Diabetes insipidus and Guillain-Barré-like syndrome following CAR-T cell therapy: a case report.

BACKGROUND: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common adverse event of CD19-directed chimeric antigen receptor (CAR) T cell therapy. Other neurological adverse events, however, have not methodically been described and studied. Furthermore, safety data on CAR-T cell therapy in patients with central nervous system (CNS) lymphoma remain limited. MAIN BODY: We here report occurrence of a Guillain-Barré-like syndrome (GBS) and central diabetes insipidus (cDI) following tisagenlecleucel therapy for relapsed high-grade lymphoma with CNS involvement. Both complications were refractory to standard treatment of ICANS. Weakness of respiratory muscles required mechanical ventilation and tracheostomy while cDI was treated with desmopressin substitution for several weeks. Muscle-nerve biopsy and nerve conduction studies confirmed an axonal pattern of nerve damage. T cell-rich infiltrates and detection of the CAR transgene in muscle-nerve sections imply a direct or indirect role of CAR-T cell-mediated inflammation. In line with current treatment guidelines for GBS, intravenous immunoglobulin was administered and gradual but incomplete recovery was observed over the course of several months. CONCLUSIONS: This case report highlights the risk of rare but severe neurological adverse events, such as acute GBS or cDI, in patients treated with CAR-T cells. It further underlines the importance of appropriate patient surveillance and systematic reporting of rare complications to eventually improve treatment.

Perioperative targeted temperature management of severely burned patients by means of an oesophageal temperature probe.

BACKGROUND: Hypothermia in severely burned patients is associated with a significant increase in morbidity and mortality. The use of an oesophageal heat exchanger tube (EHT) can improve perioperative body temperatures in severely burned patients. The aim of this study was to investigate the intraoperative warming effect of oesophageal heat transfer in severe burn patients. METHODS: Single-centre retrospective study performed at the Burns Centre of the University Hospital Zurich. Between January 2020 and May 2021 perioperative temperature management with EHT was explored in burned patients with a total body surface area (TBSA) larger than 30%. Data from patients, who received perioperative temperature management by EHT, were compared to data from the same patients during interventions performed under standard temperature management matching for length and type of intervention. RESULTS: A total of 30 interventions (15 with and 15 without EHT) in 10 patients were analysed. Patient were 38 [26-48] years of age, presented with severe burns covering a median of 50 [42-64] % TBSA and were characterized by an ABSI of 10 [8-12] points. When receiving EHT management patients experienced warming at 0.07 °C per minute (4.2 °C/h) compared to a temperature loss of - 0.03 °C per minute (1.8 °C/h) when only receiving standard temperature management (p < 0.0001). No adverse or serious adverse events were reported. CONCLUSION: The use of an oesophageal heat transfer device was effective and safe in providing perioperative warming to severely burned patients when compared to a standard temperature management protocol. By employing an EHT as primary temperature management device perioperative hypothermia in severely burned patients can possibly be averted, potentially leading to reduced hypothermia-associated complications.

Healthy women with severe early life trauma show altered neural facilitation of emotion inhibition under acute stress.

BACKGROUND: Across psychopathologies, trauma-exposed individuals suffer from difficulties in inhibiting emotions and regulating attention. In trauma-exposed individuals without psychopathology, only subtle alterations of neural activity involved in regulating emotions have been reported. It remains unclear how these neural systems react to demanding environments, when acute (non-traumatic but ordinary) stress serves to perturbate the system. Moreover, associations with subthreshold clinical symptoms are poorly understood. METHODS: The present fMRI study investigated response inhibition of emotional faces before and after psychosocial stress situations. Specifically, it compared 25 women (mean age 31.5 ± 9.7 years) who had suffered severe early life trauma but who did not have a history of or current psychiatric disorder, with 25 age- and education-matched trauma-naïve women. RESULTS: Under stress, response inhibition related to fearful faces was reduced in both groups. Compared to controls, trauma-exposed women showed decreased left inferior frontal gyrus (IFG) activation under stress when inhibiting responses to fearful faces, while activation of the right anterior insula was slightly increased. Also, groups differed in brain-behaviour correlations. Whereas stress-induced false alarm rates on fearful stimuli negatively correlated with stress-induced IFG signal in controls, in trauma-exposed participants, they positively correlated with stress-induced insula activation. CONCLUSION: Neural facilitation of emotion inhibition during stress appears to be altered in trauma-exposed women, even without a history of or current psychopathology. Decreased activation of the IFG in concert with heightened bottom-up salience of fear related cues may increase vulnerability to stress-related diseases.

Resting-state functional connectivity after hydrocortisone administration in patients with post-traumatic stress disorder and borderline personality disorder.

In a previous study, we found that - in contrast to healthy individuals - patients with borderline personality disorder (BPD) and post-traumatic stress disorder (PTSD) showed better memory retrieval performance after hydrocortisone administration compared to placebo. As these results suggest an altered function of corticosteroid receptors in the brain in PTSD and BPD, we examined the effect of hydrocortisone on brain activation in both disorders. We recruited 40 female healthy controls, 20 female unmedicated patients with PTSD and 18 female unmedicated patients with BPD. We conducted a placebo-controlled cross-over study, in which all participants underwent two resting state MRI measurements after they received either a placebo or 10 mg hydrocortisone orally and in randomized order. There was a time interval of one week between the measurements. We analysed resting state functional connectivity (RSFC) with the hippocampus and the amygdala as seed regions. Compared to healthy controls, both patient groups showed reduced hippocampus RSFC to dorsomedial prefrontal cortex (dmPFC). Positive hippocampus dmPFC RSFC correlated negatively with childhood trauma (r = -0.47) and with severity of clinical symptoms, measured with the Borderline Symptom List (r = -0.44) and the Posttraumatic Stress Diagnostic Scale (r = -0.45). We found neither differences in amygdala RSFC nor an effect of hydrocortisone administration. Childhood trauma might lead to decreased positive hippocampus dmPFC RSFC. This might explain symptoms of PTSD and BPD that are characterized by dysfunctional fear regulation.

Effects of hydrocortisone on autobiographical memory retrieval in patients with posttraumatic stress disorder and borderline personality disorder: the role of childhood trauma.

In a previous study, we found that patients with posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD) showed better autobiographical memory (AM) retrieval after hydrocortisone administration than after placebo administration. Here we investigate the neural correlates of AM retrieval after hydrocortisone administration in patients with PTSD or BPD. We recruited 78 female participants for this placebo-controlled crossover study: 40 healthy controls, 20 patients with PTSD, and 18 patients with BPD (all without medication). All participants received an oral placebo or 10 mg hydrocortisone in a randomized order before performing an AM task. Neural activity was monitored during the task by functional magnetic resonance imaging. Neural activation did not differ between the three groups during AM retrieval, neither in the placebo condition nor after hydrocortisone intake. Multiple regression analysis revealed that Childhood Trauma Questionnaire scores correlated positively with hydrocortisone effects on activation in the anterior medial prefrontal cortex (amPFC), ventrolateral prefrontal cortex (vlPFC), posterior cingulate cortex (PCC), angular gyrus, and cerebellum. These results suggest that hydrocortisone-induced neural activation pattern during AM retrieval is related to childhood trauma. Previously described effects in the hippocampus, which were absent in the current study, might be related to PTSD caused by trauma in adulthood. The effects of hydrocortisone on brain activation and how these effects are influenced by childhood trauma, trauma in adulthood, and PTSD symptoms should be determined in future studies.

Psychophysiological stress response and memory in borderline personality disorder.

Background: Previously, we found that patients with borderline personality disorder (BPD) but not healthy controls (HC) showed improved memory retrieval after hydrocortisone administration. Objective: In this study, we examined whether increases in endogenous cortisol after psychosocial stress are associated with memory function in patients with BPD and in healthy individuals. Methods: We recruited 49 female patients with BPD and 49 female HC. All participants were exposed to a psychosocial stressor, the Trier Social Stress Test (TSST) and a control condition (Placebo (P-)TSST) in randomized order. Salivary cortisol, alpha amylase (sAA) and blood pressure were measured in response to stress. Subsequently, we examined free recall of a previously learned word list, autobiographical memory, and working memory. Results: We found a stress*time*group interaction effect for the cortisol response and for sAA to stress, which is mainly triggered by a slightly different increase in cortisol between groups from pre to post TSST. Furthermore, BPD patients showed a less pronounced increase in diastolic blood pressure compared to HC after stress. There was no effect of stress on memory performance in any tests, either in healthy controls or in patients with BPD. Conclusion: Our results suggest a slightly blunted response of the HPA axis and the sympathetic nervous system to stress in BPD compared to healthy women. In contrast to hydrocortisone administration, psychosocial stress did not improve memory retrieval in BPD patients. This might be explained by lower cortisol concentrations and parallel increases in norepinephrine and negative affect after stress.

Antecedentes: Previamente, encontramos que los pacientes con trastorno de personalidad límite (TPL), contrariamente a los controles sanos (CS), mostraron una mejor recuperación de memoria después de la administración de hidrocortisona.Objetivo: En este estudio, examinamos si los aumentos en el cortisol endógeno, después del estrés psicosocial están asociados con el funcionamiento de la memoria en pacientes con TPL y en individuos sanos.Métodos: Se reclutaron 49 pacientes de sexo femenino con TPL y 49 mujeres CS. Todas las participantes fueron expuestas a un estresante psicosocial, la Prueba de estrés social de Trier (TSST) y una condición de control (Placebo (P-) TSST) en orden aleatorio. El cortisol salival, la alfa amilasa (sAA) y la presión arterial se midieron en respuesta al estrés. Posteriormente, examinamos la recuperación libre de una lista de palabras previamente aprendida, la memoria autobiográfica y memoria de trabajo.Resultados: Encontramos un efecto de interacción grupal estrés*tiempo* para la respuesta de cortisol y para sAA al estrés, gatillada principalmente por un aumento ligeramente diferente en el cortisol entre los grupos desde el pre al post TSST. Además, las pacientes con TPL mostraron un aumento menos pronunciado en la presión arterial diastólica en comparación con las CS después del estrés. No hubo efecto del estrés en el rendimiento de la memoria en ninguna prueba, ni en controles sanos ni en pacientes con TLP.Conclusión: Nuestros resultados sugieren una respuesta ligeramente atenuada del eje Hipotálamo-Hipófisis-Adrenal y del sistema nervioso simpático al estrés en TPL en comparación con mujeres sanas. En contraste con la administración de hidrocortisona, el estrés psicosocial no mejoró la recuperación de la memoria en pacientes con TPL. Esto podría explicarse por menores concentraciones de cortisol y aumentos paralelos de norepinefrina y afecto negativo después del estrés.

Neural correlates of glucocorticoids effects on autobiographical memory retrieval in healthy women.

It is well known that elevated cortisol after stress or after exogenous administration impairs episodic memory retrieval including autobiographical memory (AM) retrieval. This impairment might be mediated by deactivation of a neural network associated with memory retrieval including the prefrontal cortex (PFC) and limbic structures. However, the neural underpinnings of these cortisol effects on AM retrieval have not been investigated yet. In this study, thirty-three healthy women received either placebo or 10 mg hydrocortisone in a double blind cross-over design before completing an AM test during fMRI. In this test, participants are asked to recall specific events from their own past in response to a cue word. In a first step, we analyzed the neural underpinnings of AM retrieval in the placebo condition. We found an activation pattern consistent with core regions involved in autobiographical memory recall, including the ventromedial PFC, anterior medial (am)PFC, inferior frontal gyrus, the posterior cingulate cortex, the tempoparietal junction, the middle temporal gyrus and the hippocampus. Further, we analyzed brain activation during AM retrieval after hydrocortisone compared to placebo. Region of interest (ROI) analyses revealed a hydrocortisone-induced deactivation during AM retrieval in the right amPFC. Results of the ROI analyses were non-significant in the left and right hippocampus, the left and right vmPFC and the left amPFC In sum, during AM retrieval hydrocortisone had the most pronounced effects on the amPFC. This might be explained by the strong involvement of this brain region in self-referential behavior, which is essential for recalling autobiographic information.

The effect of cortisol on autobiographical memory retrieval depends on remoteness and valence of memories.

There is evidence that specificity of autobiographical memory (AM) retrieval is impaired by cortisol. However, it is unknown whether glucocorticoids differentially influence the retrieval of recent versus remote AMs. Therefore, the aim of the current study was to investigate the effects of cortisol on AM retrieval, in terms of memory specificity, with respect to remoteness of the retrieved memories. A placebo controlled, double blind study was conducted. Thirty female and 24 male healthy participants (mean age 24.5, SD=3.7) received either placebo or 10mg hydrocortisone before completing an autobiographical memory test. Participants showed higher memory specificity for recent memories compared to remote ones. There was no main effect of cortisol on AM retrieval. However, interaction effects suggest that cortisol affects remote, but not recent memories, which seems to depend upon valence.

Effects of hydrocortisone on false memory recognition in healthy men and women.

Most of the studies focusing on the effect of stress on false memories by using psychosocial and physiological stressors yielded diverse results. In the present study, we systematically tested the effect of exogenous hydrocortisone using a false memory paradigm. In this placebo-controlled study, 37 healthy men and 38 healthy women (mean age 24.59 years) received either 10 mg of hydrocortisone or placebo 75 min before using the false memory, that is, Deese-Roediger-McDermott (DRM), paradigm. We used emotionally charged and neutral DRM-based word lists to look for false recognition rates in comparison to true recognition rates. Overall, we expected an increase in false memory after hydrocortisone compared to placebo. No differences between the cortisol and the placebo group were revealed for false and for true recognition performance. In general, false recognition rates were lower compared to true recognition rates. Furthermore, we found a valence effect (neutral, positive, negative, disgust word stimuli), indicating higher rates of true and false recognition for emotional compared to neutral words. We further found an interaction effect between sex and recognition. Post hoc t tests showed that for true recognition women showed a significantly better memory performance than men, independent of treatment. This study does not support the hypothesis that cortisol decreases the ability to distinguish between old versus novel words in young healthy individuals. However, sex and emotional valence of word stimuli appear to be important moderators. (PsycINFO Database Record

Mineralocorticoid receptor function in depressed patients and healthy individuals.

BACKGROUND: Many studies have shown disturbed glucocorticoid receptor (GR) in depressed patients. In contrast, only few studies targeted mineralocorticoid receptor (MR) function with inconclusive results. We examined the effects of the MR antagonist spironolactone on cortisol secretion in depressed patients and healthy individuals. METHODS: Forty-eight unmedicated depressed patients (mean age 41.6years) and 45 age- and sex-matched healthy participants (40.7years) received the MR antagonist spironolactone (300mg) or placebo with three days apart in a randomized, double-blind, within-subject cross-over design. We measured salivary cortisol before ingestion of study medication (baseline) as well as +60min, +90min, +120min, +150min and 180min after baseline. RESULTS: Repeated-measures ANOVA for area under the curve (AUCg) cortisol revealed a treatment effect with higher cortisol after spironolactone and a treatment by group interaction. Post-hoc analyses revealed higher cortisol in depressed patients compared to healthy participants in the placebo condition. In the spironolactone condition, the cortisol levels were not significantly different. CONCLUSIONS: Potentially, impaired MR or GR signaling could be responsible for higher cortisol levels in depressed patients in the placebo condition. However, after MR blockade that increased cortisol secretion across groups leading to higher GR occupation, we found no differences between depressed patients and healthy controls. Thus, our results argue for depression-associated alterations in MR signaling rather than disturbed GR-mediated feedback inhibition.

Does fludrocortisone influence autobiographical memory retrieval? A study in patients with major depression, patients with borderline personality disorder and healthy controls.

There is evidence that stimulation of mineralocorticoid receptors (MR) enhances memory in healthy subjects and in patients with major depression (MDD). In contrast, in patients with borderline personality disorder (BPD), this effect seems to be task dependent. The aim of this study was to investigate the effect of MR stimulation on autobiographical memory retrieval in healthy individuals, patients with MDD, and patients with BPD. We conducted a placebo-controlled study in an intra-individual cross-over design. Twenty-four patients with MDD, 37 patients with BPD, and 67 healthy participants completed an autobiographical memory test after receiving 0.4 mg fludrocortisone, a mineralocorticoid receptor preferring agonist, or placebo in a randomized order. Healthy subjects, patients with MDD, and patients with BPD did not differ in their autobiographical memory retrieval. Furthermore, the administration of fludrocortisone had no effect on autobiographical memory. In conclusion, the stimulation of MR does not influence autobiographical memory retrieval in healthy subjects, patients with MDD, and patients with BPD. Our results do not support a role of MR in autobiographical memory.

Stimulation of the mineralocorticoid receptor improves memory in young and elderly healthy individuals.

Glucocorticoids play an important role in cognitive function and act on glucocorticoid receptors and mineralocorticoid receptors (MRs) in the brain. Previously, the blockade of the MR has been shown to impair visuospatial and working memory in healthy young men. Here, we investigated the effects of the MR agonist fludrocortisone on memory in young and elderly healthy individuals. Thirty-one young (mean age 25.4 ± 4.6 years) and 22 elderly (mean age 63.2 ± 8.2 years) healthy participants received the MR agonist fludrocortisone (0.4 mg) or placebo at least 3 days apart in a randomized, double-blind within-subject cross-over design. We measured verbal memory (auditory verbal learning test), nonverbal memory (Rey/Taylor complex figure test), and working memory (digit-span task). As expected, young participants performed significantly better than elderly individuals in visuospatial memory (effect of group: F = 42.7, p < 0.01), verbal memory (F = 33.1, p < 0.01), and working memory (digit-span backward: F = 4.5, p = 0.04). For visuospatial memory (F = 5.0, p = 0.03) and short-term and working memory (digit-span forward: F = 4.2, p = 0.05), we found a significant treatment effect indicating better memory performance after fludrocortisone compared with placebo across groups. In concert with the previous studies, our data suggest a role of the MR in memory function. A cognitive enhancing effect by MR stimulation warrants future studies.

Enhanced emotional empathy after mineralocorticoid receptor stimulation in women with borderline personality disorder and healthy women.

The mineralocorticoid receptor (MR) is highly expressed in the hippocampus and prefrontal cortex. MR have an important role in appraisal processes and in modulating stress-associated emotional reactions but it is not known whether the MR affects empathy. Borderline personality disorder (BPD) is characterized by disturbed emotion regulation and alterations in empathy. In the current study, we examined whether stimulation of the MR enhances empathy in patients with BPD and healthy individuals. In a placebo-controlled study, we randomized 38 women with BPD and without psychotropic medication, and 35 healthy women to either placebo or 0.4 mg fludrocortisone, an MR agonist. Subsequently, all participants underwent two tests of social cognition, the Multifaceted Empathy Test (MET) and the Movie for the Assessment of Social Cognition (MASC), measuring cognitive and emotional facets of empathy. Eighteen BPD patients and 18 healthy women received placebo, whereas 20 BPD patients and 17 healthy women received fludrocortisone. In the MET, fludrocortisone enhanced emotional empathy across groups, whereas cognitive empathy was not affected. In the MASC, no effect of fludrocortisone could be revealed. In both tests, BPD patients and healthy women did not differ significantly in cognitive and emotional empathy and in their response to fludrocortisone. Stimulation of MR enhanced emotional empathy in healthy women and in BPD patients. Whether fludrocortisone might have a therapeutic role in psychotherapeutic processes, remains to be elucidated.