Assessment of disability in idiopathic inflammatory myopathy: a call for linearity.

OBJECTIVES: To evaluate the clinimetric properties of the Academic Medical Centre Disability Score (ALDS) in patients with idiopathic inflammatory myopathy (IIM). METHODS: We used prospectively collected data of IIM patients who completed a phase-2 study with first-line IVIG monotherapy. The ALDS is a patient-reported questionnaire which contains 25 items relevant for disability in myositis. ALDS and all core set measures (CSMs) for myositis [including HAQ-Disability Index (HAQ-DI)] were evaluated at baseline and 9 weeks follow-up. In addition, the 2016 ACR/EULAR myositis response criteria outcome called Total Improvement Score (TIS) was evaluated at 9 weeks. We examined floor/ceiling effects, reliability and construct validity of the ALDS. To examine known-group validity, ALDS change scores over time were compared with TIS and physician impression of clinical response. RESULTS: Nineteen patients with IIM [median age 59 years, 12 (63%) female] were enrolled. At baseline, ALDS showed a median score of 65.4 (IQR 58.2-73.5), good Cronbach's alpha (α = 0.84) and a small ceiling effect (11%). Construct validity was confirmed by moderate to strong correlations between ALDS and HAQ-DI [rs = -0.57 (baseline); -0.86 (follow-up)]. ALDS change score correlated with TIS (rs = 0.70), discriminated between responders and non-responders (TIS ≥ 40; P = 0.001), between groups based on physician impression of clinical response (P = 0.03), and detected deterioration. CONCLUSION: The ALDS showed promising clinimetric properties and detected relevant changes in disability in patients with myositis. These results warrant further investigations.

Ultrasound and MR muscle imaging in new onset idiopathic inflammatory myopathies at diagnosis and after treatment: a comparative pilot study.

OBJECTIVES: To prospectively compare ultrasound (US) and whole-body MRI for detection of muscle abnormalities compatible with idiopathic inflammatory myopathies (IIM). METHODS: Newly diagnosed IIM patients underwent US (14 muscles) and MRI (36 muscles) at diagnosis and after nine weeks monotherapy with intravenous immunoglobulin. Muscles were compatible with IIM when quantitative US echo-intensity (EI) z scores was ≥1.5, semi-quantitative US Heckmatt score was ≥2, qualitative US was abnormal, or when MRI showed oedema on T2-weighted images. At patient level, findings were classified as abnormal when quantitative US EI z scores was >1.5 (n = 3 muscles), >2.5 (n = 2 muscles) or >3.5 (n = 1 muscle), or if ≥3 muscles showed abnormalities as described above for the other diagnostic methods. RESULTS: At diagnosis, in 18 patients US of 252 muscles revealed abnormalities in 36 muscles (14%) with quantitative, in 153 (61%) with semi-quantitative and in 168 (67%) with qualitative analysis. MRI showed oedema in 476 out of 623 muscles (76%). Five patients (28%) reached abnormal classification with quantitative US, 16 (89%) with semi-quantitative and qualitative US, and all patients (100%) with MRI. Nine-week follow-up of 12 patients showed no change over time with quantitative US or MRI, and a decrease in abnormalities with semi-quantitative US (P <0.01), and qualitative US (P <0.01). CONCLUSION: At diagnosis, MRI was more sensitive than US to detect muscle abnormalities compatible with IIM. Semi-quantitative US and qualitative US detected abnormalities in the majority of the patients while evaluating fewer muscles than MRI and showed change over time after nine weeks of treatment.

Electrodiagnostic subtyping in Guillain-Barré syndrome: Use of criteria in practice based on a survey study in IGOS.

Electrodiagnostic (EDx) studies are helpful in diagnosing and subtyping of Guillain-Barré syndrome (GBS). Published criteria for differentiation into GBS subtypes focus on cutoff values, but other items receive less attention, although they may influence EDx subtyping: (a) extensiveness of EDx testing, (b) nerve-specific considerations, (c) distal compound muscle action potential (CMAP)-amplitude requirements, (d) criteria for conduction block and temporal dispersion. The aims of this study were to investigate how these aspects were approached by neuromuscular EDx experts in practice and how this was done in previously published EDx criteria for GBS. A completed questionnaire was returned by 24 (of 49) members of the electrophysiology expertise group from the International GBS Outcome Study. Six published EDx criteria for GBS subtyping were compared regarding these aspects. The indicated minimal number of motor nerves to study varied among respondents and tended to be more extensive in equivocal than normal studies. Respondents varied considerably regarding usage of compression sites for subtyping (median/wrist, ulnar/elbow, peroneal/fibular head): 29% used all variables from all sites, 13% excluded all sites, and 58% used only some sites and/or variables. Thirty-eight percent of respondents required a minimal distal CMAP amplitude to classify distal motor latency as demyelinating, and 58% did for motor conduction velocity. For proximal/distal CMAP-amplitude ratio and F-wave latency, a requisite minimal CMAP amplitude was more often required (79%). Also, the various published criteria sets showed differences on all items. Practical use of EDx criteria for subtyping GBS vary extensively across respondents, potentially lowering the reproducibility of GBS subtyping.

Intravenous immunoglobulins as first-line treatment in idiopathic inflammatory myopathies: a pilot study.

OBJECTIVES: We explored efficacy and safety of IVIg as first-line treatment in patients with an idiopathic inflammatory myopathy. METHODS: In this investigator-initiated phase 2 open-label study, we included 20 adults with a newly diagnosed, biopsy-proven idiopathic inflammatory myopathy, and a disease duration of less than 9 months. Patients with IBM and prior use of immunosuppressants were excluded. The standard treatment regimen consisted of IVIg (Privigen) monotherapy for 9 weeks: a loading dose (2 g/kg body weight) and two subsequent maintenance doses (1 g/kg body weight) with a 3-week interval. The primary outcome was the number of patients with at least moderate improvement on the 2016 ACR/EULAR Total Improvement Score. Secondary outcomes included time to improvement, the number of patients requiring rescue medication and serious adverse events. RESULTS: We included patients with DM (n = 9), immune-mediated necrotizing myopathy (n = 6), non-specific myositis/overlap myositis (n = 4) and anti-synthetase syndrome (n = 1). One patient was excluded from analyses because of minimal weakness resulting in a ceiling effect. Eight patients (8/19 = 42.0%; Clopper-Pearson 95% CI: 19.6, 64.6) had at least moderate improvement by 9 weeks. Of these, six reached improvement by 3 weeks. Seven patients required rescue medication due to insufficient efficacy and prematurely ended the study. Three serious adverse events occurred, of which one was pulmonary embolism. CONCLUSION: First-line IVIg monotherapy led to at least moderate improvement in nearly half of patients with a fast clinical response in the majority of responders. TRIAL REGISTRATION: Netherlands Trial Register identifier, NTR6160.

Quantitative magnetic resonance imaging of the brachial plexus shows specific changes in nerve architecture in chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and motor neuron disease.

BACKGROUND: The immunological pathophysiologies of chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) differ considerably, but neither has been elucidated completely. Quantitative magnetic resonance imaging (MRI) techniques such as diffusion tensor imaging, T2 mapping, and fat fraction analysis may indicate in vivo pathophysiological changes in nerve architecture. Our study aimed to systematically study nerve architecture of the brachial plexus in patients with CIDP, MMN, motor neuron disease (MND) and healthy controls using these quantitative MRI techniques. METHODS: We enrolled patients with CIDP (n = 47), MMN (n = 29), MND (n = 40) and healthy controls (n = 10). All patients underwent MRI of the brachial plexus and we obtained diffusion parameters, T2 relaxation times and fat fraction using an automated processing pipeline. We compared these parameters between groups using a univariate general linear model. RESULTS: Fractional anisotropy was lower in patients with CIDP compared to healthy controls (p < 0.001), patients with MND (p = 0.010) and MMN (p < 0.001). Radial diffusivity was higher in patients with CIDP compared to healthy controls (p = 0.015) and patients with MND (p = 0.001) and MMN (p < 0.001). T2 relaxation time was elevated in patients with CIDP compared to patients with MND (p = 0.023). Fat fraction was lower in patients with CIDP and MMN compared to patients with MND (both p < 0.001). CONCLUSION: Our results show that quantitative MRI parameters differ between CIDP, MMN and MND, which may reflect differences in underlying pathophysiological mechanisms.

Prognostic value of nerve ultrasonography: A prospective multicenter study on the natural history of chronic inflammatory neuropathies.

BACKGROUND AND OBJECTIVE: Nerve ultrasound is a promising new tool in chronic inflammatory neuropathies. The aim of this study was to determine its prognostic value in a prospective multicenter cohort study including incident and prevalent patients with CIDP and MMN. METHODS: We enrolled 126 patients with CIDP, and 72 with MMN; 71 were treatment-naive. Patients with chronic idiopathic axonal polyneuropathy (CIAP; n = 35) were considered as disease controls. Standardized neurological examination, questionnaires, and nerve ultrasonography were obtained at time of inclusion and 1-year follow-up. Nerve size development over time and correlation between nerve size and clinical outcome measures were determined using linear mixed effects models. RESULTS: Nerve size development over time was heterogeneous. Only in MMN was there a correlation between C5 nerve root size and deterioration of grip strength (-1.3 kPa/mm2 (95% confidence interval [CI] -2.3 to -0.2). No other significant correlations between nerve size and clinical outcome measures were found. In MMN, presence of nerve enlargement at inclusion predicted deterioration of grip strength, and MMN patients with enlargement confined to the brachial plexus seemed to have more favorable outcomes. No other predictive effects of sonographic nerve size were found. CONCLUSIONS: The present study indicates that the natural course of nerve size development in CIDP and MMN is heterogeneous, and that the prognostic value of sonographic nerve enlargement is limited. It had some predictive effect in patients with MMN. Further research in specific subgroups of chronic inflammatory neuropathy is necessary to determine the usefulness of nerve ultrasonography after the diagnostic phase.

Diagnostic challenges in chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) consists of a spectrum of autoimmune diseases of the peripheral nerves, causing weakness and sensory symptoms. Diagnosis often is challenging, because of the heterogeneous presentation and both mis- and underdiagnosis are common. Nerve conduction study (NCS) abnormalities suggestive of demyelination are mandatory to fulfil the diagnostic criteria. On the one hand, performance and interpretation of NCS can be difficult and none of these demyelinating findings are specific for CIDP. On the other hand, not all patients will be detected despite the relatively high sensitivity of NCS abnormalities. The electrodiagnostic criteria can be supplemented with additional diagnostic tests such as CSF examination, MRI, nerve biopsy, and somatosensory evoked potentials. However, the evidence for each of these additional diagnostic tests is limited. Studies are often small without the use of a clinically relevant control group. None of the findings are specific for CIDP, meaning that the results of the diagnostic tests should be carefully interpreted. In this update we will discuss the pitfalls in diagnosing CIDP and the value of newly introduced diagnostic tests such as nerve ultrasound and testing for autoantibodies, which are not yet part of the guidelines.

Hypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical and molecular heterogeneities.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes implicated in several dominant and recessive disease phenotypes. The canonical function of ARSs is to couple an amino acid to a cognate transfer RNA (tRNA). We identified three novel disease-associated missense mutations in the alanyl-tRNA synthetase (AARS) gene in three families with dominant axonal Charcot-Marie-Tooth (CMT) disease. Two mutations (p.Arg326Trp and p.Glu337Lys) are located near a recurrent pathologic change in AARS, p.Arg329His. The third (p.Ser627Leu) is in the editing domain of the protein in which hitherto only mutations associated with recessive encephalopathies have been described. Yeast complementation assays demonstrated that two mutations (p.Ser627Leu and p.Arg326Trp) represent loss-of-function alleles, while the third (p.Glu337Lys) represents a hypermorphic allele. Further, aminoacylation assays confirmed that the third mutation (p.Glu337Lys) increases tRNA charging velocity. To test the effect of each mutation in the context of a vertebrate nervous system, we developed a zebrafish assay. Remarkably, all three mutations caused a pathological phenotype of neural abnormalities when expressed in zebrafish, while expression of the human wild-type messenger RNA (mRNA) did not. Our data indicate that not only functional null or hypomorphic alleles, but also hypermorphic AARS alleles can cause dominantly inherited axonal CMT disease.

Variation in SIPA1L2 is correlated with phenotype modification in Charcot- Marie- Tooth disease type 1A.

OBJECTIVE: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb duplication event involving the gene PMP22. METHODS: We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal-induced proliferation-associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation. RESULTS: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10-7 ). Coimmunoprecipitation and mass spectroscopy studies identified ß-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a myelination-associated coexpressed network regulated by the master transcription factor SOX10. Importantly, in vitro knockdown of SIPA1L2 in Schwannoma cells led to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development. INTERPRETATION: SIPA1L2 is a potential genetic modifier of CMT1A phenotypic expressions and offers a new pathway to therapeutic interventions. ANN NEUROL 2019;85:316-330.

Efficacy of a physical activity programme combining individualized aerobic exercise and coaching to improve physical fitness in neuromuscular diseases (I'M FINE): study protocol of a randomized controlled trial.

BACKGROUND: In individuals with neuromuscular diseases (NMD), symptoms of muscle weakness, fatigue and pain may limit physical activity. Inactivity leads to reduced physical fitness, which further complicates daily life functioning. Due to inconclusive evidence regarding exercise in NMD, the optimal training approach and strategies to preserve an active lifestyle remain to be determined. The physical activity programme I'M FINE, consisting of individualized aerobic exercise to improve physical fitness and coaching to preserve an active lifestyle, was therefore developed. The primary objective of this study will be to evaluate the efficacy of the I'M FINE programme in terms of improved physical fitness in individuals with slowly progressive NMD, compared to usual care. METHODS: A multicentre, assessor-blinded, two armed, randomized controlled trial will be conducted in a sample of 90 individuals with slowly progressive NMD. Participants motivated to improve their reduced physical fitness will be randomized (ratio 1:1) to the I'M FINE intervention or usual care. The I'M FINE intervention consists of a six-month physical activity programme, including individualized home-based aerobic exercise to improve physical fitness (i.e. peak oxygen uptake), and motivational interviewing coaching (e.g. goal setting, self-management) to adopt and preserve an active lifestyle. Measurements will be performed at baseline, post-intervention, and at 12- and 18-months follow-up. The primary outcome is peak oxygen uptake (VO2 peak) directly post intervention. Main secondary outcomes are physical capacity, muscle strength, self-efficacy, daily activity, quality of life and markers of metabolic syndrome. The primary analysis compares change in VO2 peak post-intervention between the intervention and usual care group, with analysis of covariance. DISCUSSION: The I'M FINE study will provide evidence regarding the efficacy of a physical activity intervention on the physical fitness and active lifestyle over the short- and long-term in individuals with slowly progressive NMD. These outcomes could potentially improve the (inter)national guidelines for efficacy of aerobic exercise programmes and provide insight in achieving a more active lifestyle in NMD. TRIAL REGISTRATION: (5/11/2018): Netherlands Trial Register NTR7609 (retrospectively registered), https://www.trialregister.nl/trial/7344. However, the Ethics Review Committee of the Amsterdam Medical Center (AMC) approved the study protocol on 7/11/2017. No adjustments were made to the approved study protocol before the first participant enrolment and registration. Registration was done after the second participant enrolment and the information in the register corresponds one on one with the approved study protocol.

Early Prediction of Intensive Care Unit-Acquired Weakness: A Multicenter External Validation Study.

OBJECTIVES: An early diagnosis of intensive care unit-acquired weakness (ICU-AW) is often not possible due to impaired consciousness. To avoid a diagnostic delay, we previously developed a prediction model, based on single-center data from 212 patients (development cohort), to predict ICU-AW at 2 days after ICU admission. The objective of this study was to investigate the external validity of the original prediction model in a new, multicenter cohort and, if necessary, to update the model. METHODS: Newly admitted ICU patients who were mechanically ventilated at 48 hours after ICU admission were included. Predictors were prospectively recorded, and the outcome ICU-AW was defined by an average Medical Research Council score <4. In the validation cohort, consisting of 349 patients, we analyzed performance of the original prediction model by assessment of calibration and discrimination. Additionally, we updated the model in this validation cohort. Finally, we evaluated a new prediction model based on all patients of the development and validation cohort. RESULTS: Of 349 analyzed patients in the validation cohort, 190 (54%) developed ICU-AW. Both model calibration and discrimination of the original model were poor in the validation cohort. The area under the receiver operating characteristics curve (AUC-ROC) was 0.60 (95% confidence interval [CI]: 0.54-0.66). Model updating methods improved calibration but not discrimination. The new prediction model, based on all patients of the development and validation cohort (total of 536 patients) had a fair discrimination, AUC-ROC: 0.70 (95% CI: 0.66-0.75). CONCLUSIONS: The previously developed prediction model for ICU-AW showed poor performance in a new independent multicenter validation cohort. Model updating methods improved calibration but not discrimination. The newly derived prediction model showed fair discrimination. This indicates that early prediction of ICU-AW is still challenging and needs further attention.

Diagnosis and treatment response in the asymmetric variant of chronic inflammatory demyelinating polyneuropathy.

The objectives were to (a) assess the diagnostic value of testing clinically affected and unaffected limbs with nerve conduction studies (NCS) in patients with the asymmetric chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) variant and to define the most useful strategy for diagnosis, and (b) describe treatment response and long-term outcome. We performed a retrospective study and included patients with a multifocal distribution of symptoms and signs, who met the probable or definite EFNS/PNS diagnostic categories for CIDP. We included 34 patients and 32 NCS datasets were available. Of these 32 patients, 25 (78%) met the electrodiagnostic criteria for definite or probable CIDP and seven (22%) for possible CIDP. Patients fulfilling the possible electrodiagnostic criteria and a supportive criterion were considered as probable CIDP. NCS of the clinically affected forearm and leg led to a probable or definite diagnosis in 13 patients (41%). Measuring both arms up to Erb's point led to a probable or definite diagnosis in 25 patients (78%), after which NCS of both legs did not contribute to additional probable or definite diagnoses. In total, 30% of patients treated with dexamethasone and 94% of patients treated with intravenous immunoglobulins (IVIg) responded. IVIg withdrawal attempts were successful in 21% of patients. After measuring the clinically affected arm up to Erb's point, NCS of the unaffected arm to Erb's point has the highest additional diagnostic yield in patients with asymmetric CIDP. Patients seem to respond better to IVIg than to corticosteroids and long-term treatment is often required, although IVIg withdrawal was successful in 21%.

Serum neurofilament light chain in chronic inflammatory demyelinating polyneuropathy.

Axonal damage in chronic inflammatory demyelinating polyneuropathy (CIDP) is the main predictor of poor outcome. We hypothesized that serum neurofilament light chain (sNfL) reflects disease activity by detecting ongoing neuro-axonal damage in CIDP. Three prospective cohorts of CIDP patients were studied: (a) patients starting induction treatment (IT cohort, N = 29) measured at baseline and 6 months after starting treatment; (b) patients on maintenance treatment (MT) starting intravenous immunoglobuline (IVIg) withdrawal (MT cohort, N = 24) measured at baseline and 6 months after IVIg withdrawal or at time of relapse; and (c) patients in long-term remission without treatment (N = 27). A single molecule array assay was used to measure sNfL. Age-matched healthy controls (N = 30) and age-specific reference values were used for comparison. At baseline, sNfL was higher in patients starting IT compared to healthy controls. Ten out of 29 IT (34%) patients have sNfL levels above the 95th percentile of age-specific cut-off values. In the MT and remission cohort, elevated sNfL levels were infrequent and not different from healthy controls. sNfL levels were correlated with electrophysiological markers of axonal damage. At follow-up assessment, patients with active disease (non-responders and patients who relapsed after IVIg withdrawal) had higher sNfL levels compared with patients with stable disease (responders and patients who were successfully withdrawn from IVIg treatment). sNfL levels were increased in a third of CIDP patients starting IT and reflected axonal damage. sNfL levels might be usable as biomarker of disease activity in a subset of CIDP patients.

Pharmacodynamics and Pharmacokinetics of Lidocaine in a Rodent Model of Diabetic Neuropathy.

BACKGROUND: Clinical and experimental data show that peripheral nerve blocks last longer in the presence of diabetic neuropathy. This may occur because diabetic nerve fibers are more sensitive to local anesthetics or because the local anesthetic concentration decreases more slowly in the diabetic nerve. The aim of this study was to investigate both hypotheses in a rodent model of neuropathy secondary to type 2 diabetes. METHODS: We performed a series of sciatic nerve block experiments in 25 Zucker Diabetic Fatty rats aged 20 weeks with a neuropathy component confirmed by neurophysiology and control rats. We determined in vivo the minimum local anesthetic dose of lidocaine for sciatic nerve block. To investigate the pharmacokinetic hypothesis, we determined concentrations of radiolabeled (C) lidocaine up to 90 min after administration. Last, dorsal root ganglia were excised for patch clamp measurements of sodium channel activity. RESULTS: First, in vivo minimum local anesthetic dose of lidocaine for sciatic nerve motor block was significantly lower in diabetic (0.9%) as compared to control rats (1.4%). Second, at 60 min after nerve block, intraneural lidocaine was higher in the diabetic animals. Third, single cell measurements showed a lower inhibitory concentration of lidocaine for blocking sodium currents in neuropathic as compared to control neurons. CONCLUSIONS: We demonstrate increased sensitivity of the diabetic neuropathic nerve toward local anesthetics, and prolonged residence time of local anesthetics in the diabetic neuropathic nerve. In this rodent model of neuropathy, both pharmacodynamic and pharmacokinetic mechanisms contribute to prolonged nerve block duration.

Elevated leukocyte count in cerebrospinal fluid of patients with chronic inflammatory demyelinating polyneuropathy.

Cerebrospinal fluid (CSF) examination is often part of the diagnostic work-up of a patient suspected of having chronic inflammatory demyelinating polyneuropathy (CIDP). According to the European Federation of Neurological Societies and the Peripheral Nerve Society (EFNS/PNS) criteria, an elevated protein level without pleocytosis (leukocytes <10 cells/µl) is supportive of the diagnosis CIDP. It is unclear how many CSF leukocytes are compatible with the diagnosis CIDP and how extensive the diagnostic work-up should be in patients with a demyelinating neuropathy and pleocytosis. We performed a retrospective study at two tertiary neuromuscular referral clinics and identified 14 out of 273 (6%) patients with CIDP with elevated CSF leukocytes (≥10 cells/µl). All these patients met the EFNS/PNS criteria for definite or probable CIDP. Eight patients (57%) presented with a subacute onset and four patients with an antecedent infection. Most patients responded well to therapy, and eight patients are currently in remission. In four patients, lumbar puncture was repeated. A spontaneous decrease in leukocytes before start of treatment was found in three patients. Our data indicate that a mild to moderate pleocytosis in CSF does not exclude the diagnosis of CIDP, especially in patients with a subacute onset of disease.

Increased Early Systemic Inflammation in ICU-Acquired Weakness; A Prospective Observational Cohort Study.

OBJECTIVES: To investigate whether patients who develop ICU-acquired weakness have a different pattern of systemic inflammatory markers compared with critically ill patients who do not develop ICU-acquired weakness. DESIGN: Prospective observational cohort study. SETTING: Mixed medical-surgical ICU of a tertiary care hospital in the Netherlands. PATIENTS: Newly admitted critically ill patients, greater than or equal to 48 hours on mechanical ventilation with a nonneurologic ICU admission diagnosis, were included. INTERVENTIONS: A panel of systemic inflammatory markers and soluble vascular adhesion molecules were measured in plasma samples of day 0, 2, and 4 after ICU admission. ICU-acquired weakness was diagnosed by manual muscle strength testing as soon as patients were awake and attentive. MEASUREMENTS AND MAIN RESULTS: Ninety-nine of 204 included patients developed ICU-acquired weakness. Principal component regression analysis, adjusted for confounders, showed that principal component 1, mainly loaded with interleukin-6, interleukin-8, interleukin-10, and fractalkine, was significantly higher in patients who developed ICU-acquired weakness (odds ratio, 1.35 [95% CI, 1.18-1.55]). Partial least squares-discriminant analysis also showed that these markers were the most important discriminative markers. Mixed-effects models of these markers showed that ICU-acquired weakness was associated with an independent 1.5- to two-fold increase in these markers. CONCLUSIONS: Systemic inflammation is increased in patients who develop ICU-acquired weakness compared with patients who do not develop ICU-acquired weakness in the first 4 days after ICU admission. This finding is consistent when adjusted for confounders, like disease severity. A group consisting of interleukin-6, interleukin-8, interleukin-10, and fractalkine was identified to be the most important.

Pseudodominant inheritance pattern in a family with CMT2 caused by GDAP1 mutations.

We report a family in which an autosomal dominantly inherited Charcot-Marie-Tooth (CMT) disease type 2 was suspected. The affected family members (proband, sister, father, and paternal aunt) showed intrafamilial clinical variability. The proband needed walking aids since adolescence because of generalized muscle weakness. The sister showed the same symptoms although to a lesser extent. The father and paternal aunt had foot deformity and atrophy of lower legs. A homozygous GDAP1 mutation was found in the proband and in the sister. Further testing showed compound heterozygous GDAP1 mutations in the father and paternal aunt. In this CMT2 family with a pseudodominant inheritance pattern DNA-diagnostics revealed the presence of both homozygous and compound heterozygous GDAP1 mutations. We recommend including multiple family members in genetic studies on CMT families.

Diffusion-prepared neurography of the brachial plexus with a large field-of-view at 3T.

PURPOSE: To study diffusion-prepared neurography optimized for a large field-of-view (FOV) to include the neck and both shoulders. In a large FOV poor homogeneity of the magnetic field (B0 ) often leads to poor image quality and possibly to poor diagnostic accuracy. The aim was therefore to find an optimal (combination of) shimming method(s) for diffusion-prepared neurography in a large FOV. MATERIALS AND METHODS: A 3D diffusion-prepared sequence with a large FOV was tested with and without the use of a susceptibility-matched pillow combined with image-based (IB) or standard shimming in six healthy volunteers on a 3T system. B0 , B1 , signal to noise ratio (SNR), and contrast to noise ratio (CNR) were compared between all protocols. Additionally, nerve visibility, fat suppression, artifacts, and overall image quality were ordinally (5-point scale) assessed by two readers. Furthermore, correlations between B0 and B1 (offset and variation) and SNR, CNR, and image quality were explored. RESULTS: The use of the susceptibility-matched pillow led to a 43% reduction of B0 variation over the brachial plexus compared to the situation without a pillow (P < 0.05). The combination of the pillow with IB-shimming and the optimized diffusion-prepared sequence resulted in good nerve visibility, good fat suppression, no artifacts that would hinder clinical diagnosis, and a good overall quality (median scores ≥4). Reducing B0 variation was associated with SNR, CNR, and the above-mentioned scored features (P < 0.05). CONCLUSION: The use of a susceptibility-matched pillow in combination with IB-shimming enables robust and high-quality neurography of the complete brachial plexus.

Assessment of intensive care unit-acquired weakness in young and old mice: An E. coli septic peritonitis model.

INTRODUCTION: There are few reports of in vivo muscle strength measurements in animal models of ICU-acquired weakness (ICU-AW). In this study we investigated whether the Escherichia coli (E. coli) septic peritonitis mouse model may serve as an ICU-AW model using in vivo strength measurements and myosin/actin assays, and whether development of ICU-AW is age-dependent in this model. METHODS: Young and old mice were injected intraperitoneally with E. coli and treated with ceftriaxone. Forelimb grip strength was measured at multiple time points, and the myosin/actin ratio in muscle was determined. RESULTS: E. coli administration was not associated with grip strength decrease, neither in young nor in old mice. In old mice, the myosin/actin ratio was lower in E. coli mice at t = 48 h and higher at t = 72 h compared with controls. CONCLUSIONS: This E. coli septic peritonitis mouse model did not induce decreased grip strength. In its current form, it seems unsuitable as a model for ICU-AW.

X-linked adrenoleukodystrophy in women: a cross-sectional cohort study.

X-linked adrenoleukodystrophy is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal transporter of very long-chain fatty acids. A defect in the ABCD1 protein results in elevated levels of very long-chain fatty acids in plasma and tissues. The clinical spectrum in males with X-linked adrenoleukodystrophy has been well described and ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. As in many X-linked diseases, it was assumed that female carriers remain asymptomatic and only a few studies addressed the phenotype of X-linked adrenoleukodystrophy carriers. These studies, however, provided no information on the prevalence of neurological symptoms in the entire population of X-linked adrenoleukodystrophy carriers, since data were acquired in small groups and may be biased towards women with symptoms. Our primary goal was to investigate the symptoms and their frequency in X-linked adrenoleukodystrophy carriers. The secondary goal was to determine if the X-inactivation pattern of the ABCD1 gene was associated with symptomatic status. We included 46 X-linked adrenoleukodystrophy carriers in a prospective cross-sectional cohort study. Our data show that X-linked adrenoleukodystrophy carriers develop signs and symptoms of myelopathy (29/46, 63%) and/or peripheral neuropathy (26/46, 57%). Especially striking was the occurrence of faecal incontinence (13/46, 28%). The frequency of symptomatic women increased sharply with age (from 18% in women <40 years to 88% in women >60 years of age). Virtually all (44/45, 98%) X-linked adrenoleukodystrophy carriers had increased very long-chain fatty acids in plasma and/or fibroblasts, and/or decreased very long-chain fatty acids beta-oxidation in fibroblasts. We did not find an association between the X-inactivation pattern and symptomatic status. We conclude that X-linked adrenoleukodystrophy carriers develop an adrenomyeloneuropathy-like phenotype and there is a strong association between symptomatic status and age. X-linked adrenoleukodystrophy should be considered in the differential diagnosis in women with chronic myelopathy and/or peripheral neuropathy (especially with early faecal incontinence). ABCD1 mutation analysis deserves a place in diagnostic protocols for chronic non-compressive myelopathy.