ABSTRACT
Two-thirds of published patients with anti-leucine rich, glioma inactivated 1 (LGI1) encephalitis develop hippocampal sclerosis (HS). It is likely that this contributes to residual cognitive long-term deficits and the risk of epilepsy. Almost all patients harbor anti-LGI1-immunoglobulin G-(IgG-) subclass 4, which is considered a "benign", non-destructive subclass. In contrast, neuropathological case studies have suggested that the classical complement cascade may contribute to mediotemporal cell death in patients with LGI1 antibodies. IgG subclasses 1, 2, or 3 are required to initiate this cascade. We hypothesized that patients with these anti-LGI1-IgG1/2/3 in addition to IgG4 have a higher risk of developing HS than patients with anti-LGI1-IgG4 alone. We retrospectively assessed all anti-LGI1 encephalitis patients from this center with anti-LGI1-IgG-subclass information and follow-up MRI available. Nine out of 20 patients had developed HS (45%). Volumetric FreeSurfer analysis confirmed the visual HS diagnoses. HS and a lower hippocampal volume were associated with anti-LGI1-IgG1/2/3. All six patients with this IgG subclass status developed HS. There was no association with older or younger age at onset, female sex, longer latency from disease onset to start of immunotherapy, less intense immunotherapy, higher serum titers of LGI1 antibodies, LGI1 antibodies in CSF or higher LGI1-specific antibody indices. There was no association between anti-LGI1-IgG1/2/3 status and neuropsychological performance, epilepsy, or general neurological performance. This confirms our hypothesis that anti-LGI1-IgG1/2/3 in serum puts patients at risk of developing HS. If these findings can be confirmed and clinically corroborated, patients with anti-LGI1-IgG1/2/3 might become candidates for anti-complement-directed immunological treatments.
ABSTRACT
Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep sequencing, we identified novel somatic RIT1 delins variants in lesional tissue of three AVM patients. RIT1 encodes a RAS-like protein that can modulate RAS-MAPK signaling. We expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of RIT1 delins in zebrafish embryos induced AVM formation, highlighting their functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings implicate RIT1 in AVM formation and provide a rationale for clinical trials with targeted treatments.
ABSTRACT
In this patient, now 42 years old, genetic generalized epilepsy (juvenile myoclonic epilepsy) manifested itself at the age of 13. At the age of 39, she experienced a status episode with prolonged ICU treatment. She was left with a left-sided hippocampal sclerosis and probably focal seizures. In addition, since the age of 24, the patient also experiences functional seizures on the background of a borderline personality disorder. While generalized epileptic seizures could be controlled with antiseizure medication (ASM), the patient was multiple times admitted to Emergency Departments for her functional seizures with subsequent intensive care treatments, including intubation. As a complication, the patient developed critical illness polyneuropathy and myopathy, resulting in wheelchair dependence. Additionally, she acquired a complex regional pain syndrome after extravasation of ASM. The report demonstrates the uncommon development of hippocampal sclerosis after a generalized tonic-clonic status epilepticus and the poor treatability of functional seizures as compared to generalized and focal seizures.
ABSTRACT
BACKGROUND: We aimed to correlate alterations in the rat sarcoma virus (RAS)/mitogen-activated protein kinase pathway in vascular anomalies to the clinical phenotype for improved patient and treatment stratification. METHODS AND RESULTS: This retrospective multicenter cohort study included 29 patients with extracranial vascular anomalies containing mosaic pathogenic variants (PVs) in genes of the RAS/mitogen-activated protein kinase pathway. Tissue samples were collected during invasive treatment or clinically indicated biopsies. PVs were detected by the targeted sequencing of panels of genes known to be associated with vascular anomalies, performed using DNA from affected tissue. Subgroup analyses were performed according to the affected genes with regard to phenotypic characteristics in a descriptive manner. Twenty-five vascular malformations, 3 vascular tumors, and 1 patient with both a vascular malformation and vascular tumor presented the following distribution of PVs in genes: Kirsten rat sarcoma viral oncogene (n=10), neuroblastoma ras viral oncogene homolog (n=1), Harvey rat sarcoma viral oncogene homolog (n=5), V-Raf murine sarcoma viral oncogene homolog B (n=8), and mitogen-activated protein kinase kinase 1 (n=5). Patients with RAS PVs had advanced disease stages according to the Schobinger classification (stage 3-4: RAS, 9/13 versus non-RAS, 3/11) and more frequent progression after treatment (RAS, 10/13 versus non-RAS, 2/11). Lesions with Kirsten rat sarcoma viral oncogene PVs infiltrated more tissue layers compared with the other PVs including other RAS PVs (multiple tissue layers: Kirsten rat sarcoma viral oncogene, 8/10 versus other PVs, 6/19). CONCLUSIONS: This comparison of patients with various PVs in genes of the RAS/MAPK pathway provides potential associations with certain morphological and clinical phenotypes. RAS variants were associated with more aggressive phenotypes, generating preliminary data and hypothesis for future larger studies.
Subject(s)
Proto-Oncogene Proteins p21(ras) , Vascular Malformations , Humans , Cohort Studies , Genetic Association Studies , Mitogen-Activated Protein Kinases/genetics , Mutation , Vascular Malformations/geneticsABSTRACT
Myelodysplastic/myeloproliferative diseases of childhood cause a relevant disease burden, and many of these diseases may have a fatal course. The use of next-generation sequencing (NGS) has led to the identification of novel genetic variants in patients with these diseases, advancing our understanding of the underlying pathophysiology. However, novel mutations can often only be interpreted as variants of unknown significance (VUS), hindering adequate diagnosis and the use of a targeted therapy. To improve variant interpretation and test targeted therapies in a preclinical setting, we are using a rapid zebrafish embryo model that allows functional evaluation of the novel variant and possible therapeutic approaches within days. Thereby, we accelerate the translation from genetic findings to treatment options. Here, we establish this workflow on a novel in-frame tandem duplication in NRAS (c.192_227dup; p.G75_E76insDS65_G75) identified by Sanger sequencing in a 2.5-year-old patient with an unclassifiable myelodysplastic/myeloproliferative neoplasm (MDS/MPN-U). We show that this variant results in a myeloproliferative phenotype in zebrafish embryos with expansion of immature myeloid cells in the caudal hematopoietic tissue, which can be reversed by MEK inhibition. Thus, we could reclassify the variant from likely pathogenic to pathogenic using the American College of Medical Genetics (ACMG) criteria.
Subject(s)
GTP Phosphohydrolases , Membrane Proteins , Myelodysplastic-Myeloproliferative Diseases , Zebrafish , Animals , Child, Preschool , Female , Humans , Male , Gene Duplication , GTP Phosphohydrolases/genetics , High-Throughput Nucleotide Sequencing , Membrane Proteins/genetics , Myelodysplastic-Myeloproliferative Diseases/genetics , Tandem Repeat Sequences , Zebrafish/geneticsABSTRACT
Extracranial arteriovenous malformations (AVMs) are regarded as rare diseases and are prone to complications such as pain, bleeding, relentless growth, and high volume of shunted blood. Due to the high vascular pressure endothelial cells of AVMs are exposed to mechanical stress. To control symptoms and lesion growth pharmacological treatment strategies are urgently needed in addition to surgery and interventional radiology. AVM cells were isolated from three patients and exposed to cyclic mechanical stretching for 24 h. Thalidomide and bevacizumab, both VEGF inhibitors, were tested for their ability to prevent the formation of circular networks and proliferation of CD31+ endothelial AVM cells. Furthermore, the effect of thalidomide and bevacizumab on stretched endothelial AVM cells was evaluated. In response to mechanical stress, VEGF gene and protein expression increased in patient AVM endothelial cells. Thalidomide and bevacizumab reduced endothelial AVM cell proliferation. Bevacizumab inhibited circular network formation of endothelial AVM cells and lowered VEGF gene and protein expression, even though the cells were exposed to mechanical stress. With promising in vitro results, bevacizumab was used to treat three patients with unresectable AVMs or to prevent regrowth after incomplete resection. Bevacizumab controlled bleeding, pulsation, and pain over the follow up of eight months with no patient-reported side effects. Overall, mechanical stress increases VEGF expression in the microenvironment of AVM cells. The monoclonal VEGF antibody bevacizumab alleviates this effect, prevents circular network formation and proliferation of AVM endothelial cells in vitro. The clinical application of bevacizumab in AVM treatment demonstrates effective symptom control with no side effects.
Subject(s)
Arteriovenous Malformations , Endothelial Cells , Humans , Endothelial Cells/metabolism , Vascular Endothelial Growth Factor A/metabolism , Bevacizumab/pharmacology , Bevacizumab/therapeutic use , Bevacizumab/metabolism , Thalidomide/metabolism , Arteriovenous Malformations/genetics , Pain/metabolismABSTRACT
OBJECTIVE: Neuroimaging studies reveal frontal lobe (FL) contributions to memory encoding. Accordingly, memory impairments are documented in frontal lobe epilepsy (FLE). Still, little is known about the structural or functional correlates of such impairments. Particularly, material specificity of functional changes in cerebral activity during memory encoding in FLE is unclear. METHODS: We compared 24 FLE patients (15 right-sided) undergoing presurgical evaluation with 30 healthy controls on a memory fMRI-paradigm of learning scenes, faces, and words followed by an out-of-scanner recognition task as well as regarding their mesial temporal lobe (mTL) volumes. We also addressed effects of FLE lateralization and performance level (normal vs. low). RESULTS: FLE patients had poorer memory performance and larger left hippocampal volumes than controls. Volume increase seemed, however, irrelevant or even dysfunctional for memory performance. Further, functional changes in FLE patients were right-sided for scenes and faces and bilateral for words. In detail, during face encoding, FLE patients had, regardless of their performance level, decreased mTL activation, while during scene and word encoding only low performing FLE patients had decreased mTL along with decreased FL activation. Intact verbal memory performance was associated with higher right frontal activation in FLE patients but not in controls. SIGNIFICANCE: Pharmacoresistant FLE has a distinct functional and structural impact on the mTL. Effects vary with the encoded material and patients' performance levels. Thus, in addition to the direct effect of the FL, memory impairment in FLE is presumably to a large part due to functional mTL changes triggered by disrupted FL networks. PLAIN LANGUAGE SUMMARY: Frontal lobe epilepsy (FLE) patients may suffer from memory impairment. Therefore, we asked patients to perform a memory task while their brain was scanned by MRI in order to investigate possible changes in brain activation during learning. FLE patients showed changes in brain activation during learning and also structural changes in the mesial temporal lobe, which is a brain region especially relevant for learning but not the origin of the seizures in FLE. We conclude that FLE leads to widespread changes that contribute to FLE patients' memory impairment.
Subject(s)
Epilepsy, Frontal Lobe , Humans , Epilepsy, Frontal Lobe/diagnostic imaging , Epilepsy, Frontal Lobe/surgery , Epilepsy, Frontal Lobe/complications , Memory/physiology , Seizures , Temporal Lobe/diagnostic imaging , Temporal Lobe/surgery , Temporal Lobe/physiology , Memory Disorders/diagnostic imaging , Memory Disorders/complications , Magnetic Resonance Imaging/methodsABSTRACT
C-terminal variants in CDC42 encoding cell division control protein 42 homolog underlie neonatal-onset cytopenia, autoinflammation, rash, and hemophagocytic lymphohistiocytosis (NOCARH). Pyrin inflammasome hyperactivation has been shown to contribute to disease pathophysiology. However, mortality of NOCARH patients remains high despite inflammasome-focused treatments. Here, we demonstrate in four NOCARH patients from three families that cell-intrinsic activation of type I interferon (IFN) is a previously unrecognized driver of autoinflammation in NOCARH. Our data show that aberrant innate immune activation is caused by sensing of cytosolic nucleic acids released from mitochondria, which exhibit disturbances in integrity and dynamics due to CDC42 dysfunction. In one of our patients, treatment with the Janus kinase inhibitor ruxolitinib led to complete remission, indicating that inhibition of type I IFN signaling may have an important role in the management of autoinflammation in patients with NOCARH.
Subject(s)
Interferon Type I , Lymphohistiocytosis, Hemophagocytic , Humans , Infant, Newborn , cdc42 GTP-Binding Protein , Inflammasomes/genetics , Lymphohistiocytosis, Hemophagocytic/etiology , Nitriles , SyndromeABSTRACT
To elaborate expert consensus patient pathways to guide patients and physicians toward efficient diagnostics and management of patients with venous malformations. Methods: VASCERN-VASCA (https://vascern.eu/) is a European network of multidisciplinary centers for Vascular Anomalies. The Nominal Group Technique was used to establish the pathways. Two facilitators were identified: one to propose initial discussion points and draw the pathways, and another to chair the discussion. A dermatologist (AD) was chosen as first facilitator due to her specific clinical and research experience. The draft was subsequently discussed within VASCERN-VASCA monthly virtual meetings and annual face-to-face meetings. Results: The Pathway starts from the clinical suspicion of a venous type malformation (VM) and lists the clinical characteristics to look for to support this suspicion. Strategies for subsequent imaging and histopathology are suggested. These aim to inform on the diagnosis and to separate the patients into 4 subtypes: (1) sporadic single VMs or (2) multifocal, (3) familial, multifocal, and (4) combined and/or syndromic VMs. The management of each type is detailed in subsequent pages of the pathway, which are color coded to identify sections on (1) clinical evaluations, (2) investigations, (3) treatments, and (4) associated genes. Actions relevant to all types are marked in separate boxes, including when imaging is recommended. When definite diagnoses have been reached, the pathway also points toward disease-specific additional investigations and recommendations for follow up. Options for management are discussed for each subtype, including conservative and invasive treatments, as well as novel molecular therapies. Conclusion: The collaborative efforts of VASCERN-VASCA, a network of the 9 Expert Centers, has led to a consensus Diagnostic and Management Pathways for VMs to assist clinicians and patients. It also emphasizes the role of multidisciplinary expert centers in the management of VM patients. This pathway will become available on the VASCERN website (http://vascern.eu/).
ABSTRACT
OBJECTIVE: Completeness as a predictor of seizure freedom is broadly accepted in epilepsy surgery. We focused on the requirements for a complete hemispherotomy and hypothesized that the disconnection of the insula contributes to a favorable postoperative seizure outcome. We analyzed surgical and nonsurgical predictors influencing long-term seizure outcome before and after a modification of our hemispherotomy technique. METHODS: We retrospectively studied surgical procedures, electroclinical parameters, magnetic resonance imaging (MRI) results, and follow-up data in all children who had undergone hemispherotomy between 2001 and 2018 at our institution. We used logistic regression models to analyze the influence of different factors on seizure outcome. RESULTS: A total of 152 patients were eligible for seizure outcome analysis only. Of these, 140 cases had complete follow-up data for ≥24 months and provide the basis for the following results. The median age at surgery was 4.3 years (range = .3-17.9 years). Complete disconnection (including the insular tissue) was achieved in 63.6% (89/140). At 2-year follow-up, seizure freedom (Engel class IA) was observed in 34.8% (8/23) with incomplete insular disconnection, whereas this was achieved in 88.8% (79/89) with complete surgical disconnection (p < .001, odds ratio [OR] = 10.41). In the latter group (n = 89), a potentially epileptogenic contralateral MRI lesion was the strongest predictor for postoperative seizure recurrence (OR = 22.20). SIGNIFICANCE: Complete surgical disconnection is the most important predictor of seizure freedom following hemispherotomy and requires disconnection of the insular tissue at the basal ganglia level. Even if the hemispherotomy is performed surgically completely, a potentially epileptogenic contralateral lesion on preoperative MRI significantly reduces the chances of postoperative seizure freedom.
Subject(s)
Epilepsy , Hemispherectomy , Humans , Child , Child, Preschool , Adolescent , Retrospective Studies , Treatment Outcome , Hemispherectomy/methods , Seizures/diagnostic imaging , Seizures/surgery , Epilepsy/diagnostic imaging , Epilepsy/surgery , Epilepsy/pathology , Magnetic Resonance Imaging , ElectroencephalographyABSTRACT
Background: Generalized lymphatic anomaly (GLA), Gorham-Stout disease (GSD), kaposiform lymphangiomatosis (KLA), and central conducting lymphatic anomaly (CCLA) are rare, multisystem lymphatic disorders, referred to as complex lymphatic anomalies (CLAs). Their etiology remains poorly understood; however, somatic activating mutations have recently been discovered, and the results of targeted treatments are promising. This study aimed to elaborate on the phenotypic description of CLA. Methods: Thirty-six consecutive patients were recruited for the "GLA/GSD Registry" of the University Hospital of Freiburg, Germany (2015-2021). Clinical data were prospectively collected provided that a signed informed consent form was obtained. The latest proposed diagnostic guidelines were retrospectively applied. Results: Thirty-two patients (38% males) were included in the study; 15 GLA, 10 GSD, 3 KLA, and 4 CCLA patients were identified. Eighty-four percent already had symptoms by the age of 15 years. Osteolysis and periosseous soft-tissue infiltration were associated with GSD (p < 0.001 and p = 0.011, respectively), ascites and protein-losing enteropathy with CCLA (p = 0.007 and p = 0.004, respectively), and consumption coagulopathy with KLA (p = 0.006). No statistically significant differences were found in organ involvement, distribution of osteolytic lesions, number of affected bones and fractures. Twenty-five patients had complications; one patient with GLA died despite multimodal treatment. Spontaneous regression was seen in one patient with untreated KLA. Conclusions: CLA are rare, and their overlapping clinical presentations make differential diagnosis difficult. The characterization of our case series contributes to the phenotypic description and differentiation of these four clinical entities. A further understanding of their pathogenesis is crucial for evaluating targeted therapies and optimizing medical care.
Subject(s)
Lymphatic Abnormalities , Lymphatic Vessels , Osteolysis, Essential , Male , Humans , Adolescent , Female , Retrospective Studies , Lymphatic Abnormalities/diagnostic imaging , Lymphatic Abnormalities/therapy , Bone and Bones , Osteolysis, Essential/diagnosis , Osteolysis, Essential/drug therapy , Osteolysis, Essential/pathology , Lymphatic Vessels/pathologyABSTRACT
BACKGROUND AND OBJECTIVES: The SLC35A2 gene, located at chromosome Xp11.23, encodes for a uridine diphosphate-galactose transporter. We describe clinical, genetic, neuroimaging, EEG, and histopathologic findings and assess possible predictors of postoperative seizure and cognitive outcome in 47 patients with refractory epilepsy and brain somatic SLC35A2 gene variants. METHODS: This is a retrospective multicenter study where we performed a descriptive analysis and classical hypothesis testing. We included the variables of interest significantly associated with the outcomes in the generalized linear models. RESULTS: Two main phenotypes were associated with brain somatic SLC35A2 variants: (1) early epileptic encephalopathy (EE, 39 patients) with epileptic spasms as the predominant seizure type and moderate to severe intellectual disability and (2) drug-resistant focal epilepsy (DR-FE, 8 patients) associated with normal/borderline cognitive function and specific neuropsychological deficits. Brain MRI was abnormal in all patients with EE and in 50% of those with DR-FE. Histopathology review identified mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy in 44/47 patients and was inconclusive in 3. The 47 patients harbored 42 distinct mosaic SLC35A2 variants, including 14 (33.3%) missense, 13 (30.9%) frameshift, 10 (23.8%) nonsense, 4 (9.5%) in-frame deletions/duplications, and 1 (2.4%) splicing variant. Variant allele frequencies (VAFs) ranged from 1.4% to 52.6% (mean VAF: 17.3 ± 13.5). At last follow-up (35.5 ± 21.5 months), 30 patients (63.8%) were in Engel Class I, of which 26 (55.3%) were in Class IA. Cognitive performances remained unchanged in most patients after surgery. Regression analyses showed that the probability of achieving both Engel Class IA and Class I outcomes, adjusted by age at seizure onset, was lower when the duration of epilepsy increased and higher when postoperative EEG was normal or improved. Lower brain VAF was associated with improved postoperative cognitive outcome in the analysis of associations, but this finding was not confirmed in regression analyses. DISCUSSION: Brain somatic SLC35A2 gene variants are associated with 2 main clinical phenotypes, EE and DR-FE, and a histopathologic diagnosis of MOGHE. Additional studies will be needed to delineate any possible correlation between specific genetic variants, mutational load in the epileptogenic tissue, and surgical outcomes.
Subject(s)
Drug Resistant Epilepsy , Epilepsy , Humans , Drug Resistant Epilepsy/genetics , Drug Resistant Epilepsy/surgery , Drug Resistant Epilepsy/pathology , Brain/diagnostic imaging , Brain/surgery , Brain/pathology , Epilepsy/genetics , Epilepsy/surgery , Epilepsy/diagnosis , Seizures/pathology , Retrospective Studies , Treatment Outcome , ElectroencephalographyABSTRACT
Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. High-risk and metastatic disease continues to be associated with very poor prognosis. RMS model systems that faithfully recapitulate the human disease and provide rapid, cost-efficient estimates of antitumor efficacy of candidate drugs are needed to facilitate drug development and personalized medicine approaches. Here, we present a new zebrafish-based xenotransplant model allowing for rapid and easily accessible drug screening using low numbers of viable tumor cells and relatively small amounts of water-soluble chemicals. Under optimized temperature conditions, embryonal RMS xenografts were established in zebrafish embryos at 3 h postfertilization (hpf). In proof-of-principle experiments, chemotherapy drugs with established clinical anti-RMS efficacy (vincristine, dactinomycin) and the mitogen-activated protein kinase kinase inhibitor trametinib were shown to significantly reduce the cross-sectional area of the tumors by 120 hpf. RMS xenograft models in zebrafish embryos henceforth could serve as a valuable addition to cell culture and mammalian models of RMS and represent a rapid and cost-effective solution for preclinical candidate drug testing.
Subject(s)
Rhabdomyosarcoma, Embryonal , Rhabdomyosarcoma , Child , Animals , Humans , Zebrafish , Heterografts , Xenograft Model Antitumor Assays , Rhabdomyosarcoma, Embryonal/drug therapy , Rhabdomyosarcoma/drug therapy , Rhabdomyosarcoma/pathology , MammalsABSTRACT
BACKGROUND: Vascular anomalies comprise a diverse group of rare diseases with altered blood flow and are often associated with coagulation disorders. The most common example is a localized intravascular coagulopathy in venous malformations leading to elevated D-dimers. In severe cases, this may progress to a disseminated intravascular coagulopathy with subsequent consumption of fibrinogen and thrombocytes predisposing to serious bleeding. A separate coagulopathy is the Kasabach-Merritt phenomenon in kaposiform hemangioendothelioma characterized by platelet trapping leading to thrombocytopenia and eventually consumptive coagulopathy. Our previous work showed impaired von Willebrand factor and platelet aggregometry due to abnormal blood flow, i.e., in ventricular assist devices or extracorporeal membrane oxygenation. With altered blood flow also present in vascular anomalies, we hypothesized that, in particular, the von Willebrand factor parameters and the platelet function may be similarly impacted. METHODS: We prospectively recruited 73 patients with different vascular anomaly entities and analyzed their coagulation parameters. RESULTS: Acquired von Willebrand syndrome was observed in both of our patients with Kasabach-Merritt phenomenon. In six out of nine patients with complex lymphatic anomalies, both the vWF antigen and activity were upregulated. Platelet aggregometry was impaired in both patients with Kasabach-Merritt phenomenon and in seven out of eight patients with an arteriovenous malformation. CONCLUSIONS: The analysis of coagulation parameters in our patients with vascular anomalies advanced our understanding of the underlying pathophysiologies of the observed coagulopathies. This may lead to new treatment options for the, in part, life-threatening bleeding risks in these patients in the future.
Subject(s)
Blood Coagulation Disorders , Blood Coagulation , Vascular Malformations , Humans , Blood Platelets , Disseminated Intravascular Coagulation/etiology , Disseminated Intravascular Coagulation/physiopathology , Hemangioendothelioma/etiology , Hemangioendothelioma/physiopathology , Kasabach-Merritt Syndrome/etiology , Kasabach-Merritt Syndrome/physiopathology , von Willebrand Factor/metabolism , Vascular Malformations/complications , Vascular Malformations/physiopathology , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/physiopathologyABSTRACT
Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear aetiology for a period of less than 24 h. Observed psychological, neuroanatomical and hormonal differences between the sexes in episodic memory suggest sex-specific differences in memory disorders such as TGA. The aim of this study was to determine sex-specific differences in cardiovascular risk profiles, recurrences and magnetic resonance imaging (MRI). In total, 372 hospitalised TGA patients between 01/2011 and 10/2021 were retrospectively analysed. Comparisons were made between female and male TGA patients and compared to 216 patients with acute stroke. In our sample, women were overrepresented (61.8%), especially compared to the general population in the 65−74 age category (χ2 = 10.6, p < 0.02). On admission, female TGA patients had significantly higher systolic blood pressure values and a higher degree of cerebral microangiopathy compared to male TGA patients, whereas acute stroke patients did not. No sex-specific differences were observed with respect to recurrences or hippocampal DWI lesions. Our data demonstrate sex-specific differences in TGA. The higher blood pressure on admission and different degree of cerebral microangiopathy in female TGA patients supports the theory of blood pressure dysregulation as a disease trigger. Distinct precipitating events in female and male patients could lead to differences in the severity and duration of blood pressure abnormalities, possibly explaining the higher incidence in female patients.
ABSTRACT
Lymphatic malformations (LMs) are developmental defects of lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size, and unexpected swelling, they may cause serious complications that threaten vital functions such as compression of the airways. A large swelling of the face or neck may also be disfiguring and thus constitute a psychological strain for patients and their families. LMs are also highly immunologically reactive, and are prone to recurrent infections and inflammation causing pain as well as chronic oozing wounds. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) is dedicated to gathering the best expertise in Europe. There are only few available guidelines on management and follow up of LMs, which commonly focus on very specific situations, such as head and neck LM (Zhou et al., 2011). It is still unclear, what constitutes an indication for treatment of LMs and how to follow up the patients. The Vascular Anomalies Working Group (VASCA-WG) of VASCERN decided to develop a diagnostic and management pathway for the management of LMs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following 2 face-to-face meetings and multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with lymphatic malformations in a practical manner; we present an algorithmic view of the results of our work.
Subject(s)
Lymphatic Abnormalities , Sclerotherapy , Humans , Sclerotherapy/adverse effects , Sclerotherapy/methods , Treatment Outcome , Lymphatic Abnormalities/diagnosis , Lymphatic Abnormalities/therapy , Lymphatic Abnormalities/etiology , Neck , Head , Retrospective StudiesABSTRACT
Anteromedial temporal lobe structures seem to support processing of faces and facial expressions. However, differential effects of unilateral left or right temporal lobe resections (TLR) on face processing, recognition of facial expressions, and on BOLD response to faces in intact brain areas are not yet fully understood. Therefore, we compared 39 patients with unilateral TLR (18 left, 21 right) and 20 healthy controls regarding recognition of facial identity and emotional facial expressions as well as BOLD response to fearful and neutral faces. We found impaired recognition of facial identity following right TLR, which was paralleled by reduced BOLD response to faces irrespective of expression in the right fusiform and lingual gyrus in postsurgical fMRI. Right TLR patients also exhibited subtle impairments of emotion recognition as they needed higher intensity of facial expressions for correct responses in a morphing task. Accuracy of emotion recognition and subjective appraisals of facial expressions did not differ between groups. There was no specific reduction of BOLD response to fearful versus neutral faces in either patient group. Our results underline the specific role of the right anteromedial temporal lobe in processing of faces and facial expressions by showing changes in face processing following right TLR in behavioral as well as imaging data.
Subject(s)
Facial Expression , Facial Recognition , Emotions/physiology , Humans , Magnetic Resonance Imaging , Recognition, Psychology , Temporal Lobe/diagnostic imaging , Temporal Lobe/physiology , Temporal Lobe/surgeryABSTRACT
We have investigated the dissociation mechanisms of the prototypical heavy polar molecule OCS into the two break-up channels of the dication, OCS2+ â O+ + CS+ and OC+ + S+, in phase-locked two-color intense laser fields. The branching ratio of the breaking of the C-O and C-S bonds followed a pronounced 2π-oscillation with a modulation depth of 11%, depending on the relative phase of the two-color laser fields. The fragment ejection direction of both break-up channels reflects the anisotropy of the tunneling ionization rate, following a 2π-periodicity, as well. The two dissociation pathways in the C-S bond breaking channel show different phase dependencies of the fragment ejection direction, which are assigned to post-ionization dynamics. These observations, resulting from the excitation with asymmetric two-color intense laser fields, supported by state-of-the-art theoretical simulations, reveal the importance of post-ionization population dynamics in addition to tunneling ionization in the molecular fragmentation processes, even for heavy polar molecules.
ABSTRACT
Enhanced visual cortex activation by negative compared to neutral stimuli is often attributed to modulating feedback from the amygdala, but evidence from lesion studies is scarce, particularly regarding differential effects of left and right amygdala lesions. Therefore, we compared visual cortex activation by negative and neutral complex scenes in an event-related fMRI study between 40 patients with unilateral temporal lobe resection (TLR; 19 left [lTLR], 21 right [rTLR]), including the amygdala, and 20 healthy controls. We found preserved hemodynamic emotion modulation of visual cortex in rTLR patients and only subtle reductions in lTLR patients. In contrast, rTLR patients showed a significant decrease in visual cortex activation irrespective of picture content. In line with this, healthy controls showed small emotional modulation of the left amygdala only, while their right amygdala was activated equally by negative and neutral pictures. Correlations of activation in amygdala and visual cortex were observed for both negative and neutral pictures in the controls. In both patient groups, this relationship was attenuated ipsilateral to the TLR. Our results support the notion of reentrant mechanisms between amygdala and visual cortex and suggest laterality differences in their emotion-specificity. While right medial temporal lobe structures including the amygdala seem to influence visual processing in general, the left medial temporal lobe appears to contribute specifically to emotion processing. Still, effects of left TLR on visual emotion processing were relatively subtle. Therefore, hemodynamic correlates of visual emotion processing are likely supported by a distributed cerebral network, challenging an amygdalocentric view of emotion processing.
Subject(s)
Amygdala , Temporal Lobe , Amygdala/diagnostic imaging , Amygdala/physiology , Amygdala/surgery , Emotions/physiology , Hemodynamics , Humans , Magnetic Resonance Imaging/methods , Photic Stimulation/methods , Temporal Lobe/diagnostic imaging , Temporal Lobe/physiology , Temporal Lobe/surgeryABSTRACT
The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN), is dedicated to gathering the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. Infantile Hemangiomas (IH) are benign vascular tumors of infancy that rapidly growth in the first weeks of life, followed by stabilization and spontaneous regression. In rare cases the extent, the localization or the number of lesions may cause severe complications that need specific and careful management. Severe IH may be life-threatening due to airway obstruction, liver or cardiac failure or may harbor a risk of functional impairment, severe pain, and/or significant and permanent disfigurement. Rare IHs include syndromic variants associated with extracutaneous abnormalities (PHACE and LUMBAR syndromes), and large segmental hemangiomas. There are publications that focus on evidence-based medicine on propranolol treatment for IH and consensus statements on the management of rare infantile hemangiomas mostly focused on PHACES syndrome. The Vascular Anomalies Working Group (VASCA-WG) decided to develop a diagnostic and management pathway for severe and rare IHs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following two face-to-face meetings and in multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with severe and rare IH in a practical manner; we present an algorithmic view of the results of our work.