Hidradenitis suppurativa/acne inversa: a practical framework for treatment optimization - systematic review and recommendations from the HS ALLIANCE working group.

Hidradenitis suppurativa (HS)/acne inversa is a debilitating chronic disease that remains poorly understood and difficult to manage. Clinical practice is variable, and there is a need for international, evidence-based and easily applicable consensus on HS management. We report here the findings of a systematic literature review, which were subsequently used as a basis for the development of international consensus recommendations for the management of patients with HS. A systematic literature review was performed for each of nine clinical questions in HS (defined by an expert steering committee), covering comorbidity assessment, therapy (medical, surgical and combinations) and response to treatment. Included articles underwent data extraction and were graded according to the Oxford Centre for Evidence-based Medicine criteria. Evidence-based recommendations were then drafted, refined and voted upon, using a modified Delphi process. Overall, 5310 articles were screened, 171 articles were analysed, and 65 were used to derive recommendations. These articles included six randomized controlled trials plus cohort studies and case series. The highest level of evidence concerned dosing recommendations for topical clindamycin in mild disease (with systemic tetracyclines for more frequent/widespread lesions) and biologic therapy (especially adalimumab) as second-line agents (following conventional therapy failure). Good-quality evidence was available for the hidradenitis suppurativa clinical response (HiSCR) as a dichotomous outcome measure in inflammatory areas under treatment. Lower-level evidence supported recommendations for topical triclosan and oral zinc in mild-to-moderate HS, systemic clindamycin and rifampicin in moderate HS and intravenous ertapenem in selected patients with more severe disease. Intralesional or systemic steroids may also be considered. Local surgical excision is suggested for mild-to-moderate HS, with wide excision for more extensive disease. Despite a paucity of good-quality data on management decisions in HS, this systematic review has enabled the development of robust and easily applicable clinical recommendations for international physicians based on graded evidence.

Personality and behavioural changes do not precede memory problems as possible signs of dementia in ageing people with Down syndrome.

OBJECTIVE: The objective was to find out whether changes in personality and adaptive functioning or memory processes decline first in ageing people with Down syndrome. METHODS: We measured these variables cross-sectionally in a Dutch sample (22 to 62 years of age) of 68 institutionalised people with Down syndrome. RESULTS: The scores on all the variables except one of the temperament scales were found to decline gradually with increasing age, but deterioration of episodic memory started earlier. CONCLUSIONS: We argued that a subset of our sample suffered from dementia. Furthermore, the data suggested that immediate memory impairment is one of the earliest signs of the disease in people with Down syndrome, just as it is in the general population. Copyright © 2016 John Wiley & Sons, Ltd.

Ustekinumab in hidradenitis suppurativa: clinical results and a search for potential biomarkers in serum.

BACKGROUND: Treatment of hidradenitis suppurativa (HS) is difficult and the search for effective therapies continues. OBJECTIVES: To evaluate the efficacy of ustekinumab and to discover a potential biomarker for HS. METHODS: Seventeen patients were included in this open-label study and treated with 45 or 90 mg ustekinumab at weeks 0, 4, 16 and 28. Proteomic technology and enzyme-linked assay analysis was applied to sera. RESULTS: Twelve patients completed the protocol. Moderate-to-marked improvement of the modified Sartorius score was achieved in 82% of patients at week 40 and the Hidradenitis Suppurativa Clinical Response 50 in 47%. With regard to the expression of 54 serum proteins, at baseline, a significant difference was observed between patients and healthy controls. Involved pathways were related to inflammation, immune cell signalling and tissue morphology/development. Good responders had milder disease and lower expression of leukotriene A4-hydrolase (LTA4H). Interleukin (IL)-2R, tumour necrosis factor-α, IL-17A and IL-17F were not elevated and did not change during treatment. CONCLUSIONS: The majority of patients improved with ustekinumab. Although no biomarker was discovered, low LTA4H concentrations with mild disease severity may be predictive of the effectiveness of ustekinumab.

Surgery under general anaesthesia in severe hidradenitis suppurativa: a study of 363 primary operations in 113 patients.

BACKGROUND: Treatment of hidradenitis suppurativa (HS) is a difficult undertaking, especially as there is no consensus on what surgical technique is preferred. At our centre severe HS (Hurley II/III) is operated under general anaesthesia, mostly with the STEEP procedure. OBJECTIVES: To investigate characteristics, surgical outcomes and patient satisfaction of HS patients who underwent deroofing or STEEP under general anaesthesia. METHODS: A clinical records-based retrospective analysis was conducted of all patients who had surgery under general anaesthesia between 1999 and 2013. Patient satisfaction was retrospectively investigated with questionnaires. RESULTS: A total of 482 operations (363 primary operations and 119 re-operations) were performed during the study period. The proportion of women in the included population was 68%. The median diagnostic delay (patient's and doctor's delay) was 6.5 years. Relapses occurred after 29.2% of primary operations. Women had higher relapse rates than men [odds ratio 2.85 (1.07;7.61)]. Hypergranulation of the wound was the most common complication and occurred in 7% of all operations. The median score patients attributed to the medical effect of surgery was eight of 10 (zero corresponding to very dissatisfied and 10 to very satisfied). CONCLUSION: The diagnostic delay in HS is long due to a lack of knowledge in both patients and health care professionals, indicating that there is a need for education. Deroofing and the STEEP are effective surgical procedures in severe cases of HS and lead to a relatively high patient satisfaction. The postoperative relapse risk is higher in women. Prospective studies are required for the development of clear guidelines on the appropriate choice of surgery.

Motor Unit Tracking Using High Density Surface Electromyography (HDsEMG) . Automated Correction of Electrode Displacement Errors.

INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Biosignal Interpretation: Ad-vanced Methods for Neural Signals and Images". OBJECTIVES: The study discusses a technique to automatically correct for effects of electrode grid displacement across serial surface EMG measurements with high-density electrode arrays (HDsEMG). The goal is to match motor unit signatures from subsequent measurements and by this, achieve automated motor unit tracking. METHODS: Test recordings of voluntary muscle contractions using HDsEMG were performed on three healthy individuals. Electrode grid displacements were mimicked in repeated recordings while measuring the exact position of the grid. A concept of accounting for translational and rotational displacements by making the projection of the recorded motor unit action potentials is first introduced. Then, this concept was tested for the performed measurements attempting the automated matching of the similar motor unit action potentials across different trials. RESULTS: The ability to perform automated correction (projection) of the isolated motor unit action potentials was first shown using large angular displacements. Then, for accidental (small) displacements of the recording grid, the ability to automatically track motor units across different measurement trials was shown. It was possible to track 10 -15% of identified motor units. CONCLUSIONS: This proof of concept study demonstrates an automated correction allowing the identification of an increased number of same motor unit action potentials across different measurements. By this, great potential is demonstrated for assisting motor unit tracking studies, indicating that otherwise electrode displacements cannot always be precisely described.

Skin-Tissue-sparing Excision with Electrosurgical Peeling (STEEP): a surgical treatment option for severe hidradenitis suppurativa Hurley stage II/III.

BACKGROUND: Surgery is the only curative treatment for removal of the persistent sinus tracts in the skin that are characteristic of severe hidradenitis suppurativa (HS). Complete resection of the affected tissue by wide excision is currently regarded as the preferred surgical technique in these cases. However, relatively large amounts of healthy tissue are removed with this method and suitable skin-tissue-saving techniques aiming at creating less-extensive surgical defects are therefore needed in severe HS. METHOD: We describe a skin-tissue-saving surgical technique for HS Hurley stage II-III disease: the Skin-Tissue-sparing Excision with Electrosurgical Peeling (STEEP) procedure. DISCUSSION: In contrast to wide excisions that generally reach into the deep subcutaneous fat, the fat is maximally spared with the STEEP procedure by performing successive tangential excisions of lesional tissue until the epithelialized bottom of the sinus tracts has been reached. From here, secondary intention healing can occur. In addition, fibrotic tissue is completely removed in the same manner as this also serves as a source of recurrence. This tissue-sparing technique results in low recurrence rates, high patient satisfaction with relatively short healing times and favourable cosmetic outcomes without contractures.

CMAP scan discontinuities: automated detection and relation to motor unit loss.

UNLABELLED: Objective To evaluate an automated method that extracts motor unit (MU) information from the CMAP scan, a high-detail stimulus-response curve recorded with surface EMG. Discontinuities in the CMAP scan are hypothesized to result from MU loss and reinnervation. METHODS: We introduce the parameter D50 to quantify CMAP scan discontinuities. D50 was compared with a previously developed manual score in 253 CMAP scans and with a simultaneously obtained motor unit number estimate (MUNE) in 173 CMAP scans. The effect of MU loss on D50 was determined with a simulation model. RESULTS: We found a high agreement (sensitivity=86.8%, specificity=96.6%) between D50 and the manual score. D50 and MUNE were significantly correlated below 80 MUs (r=0.65, n=68, p<0.001), but not when MUNE was larger than 120 MUs (r=0.23, n=59, p=0.08). CONCLUSIONS: Discontinuities in the CMAP scan as expressed by a decreased D50 are related to significant MU loss. The determination of D50 is objective, quantitative, and less time-consuming than both manual scoring and many existing MUNE methods. SIGNIFICANCE: D50 is potentially useful to monitor neurogenic disorders and moderate to severe MU loss.

Decreased excitability of the distal motor nerve of young patients with type 1 diabetes mellitus.

OBJECTIVE: The compound muscle action potential (CMAP) scan is a novel neurophysiological technique that appears more sensitive in detecting peripheral motor neuropathy than conventional methods. This study explores the value of the CMAP scan for the detection of subclinical diabetic peripheral motor neuropathy. METHODS: In this cross-sectional pilot study, CMAP scanning of the peroneal nerve was performed in (i) 13 well-controlled patients (8-25 yr old) with type 1 diabetes mellitus (T1DM) duration between 2.5 and 5 yr; (ii) 17 patients (10-25 yr old) with a duration of T1DM of at least 10 yr, poorly controlled and/or with microvascular complications and (iii) 13 adults with T1DM and established clinical diabetic peripheral neuropathy (DPN). Various CMAP scan variables, including measures of axonal excitability and axonal loss and reinnervation, were compared between patients and healthy controls. RESULTS: Axonal excitability was significantly decreased in the young patient groups as compared to their controls. The CMAP scan measures of axonal loss and reinnervation differed only between patients with clinical DPN and their controls. CONCLUSIONS: Motor nerve axonal excitability seems to be reduced early in T1DM, even in well-controlled young patients, and probably before (irreversible) axonal damage occurs. These changes can be measured by the CMAP scan, which makes this a promising tool for detecting nerve dysfunction in T1DM.

Systemic therapy with immunosuppressive agents and retinoids in hidradenitis suppurativa: a systematic review.

Hidradenitis suppurativa (HS) is a difficult disease to treat. Although the pathogenesis of this inflammatory skin disease is largely unknown, the important role of the immune system has been demonstrated in both experimental and clinical studies. Clinicians are therefore increasingly prescribing systemic treatments with immunosuppressive agents, but the more traditionally used systemic retinoids, especially isotretinoin, also remain relatively common therapies. In order to provide an overview of all currently available systemic immunosuppressive agents and retinoids for the treatment of HS, a systematic search was performed using the Medline and Embase databases. All published papers concerning systemic retinoids or immunosuppressive treatments for HS in adults were included. The primary endpoints were the percentages of significant responders, moderate responders and nonresponders. Other endpoints were the relapse rate and adverse events. In total 87 papers were included, comprising 518 patients with HS who were treated with systemic retinoids, biological agents or another immunosuppressive agents, including colchicine, ciclosporin, dapsone or methotrexate. The highest response rates were observed with infliximab, adalimumab and acitretin. Overall, the quality of evidence was low and differed between the agents, making direct comparisons difficult. However, based on the amount of evidence, infliximab and adalimumab were the most effective agents. Acitretin was also effective in HS, although the quality of the evidence was low. The therapeutic effect of isotretinoin is questionable. Randomized controlled trials are needed to confirm the effectiveness of acitretin, and to identify the most effective immunosuppressive agents in HS.

The Eurotransplant donor risk index in liver transplantation: ET-DRI.

Recently we validated the donor risk index (DRI) as conducted by Feng et al. for the Eurotransplant region. Although this scoring system is a valid tool for scoring donor liver quality, for allocation purposes a scoring system tailored for the Eurotransplant region may be more appropriate. Objective of our study was to investigate various donor and transplant risk factors and design a risk model for the Eurotransplant region. This study is a database analysis of all 5939 liver transplantations from deceased donors into adult recipients from the 1st of January 2003 until the 31st of December 2007 in Eurotransplant. Data were analyzed with Kaplan-Meier and Cox regression models. From 5723 patients follow-up data were available with a mean of 2.5 years. After multivariate analysis the DRI (p < 0.0001), latest lab GGT (p = 0.005) and rescue allocation (p = 0.007) remained significant. These factors were used to create the Eurotransplant Donor Risk Index (ET-DRI). Concordance-index calculation shows this ET-DRI to have high predictive value for outcome after liver transplantation. Therefore, we advise the use of this ET-DRI for risk indication and possibly for allocation purposes within the Eurotrans-plant region.

Ultrasound-guided needle positioning near the sciatic nerve to elicit compound muscle action potentials from the gastrocnemius muscle of the rat.

The use of ultrasound-guided electrode positioning in near-nerve myography was investigated. This is a minimally invasive technique that allows repeated measurements to increase accuracy and hence decreases animal numbers. Ultrasound imaging of the sciatic nerve was performed in nine rats using a 55 MHz high-end transducer. Once visualised, a monopolar needle electrode was placed through the skin near this nerve. Upon stimulation, two surface electrodes, placed over the gastrocnemius muscle, recorded compound muscle action potentials (CMAPs). Reproducibility was tested having two teams of investigators perform the recordings consecutively. Reliability of the procedure was determined by comparing the ultrasound method to the conventional technique, which requires an incision through muscle and skin to expose the sciatic nerve. In all animals the sciatic nerve was visible on ultrasound images. Both methods showed CMAP latencies (duration was determined as the time interval between the onset latency and positive peak). The conventional method had a mean latency of 3.4±0.5 ms, our method had a mean latency of 3.3±0.5 ms. Reproducibility was excellent (observed latencies and amplitudes: 3.3 versus 3.3 ms and 25.6±5.1 mV versus 22.5±8.8 mV) resulting in a coefficient of variation for duration of 2.1% and for amplitude 6.7%. Interclass correlation coefficient was 0.828 for duration. Comparing the three different measurements no significant differences were found and our new method can therefore be considered reliable and comparable to the conventional method. Ultrasound-guided near-nerve needle positioning is a reproducible and reliable minimally invasive method for selectively eliciting CMAPs, which allows repeated CMAP measurements for studying nerve regeneration in rats.

Exploring the Flynn effect in mentally retarded adults by using a nonverbal intelligence test for children.

Increases in the scores on IQ tests across generations have been called the Flynn effect (FE). One of the unresolved questions is whether the FE affects all subsamples of the intellectual ability distribution equally. The present study was aimed at determining the size of the FE in moderately mentally retarded individuals. A nonverbal intelligence test developed for children, the Snijders-Oomen Nonverbal Intelligence Test (SON), was administered to 32 retarded adults with a mental age of 3-6 years. Sixty-nine children with a biological age in the same range and with normal intelligence served as a comparison group. Both an older and a more recent version of the SON were presented to all participants in a counterbalanced order. The proportion of items answered correctly was taken as a measure of the dependent variable. It was found that a FE existed in both the group of children and in the group of retarded adults, but that the FE was largest in the latter group. The importance of not using obsolete test norms when diagnosing mental retardation was stressed, and possible causes of the Flynn effect were discussed.

Time varying neonatal seizure localization.

BACKGROUND: A common cause for damage to the neonatal brain is a shortage in the oxygen supply to the brain or asphyxia. Neonatal seizures are the most frequent manifestation of neonatal neurologic disorders. Multichannel EEG recordings allow topographic localization of seizure foci. OBJECTIVES: We want to objectively determine the spatial distribution of the seizure on the scalp, the location in time and order the dominant sources in the brain based on their strength. METHODS: In this paper we combine a method based on higher order CP-decomposition with subsequent singular value decomposition (SVD). RESULTS: We illustrate the abilities of the method on simulated as well as on real neonatal seizure EEG. CONCLUSIONS: The proposed method provides reliable time and spatial information about the seizure, gives a clear overview of what is going on in the EEG and allows easy interpretation.

Size does matter: the influence of motor unit potential size on statistical motor unit number estimates in healthy subjects.

OBJECTIVE: The statistical method of motor unit number estimation (MUNE) assumes that all motor unit potentials (MUPs) have the same size. The present study aims to evaluate the consequences of this assumption as well as its implications for the validity of statistical MUNEs. METHODS: We performed statistical and multiple point stimulation (MPS) MUNE with an array of 120 electrodes on the thenar muscles of 15 healthy subjects. These recordings allow isolation and quantification of the effect of non-uniform MUP size on MUNE, because the differences in submaximal CMAP size (and, hence, in MUNE) between electrodes are due almost entirely to differences in (summed) MUP size. RESULTS: We found no correlation between statistical and MPS MUNEs. Statistical MUNEs proved very sensitive to small variations in the "bandwidth" (variance) of the response series; MUNEs from electrodes only 8mm apart could deviate by as much as 60%. This variation in bandwidth resulted from spatial (and, hence, size) differences between the contributing MUPs. CONCLUSIONS: Statistical MUNEs are very sensitive to violation of the uniform MUP-size assumption, to an extent that blurs any correlation with MPS MUNE in healthy subjects. SIGNIFICANCE: Statistical MUNE cannot be used to detect mild to moderate motor unit losses.