Imaging blood-brain barrier dysfunction in drug-resistant epilepsy: A multi-center feasibility study.

OBJECTIVE: Blood-brain barrier dysfunction (BBBD) has been linked to various neurological disorders, including epilepsy. This study aims to utilize dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to identify and compare brain regions with BBBD in patients with epilepsy (PWE) and healthy individuals. METHODS: We scanned 50 drug-resistant epilepsy (DRE) patients and 58 control participants from four global specialized epilepsy centers using DCE-MRI. The presence and extent of BBBD were analyzed and compared between PWE and healthy controls. RESULTS: Both greater brain volume and higher number of brain regions with BBBD were significantly present in PWE compared to healthy controls (p < 10-7). No differences in total brain volume with BBBD were observed in patients diagnosed with either focal seizures or generalized epilepsy, despite variations in the affected regions. Overall brain volume with BBBD did not differ in PWE with MRI-visible lesions compared with non-lesional cases. BBBD was observed in brain regions suspected to be related to the onset of seizures in 82% of patients (n = 39) and was typically identified in, adjacent to, and/or in the same hemisphere as the suspected epileptogenic lesion (n = 10). SIGNIFICANCE: These findings are consistent with pre-clinical studies that highlight the role of BBBD in the development of DRE and identify microvascular stabilization as a potential therapeutic strategy.

Paroxysmal slow wave events predict epilepsy following a first seizure.

OBJECTIVE: Management of a patient presenting with a first seizure depends on the risk of additional seizures. In clinical practice, the recurrence risk is estimated by the treating physician using the neurological examination, brain imaging, a thorough history for risk factors, and routine scalp electroencephalogram (EEG) to detect abnormal epileptiform activity. The decision to use antiseizure medication can be challenging when objective findings are missing. There is a need for new biomarkers to better diagnose epilepsy following a first seizure. Recently, an EEG-based novel analytical method was reported to detect paroxysmal slowing in the cortical network of patients with epilepsy. The aim of our study is to test this method's sensitivity and specificity to predict epilepsy following a first seizure. METHODS: We analyzed interictal EEGs of 70 patients admitted to the emergency department of a tertiary referral center after a first seizure. Clinical data from a follow-up period of at least 18 months were available. EEGs of 30 healthy controls were also analyzed and included. For each EEG, we applied an automated algorithm to detect paroxysmal slow wave events (PSWEs). RESULTS: Of patients presenting with a first seizure, 40% had at least one additional recurring seizure and were diagnosed with epilepsy. Sixty percent did not report additional seizures. A significantly higher occurrence of PSWEs was detected in the first interictal EEG test of those patients who were eventually diagnosed with epilepsy. Conducting the EEG test within 72 h after the first seizure significantly increased the likelihood of detecting PSWEs and the predictive value for epilepsy up to 82%. SIGNIFICANCE: The quantification of PSWEs by an automated algorithm can predict epilepsy and help the neurologist in evaluating a patient with a first seizure.

Segmental Pigmentation Disorder: Clinical Manifestations and Epidemiological Features in 144 patients, a Retrospective Case-control Study.

Segmental pigmentation disorder (SPD) is characterized by hypo- or hyper-pigmented patches segmentally distributed, present in infancy, more prominently in darker-skinned children. The aim of this study was to define the demographic and clinical characteristics of SPD in a large series of patients. This was a retrospective case-control study at 2 paediatric dermatology centres in Israel. Data were collected through a telephone questionnaire and medical records. The study group consisted of 144 individuals with SPD and 144 individuals visiting the same institutions matched for age and sex. Median age of onset of SPD was near birth; 51% of patients were Sephardic Jews, and patients were followed up for a median period of 27 years. The patches were located on the torso (43%), mostly hypopigmented (52%), and remained of the same intensity and size in 55% and 41% of cases, accordingly. No differences in extracutaneous morbidities were found between SPD and control patients. This study delineates the demographic and clinical characteristics of SPD, confirms that cutaneous findings in SPD are more prominent in darker skin, tends not to expand in size or accentuate throughout the years, nor to be associated with extracutaneous morbidities.

Superimposed type 2 segmental atopic dermatitis: case series and review of the literature.

Generalized acquired dermatoses can seldom manifest more prominently or exclusively along the lines of Blaschko. Six individuals with segmental atopic dermatitis (AD) have been reported to date. We present three additional cases of segmental cutaneous manifestations superimposed on generalized AD, and review the relevant literature.

[LINEAR MYCOSIS FUNGOIDES IN A BLASCHKOID DISTRIBUTION].

INTRODUCTION: Mycosis fungoides (MF) is the most common type of primary cutaneous T cell lymphoma. Many clinicopathological variants of MF have been described in the literature, though only a few presented in a segmental pattern. There are several unique patterns of distribution of skin diseases, one of which is the Blaschko Lines. Congenital skin diseases develop in a Blaschkoid pattern due to mosaicism. In contrast, according to Happle, the development of acquired skin diseases in a similar pattern is explained by superimposed segmental manifestation - a process which involves mosaicism overlapping a preexisting congenital mutation. The theories by which previous case reports explained the segmental appearance of MF did not cover the molecular basis for their development. We report a case of a patient who presented with MF in a unique segmental distribution consistent with the Blaschko lines. The patient was found to have an acquired mosaic mutation in GNAS gene exclusively in the involved skin which represents a superimposed segmental manifestation according to Happle's theory. This case demonstrates the hidden potential of these rare cases which allows a better understanding of the pathogenesis by which acquired diseases develop. This is a basis for further research that could help identify new therapeutic targets for MF and other diseases that share its genetic etiology.

Glutathione S-transferase polymorphisms in patients with photosensitive and non-photosensitive drug eruptions.

BACKGROUND: Glutathione S-transferases (GSTs) play a critical role in cellular protection against oxidative damage. Polymorphisms in three major GST loci have been described. A number of studies have looked for an association between GSTs and skin diseases. PURPOSE: To ascertain the possibility that polymorphisms in the GSTM1, GSTT1, and GSTP1 genes may predict the development of photo-induced and non-photo-induced drug eruptions. METHODS: A cohort of 40 patients with drug eruptions, 10 of whom had developed a photo-induced drug reaction, and matched controls (116 for GSTM1 and GSTT1, 120 for GSTP1) were studied. Genotyping was conducted using direct sequencing and polymerase chain reaction. RESULTS: The GSTP1 Val/Val genotype was significantly associated with non-photosensitive drug eruptions (OR = 3.64, P value = 0.038), whereas associations observed between GSTP1, GSTM1, GSTT1 polymorphisms and photosensitive drug eruptions did not reach statistical significance. CONCLUSIONS: Variations in GSTP1 may affect the risk to develop non-photo-induced drug eruptions. These results warrant confirmatory studies in a larger patient sample.

Identification of a Functional Risk Variant for Pemphigus Vulgaris in the ST18 Gene.

Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease caused by disruption of intercellular adhesion due to auto-antibodies directed against epithelial components. Treatment is limited to immunosuppressive agents, which are associated with serious adverse effects. The propensity to develop the disease is in part genetically determined. We therefore reasoned that the delineation of PV genetic basis may point to novel therapeutic strategies. Using a genome-wide association approach, we recently found that genetic variants in the vicinity of the ST18 gene confer a significant risk for the disease. Here, using targeted deep sequencing, we identified a PV-associated variant residing within the ST18 promoter region (p<0.0002; odds ratio = 2.03). This variant was found to drive increased gene transcription in a p53/p63-dependent manner, which may explain the fact that ST18 is up-regulated in the skin of PV patients. We then discovered that when overexpressed, ST18 stimulates PV serum-induced secretion of key inflammatory molecules and contributes to PV serum-induced disruption of keratinocyte cell-cell adhesion, two processes previously implicated in the pathogenesis of PV. Thus, the present findings indicate that ST18 may play a direct role in PV and consequently represents a potential target for the treatment of this disease.

Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis.

Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs), the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using whole exome sequencing, we identified 2 frameshift and 2 missense mutations in TSPEAR segregating with the disease phenotype in 3 families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR) protein, whose function is poorly understood. TSPEAR knock-down resulted in altered expression of genes known to be regulated by NOTCH and to be involved in murine hair and tooth development. Pathway analysis confirmed that down-regulation of TSPEAR in keratinocytes is likely to affect Notch signaling. Accordingly, using a luciferase-based reporter assay, we showed that TSPEAR knock-down is associated with decreased Notch signaling. In addition, NOTCH1 protein expression was reduced in patient scalp skin. Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.

Comparative Study of Frozen and Paraffin-Embedded Sections: Evaluation of Inflammatory Dermatoses.

BACKGROUND: Frozen section (FS) is often performed when histopathological evaluations are urgently required for implementation of therapeutic measures. In dermatology, this method is most commonly used to evaluate excision margins of tumors. FS are also routinely employed to differentiate toxic epidermal necrolysis from staphylococcal scalded skin syndrome. However, little is currently known about the performance of FS in the diagnosis of inflammatory dermatoses. OBJECTIVES: To compare histopathological diagnoses in a series of patients with a clinical diagnosis of an inflammatory dermatosis for which FS and paraffin-section (PS) specimens were obtained on the same day. METHODS: We conducted a single-center retrospective analysis of 43 cases. All histological slides were reviewed by a single dermato-pathologist. Concordance was calculated between FS and PS. RESULTS: Patients were divided into three groups according to diagnosis: papulosquamous diseases (group I), drug eruptions (group II), and a heterogeneous group (group III) that included cases of bullous vasculitis and Sweet syndrome. Among the three groups, the results of FS and of PS were discordant only in five cases (5/43, 11.6%). Compared to PS, FS had a sensitivity of 92.9% [95% confidence interval (95%CI) 64.17-99.63%] and a specificity of 100% in group I, sensitivity of 90.9% (95%CI 57.12-99.52%) and specificity of 100% in group II, and sensitivity of 83.33% (95%CI 60.78-94.16%) and specificity of 100% in group III. The degree of agreement between the results of the FS and of the PS was almost perfect (kappa = 0.95, 0.93 and 0.85 respectively). CONCLUSIONS: This study suggests that FS is a valid approach for the rapid diagnosis of inflammatory dermatoses. This method is as specific as PS, although it is less sensitive.

Brain system for mental orientation in space, time, and person.

Orientation is a fundamental mental function that processes the relations between the behaving self to space (places), time (events), and person (people). Behavioral and neuroimaging studies have hinted at interrelations between processing of these three domains. To unravel the neurocognitive basis of orientation, we used high-resolution 7T functional MRI as 16 subjects compared their subjective distance to different places, events, or people. Analysis at the individual-subject level revealed cortical activation related to orientation in space, time, and person in a precisely localized set of structures in the precuneus, inferior parietal, and medial frontal cortex. Comparison of orientation domains revealed a consistent order of cortical activity inside the precuneus and inferior parietal lobes, with space orientation activating posterior regions, followed anteriorly by person and then time. Core regions at the precuneus and inferior parietal lobe were activated for multiple orientation domains, suggesting also common processing for orientation across domains. The medial prefrontal cortex showed a posterior activation for time and anterior for person. Finally, the default-mode network, identified in a separate resting-state scan, was active for all orientation domains and overlapped mostly with person-orientation regions. These findings suggest that mental orientation in space, time, and person is managed by a specific brain system with a highly ordered internal organization, closely related to the default-mode network.

SVEP1 plays a crucial role in epidermal differentiation.

SVEP1 is a recently identified multidomain cell adhesion protein, homologous to the mouse polydom protein, which has been shown to mediate cell-cell adhesion in an integrin-dependent manner in osteogenic cells. In this study, we characterized SVEP1 function in the epidermis. SVEP1 was found by qRT-PCR to be ubiquitously expressed in human tissues, including the skin. Confocal microscopy revealed that SVEP1 is normally mostly expressed in the cytoplasm of basal and suprabasal epidermal cells. Downregulation of SVEP1 expression in primary keratinocytes resulted in decreased expression of major epidermal differentiation markers. Similarly, SVEP1 downregulation was associated with disturbed differentiation and marked epidermal acanthosis in three-dimensional skin equivalents. In contrast, the dispase assay failed to demonstrate significant differences in adhesion between keratinocytes expressing normal vs low levels of SVEP1. Homozygous Svep1 knockout mice were embryonic lethal. Thus, to assess the importance of SVEP1 for normal skin homoeostasis in vivo, we downregulated SVEP1 in zebrafish embryos with a Svep1-specific splice morpholino. Scanning electron microscopy revealed a rugged epidermis with perturbed microridge formation in the centre of the keratinocytes of morphant larvae. Transmission electron microscopy analysis demonstrated abnormal epidermal cell-cell adhesion with disadhesion between cells in Svep1-deficient morphant larvae compared to controls. In summary, our results indicate that SVEP1 plays a critical role during epidermal differentiation.

Tinea capitis outbreak among paediatric refugee population, an evolving healthcare challenge.

Outbreaks of tinea capitis (TC) represent a major medical and economic burden. Population migrations have become a phenomenon of increasing relevance for medical conditions management. Given the recent massive arrival of immigrants, we sought to determine epidemiologic trends for TC among paediatric populations at the Tel Aviv Medical Center. We conducted a retrospective study of all TC cases diagnosed between 2010 and 2014 in a paediatric dermatology unit of a tertiary medical centre, serving as a referral centre for the paediatric refugee population from the great Tel Aviv area. Epidemiologic, clinical and treatment data including effectiveness and safety were reviewed. In all, 145 children met the inclusion criteria. Trend analyses showed increases in TC rates over the study period. Incidence rates were higher in boys than in girls. Children of African origin had the highest TC incidence rates as compared with other ethnic groups. Trichophyton violaceum and Microsporum audouinii were the predominant causative organisms. Treatment with griseofulvin was satisfactory in all cases. There was a significant increase in TC incidence rates in the Tel Aviv area over the study period. TV and MA were the predominant organisms. These trends may be a result of poor living conditions and crowded school premises.

Reversible functional connectivity disturbances during transient global amnesia.

OBJECTIVE: Transient global amnesia (TGA), an abrupt occurrence of severe anterograde episodic amnesia accompanied by repetitive questioning, has been known for more than 50 years. Despite extensive research, there is no clear evidence for the underlying pathophysiological basis of TGA. Moreover, there is no neuroimaging method to evaluate TGA in real time. METHODS: Here we used resting-state functional magnetic resonance imaging recorded in 12 patients during the acute phase of TGA together with connectivity and cluster analyses to detect changes in the episodic memory network in TGA. RESULTS: Our results show a significant reduction in functional connectivity of the episodic memory network during TGA, which is more pronounced in the hyperacute phase than in the postacute phase. This disturbance is bilateral, and reversible after recovery. Although the hippocampus and its connections are significantly impaired, other parts of the episodic memory network are also impaired. Similar results were obtained for the analysis of the episodic memory network whether it was defined in a data-driven or literature-based manner. INTERPRETATION: These results suggest that TGA is related to a functional disturbance in the episodic memory network, and supply a neuroimaging correlate of TGA during the acute phase.

Pemphigus vulgaris is characterized by low IgG reactivities to specific self-antigens along with high IgG reactivity to desmoglein 3.

Pemphigus vulgaris (PV) is an autoimmune skin disease, which has been characterized by IgG autoantibodies to desmoglein 3. Here we studied the antibody signatures of PV patients compared with healthy subjects and with patients with two other autoimmune diseases with skin manifestations (systemic lupus erythematosus and scleroderma), using an antigen microarray and informatics analysis. We now report a previously unobserved phenomenon--patients with PV, compared with the healthy subjects and the two other diseases, show a significant decrease in IgG autoantibodies to a specific set of self-antigens. This novel finding demonstrates that an autoimmune disease may be associated with a loss of specific, healthy IgG autoantibodies and not only with a gain of specific, pathogenic IgG autoantibodies.

Clinical considerations and key issues in the management of patients with Erdheim-Chester Disease: a seven case series.

BACKGROUND: Erdheim-Chester Disease (ECD), a non Langerhans' cell histiocytosis of orphan nature and propensity for multi-systemic presentations, comprises an intricate medical challenge in terms of diagnosis, treatment and complication management. OBJECTIVES: The objectives are to report the clinical, radiological and pathological characteristics, as well as cardinal therapeutic approaches to ECD patients and to provide clinical analyses of the medical chronicles of these complex patients. METHODS: Patients with biopsy proven ECD were audited by a multi-disciplinary team of specialists who formed a coherent timeline of all the substantial clinical events in the evolution of their patients' illness. RESULTS: Seven patients (five men, two women) were recruited to the study. The median age at presentation was 53 years (range: 39 to 62 years). The median follow-up time was 36 months (range: 1 to 72 months). Notable ECD involvement sites included the skeleton (seven), pituitary gland (seven), retroperitoneum (five), central nervous system (four), skin (four), lungs and pleura (four), orbits (three), heart and great vessels (three) and retinae (one). Prominent signs and symptoms were fever (seven), polyuria and polydipsia (six), ataxia and dysarthria (four), bone pain (four), exophthalmos (three), renovascular hypertension (one) and dyspnea (one). The V600E BRAF mutation was verified in three of six patients tested. Interferon-α treatment was beneficial in three of six patients treated. Vemurafenib yielded dramatic neurological improvement in a BRAF mutated patient. Infliximab facilitated pericardial effusion volume reduction. Cladribine improved cerebral blood flow originally compromised by perivenous lesions. CONCLUSIONS: ECD is a complex, multi-systemic, clonal entity coalescing both neoplastic and inflammatory elements and strongly dependent on impaired RAS/RAF/MEK/ERK signaling.

Molecular analysis of a series of Israeli families with Comèl-Netherton syndrome.

BACKGROUND: Comèl-Netherton syndrome is a rare congenital autosomal recessive disorder characterized by congenital ichthyosis, hair shaft abnormalities and atopic diathesis. It is caused by mutations in SPINK5, which encodes the serine protease inhibitor LEKTI. OBJECTIVES: To delineate the spectrum of mutations carried by a series of Israeli patients in an attempt to establish an effective diagnostic strategy for this disease in Israel. METHODS: Mutations were identified by direct sequencing of the entire coding sequence of SPINK5 and confirmed using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Three mutations were identified in seven families, of which two were novel. All mutations were predicted to result in premature termination of protein translation. CONCLUSIONS: This report presents the first case series of patients affected with Comèl-Netherton syndrome in Israel and suggests that some mutations reoccur in a substantial portion of cases in our country, a fact that should be taken into consideration when designing molecular analysis in new cases.

Concomitant occurrence of pyoderma gangrenosum and erythema nodosum in inflammatory bowel disease.

Erythema nodosum and pyoderma gangrenosum are common skin manifestations in inflammatory bowel diseases. Curiously, these two cutaneous features have seldom been reported to occur simultaneously. We present three patients affected with inflammatory bowel disease with concomitant erythema nodosum and pyoderma gangrenosum.

Diffusion-weighted imaging at b1000 for identifying intracerebral hemorrhage: preliminary sensitivity, specificity, and inter-rater variability.

BACKGROUND: Noncontrast computed tomography (NCCT) is the gold standard to detect intracerebral hemorrhage (ICH) and ischemic stroke (IS) in patients presenting with acute focal syndromes. Diffusion-weighted magnetic resonance imaging (DW-MRI) obtained at b1000 is highly sensitive to identify acute IS but its sensitivity and specificity to detect ICH has not been systematically studied. METHODS: Patients with a diagnosis of ICH on NCCT were prospectively enrolled and underwent DW-MRI at b1000. Patients with suspected ischemia and a negative NCCT served as controls. All diffusion-weighted imaging (DWI) scans were evaluated blindly by 4 experienced raters. Sensitivity, specificity, and inter-rater variability of the DWI b1000 scans for detection of ICH were determined. RESULTS: In this preliminary pilot study, 15 patients with ICH and 17 patients with IS were included. All ICH lesions seen on NCCT showed a typical pattern on DW-MRI at b1000 with a hypointense core surrounded by a hyperintense rim. ICH volumes and size were similar on NCCT and MRI. All cases of IS were identified on the DWI scans but none were apparent on NCCT. The mean sensitivity and specificity of DW-MRI at b1000 for ICH were 94% and 93.5%, respectively, and the inter-rater variability for ICH detection on DWI was excellent (κ = .84). CONCLUSIONS: DW-MRI at b1000 has a diagnostic yield similar to NCCT for detecting ICH and superior to NCCT for detecting IS. Therefore, DW-MRI may be considered as the initial screening tool for imaging patients presenting with focal neurologic symptoms suggestive of stroke.