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Chimeric antigen receptor (CAR)-expressing T cells now offer an effective treatment option for people with previously refractory B cell malignancies and are under development for a wide range of other tumours. However, neurological toxicity is a common complication of CAR-T cell therapy, seen in over 50% of recipients in some cohorts. Since 2018, the term immune effector cell-associated neurotoxicity syndrome (ICANS) has been used to describe and grade neurotoxicity seen after CAR-T cells and other similar therapies. ICANS following CAR-T therapy is usually self-limiting but can necessitate admission to the intensive care unit and is rarely fatal. As CAR-T therapies enter routine clinical practice, it is important for neurologists to be aware of the nature of neurological complications. Here, we summarise the clinical manifestations, mechanisms, investigations and recommended treatment of CAR-T-related neurotoxicity, focusing on the licensed CD19 products.

Background To elucidate the incidence of acute kidney injury (AKI) after out-of-hospital cardiac arrest (OHCA) and to examine the impact of target temperature management (TTM) and early coronary angiography on renal function. Methods Post hoc analysis of the TTM trial, a multinational randomised controlled trial comparing target temperature of 33 °C versus 36 °C in patients with return of spontaneous circulation after OHCA. The impact of TTM and early angiography (within 6 h of OHCA) versus late or no angiography on the development of AKI during the 7-day period after OHCA was analysed. AKI was defined according to modified KDIGO criteria in patients surviving beyond day 2 after OHCA. Results Following exclusions, 853 of 939 patients enrolled in the main trial were analysed. Unadjusted analysis showed that significantly more patients in the 33 °C group had AKI compared to the 36 °C group [211/431 (49%) versus 170/422 (40%) p  = 0.01], with a worse severity ( p  = 0.018). After multivariable adjustment, the difference was not significant (odds ratio 0.75, 95% confidence interval 0.54–1.06, p  = 0.10]. Five hundred seventeen patients underwent early coronary angiography. Although the unadjusted analysis showed less AKI and less severe AKI in patients who underwent early angiography compared to patients with late or no angiography, in adjusted analyses, early angiography was not an independent risk factor for AKI (odds ratio 0.73, 95% confidence interval 0.50–1.05, p  = 0.09). Conclusions In OHCA survivors, TTM at 33 °C compared to management at 36 °C did not show different rates of AKI and early angiography was not associated with an increased risk of AKI. Trial registration NCT01020916 . Registered on www.ClinicalTrials.gov 26 November 2009 (main trial).

Prophylaxis, an ancient practice in medicine and healthcare [1], has become a victim of its own success. It is now intrinsically rooted in medical behavior and stands out as a significant example of framing bias in patient care, i.e., a tendency to selectively display and promote positive aspects of an idea [2]. Most medical conditions are considered ominous, so prophylactic strategies are considered a priori good [1]. By avoiding disease, prophylaxis sounds better than cure. This rationale is present in several reports on the effects of prophylactic treatments, which use optimistic jargon to compel the reader, including magnification of the problem to be prevented, inappropriate measurement of adverse events, quoting the number of lives saved, number of events avoided, and numbers needed to treat [3–6]. It is uncommon to see the same focus on the direct harms of prophylaxis. These are rarely adequately reported, and uncertainty is not always acknowledged.

Background Traumatic brain injury (TBI) is a significant cause of death and disability in young adults, but not much is known about the incidence and characteristics of blood–brain barrier (BBB) dysfunction in this group. In this proof of concept study, we sought to quantify the incidence of BBB dysfunction (defined as a cerebrospinal fluid (CSF)–plasma albumin quotient of ≥0.007) and examine the relationship between plasma and CSF levels of proteins and electrolytes, in patients with severe TBI. Methods We recruited 30 patients, all of whom were receiving hypertonic 20 % saline infusion for intracranial hypertension and had external ventricular drains in situ. Simultaneous CSF and blood samples were obtained. Biochemical testing was performed for sodium, osmolality, potassium, glucose, albumin, immunoglobulin-G, and total protein. Results Eleven patients (37 %) showed evidence of impairment of passive BBB function, with a CSF–plasma albumin quotient of ≥0.007. There were strong positive correlations seen among CSF–plasma albumin quotient and CSF–plasma immunoglobulin-G quotient and CSF–plasma total protein quotient ( r  = 0.967, P  < 0.001 and r  = 0.995, P  < 0.001, respectively). We also found a higher maximum intracranial pressure (24 vs. 21 mmHg, P  = 0.029) and a trend toward increased mortality (27 vs. 11 %, P  = 0.33) in patients with BBB disruption. Conclusions In summary, passive BBB dysfunction is common in patients with severe TBI, and may have important implications for effectiveness of osmotherapy and long-term outcomes. Also, our results suggest that the CSF–plasma total protein quotient, a measurement which is readily available, can be used instead of the CSF–plasma albumin quotient for evaluating BBB dysfunction.

Background To date, targeted temperature management (TTM) is the only neuroprotective intervention after resuscitation from cardiac arrest that is recommended by guidelines. The evidence on the effects of TTM is unclear. Methods/design The Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM2) trial is an international, multicentre, parallel group, investigator-initiated, randomised, superiority trial in which TTM with a target temperature of 33 °C after cardiac arrest will be compared with a strategy to maintain normothermia and active treatment of fever (≥ 37.8 °C). Prognosticators, outcome assessors, the steering group, the trial coordinating team, and trial statisticians will be blinded to treatment allocation. The primary outcome will be all-cause mortality at 180 days after randomisation. We estimate a 55% mortality in the targeted normothermia group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The secondary neurological outcome will be poor functional outcome (modified Rankin scale 4–6) at 180 days after cardiac arrest. In this paper, a detailed statistical analysis plan is presented, including a comprehensive description of the statistical analyses, handling of missing data, and assessments of underlying statistical assumptions. Final analyses will be conducted independently by two qualified statisticians following the present plan. Discussion This SAP, which was prepared before completion of enrolment, should increase the validity of the TTM trial by mitigation of analysis-bias.