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Immune checkpoint inhibition unleashes the power of the immune system against tumour cells. Immune checkpoint inhibitors (ICIs) block the inhibitory effects of cytotoxic T-lymphocyte associated protein 4, programmed death protein 1, programmed death ligand 1 and lymphocyte activation gene 3 molecules on T-cells, and so enhance physiological cytotoxic effects. ICIs can significantly improve survival from cancers, including those previously associated with poor treatment response, such as metastatic melanoma. However, on-target off-tumour effects of ICIs result in immune-related adverse events. These toxicities are common and require new multidisciplinary expertise to manage. ICI neurotoxicity is relatively rare but ominous due to its severity, heterogenous manifestations and potential for long-term disability. Neurotoxic syndromes are novel and often present precipitously. Here, we describe ICI mechanisms of action, their impact on cancer outcomes and their frequency of immune-related adverse events. We focus particularly on neurotoxicity. We discuss the current appreciation of neurotoxic syndromes, management strategies and outcomes based on clinical expertise and consensus, multi-specialty guidance. The use of immunotherapy is expanding exponentially across multiple cancer types and so too will our approach to these cases., Competing Interests: Competing interests: ASC is supported by clinical research funding from the NIHR BRC. FWV is supported by a Guarantors of Brain postdoctoral clinical fellowship., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Neurological disease caused by toxins is widespread but under-recognised. Despite increasing public interest and a growing number of novel potential neurotoxins, diagnosis of neurotoxic disease is often delayed or missed, resulting in poorer patient outcomes. This article discusses neurotoxic syndromes using a systems-based approach, focusing on environmental and occupational agents. We do not discuss recreational drugs, pharmaceutical agents or developmental neurotoxins in detail. We aim to provide neurologists with a working understanding of the scenarios in which a clinical presentation may be due to a neurotoxin and how to approach confirmation of the diagnosis., Competing Interests: Competing interests: FWV is supported by a Guarantors of Brain postdoctoral clinical fellowship., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aciclovir-induced neurotoxicity results from the accumulation of aciclovir and its metabolite 9-carboxymethoxymethylguanine (CMMG). It occurs predominantly in older patients with impaired renal function and is characterised by a combination of confusion and psychiatric changes. Seizures, myoclonus and dysarthria may also occur. Critically, peritoneal dialysis has little effect on reversing the toxic effects of aciclovir. We describe a woman in her 70s with renal failure who developed confusion and seizures after receiving aciclovir. She was ultimately diagnosed with aciclovir-induced neurotoxicity, confirmed by an elevated serum CMMG concentration. This condition is likely to be underdiagnosed and the neurologist's primary challenge is differentiating aciclovir-induced neurotoxicity from viral encephalitis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The negative impact of smoking in multiple sclerosis is well established; however, there is much less evidence as to whether smoking cessation is beneficial to progression in multiple sclerosis. Adults with multiple sclerosis registered on the United Kingdom Multiple Sclerosis Register (2011-20) formed this retrospective and prospective cohort study. Primary outcomes were changes in three patient-reported outcomes: normalized Multiple Sclerosis Physical Impact Scale (MSIS-29-Phys), normalized Multiple Sclerosis Walking Scale (MSWS-12) and the Hospital Anxiety and Depression Scale (HADS). Time to event outcomes were clinically significant increases in the patient-reported outcomes. The study included 7983 participants; 4130 (51.7%) of these had ever smoked, of whom 1315 (16.5%) were current smokers and 2815/4130 (68.2%) were former smokers. For all patient-reported outcomes, current smokers at the time of completing their first questionnaire had higher patient-reported outcomes scores indicating higher disability compared to those who had never smoked (∼10 points difference in MSIS-29-Phys and MSWS-12; 1.5-1.8 points for HADS-Anxiety and HADS-Depression). There was no improvement in patient-reported outcomes scores with increasing time since quitting in former smokers. Nine hundred and twenty-three participants formed the prospective parallel group, which demonstrated that MSIS-29-Phys [median (IQR) 5.03 (3.71, 6.34)], MSWS-12 [median (IQR) 5.28 (3.62, 6.94)] and HADS-Depression [median (IQR) 0.71 (0.47, 0.96)] scores worsened over a period of 4 years, whereas HADS-Anxiety remained stable. Smoking status was significant at Year 4; current smokers had higher MSIS-29-Phys and HADS-Anxiety scores [median (IQR) 3.05 (0.22, 5.88) and 1.14 (0.52, 1.76), respectively] while former smokers had a lower MSIS-29-Phys score of -2.91 (-5.03, -0.79). A total of 4642 participants comprised the time to event analysis. Still smoking was associated with a shorter time to worsening event in all patient-reported outcomes (MSIS-29-Phys: n = 4436, P = 0.0013; MSWS-12: n = 3902, P = 0.0061; HADS-Anxiety: n = 4511, P = 0.0017; HADS-Depression: n = 4511, P < 0.0001). Worsening in motor disability (MSIS-29-Phys and MSWS-12) was independent of baseline HADS-Anxiety and HADS-Depression scores. There was no statistically significant difference in the rate of worsening between never and former smokers. When smokers quit, there is a slowing in the rate of motor disability deterioration so that it matches the rate of motor decline in those who have never smoked. This suggests that smoking cessation is beneficial for people with multiple sclerosis., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: A noninvasive intracranial pressure (ICP) estimation method is proposed that incorporates a model-based approach within a probabilistic framework to mitigate the effects of data and modeling uncertainties., Methods: A first-order model of the cerebral vasculature relates measured arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV) to ICP. The model is driven by the ABP waveform and is solved for a range of mean ICP values to predict the CBFV waveform. The resulting errors between measured and predicted CBFV are transformed into likelihoods for each candidate ICP in two steps. First, a baseline ICP estimate is established over five data windows of 20 beats by combining the likelihoods with a prior distribution of the ICP to yield an a posteriori distribution whose median is taken as the baseline ICP estimate. A single-state model of cerebral autoregulatory dynamics is then employed in subsequent data windows to track changes in the baseline by combining ICP estimates obtained with a uniform prior belief and model-predicted ICP. For each data window, the estimated model parameters are also used to determine the ICP pulse pressure., Results: On a dataset of thirteen pediatric patients with a variety of pathological conditions requiring invasive ICP monitoring, the method yielded for mean ICP estimation a bias (mean error) of 0.6 mmHg and a root-mean-squared error of 3.7 mmHg., Conclusion: These performance characteristics are well within the acceptable range for clinical decision making., Significance: The method proposed here constitutes a significant step towards robust, continuous, patient-specific noninvasive ICP determination.

A 28-year-old man presented with a sudden onset of left leg pain and swelling. There was no history of preceding trauma. Initial blood tests were unremarkable, ultrasound imaging showed extensive subcutaneous oedema. He then developed similar symptoms in his right leg, followed by both arms, and finally his forehead. A fluctuating peripheral eosinophilia subsequently developed. Biopsies of the arm and forehead showed an evolving panniculitis. The clinical features, peripheral eosinophilia, imaging and histology were consistent with a diagnosis of eosinophilic fasciitis. The patient received a course of steroids with complete resolution of his symptoms. Eosinophilic fasciitis is an uncommon condition but one that may be encountered by acute physicians. Early recognition and treatment is important to prevent complications., (© Royal College of Physicians 2020. All rights reserved.)

Objective: In the search for a reliable, cooperation-independent, noninvasive alternative to invasive intracranial pressure (ICP) monitoring in children, various approaches have been proposed, but at the present time none are capable of providing fully automated, real-time, calibration-free, continuous and accurate ICP estimates. The authors investigated the feasibility and validity of simultaneously monitored arterial blood pressure (ABP) and middle cerebral artery (MCA) cerebral blood flow velocity (CBFV) waveforms to derive noninvasive ICP (nICP) estimates., Methods: Invasive ICP and ABP recordings were collected from 12 pediatric and young adult patients (aged 2-25 years) undergoing such monitoring as part of routine clinical care. Additionally, simultaneous transcranial Doppler (TCD) ultrasonography-based MCA CBFV waveform measurements were performed at the bedside in dedicated data collection sessions. The ABP and MCA CBFV waveforms were analyzed in the context of a mathematical model, linking them to the cerebral vasculature's biophysical properties and ICP. The authors developed and automated a waveform preprocessing, signal-quality evaluation, and waveform-synchronization "pipeline" in order to test and objectively validate the algorithm's performance. To generate one nICP estimate, 60 beats of ABP and MCA CBFV waveform data were analyzed. Moving the 60-beat data window forward by one beat at a time (overlapping data windows) resulted in 39,480 ICP-to-nICP comparisons across a total of 44 data-collection sessions (studies). Moving the 60-beat data window forward by 60 beats at a time (nonoverlapping data windows) resulted in 722 paired ICP-to-nICP comparisons., Results: Greater than 80% of all nICP estimates fell within ± 7 mm Hg of the reference measurement. Overall performance in the nonoverlapping data window approach gave a mean error (bias) of 1.0 mm Hg, standard deviation of the error (precision) of 5.1 mm Hg, and root-mean-square error of 5.2 mm Hg. The associated mean and median absolute errors were 4.2 mm Hg and 3.3 mm Hg, respectively. These results were contingent on ensuring adequate ABP and CBFV signal quality and required accurate hydrostatic pressure correction of the measured ABP waveform in relation to the elevation of the external auditory meatus. Notably, the procedure had no failed attempts at data collection, and all patients had adequate TCD data from at least one hemisphere. Last, an analysis of using study-by-study averaged nICP estimates to detect a measured ICP > 15 mm Hg resulted in an area under the receiver operating characteristic curve of 0.83, with a sensitivity of 71% and specificity of 86% for a detection threshold of nICP = 15 mm Hg., Conclusions: This nICP estimation algorithm, based on ABP and bedside TCD CBFV waveform measurements, performs in a manner comparable to invasive ICP monitoring. These findings open the possibility for rational, point-of-care treatment decisions in pediatric patients with suspected raised ICP undergoing intensive care.

Objectives: Time-averaged intracranial pressure-to-blood pressure Fisher-transformed Pearson correlation (PRx) is used to assess cerebral autoregulation and derive optimal cerebral perfusion pressure. Empirically, impaired cerebral autoregulation is considered present when PRx is positive; greater difference between time series median cerebral perfusion pressure and optimal cerebral perfusion pressure (ΔCPP) is associated with worse outcomes. Our aims are to better understand: 1) the potential strategies for targeting optimal cerebral perfusion pressure; 2) the relationship between cerebral autoregulation and PRx; and 3) the determinants of greater ΔCPP., Design: Mechanistic simulation using a lumped compartmental model of blood pressure, intracranial pressure, cerebral autoregulation, cerebral blood volume, PaCO2, and cerebral blood flow., Setting: University critical care integrative modeling and precision physiology research group., Subjects: None, in silico studies., Interventions: Simulations in blood pressure, intracranial pressure, PaCO2, and impairment of cerebral autoregulation, with examination of "output" cerebral perfusion pressure versus PRx-plots, optimal cerebral perfusion pressure, and ΔCPP., Measurements and Main Results: In regard to targeting optimal cerebral perfusion pressure, a shift in mean blood pressure or mean intracranial pressure with no change in mean blood pressure, with intact cerebral autoregulation, impacts optimal cerebral perfusion pressure. Second, a positive PRx occurs even with intact cerebral autoregulation. In relation to ΔCPP, for a given input blood pressure profile, with constant intracranial pressure, altering the degree of impairment in cerebral autoregulation or the level of PaCO2 maintains differences to within ±5 mm Hg. Change in intracranial pressure due to either an intermittently prolonged pattern of raised intracranial pressure or terminal escalation shows ΔCPP greater than 10 mm Hg and less than -10 mm Hg, respectively., Conclusions: These mechanistic simulations provide insight into the empiric basis of optimal cerebral perfusion pressure and the significance of PRx and ΔCPP. PRx and optimal cerebral perfusion pressure deviations do not directly reflect changes in cerebral autoregulation but are, in general, related to the presence of complex states involving well-described clinical progressions with raised intracranial pressure.

Background: We sought to classify type and distribution of acute infarction and hemorrhage on head computed tomography (CT) during pediatric extracorporeal membrane oxygenation (ECMO). We also analyzed the occurrence of seizures on electroencephalography and outcomes between those with and without CT abnormalities., Methods: We conducted a single center observational study in pediatric intensive care units. The medical records of 179 children who underwent ECMO between 2009 and 2013 were reviewed. No interventions were done., Results: A total of 46% (82/179) of children underwent CT. Of these, 60% (49/82) had acute pathology. Cerebral infarction occurred in 55% (27/49) and hemorrhage in 41% (20/49). Infarction was arterial in 67% (18/27) with a preponderance in the middle cerebral artery territory (17 patients). Infarction was bilateral in 41% (11/27) and not specific to the side of cannulation in the rest. Sensitivity and specificity for head ultrasound in predicting infarction on CT were 100% and 53%, respectively. A total of 36% (65/179) underwent continuous encephalography monitoring; 22% (14/65) of these had electrographic seizures. Electrographic seizures were increased in those with infarction (odds ratio [OR], 6.81; 95% confidence interval [CI], 1.98 to 23.43). Survival was reduced with both infarction (OR, 0.22; 95% CI, 0.09 to 0.54) and hemorrhage (OR, 0.31; 95% CI, 0.13 to 0.72). Children with CT abnormalities had more unfavorable outcomes (P = 0.01)., Conclusions: Head ultrasound is insufficient to rule out infarction. Infarction is middle cerebral artery predominant and associated with an increased risk of electrographic seizures., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Monitoring of intracranial pressure (ICP) is indicated in patients with a variety of conditions affecting the brain and cerebrospinal fluid space. The measurement of ICP, however, is highly invasive as it requires placement of a catheter in the brain tissue or cerebral ventricular spaces. Several noninvasive techniques have been proposed to overcome this issue, and one class of approaches is based on analyzing cerebral blood flow velocity (CBFV) and arterial blood pressure (ABP) waveforms to infer ICP. Here, we analyze a physiologic model linking ICP to CBFV and ABP and present a regression-based approach to estimating ICP. We tested the model on 20 datasets recorded from three patients in intensive care. Our estimates achieve a mean error (bias) of -1.12 mmHg and a standard deviation of the error of 5.56 mmHg, for a root-mean-square error of 5.68 mmHg, when compared against the invasive ICP measurement. Since transcranial Doppler ultrasound based CBFV measurements depend on the Doppler angle φ between the direction of the ultrasound beam and the (main) direction of blood flow velocity, we investigated the robustness of our ICP estimates against variations in φ. Our results show a change in the estimated ICP that is <;1 mmHg if we assume φ ~ N(μ; σ 2 ), with μ = 0 and σ = 10°.

Objective: To evaluate clinical trials of hypothermia management on outcome in pediatric patients with severe traumatic brain injury using conventional and Bayesian meta-analyses., Data Sources: Screening of PubMed and other databases to identify randomized controlled trials of hypothermia for pediatric severe traumatic brain injury published before September 2016., Study Selection: Four investigators assessed and reviewed randomized controlled trial data., Data Extraction: Details of trial design, patient number, Glasgow Coma Scale score, hypothermia and control normothermia therapy, and outcome of mortality were collated., Data Synthesis: In conventional meta-analysis, random-effects models were expressed as odds ratio (odds ratio with 95% credible-interval). Bayesian outcome probabilities were calculated as probability of odds ratio greater than or equal to 1. In seven randomized controlled trials (n = 472, patients 0-17 yr old), there was no difference in mortality (hypothermia vs normothermia) with pooled estimate 1.42 (credible-interval, 0.77-2.61; p = 0.26). Duration of hypothermia (24, 48, or 72 hr) did not show difference in mortality. (Similar results were found using poor outcome.) Bayesian analyses of randomized controlled trials ordered by time of study completed recruitment showed, after the seventh trial, chance of relative risk reduction of death by greater than 20% is 1-in-3. An optimistic belief (0.90 probability that relative risk reduction of death > 20% hypothermia vs normothermia) gives a chance of relative risk reduction of death by greater than 20% of 1-in-2., Conclusions: Conventional meta-analysis shows the null hypothesis-no difference between hypothermia versus normothermia on mortality and poor outcome-cannot be rejected. However, Bayesian meta-analysis shows chance of relative risk reduction of death greater than 20% with hypothermia versus normothermia is 1-in-3, which may be further altered by one's optimistic or skeptical belief about a patient.

Background: Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease., Methods and Results: Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0-100)., Conclusions: Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease., (© 2016 American Heart Association, Inc.)

Objectives: This study sought to assess the value of differing pre-operative measures in prediction of post-operative non-surgical site infection (NSSI) and length of hospital stay following hip fracture surgery. Methods: All patients admitted during a one year period with a hip fracture to our department were included in the study (n=207). Primary outcome measures were ten independent risk factors correlated to the development of non-surgical site infection following surgery for hip fracture. Secondary outcome measures were duration of hospital stay and inpatient mortality. Results: The patients who had severe cognitive impairment had a 71.0% risk of developing non-surgical site infection. Patients who had multiple medical co-morbidities also had increased risk of developing non-surgical site infection at 59.1%. Patients who developed NSSI on average stayed in hospital 13.1 days longer than patients who did not (31.6 vs. 18.5, p < .001). Conclusions: This study demonstrates the importance of reducing post-operative infection in hip fracture patients in view of reducing morbidity, mortality and cost. These patients can be stratified by risk factors and interventions can be employed in view of reducing inpatient post-operative infection rates in this cohort., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Microtubules play a crucial role in the generation, migration and differentiation of nascent neurons in the developing vertebrate brain. Mutations in the constituents of microtubules, the tubulins, are known to cause an array of neurological disorders, including lissencephaly, polymicrogyria and microcephaly. In this study we explore the genetic and cellular mechanisms that cause TUBB5-associated microcephaly by exploiting two new mouse models: a conditional E401K knock-in, and a conditional knockout animal. These mice present with profound microcephaly due to a loss of upper-layer neurons that correlates with massive apoptosis and upregulation of p53. This phenotype is associated with a delay in cell cycle progression and ectopic DNA elements in progenitors, which is dependent on the dosage of functional Tubb5. Strikingly, we report ectopic Sox2-positive progenitors and defects in spindle orientation in our knock-in mouse line, which are absent in knockout animals. This work sheds light on the functional repertoire of Tubb5, reveals that the E401K mutation acts by a complex mechanism, and demonstrates that the cellular pathology driving TUBB5-associated microcephaly is cell death., (© 2016. Published by The Company of Biologists Ltd.)