuropathies.

Pompe's disease (glycogen storage disease type II) is an autosomal recessive myopathy caused by lysosomal alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) is currently under development for this disease. We evaluated the morphological changes in muscle tissue of four children with infantile Pompe's disease who received recombinant human alpha-glucosidase from rabbit milk for 72 weeks. The patients were 2.5-8 months of age at entry. Prior to treatment, all patients showed lysosomal glycogen storage in skeletal and smooth muscle cells, vascular endothelium, Schwann cells, and perineurium. The first response to treatment was noticed in vascular endothelium and in peripheral nerves after 12 weeks of treatment at an enzyme dose of 15-20 mg/kg. Increasing the dose to 40 mg/kg led, after 72 weeks of treatment, to a reduction of glycogen storage and substantial improvement of muscle architecture in the least affected patient. Not all patients responded equally well, possibly due to differences in degree of glycogen storage and concomitant muscle pathology at the start of treatment. We conclude that intravenous administration of recombinant human alpha-glucosidase from rabbit milk can improve muscle morphology in classic infantile Pompe's disease when treatment is started before irreversible damage has occurred.

We investigated whether 5 to 20mg per week oral methotrexate could slow down disease progression in 44 patients with inclusion body myositis in a randomized double-blind placebo-controlled study over 48 weeks. Mean change of quantitative muscle strength testing sum scores was the primary study outcome measure. Quantitative muscle strength testing sum scores declined in both treatment groups, -0.2% for methotrexate and -3.4% for placebo (95% confidence interval = -2.5% to +9.1% for difference). There were also no differences in manual muscle testing sum scores, activity scale scores and patients' own assessments after 48 weeks of treatment. Serum creatine kinase activity decreased significantly in the methotrexate group. We conclude that oral methotrexate did not slow down progression of muscle weakness but decreased serum creatine kinase activity.

A new handicap measure, the Rotterdam nine-item handicap scale, was developed and its validity, reliability, and responsiveness evaluated in patients with immune-mediated polyneuropathies. We evaluated 113 stable patients, of whom 83 had Guillain--Barre syndrome (GBS), 22 had chronic inflammatory demyelinating polyneuropathy (CIDP), and 8 had a gammopathy-related polyneuropathy. We also studied 20 patients with recently diagnosed GBS (n = 7) or CIDP (n = 13) and changing clinical conditions (longitudinal group). Significant discriminatory validity and correlation with the Rankin scale were demonstrated for the Rotterdam nine-item handicap scale (stable group: Spearman's test, r = minus sign.76 to minus sign.78; longitudinal group: intraclass correlation coefficient, r =.83; P .8) were obtained for the Rotterdam nine-item handicap scale. In contrast to the Rankin scale, the Rotterdam scale not only provided information regarding mobility but also highlighted physical independence, occupation, and social integration. These results illustrate the clinical usefulness of the Rotterdam nine-item handicap scale under these conditions.

GM1b is a minor ganglioside in human peripheral nerves. Serum anti-GM1b antibodies frequently are present in patients with Guillain-Barre syndrome (GBS). In this collaborative study, we investigated the antecedent infections, clinical features, and response to treatment of GBS patients with anti-GM1b antibodies. Of 132 GBS patients who participated in the Dutch GBS trial that compared the effect of intravenous immunoglobulins and plasma exchange, 25 (19%) patients had anti-GM1b antibodies. IgM antibodies were present in 14, IgG antibodies in 15, and both isotypes in 4 patients. The 25 patients with anti-GM1b antibodies had a clinical pattern distinct from that of the other 107 GBS patients. They more often had an episode of gastrointestinal illness and frequently showed serological evidence of recent infection by Campylobacter jejuni. The anti-GM1b-positive subgroup was marked by more rapidly progressive, more severe, and predominantly distal weakness. Cranial nerve involvement and sensory deficits were less common in the patients with anti-GM1b antibodies. The presence of anti-GM1b antibodies was associated with slower recovery. The clinical manifestations predominantly were associated with anti-GM1b antibodies of the IgG isotype. Fourteen (56%) of the 25 patients with anti-GM1b antibodies also had anti-GM1 antibodies. The group of patients with both antibodies was clinically more homogeneous and had a more rapidly progressive, pure motor neuropathy. The subgroup of anti-GM1b-positive GBS patients responded well to treatment with immunoglobulins but not to plasmapheresis. The distinctive clinical features of the patients with anti-GM1b antibodies show that acute motor neuropathy represents a specific subgroup within GBS and that recognizing these patients may have consequences as to the choice of therapy.

The group of patients with Guillain-Barr'e syndrome (GBS) is very heterogenous with regard to antecedent infections, immunological parameters, clinical manifestations, and response to treatment. In this study, the presumed pathogenic factors anti-GM1 antibodies and Campylobacter jejuni infections were related to the clinical characteristics. Serum from 154 patients with GBS, 63 patients with other neurological diseases (OND), and 50 normal controls (NC) were tested for the presence of antibodies against GM1 and C. jejuni. Anti-GM1 antibodies were detected in 31 (20%) GBS patients, 5 (8%) OND patients, and in none of the NC. Evidence for a recent C. jejuni infection was found in 49 (32%) GBS patients and less often in OND patients (11%) or NC (8%). In GBS patients, the presence of anti-GM1 antibodies was significantly associated with C. jejuni infections. The subgroup of GBS patients with anti-GM1 antibodies suffered more often from a rapidly progressive and more severe neuropathy with predominantly distal distribution of weakness, without deficits of cranial nerves or sensory disturbances. The subgroup with C. jejuni infection also more often had a severe pure motor variant of GBS. Recovery of the patients with anti-GM1 antibodies and C. jejuni infections was not as good after plasma exchange compared with intravenous immunoglobulins.

We have analyzed the role and regulation of autoantibodies in inflammatory demyelinating polyneuropathy (GBS/CIDP). The clinical significance of pathogenic autoantibodies to peripheral nerve tissue is suggested by the beneficial response of many of these patients to plasmapheresis and treatment with high doses of polyspecific IVIgG. Recovery, whether spontaneous or therapeutically-induced, is associated with anti-idiotypic suppression of the antoantibodies. Preliminary results suggest that these autoantibodies share cross-reactive idiotypes or, alternatively, that the regulatory anti-idiotypic antibodies are multireactive.