European guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part I.

This guideline on mucous membrane pemphigoid (MMP) has been elaborated by the Task Force for Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology (EADV) with a contribution of physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline encompassing a systematic review of the literature until June 2019 in the MEDLINE and EMBASE databases. This first part covers methodology, the clinical definition of MMP, epidemiology, MMP subtypes, immunopathological characteristics, disease assessment and outcome scores. MMP describes a group of autoimmune skin and mucous membrane blistering diseases, characterized by a chronic course and by predominant involvement of the mucous membranes, such as the oral, ocular, nasal, nasopharyngeal, anogenital, laryngeal and oesophageal mucosa. MMP patients may present with mono- or multisite involvement. Patients' autoantibodies have been shown to be predominantly directed against BP180 (also called BPAG2, type XVII collagen), BP230, laminin 332 and type VII collagen, components of junctional adhesion complexes promoting epithelial stromal attachment in stratified epithelia. Various disease assessment scores are available, including the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI), the Autoimmune Bullous Skin disorder Intensity Score (ABSIS), the 'Cicatrising Conjunctivitis Assessment Tool' and the Oral Disease Severity Score (ODSS). Patient-reported outcome measurements (PROMs), including DLQI, ABQOL and TABQOL, can be used for assessment of quality of life to evaluate the effectiveness of therapeutic interventions and monitor disease course.

European Guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part II.

This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline that systematically reviewed the literature on mucous membrane pemphigoid (MMP) in the MEDLINE and EMBASE databases until June 2019, with no limitations on language. While the first part of this guideline addressed methodology, as well as epidemiology, terminology, aetiology, clinical presentation and outcome measures in MMP, the second part presents the diagnostics and management of MMP. MMP should be suspected in cases with predominant mucosal lesions. Direct immunofluorescence microscopy to detect tissue-bound IgG, IgA and/or complement C3, combined with serological testing for circulating autoantibodies are recommended. In most patients, serum autoantibodies are present only in low levels and in variable proportions, depending on the clinical sites involved. Circulating autoantibodies are determined by indirect IF assays using tissue substrates, or ELISA using different recombinant forms of the target antigens or immunoblotting using different substrates. The major target antigen in MMP is type XVII collagen (BP180), although in 10-25% of patients laminin 332 is recognized. In 25-30% of MMP patients with anti-laminin 332 reactivity, malignancies have been associated. As first-line treatment of mild/moderate MMP, dapsone, methotrexate or tetracyclines and/or topical corticosteroids are recommended. For severe MMP, dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first-line regimens. Additional recommendations are given, tailored to treatment of single-site MMP such as oral, ocular, laryngeal, oesophageal and genital MMP, as well as the diagnosis of ocular MMP. Treatment recommendations are limited by the complete lack of high-quality randomized controlled trials.

ERP components associated with an indirect emotional stop signal task in healthy and depressed participants.

Recent research has provided evidence to suggest that emotional stimuli may interfere with response inhibition, due to automatic capture of attention. Whilst previous studies have provided data regarding changes to event-related potentials (ERPs) in emotional Go/NoGo tasks, few studies to-date have utilized an emotional stop signal task (SST). Thirty-five participants were included in the study; 21 healthy controls and 14 depressed. An indirect emotional SST was employed, which consisted of the presentation of neutral, negative or positive visual images. The primary two-choice reaction time task required responding to frame colour (blue or green), whilst in 33% of trials an auditory stop signal was presented, with stop signal delay adjusted according to an adaptive tracking procedure. ERPs associated with both the primary visual task and the auditory SST were analysed using temporal principle components analysis (tPCA). In the primary task, reaction times were found to be slower for negative compared to neutral images. Stop signal reaction time (SSRT) was not found to be affected by image category or depression status. However, the NoGo-N2 component was found to be reduced for positive images, whilst the NoGo-P3 component was reduced for both positive and negative images in comparison to neutral images in the stop signal task. This effect was found to be enhanced for the depressed participants, indicating that inhibitory processing in the presence of positive stimuli may be inhibited to a greater extent in depressed individuals than in healthy controls. These findings provide further evidence for the ability of emotional valence and major depressive disorder to influence inhibitory processing.

EEG and electrodermal activity in girls with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: This study investigated the Hypoarousal Model of Attention-Deficit/Hyperactivity Disorder (AD/HD) in girls. METHODS: 40 girls with AD/HD and 40 girl controls (aged 7-12 years) had an eyes-closed resting EEG recorded from 19 electrodes and Fourier transformed. Estimates for total power, absolute and relative power in the delta, theta, alpha, beta and gamma frequency bands, and theta/beta ratio were analysed in nine cortical regions. Skin conductance level (SCL) was simultaneously recorded. Regression analyses explored relationships between symptoms and physiology. RESULTS: Compared with controls, girls with AD/HD had globally elevated relative delta, globally reduced absolute beta, and globally reduced absolute and relative gamma activity. Girls with AD/HD also had lower mean SCL. Inattentive symptoms were predicted by elevated frontal relative delta, reduced SCL, and reduced temporal relative gamma activity, while elevated hyperactive-impulsive symptoms correlated with elevated frontal relative delta activity in both the patient and control groups. CONCLUSIONS: These EEG results are comparable with the limited female AD/HD literature. Girls with AD/HD are hypoaroused, indicated by reduced SCL, and appear to have an anomalous arousal mechanism. Absolute and relative gamma results are similar to previous findings in AD/HD children. Symptom correlations with physiology offer intriguing insights for future research. SIGNIFICANCE: This is the first study to examine CNS arousal exclusively in girls with AD/HD.

Fast, transient cardiac accelerations and decelerations during fear conditioning in rats.

The current study reports on a number of heart rate responses observed in rats subjected to a discriminatory Pavlovian fear conditioning procedure. Rats learned that a series of six auditory pips was followed by a footshock when presented alone, but not when the pip series was preceded by a visual safety signal. Each auditory pip in the series evoked a fast transient (<1s) cardiac deceleration. This was the case on both trials followed by shock and on trials not followed by shock. The onset of the safety light evoked a similar fast deceleration. We propose that these transient decelerations are similar to the human Evoked Cardiac Response 1 (ECR1), a brief modest deceleration evoked by simple sensory stimuli that is thought to reflect an early process of stimulus registration. Immediately following these pip-evoked decelerations, modest fast accelerations were observed. These accelerations were larger when the pip series was followed by shock than when it was not followed by shock. We propose a potential linkage between these accelerations and the human acceleratory ECR2 component, which is associated with more elaborate processing following stimulus registration; something likely to take place when the pip series predicts an aversive event. Both the ECR1- and ECR2-like responses were embedded within a slow, gradual heart rate increase across the entire pip series. This tonic increase was significantly larger on trials with footshock and is therefore probably associated with anticipatory fear of the upcoming shock. An additional special type of cardiac response was found to the first pip in the series not preceded by the safety signal; here, a much larger and more sustained deceleration was apparent. This response appears relatable to the prolonged deceleration reported in humans in response to aversive picture content. We discuss the cardiac responses found in rats in the current study in the context of heart rate responses known in the human literature.

Patient-reported outcomes in primary Sjogren's syndrome: comparison of the long and short versions of the Profile of Fatigue and Discomfort--Sicca Symptoms Inventory.

OBJECTIVES: The long-form 64-item Profile of Fatigue and Discomfort--Sicca Symptoms Inventory (PROFAD-SSI) questionnaire was developed as a patient-reported assessment tool for use in primary SS (PSS) and other rheumatic disorders. In this study, we assess whether the (shorter and more practical) 19-item PROFAD-SSI-SF (short form) gives similar results and whether a still briefer version using visual analogue scales (VASs) is feasible. METHODS: Questionnaire surveys comprising the long and short versions of the PROFAD-SSI were mailed to 43 patients with PSS and 50 patients with RA, who were asked to complete these contemporaneously as well as repeating the process 1 month later. PSS patients also completed a series of VASs comprising fatigue and sicca domains of the SSI. RESULTS: Surveys were returned from 35 PSS patients and 35 RA patients. All domains of the long- and short-form PROFAD-SSI showed strong correlations (Spearman rho between 0.779 and 0.996, P < 0.01). Factor analysis generally confirmed the previously validated domain structure with Cronbach's alpha = 0.99. The PROFAD-SF somatic fatigue domain correlated more strongly with a fatigue VAS than did the mental fatigue domain. The SSI-SF domain scores correlated with equivalent VAS scores. CONCLUSION: The long- and short-form PROFAD-SSI questionnaires correlate closely suggesting that the PROFAD-SF is valid as an outcome tool. Preliminary data also suggest that an even briefer form with compression of the domains into single VAS is also feasible.

The Sjögren's Syndrome Damage Index--a damage index for use in clinical trials and observational studies in primary Sjögren's syndrome.

OBJECTIVE: To validate a tool for assessment of accumulated damage in patients with Primary SS (PSS). METHODS: Of the total 114 patients fulfilling American-European Consensus Group (AECG) criteria for PSS 104 were included in the study and assessed by rheumatologists at T (time) = 0 months and T = 12 months. On each occasion, damage and activity data, and autoantibody status were collected. SF-36 and Profile of Fatigue and Discomfort-Sicca Symptoms Inventory (PROFAD-SSI) questionnaires were completed. Cross-sectional analysis of this data was subject to a process of expert validation by 11 ophthalmologists, 14 oral medicine specialists and 8 rheumatologists. Items were removed from the index if >or= 50% of respondents recommended exclusion. Statistical validation was performed on remaining items. Spearman's rank analysis was used to investigate associations between damage scores and other disease status measures and Wilcoxon matched-pair analysis to assess sensitivity to change in the damage score. RESULTS: Based on the expert validation, a 29-item damage score was agreed incorporating ocular, oral and systemic domains. Total damage score correlated with disease duration at study entry (r = 0.436; P < 0.001), physical function as measured by SF-36 (r = 0.250, T = 0 months; r = 0.261 T = 12 months) and activity as measured by the Sjögren's Systemic Clinical Activity Index (r = 0.213, T = 0 months; r = 0.215, T =12 months). Ocular damage score correlated with the 'eye dry' domain of PROFAD-SSI (r = 0.228, T = 0 months; r = 0.365, T = 12 months). Other associations not present on both assessments were considered clinically insignificant. On Wilcoxon analysis, the index was sensitive to change over 12 months (z = -3.262; P < 0.01). CONCLUSION: This study begins validation of a tool for collection of longitudinal damage data in PSS. We recommend further trial in both the experimental and clinical environment.

Unregistered visual impairment: is registration a failing system?

BACKGROUND/AIMS: To assess the current level of under-registration of blindness and partial sight among patients attending a large teaching hospital, and to determine any risk factors for under-registration. METHODS: Medical records of all patients attending general ophthalmology outpatient clinics over a 3 month period were included in a retrospective analysis of registration rates; questionnaire survey assessing the level of knowledge of registration practices among 35 ophthalmologists working in the West Midlands. RESULTS: 146/2161 (7%) patients were eligible for blind or partial sight registration, or were in possession of a completed BD8 form. Of these 146 patients, 65 (45%) were unregistered with 18 fulfilling the criteria for blind and 47 for partially sight. In addition, 32/81 (40%) registered patients appeared to have been inappropriately registered. Partially sighted patients were more likely to be unregistered than blind patients (OR 2.31, 95% CI 1.15 to 4.63, p = 0187), and patients from ethnic minorities were more than three times more likely to be unregistered than white patients (OR 3.23, 95% CI 1.56 to 6.65, p = 0.0015). A patient with a treatable condition was more likely to be unregistered than a patient with an untreatable condition (OR 4.87, 95% CI 2.10 to 11.33, p = 0.0002). The overall level of knowledge of registration practices among doctors was found to be low and there was no indication of increasing knowledge with increasing experience. CONCLUSIONS: There has been little improvement in registration rates of visually impaired patients over the past decade. Ophthalmologists lack the necessary knowledge to cater for visually impaired patients' needs.

Target-to-target interval versus probability effects on P300 in one- and two-tone tasks.

The P3(00) is an electrophysiological index of neural processing that varies with such stimulus parameters as interstimulus interval (ISI) and target probability, with a common view being that it reflects an endogenous form of memory update. Building on previous research, we argue that relations between P3 amplitude and both ISI and probability may be attributable to the target-to-target interval (TTI). Employing between-subject (Experiment 1; N = 24) and within-subject (Experiment 2; N = 10) designs, the present paper addresses this by testing subjects on a standard two-tone auditory oddball task as well as a one-tone task. In both studies, P3 amplitude increased and latency decreased linearly with TTI, and these relations were relatively unaffected by ISI or probability. This suggests that ISI and probability per se do not independently affect P3 amplitude, and that TTI offers a strong explanation of the reported relations between P3 amplitude and both ISI and probability.

Hyperkinetic disorder in the ICD-10: EEG evidence for a definitional widening?

This study investigated EEG differences between children with Hyperkinetic Disorder (HKD), HKD sub-threshold attention deficit (HKDsub), and control children, in order to determine from an EEG perspective whether children with HKDsub represent a valid clinical disorder. Twenty-four boys were included in each of the three age-matched groups. The HKD group had greater total power and absolute delta and theta, more relative theta, and less relative alpha and beta than the control group. The HKDsub group had EEG profiles which were different from both control children and children with HKD, with the HKDsub group having EEG results generally between the HKD and control group. Additionally, a number of topographic differences were found in the frontal regions which suggest that the two HKD groups have independent EEG components. These results support the inclusion of a diagnostic category of attention deficit in future editions of the ICD.

EEG-defined subtypes of children with attention-deficit/hyperactivity disorder.

OBJECTIVES: This study investigated the presence of EEG clusters within a sample of children with the combined type of attention-deficit/hyperactivity disorder (ADHD). METHODS: Subjects consisted of 184 boys with ADHD and 40 age-matched controls. EEG was recorded from 21 sites during an eyes-closed resting condition and Fourier transformed to provide estimates for total power, and relative power in the delta, theta, alpha and beta bands, and for the theta/beta ratio. Factor analysis was used to group sites into 3 regions, covering frontal, central and posterior regions. These data were subjected to cluster analysis. RESULTS: Three distinct EEG clusters of children with ADHD were found. These were characterized by (a) increased slow wave activity and deficiencies of fast wave, (b) increased high amplitude theta with deficiencies of beta activity, and (c) an excess beta group. CONCLUSIONS: These results indicate that children with ADHD do not constitute a homogenous group in EEG profile terms. This has important implications for studies of the utility of EEG in the diagnosis of ADHD. Efforts aimed at using EEG as a tool to discriminate ADHD children from normals must recognize the variability within the ADHD population if such a tool is to be valid and reliable in clinical practice.

Excess beta activity in children with attention-deficit/hyperactivity disorder: an atypical electrophysiological group.

Studies of children with attention deficit/hyperactivity disorder (ADHD) have typically found elevated levels of slow wave activity in their EEGs, but in two of our previous studies, a small subset of ADHD children with excess beta activity in the EEG was identified. The aim of this study was to determine whether children with excess beta activity represent a distinct electrophysiological subtype of ADHD, to quantify the differences in their EEGs, and to determine if this group of children with ADHD have behavioural profiles different from other children with ADHD. Results indicated that children with excess beta represent a small independent subset of children diagnosed with ADHD, which primarily consists of children with a diagnosis of ADHD combined type. Behaviourally, this group was similar to other children with ADHD, although the excess-beta group were more prone to temper tantrums and to be moody. The excess in beta activity was found primarily in the frontal regions and may be associated with frontal lobe self-regulation and inhibition control.

Topographic distribution and developmental timecourse of auditory event-related potentials in two subtypes of attention-deficit hyperactivity disorder.

The effect of age on the topographic distribution of auditory event-related potentials (ERPs) recorded during a two-tone discrimination, or oddball, task was examined in two subtypes of attention deficit/hyperactivity disorder (AD/HD) as defined by the most recent diagnostic manual, DSM-IV. EEG was recorded at 17 sites from AD/HD predominantly inattentive type (n=50) and AD/HD combined type (n=50) subjects aged from 8 to 17 years 11 months. ERP components were quantified at each site. Results revealed topographic differences from controls (n=50) that were common to both subtypes (e.g. target and standard P2 amplitude, and standard P2 latency) or unique to a particular subtype of AD/HD (Inattentive type: target N1, N2, P3b and standard N2 amplitude, target P2 latency; Combined type: target N1, P2, N2 and P3b amplitude, target N2 and standard N1 latency). These group differences showed different age effects. The across-region results revealed differing patterns of abnormal component development for each subtype, indicating a qualitative difference in information processing stage deficits in each of these AD/HD subtypes.

Electroencephalogram differences in two subtypes of attention-deficit/hyperactivity disorder.

This study investigated EEG differences between children with two subtypes of Attention-Deficit/Hyperactivity Disorder (ADHD) and normal control subjects. EEG was recorded during an eyes-closed resting condition and Fourier transformed to provide absolute and relative power estimates for the delta, theta, alpha, and beta bands, and the mean frequency for each band was calculated. Ratio coefficients were also calculated between frequency bands. Mean group differences were found in the theta, alpha, and beta bands between all three groups. Similarly, differences were found between all three groups for the theta/alpha and theta/beta ratios and for the mean frequency of the total EEG. These results support a model of ADHD resulting from a developmental deviation rather than a maturational lag in the central nervous system. Differences between the clinical groups in frontal activity suggest that different neuroanatomical systems are involved in the different subtypes of ADHD.

Age and sex effects in the EEG: development of the normal child.

OBJECTIVES: This study investigated age-related changes and sex differences in the EEGs of normal children. METHODS: Forty boys and 40 girls, between the ages of 8 and 12 years, participated in this study. The EEG was recorded during an eyes-closed resting condition and Fourier transformed to provide estimates for total power, absolute and relative power in the delta, theta, alpha and beta bands, and for theta/alpha and theta/beta ratios. RESULTS: Absolute delta activity decreased with age. Relative delta and theta decreased and alpha and beta increased with increasing age. The theta/alpha and theta/beta ratios decreased with increasing age. All of these indicated a developmental reduction in slow wave activity. Maturational differences were found in the rates of change between the midline and the two hemispheres. In the absolute delta and the theta/beta ratio, the midline and the two hemispheres became more equipotential with age. In the beta band, power increased at a greater rate than in the two hemispheres. Sex differences were found, with males having less theta and more alpha than females. CONCLUSIONS: These results indicated that maturation occurs earlier at the midline than in the two hemispheres. Females were also found to have a developmental lag in the EEG compared with males.

Age and sex effects in the EEG: differences in two subtypes of attention-deficit/hyperactivity disorder.

OBJECTIVES: This study investigated age-related changes and sex differences in the EEGs of two groups of children with attention-deficit/hyperactivity disorder (ADHD) combined type and ADHD predominantly inattentive type, in comparison with a control group of normal children. METHODS: Forty boys and forty girls were included in each group. The EEG was recorded during an eyes-closed resting condition and Fourier transformed to provide estimates for total power, absolute and relative power in the delta, theta, alpha and beta bands, and for theta/alpha and theta/beta ratios. RESULTS: Total power, relative alpha, and the theta/alpha and theta/beta ratios were differentiated between all 3 groups. Sex differences between the ADHD subjects and the control group were greater in males than females and matured faster in males. With increasing age, the EEG of the ADHD inattentive group was found to change at a similar rate to the changes found in the normal group, with the differences in power levels remaining constant. In the ADHD combined group, the power was found to change at a greater rate than in the ADHD inattentive group, with power levels of the two ADHD groups becoming similar with age. CONCLUSIONS: These results are supportive of a two-component model of ADHD, with the hyperactive/impulsive component maturing with age and the inattentive component remaining more stable.

Elite pistol shooters: physiological patterning of best vs. worst shots.

This study examined patterns of physiological activity in elite pistol shooters and compared them with novice shooters. Heart rate and electrodermal activity were recorded for three 150-s epochs. Participants performed part of the Standard Pistol Shooting Protocol, firing five rounds at a target 25 m distant within the first 150 s epoch. In the second epoch, baseline data were recorded with the participant standing at rest. The third epoch was a repetition of the first epoch. For each shot, values of heart rate and skin conductance were calculated at half-second intervals from 20 s before to 10 s after the shot. In experts there was a slow reduction in skin conductance and heart rate levels prior to the shot, and a 'rebound' increase immediately following the shot, which were not apparent in the novice shooters. Pre-shot electrodermal levels for the expert shooters were lower for the best compared with the worst shots, and the duration of the pre-shot cardiac deceleration was longer and more systematic for best than for worst shots. The physiological profiles supported interpretation in terms of two separate state processes, arousal and vigilance, rather than a single construct. These physiological differences are discussed in terms of differential engagement with the task and its associated attentional narrowing in expert pistol shooters.

Nasal bilevel positive airway pressure therapy in children with a sleep-related breathing disorder and attention-deficit hyperactivity disorder: effects on electrophysiological measures of brain function.

OBJECTIVE: To examine the effect of nasal bilevel positive airway pressure (BiPAP) treatment for concurrent sleep-related breathing disorders (SRBDs) and attention-deficit hyperactivity disorder (ADHD) on electrophysiological measures of spontaneous brain activity and auditory stimulus processing. METHODS: Nineteen children diagnosed with both SRBD and ADHD participated. Electroencephalogram (EEG) activity was recorded during a resting period and an auditory oddball task before beginning BiPAP treatment, after 6 months on treatment, and after a subsequent 1 week non-treatment period. Treatment effects on EEG and event-related potentials (ERPs) to target stimuli were examined via topographic analysis. RESULTS: Thirteen of the initial 19 children completed 6 months of BiPAP therapy, with six lost mainly due to compliance problems. Children on BiPAP therapy showed a significant decrease in slow-wave (delta and theta) and an increase in fast wave (beta) EEG activity. The P3 component of the ERP showed treatment effects in amplitude and latency. CONCLUSIONS: The electrophysiological data suggest that SRBDs may contribute to ADHD symptomatology. Treatment of SRBD with BiPAP therapy in children with concurrent ADHD can lead to significant changes, in the direction of normalization, of the typical electrophysiological features of ADHD.

EEG alpha activity and the ERP to target stimuli in an auditory oddball paradigm.

Peak-to-peak amplitudes of the N1P2 and N2P3 components in the target ERPs from a fixed interstimulus interval auditory oddball paradigm were investigated as a function of within-subject pre-stimulus levels of alpha activity. Fourteen subjects were each presented with 600 auditory stimuli in a two-tone auditory oddball paradigm which required a button-press to targets, presented with 50% probability. Pre-stimulus alpha activity at Pz was assessed for each trial by digital filtering from 8 to 13 Hz, and alpha RMS amplitude was used to sort the ERPs at Pz and Cz. A direct relationship was obtained between component amplitudes at both Pz and Cz and pre-stimulus alpha level at Pz. Component latencies were strongly related to post-stimulus alpha peaks and troughs. These data confirm the intimate relationship between central nervous system activation, as evidenced by spontaneous EEG in the pre-stimulus period, and the ERP resulting from stimulus presentation.

EOG correction: comparing different calibration methods, and determining the number of epochs required in a calibration average.

OBJECTIVE: A form of EOG correction called the 'aligned-artifact average' (AAA) method has been advanced by the authors. In contrast to many previous methods, this used a correction coefficient (B), based on an average of eye movements rather than raw data, to remove eye movement related contamination from the EEG. The first part of this study was aimed at determining whether a variation of this procedure that is more easily implemented would produce a similar correction. The second part was designed to determine the number of epochs needed in an average to correct adequately. METHODS: Subjects performed a series of eye movement tasks whilst EEG and EOG data were recorded. Data were manipulated according to either the AAA or an alternate new ERP method (NERP) and the resultant Bs were compared in part A. In part B, averages were created from varying numbers of epochs, and the resultant r(2)-values were compared. RESULTS: The AAA and NERP methods produced the same Bs, and averages with at least 40 epochs were required for adequate B estimation for both VEOG and HEOG. CONCLUSION: There is no difference between the AAA and NERP methods and thus it is acceptable to use the more easily implemented NERP method for EOG correction. It is recommended that when applying this procedure, at least 40 epochs should be used to make up the averages from which to calculate correction coefficients.