Treating seronegative neuromyelitis optica spectrum disorder with inebilizumab: a case report.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a devastating inflammatory disease of the central nervous system that is often severely disabling from the outset. The lack of pathognomonic aquaporin 4 (AQP4) antibodies in seronegative NMOSD not only hinders early diagnosis, but also limits therapeutic options, in contrast to AQP4 antibody-positive NMOSD, where the therapeutic landscape has recently evolved massively. Case presentation: We report a 56-year-old woman with bilateral optic neuritis and longitudinally extensive myelitis as the index events of a seronegative NMOSD, who was successfully treated with inebilizumab. Conclusion: Treatment with inebilizumab may be considered in aggressive seronegative NMOSD. Whether broader CD19-directed B cell depletion is more effective than treatment with rituximab remains elusive.

Large diameter hemicraniectomy does not improve long-term outcome in malignant infarction.

INTRODUCTION: In malignant cerebral infarction decompressive hemicraniectomy has demonstrated beneficial effects, but the optimum size of hemicraniectomy is still a matter of debate. Some surgeons prefer a large-sized hemicraniectomy with a diameter of more than 14 cm (HC > 14). We investigated whether this approach is associated with reduced mortality and an improved long-term functional outcome compared to a standard hemicraniectomy with a diameter of less than 14 cm (HC ≤ 14). METHODS: Patients from the DESTINY (DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY) registry who received hemicraniectomy were dichotomized according to the hemicraniectomy diameter (HC ≤ 14 cm vs. HC > 14 cm). The primary outcome was modified Rankin scale (mRS) score ≤ 4 after 12 months. Secondary outcomes were in-hospital mortality, mRS ≤ 3 and mortality after 12 months, and the rate of hemicraniectomy-related complications. The diameter of the hemicraniectomy was examined as an independent predictor of functional outcome in multivariable analyses. RESULTS: Among 130 patients (32.3% female, mean (SD) age 55 (11) years), the mean hemicraniectomy diameter was 13.6 cm. 42 patients (32.3%) had HC > 14. There were no significant differences in the primary outcome and mortality by size of hemicraniectomy. Rate of complications did not differ (HC ≤ 14 27.6% vs. HC > 14 36.6%, p = 0.302). Age and infarct volume but not hemicraniectomy diameter were associated with outcome in multivariable analyses. CONCLUSION: In this post-hoc analysis, large hemicraniectomy was not associated with an improved outcome or lower mortality in unselected patients with malignant middle cerebral artery infarction. Randomized trials should further examine whether individual patients could benefit from a large-sized hemicraniectomy. CLINICAL TRIAL REGISTRATION INFORMATION: German Clinical Trials Register (URL: https://www.drks.de ; Unique Identifier: DRKS00000624).

Deep phenotyping as a contribution to personalized depression therapy: the GEParD and DaCFail protocols.

Depressive patients suffer from a complex of symptoms of varying intensity compromising their mood, emotions, self-concept, neurocognition, and somatic function. Due to a mosaic of aetiologies involved in developing depression, such as somatic, neurobiological, (epi-)genetic factors, or adverse life events, patients often experience recurrent depressive episodes. About 20-30% of these patients develop difficult-to-treat depression. Here, we describe the design of the GEParD (Genetics and Epigenetics of Pharmaco- and Psychotherapy in acute and recurrent Depression) cohort and the DaCFail (Depression-associated Cardiac Failure) case-control protocol. Both protocols intended to investigate the incremental utility of multimodal biomarkers including cardiovascular and (epi-)genetic markers, functional brain and heart imaging when evaluating the response to antidepressive therapy using comprehensive psychometry. From 2012 to 2020, 346 depressed patients (mean age 45 years) were recruited to the prospective, observational GEParD cohort protocol. Between 2016 and 2020, the DaCFail case-control protocol was initiated integrating four study subgroups to focus on heart-brain interactions and stress systems in patients > 50 years with depression and heart failure, respectively. For DaCFail, 120 depressed patients (mean age 60 years, group 1 + 2), of which 115 also completed GEParD, and 95 non-depressed controls (mean age 66 years) were recruited. The latter comprised 47 patients with heart failure (group 3) and 48 healthy subjects (group 4) of a population-based control group derived from the Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study. Our hypothesis-driven, exploratory study design may serve as an exemplary roadmap for a standardized, reproducible investigation of personalized antidepressant therapy in an inpatient setting with focus on heart comorbidities in future multicentre studies.

Association of Infarct Volume Before Hemicraniectomy and Outcome After Malignant Infarction.

OBJECTIVE: To determine the impact of infarct volume before hemicraniectomy in malignant middle cerebral artery infarction (MMI) as an independent predictor for patient selection and outcome prediction, we retrospectively analyzed data of 140 patients from a prospective multicenter study. METHODS: Patients from the Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY) Registry who underwent hemicraniectomy after ischemic infarction of >50% of the middle cerebral artery territory were included. Functional outcome according to the modified Rankin Scale (mRS) was assessed at 12 months. Unfavorable outcome was defined as mRS score of 4 to 6. Infarct size was quantified semiautomatically from CT or MRI before hemicraniectomy. Subgroup analyses in patients fulfilling inclusion criteria of randomized trials in younger patients (age ≤60 years) were predefined. RESULTS: Among 140 patients with complete datasets (34% female, mean [SD] age 54 [11] years), 105 (75%) had an unfavorable outcome (mRS score >3). Mean (SD) infarct volume was 238 (63) mL. Multivariable logistic regression identified age (odds ratio [OR] 1.08 per 1-year increase, 95% confidence interval [CI] 1.02-1.13, p = 0.004), infarct size (OR 1.27 per 10-mL increase, 95% CI 1.12-1.44, p < 0.001), and NIH Stroke Scale score (OR 1.10, 95% CI 1.01-1.20, p = 0.030) before hemicraniectomy as independent predictors of unfavorable outcome. Findings were reproduced in patients fulfilling inclusion criteria of randomized trials in younger patients. Infarct volume thresholds for prediction of unfavorable outcome with high specificity (94% in overall cohort and 92% in younger patients) were >258 mL before hemicraniectomy. CONCLUSION: Outcome in MMI depends strongly on age and infarct size before hemicraniectomy. Standardized volumetry may be helpful in the process of decision-making concerning hemicraniectomy.

Childhood trauma dependent anxious depression sensitizes HPA axis function.

Anxious depression is a common subtype of major depressive disorder (MDD) and is associated with greater severity and poorer outcome. Alterations of the hypothalamic-pituitary-adrenal (HPA) axis, especially of the glucocorticoid receptor (GR) function, are often observed in MDD, but evidence lacks for anxious depression. Childhood adversity is known to influence both the HPA axis and risk of MDD. Therefore, we investigated GR-function in anxious depression dependent on childhood adversity. We enrolled 144 depressed in-patients (49.3% females). Anxious depression was defined using the Hamilton Depression Rating Scale (HAM-D) anxiety/somatization factor score ≥7. Blood draws were performed at 6 pm before and 3 h after 1.5 mg dexamethasone ingestion for measurement of cortisol, ACTH and blood count to assess GR-function and the immune system. In a subgroup of n = 60 FKBP5 mRNA controlled for FKBP5 genotype was measured before and after dexamethasone. Childhood adversity was evaluated using the Childhood Trauma Questionnaire (CTQ). We identified 78 patients (54.2%) with anxious depression who showed a greater severity and worse outcome. These patients were more often exposed to sexual abuse (30% vs. 16%/p = 0.04) and emotional neglect (76% vs. 58%/p = 0.02) than patients with non-anxious depression. Anxious depressed patients showed an enhanced GR-induced FKBP5 mRNA expression (F = 5.128; p = 0.03) and reduced cortisol levels, partly dependent on sexual abuse (F = 7.730; p = 0.006). Additionally, the GR-induced leukocyte response was enhanced in patients with sexual abuse (F = 7.176; p = 0.008). Anxious depression in dependence of childhood trauma is associated with heightened sensitivity of the HPA axis and the immune system which should be considered for treatment algorithms and targets.