Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation

Background The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K). Methods Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal–Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate. Results Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002). Conclusion In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making

Rasmussen encephalitis: Predisposing factors and their potential role in unilaterality

Fauser S, Elger CE, Wörmann F, Bien C. Rasmussen encephalitis: Predisposing factors and their potential role in unilaterality. Epilepsia. 2021.OBJECTIVE: Rasmussen encephalitis (RE) is a progressive and destructive inflammatory disease of one hemisphere. Its cause is unknown. We investigated comorbidity and laterality factors that might predispose to RE.; METHODS: We retrospectively compared the histories of 160 RE patients to those with genetic generalized epilepsy (n=154) and those with focal cortical dysplasia Type II (FCD II; n=148).; RESULTS: The median/mean age at symptom onset in RE was 7/10years (range = 1-53years), and 58.1% of the patients were female. The female sex predominated in RE patients, with age > 7years at disease manifestation. The left hemisphere was affected in 65.6%. Perinatal complications (preterm birth, twin pregnancies, early acquired brain lesions) were more frequent in RE than in control patients. Ipsilateral facial autoimmune conditions (scleroderma en coup de sabre, uveitis, or chorioretinitis) were only observed in RE patients (6.9%). Onset of RE was more frequently associated with fever than that of FCD II. In 33.1% of RE patients, ≥1 potential risk factor was found. Interestingly, 11.9% of patients had one-sided early brain lesions or facial autoimmune lesions ipsilateral to subsequent RE; none had such a lesion contralaterally.; SIGNIFICANCE: Perinatal complications and facial autoimmune conditions may act as predisposing factors for RE. Fever might trigger RE manifestation. Further genetic or infectious contributors may be identified in the future. Single or combined hits may be required to elicit or facilitate the start of the disease. Ipsilateral early comorbid lesions or facial autoimmune processes might in part explain the enigmatic unilaterality of RE. © 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy

De novo aphasic status epilepticus: Finally making the diagnosis by long-term EEG

Kantzeli A, Brandt C, Tomka-Hoffmeister M, Wörmann F, Bien C. De novo aphasic status epilepticus: Finally making the diagnosis by long-term EEG. Epilepsy & Behavior Reports. 2022;17: 100513.Aphasic status epilepticus (SE) is a rare manifestation of non-convulsive SE (NCSE) and may occasionally be under-recognized. We report a 69-year-old male patient with a pre-existing left parietal oligodendroglioma WHO III after two resections and radio-chemotherapy. The patient was left with some word finding difficulties but had no history of overt seizures. He developed aphasic NCSE, which was only detected by long-term electroencephalography (EEG) monitoring. The 24-hour EEG revealed paroxysmal rhythmic theta-delta activity in left posterior regions that propagated to left temporo-parietal areas. Rhythmic activity appeared every 15-30min and lasted for 10-110s. Aphasia was continuously present with superimposed short-lasting clinical deteriorations during the day. Magnetic resonance imaging showed peri-ictal edema on diffusion-weighted images in the insula and fronto-parietal cortex, which supported the diagnosis of SE. NCSE persisted for seven months. The patient recovered upon addition of intravenous phenytoin. One should not only consider aphasic SE when language impairment is episodic, but also when there are prolonged manifestations, especially when the typical differential diagnoses have been excluded. Intravenous therapy may be required to terminate NCSE. With this report, we would like to draw attention to aphasic SE as a rare phenomenon that may be difficult to diagnose and delay management in clinical practice. © 2021 The Author(s)

Reading and the visual word form area (VWFA)-Management and clinical experience at one epilepsy surgery center

Cloppenborg T, Mertens M, Hopf J, et al. Reading and the visual word form area (VWFA)-Management and clinical experience at one epilepsy surgery center. Epilepsy & Behavior. 2021;124: 108274.Objective: Presurgical evaluation has no established routine to assess reading competence and to identify essential "not to resect" reading areas. Functional models describe a visual word form area (VWFA) located in the midfusiform gyrus in the dominant ventral occipito-temporal cortex (vOTC) as essential for reading. We demonstrate the relevance and feasibility of invasive VWFA-mapping. Methods: Four patients with epilepsy received invasive VWFA-mapping via left temporo-basal strip electrodes. Co-registration of the results and additional data from the literature led to the definition of a region of interest (ROI) for a retrospective assessment of postoperative reading deficits by a standardized telephone-interview in patients with resections in this ROI between 2004 and 2018. Results: Electrical cortical stimulation disturbed whole word recognition and reading in four patients with structural epilepsy. Stimulation results showed distribution in the basal temporal lobe (dorsal mesencephalon to preoccipital notch). We identified 34 patients with resections in the ROI of the dominant hemisphere. Of these, 15 (44.1%) showed a postoperative reading deficit with a mean duration of 18.2 months (+/-32.4, 0.5-122). Six patients suffered from letter-by-letter (LBL) reading. Two patients had permanent LBL reading after resection in the ROI. Significance: We present evidence on the functional relevance of the vOTC for reading by (1) extra operative cortical stimulation of the VWFA and by (2) a retrospective case study of reading deficits in patients operated in this area. Reading assessments and data concerning essential reading structures should be included in the presurgical evaluation of patients with lesions in the left vOTC. (c) 2021 Elsevier Inc. All rights reserved

Effects of left and right medial temporal lobe resections on hemodynamic correlates of negative and neutral scene processing

Reisch LM, Wegrzyn M, Mielke M, et al. Effects of left and right medial temporal lobe resections on hemodynamic correlates of negative and neutral scene processing. Human Brain Mapping. 2022.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. © 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC

LGI1 encephalitis: potentially complement-activating anti-LGI1-IgG subclasses 1/2/3 are associated with the development of hippocampal sclerosis

Bien C, Rada A, Mertens M, et al. LGI1 encephalitis: potentially complement-activating anti-LGI1-IgG subclasses 1/2/3 are associated with the development of hippocampal sclerosis. Journal of neurology. 2024.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. © 2024. The Author(s)

Hemodynamic correlates of emotion regulation in frontal lobe epilepsy patients and healthy participants

Benzait A, Krenz V, Wegrzyn M, et al. Hemodynamic correlates of emotion regulation in frontal lobe epilepsy patients and healthy participants. Human Brain Mapping . 2022.The ability to regulate emotions is indispensable for maintaining psychological health. It heavily relies on frontal lobe functions which are disrupted in frontal lobe epilepsy. Accordingly, emotional dysregulation and use of maladaptive emotion regulation strategies have been reported in frontal lobe epilepsy patients. Therefore, it is of clinical and scientific interest to investigate emotion regulation in frontal lobe epilepsy. We studied neural correlates of upregulating and downregulating emotions toward aversive pictures through reappraisal in 18 frontal lobe epilepsy patients and 17 healthy controls using functional magnetic resonance imaging. Patients tended to report more difficulties with impulse control than controls. On the neural level, patients had diminished activity during upregulation in distributed left-sided regions, including ventrolateral and dorsomedial prefrontal cortex, angular gyrus and anterior temporal gyrus. Patients also showed less activity than controls in the left precuneus for upregulation compared to downregulation. Unlike controls, they displayed no task-related activity changes in the left amygdala, whereas the right amygdala showed task-related modulations in both groups. Upregulation-related activity changes in the left inferior frontal gyrus, insula, orbitofrontal cortex, anterior and posterior cingulate cortex, and precuneus were correlated with questionnaire data on habitual emotion regulation. Our results show that structural or functional impairments in the frontal lobes disrupt neural mechanisms underlying emotion regulation through reappraisal throughout the brain, including posterior regions involved in semantic control. Findings on the amygdala as a major target of emotion regulation are in line with the view that specifically the left amygdala is connected with semantic processing networks

Abstract-Nummer 119.

Beyer A, Friedrich A, Zuhorn F, et al. Geschlechter-spezifische Unterschiede bei Patienten und Patientinnen mit transienter globaler Amnesie (TGA). In: Deutsche Gesellschaft für Neurologie, ed. Neurowoche 2022 - Abstracts. Berlin; 2022.Hintergrund: Die transiente globale Amnesie (TGA) ist definiert als akute Gedächtnisstörung unklarer Ätiologie für einen Zeitraum von weniger als 24 Stunden. Im Vordergrund steht eine antero- und retrograde Amnesie ohne fokal-neurologische Auffälligkeiten. Es gibt zahlreiche Untersuchungen zur Fragestellung möglicher Einflussfaktoren beim Auftreten und einem Rezidiv einer TGA. Geschlechter-spezifische Unterschiede wurden bislang nur wenig adressiert. Beobachtete psychologische, neuroanatomische und hormonelle Unterschiede zwischen den Geschlechtern im episodischen Gedächtnis legen Geschlechter-spezifische Unterschiede bei Gedächtnisstörungen wie der TGA nahe. Ziele: Evaluation möglicher Geschlechter-spezifischer Unterschiede bei TGA-Patienten und -Patientinnen in Bezug auf das kardiovaskuläre Risikoprofil, Rezidivrate und Magnetresonanztomographie (MRT)-Befunde. Methoden: 372 hospitalisierte TGA-Patienten und -Patientinnen zwischen 01/2011 und 10/2021 wurden retrospektiv auf Geschlechterunterschiede des kardiovaskulären Risikoprofils, Rezidivrate und Magnetresonanztomographie (MRT)-Befunden untersucht. Ergebnisse: Frauen waren in unserer Stichprobe überrepräsentiert (61,8 %), wobei die altersadjustierten Prävalenzraten sich nicht zwischen den Geschlechtern unterschieden. Die Stichprobe zeigte eine leichte Überrepräsentation von Frauen im Vergleich zur Allgemeinbevölkerung in der Alterskategorie 65-74 (χ2=10,6, p<0,02). Weibliche TGA-Patienten und -Patientinnen hatten bei der Aufnahme signifikant höhere systolische Blutdruckwerte (173,2±23,4 mm Hg versus 165,8±22,0 mm Hg, p=0,007). Im Einklang mit den erwarteten und bereits früher berichteten Geschlechterunterschieden wurden darüber hinaus höhere Serumcholesterinwerte (221,6±40,7 mg/dl versus 207,6±45,5 mg/dl; p=0,005) und höhere Werte des C-reaktiven Proteins (2,8±6,4 mg/l versus 1,7±1,8 mg/l; p<0,05) festgestellt. Frauen zeigten einen höheren Schweregrad der zerebralen Mikroangiopathie gemessen anhand der Einteilung nach Fazekas als männliche TGA-Patienten und -Patientinnen (Mann-Whitney U=14.147,500, z=2,338, p=0,019; Effektgröße nach Cohen 0,22). Es bestanden keine Geschlechter-spezifischen Unterschiede in der TGA-Rezidivrate und in der Häufigkeit oder Lateralisierung der nachgewiesenen punktförmigen hippokampalen DWI-Läsionen im MRT. Schlussfolgerungen: Unsere Daten zeigen Geschlechter-spezifische Unterschiede bei TGA-Patienten und -Patientinnen. Der höhere Blutdruck bei der Aufnahme von weiblichen TGA-Patientinnen unterstützt die Theorie der Blutdruckdysregulation als Krankheitsauslöser. Unterschiedliche auslösende Ereignisse bei weiblichen und männlichen Patientinnen könnten zu Unterschieden in der Schwere und Dauer der Blutdruckanomalien führen, was möglicherweise die höhere Inzidenz bei weiblichen Patientinnen erklärt. Bei Frauen ist häufiger psychischer Stress als Auslöser einer TGA nachweisbar, was zu einer Aktivierung des sympathischen Nervensystems sowie des sympathischen Nebennierenrindenmarksystems mit Freisetzung von Katecholaminen führt. Die Aktivierung der Hypothalamus-Hypophysen-NebennierenAchse, die hypothalamische Freisetzung des Corticotropin-Releasing-Faktors, hypophysäre Freisetzung von adrenocorticotropem Hormon und Cortisol führt zu einer über Stunden anhaltenden Blutdruckerhöhung. Bei Männern steht im Gegensatz dazu häufiger körperliche Aktivität mit nachfolgendem kurzfristigen Anstieg des Blutdrucks und einer Normalisierung innerhalb von Minuten nach Ende der Aktivität im Vordergrund. Dieses pathophysiologische Verständnis und nachgewiesene Geschlechter-spezifische Unterschiede bei auslösenden Ereignissen vor einer TGA könnten erklären, warum Frauen bei der Aufnahme höhere Blutdruckwerte aufweisen als Männer. Die unterschiedliche Dauer der hypertensiven Entgleisungen könnte darüber hinaus eine mögliche Erklärung für das unterschiedliche Ausmaß der zerebralen Mikroangiopathie sein. Hier sind weitere Studien allerdings erforderlich

Caudate hyperactivation during the processing of happy faces in borderline personality disorder

Lamers A, Töpper M, Fernando S, et al. Caudate hyperactivation during the processing of happy faces in borderline personality disorder. Neuropsychologia. 2021;163: 108086.BACKGROUND: Emotion dysfunction and anhedonia are main problems in borderline personality disorder (BPD). In the present functional magnetic resonance imaging (fMRI) study, we investigated neural activation during the processing of happy faces and its correlates with habitual emotion acceptance in patients with BPD.; METHODS: 22 women with BPD and 26 female healthy controls watched movie clips of happy and neutral faces during fMRI without any instruction of emotion regulation. To associate neural activation with habitual emotion acceptance, we included individual scores of the Emotion Acceptance Questionnaire (EAQ) as a covariate in brain data analysis.; RESULTS: All participants showed amygdala, temporal and occipital activation during the processing of happy compared to neutral faces. Compared with healthy controls, patients with BPD showed significantly more activation within the bilateral caudate. We did not find significant correlations with emotion acceptance.; CONCLUSIONS: Our results indicate caudate hyperactivation in patients with BPD during the processing of happy faces. Although patients reported significantly less emotion acceptance of positive emotions, an association with neural activation was not detectable. Copyright © 2021 Elsevier Ltd. All rights reserved