Leber's hereditary optic neuropathy with late disease onset: clinical and molecular characteristics of 20 patients

Background: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. Here we describe the clinical and molecular characteristics of 20 patients with disease onset after the age of 50 years (late onset-LHON). Methods: From a cohort of 251 affected and 277 unaffected LHON carriers, we identified 20 patients with onset of visual loss after the age of 50 years. Using structured questionnaires, data including basic demographic details, age of onset, progression of visual loss and severity as well as exposure to possible environmental triggers including alcohol, smoking and illicit drugs were retrospectively collected. Groups were compared using the Mann-Whitney-U-Test for two independent groups of sampled data. Results: The proportion of late onset-LHON in our cohort was 8% (20 patients, 15 males, 5 females). The mtDNA mutations m. 11778G  > A and m. 3460G  > A were found in 16 and 4 patients, respectively. Among 89 asymptomatic carriers above the age of 50 years (28 males, 61 females), the mtDNA mutations m. 11778G > A, m. 3460G  > A and m. 14484 T  > C were found in 60, 12 and 17 carriers, respectively. Late onset-LHON patients had significantly higher mean cumulative tobacco and alcohol consumption compared with unaffected carriers. However, there was no significant difference between late onset-and typical LHON patients with regard to daily tobacco and weekly alcohol consumption before disease onset. Conclusion: As already shown for typical LHON, alcohol consumption and smoking are important trigger factors also for the late manifestation. LHON should be considered in the differential diagnosis of subacute blindness even in older patients

Cost-effectiveness of short-protocol emergency brain MRI after negative non-contrast CT for minor stroke detection

OBJECTIVES To investigate the cost-effectiveness of supplemental short-protocol brain MRI after negative non-contrast CT for the detection of minor strokes in emergency patients with mild and unspecific neurological symptoms. METHODS The economic evaluation was centered around a prospective single-center diagnostic accuracy study validating the use of short-protocol brain MRI in the emergency setting. A decision-analytic Markov model distinguished the strategies \textquotedblno additional imaging\textquotedbl and \textquotedbladditional short-protocol MRI\textquotedbl for evaluation. Minor stroke was assumed to be missed in the initial evaluation in 40% of patients without short-protocol MRI. Specialized post-stroke care with immediate secondary prophylaxis was assumed for patients with detected minor stroke. Utilities and quality-of-life measures were estimated as quality-adjusted life years (QALYs). Input parameters were obtained from the literature. The Markov model simulated a follow-up period of up to 30 years. Willingness to pay was set to $100,000 per QALY. Cost-effectiveness was calculated and deterministic and probabilistic sensitivity analysis was performed. RESULTS Additional short-protocol MRI was the dominant strategy with overall costs of$26,304 (CT only: $27,109). Cumulative calculated effectiveness in the CT-only group was 14.25 QALYs (short-protocol MRI group: 14.31 QALYs). In the deterministic sensitivity analysis, additional short-protocol MRI remained the dominant strategy in all investigated ranges. Probabilistic sensitivity analysis results from the base case analysis were confirmed, and additional short-protocol MRI resulted in lower costs and higher effectiveness. CONCLUSION Additional short-protocol MRI in emergency patients with mild and unspecific neurological symptoms enables timely secondary prophylaxis through detection of minor strokes, resulting in lower costs and higher cumulative QALYs. KEY POINTS • Short-protocol brain MRI after negative head CT in selected emergency patients with mild and unspecific neurological symptoms allows for timely detection of minor strokes. • This strategy supports clinical decision-making with regard to immediate initiation of secondary prophylactic treatment, potentially preventing subsequent major strokes with associated high costs and reduced QALY. • According to the Markov model, additional short-protocol MRI remained the dominant strategy over wide variations of input parameters, even when assuming disproportionally high costs of the supplemental MRI scan

Gene–environment interactions in Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460G>A, m.11778G>A and m.14484T>C. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake

Kulturen des Entscheidens

Der Band thematisiert Entscheiden als eine soziale Praxis, die keineswegs selbstverständlich sondern in hohem Maße voraussetzungsvoll ist und die mit unterschiedlichen Zumutungen einhergeht. Entscheiden nimmt je nach sozialen Umständen ganz unterschiedliche Formen an und unterliegt demnach dem historischen Wandel. Die Beiträge des Bandes gehen anhand ausgewählter Fallbeispiele, die vom mittelalterlichen Europa bis hin zum gegenwärtigen Indien reichen, unterschiedlichen Aspekten von Kulturen des Entscheidens nach. Sie nehmen Narrative und Praktiken des Entscheidens ebenso in den Blick wie den Einsatz von Ressourcen in Prozessen des Entscheidens und diskutieren Ansätze, Entscheiden in einer geistes- und kulturwissenschaftlichen Perspektive zu analysieren. Der Band zeigt so die vielfältigen Möglichkeiten auf, wie Entscheiden untersucht werden kann, wenn dieses als eine historisch wandelbare soziale Praxis und als kulturell diverses Phänomen begriffen wird

Leber's hereditary optic neuropathy with late disease onset: clinical and molecular characteristics of 20 patients

Background: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. Here we describe the clinical and molecular characteristics of 20 patients with disease onset after the age of 50 years (late onset-LHON). Methods: From a cohort of 251 affected and 277 unaffected LHON carriers, we identified 20 patients with onset of visual loss after the age of 50 years. Using structured questionnaires, data including basic demographic details, age of onset, progression of visual loss and severity as well as exposure to possible environmental triggers including alcohol, smoking and illicit drugs were retrospectively collected. Groups were compared using the Mann-Whitney-U-Test for two independent groups of sampled data. Results: The proportion of late onset-LHON in our cohort was 8% (20 patients, 15 males, 5 females). The mtDNA mutations m. 11778G  > A and m. 3460G  > A were found in 16 and 4 patients, respectively. Among 89 asymptomatic carriers above the age of 50 years (28 males, 61 females), the mtDNA mutations m. 11778G > A, m. 3460G  > A and m. 14484 T  > C were found in 60, 12 and 17 carriers, respectively. Late onset-LHON patients had significantly higher mean cumulative tobacco and alcohol consumption compared with unaffected carriers. However, there was no significant difference between late onset-and typical LHON patients with regard to daily tobacco and weekly alcohol consumption before disease onset. Conclusion: As already shown for typical LHON, alcohol consumption and smoking are important trigger factors also for the late manifestation. LHON should be considered in the differential diagnosis of subacute blindness even in older patients

Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy - a case report

BACKGROUND Prolonged myelosuppression following CD19-directed CAR T-cell transfusion represents an important, yet underreported, adverse event. The resulting neutropenia and multifactorial immunosuppression can facilitate severe infectious complications. CASE PRESENTATION We describe the clinical course of a 59-year-old patient with relapsed/refractory DLBCL who received Axicabtagene-Ciloleucel (Axi-cel). The patient developed ASTCT grade I CRS and grade IV ICANS, necessitating admission to the neurological ICU and prolonged application of high-dose corticosteroids and other immunosuppressive agents. Importantly, neutropenia was profound (ANC < 100/μl), G-CSF-refractory, and prolonged, lasting more than 50 days. The patient developed severe septic shock 3 weeks after CAR transfusion while receiving anti-fungal prophylaxis with micafungin. His clinical status stabilized with broad anti-infective treatment and intensive supportive measures. An autologous stem cell backup was employed on day 46 to support hematopoietic recovery. Although the counts of the patient eventually started to recover, he developed an invasive pulmonary aspergillosis, which ultimately lead to respiratory failure and death. Postmortem examination revealed signs of Candida glabrata pancolitis. CONCLUSIONS This case highlights the increased risk for fatal infectious complications in patients who present with profound and prolonged cytopenia after CAR T-cell therapy. We describe a rare case of C. glabrata pancolitis associated with multifactorial immunosuppression. Although our patient succumbed to a fatal fungal infection, autologous stem cell boost was able to spur hematopoiesis and may represent an important therapeutic strategy for DLBCL patients with CAR T-cell associated bone marrow aplasia who have underwent prior stem cell harvest

Reduction in Radiation Exposure of CT Perfusion by Optimized Imaging Timing Using Temporal Information of the Preceding CT Angiography of the Carotid Artery in the Stroke Protocol

(1) Background: CT perfusion (CTP) is a fast, robust and widely available but dose-exposing imaging technique for infarct core and penumbra detection. Carotid CT angiography (CTA) can precede CTP in the stroke protocol. Temporal information of the bolus tracking series of CTA could allow for better timing and a decreased number of scans in CTP, resulting in less radiation exposure, if the shortening of CTP does not alter the calculated infarct core and penumbra or the resulting perfusion maps, which are essential for further treatment decisions. (2) Methods: 66 consecutive patients with ischemic stroke proven by follow-up imaging or endovascular intervention were included in this retrospective study approved by the local ethics committee. In each case, six simulated, stepwise shortened CTP examinations were compared with the original data regarding the perfusion maps, infarct core, penumbra and endovascular treatment decision. (3) Results: In simulated CTPs with 26, 28 and 30 scans, the infarct core, penumbra and PRR values were equivalent, and the resulting clinical decision was identical to the original CTP. (4) Conclusions: The temporal information of the bolus tracking series of the carotid CTA can allow for better timing and a lower radiation exposure by eliminating unnecessary scans in CTP