Neuropsychological outcomes of patients with haematological malignancies undergoing chimeric antigen receptor T-cell therapy: protocol for a prospective study.

Introduction: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common side-effect of chimeric antigen receptor T-cell (CAR-T) therapy, with symptoms ranging from mild to occasionally life-threatening. The neurological, cognitive, psychiatric and psychosocial sequelae of ICANS are diverse and not well defined, posing a challenge for diagnosis and management. The recovery trajectory of the syndrome is uncertain. Patients are rarely examined in this population pretherapy, adding a layer of complexity to specifying symptoms pertinent solely to CAR-T treatment. We present a protocol of a prospective longitudinal research study of adult patients in a single Australian haematology service undergoing CAR-T therapy. The study will describe neurocognitive features specific to ICANS, characterise the underlying syndrome, capture recovery, identify predictors of differential postinfusion outcomes and determine a set of cognitive instruments necessary to monitor patients acutely. Methods and analysis: This is a prospective longitudinal study that comprises neuropsychological and neurological examinations occurring prior to CAR-T, during the acute post-treatment period, 28 days, 6 months and 12 months post infusion. Data will be sourced from objective psychometric measures, clinical examinations, self-report questionnaires of psychopathology and accounts of subjective cognitive complaint. Ethics and dissemination: This study aims to guide diagnosis, management and monitoring of neurocognitive features of CAR-T cell therapy. Results of this study will be disseminated through publication in peer-reviewed journals and presentations at scientific conferences. All procedures involving human subjects/patients were approved by the Peter MacCallum Cancer Centre Human Research Ethics Committee (21/145).

Patterns of neurotoxicity among patients receiving chimeric antigen receptor T-cell therapy: A single-centre cohort study.

BACKGROUND AND PURPOSE: Immune effector cell-associated neurotoxicity syndrome (ICANS) is an important complication of chimeric antigen receptor T-cell (CAR-T) therapy. This study aims to identify the patterns of neurotoxicity among patients with ICANS at a tertiary referral centre in Australia. METHODOLOGY: This single-centre, prospective cohort study included all consecutively recruited patients who underwent CAR-T therapy for eligible haematological malignancies. All patients underwent a comprehensive neurological assessment and cognitive screening before CAR-T infusion, during the development of ICANS, and 1 month after treatment. Baseline demographic characteristics, incidence, and neurological patterns of neurotoxicity management were evaluated. RESULTS: Over a 19-month period, 23% (12) of the 53 eligible patients developed neurotoxicity (10/12 [83%] being grade 1). All patients showed changes in handwriting and tremor as their initial presentation. Changes in cognition were manifested in most of the patients, with a more substantial drop noted in their Montreal Cognitive Assessment compared to immune effector cell-associated encephalopathy scores. All manifestations of neurotoxicity were short-lived and resolved within a 1-month period, with a mean duration of 8.2 days (range = 1-33). CONCLUSIONS: The patterns of CAR-T-related neurotoxicity often include change in handwriting, tremor, and mild confusional state, especially early in their evolution. These may remain undetected by routine neurological surveillance. These features represent accessible clinical markers of incipient ICANS.

Secondary headaches - red and green flags and their significance for diagnostics.

A small percentage of patients suffer from a secondary headache syndrome. It is imperative that clinicians are able to differentiate primary headache syndromes from secondary headache syndromes, as failure to do so significantly worsens morbidity and mortality. Recent advances in our understanding of pathobiological mechanisms offer useful information on these enigmatic disorders. We now understand that the causes of secondary headache syndromes can vary significantly - these may be infectious, inflammatory, vascular, traumatic or structural in origin. A well-taken history and targeted physical examination coupled with appropriate investigations can enable these syndromes to be recognized consistently and thus allow their timely and appropriate treatment. Along with their epidemiology, some of their key characteristics shall thus be discussed in this review so as to aid the busy clinician at the bedside. Red flags including sudden onset, high pain intensity, pattern of change of a preexisting headache, focal neurological signs or seizure, systemic signs and precipitation by physical activity can guide the clinician to suspect a secondary headache. Importantly a preexisting headache is not an exclusion of a secondary headache - it might even be a predisposition in certain cases.

A Narrative Review on the Non-Pharmacologic Interventions in Post-Stroke Depression.

Stroke is a major cause of death and disability globally. Post-stroke depression (PSD) is a major driver for poor recovery and poor quality of life with extra burden for the patient and the caregiver. We have previously shown the inflammatory basis of PSD with associated bioenergetic failure, disruption of the blood-brain barrier, cell death, and persistent maladapted inflammation, making the PSD a norm rather than the exception, highlighting the unmet need for therapeutic intervention in PSD across the recovery trajectory. In this era, various interventions are focused on pharmacotherapy; however, non-pill-based medication should also be explored as post-stroke patients are likely to suffer from the adverse effects of polypharmacy. This narrated review explores the status of non-pharmacological interventions in managing PSD. We performed a PubMed search using pre-specified keywords looking at various non-pharmacologic approaches for the management of PSD. Worldwide, approaches such as non-invasive brain stimulation, behavioral and psychosocial therapy, as well as exercise, acupuncture, music, literature, and art therapies are available as monotherapy or adjunctive treatment for PSD. While current literature shows convincing results on the benefits of non-pharmacologic interventions, more robust studies are necessary to determine its utility in PSD.

Systematic Review of Existing Stroke Guidelines: Case for a Change.

Methods: We systematically searched for guideline recommendation on the day-to-day use of peripheral inflammatory markers such as NLR published in the English language between January 1, 2005, and October 2020. Any other evidence of system biology-based approach or recommendation was explored within the selected guidelines for this scoping review. Only the latest guideline per writing group was selected. Each guideline was analyzed independently by 2 to 4 authors to determine clinical scenarios explained/given, scientific evidence used, and recommendations presented in the context of system biology. Results: The scoping review found 2,911 titles at the beginning of the search. Final review included with 15 guidelines. Stroke-related organizations wrote sixty-five percent of the guidelines while national ministries wrote a fewer number of guidelines. We were primarily interested in recommendations for acute management in AIS published in the English language. Fifteen eligible guidelines were identified from 15 different countries/regions. None of the guidelines recommended the routine use of peripheral markers of inflammation, such as NLR, among their acute assessment and management recommendations. None of the existing guidelines explored the system biology approach to one of the most complex diseases affecting the human brain, stroke. Conclusions: This systematic review has identified a significant evidence-practice gap in all existing national stroke guidelines published in English medium as of October 2020. These guidelines included the only current "living stroke guidelines," stroke guidelines from Australia with a real opportunity to modernize the living stroke guidelines with systems biology approach, and provide 2020 vision towards better stroke care globally. Investigation of complex disease such as stroke is best served through a systems biology approach. One of the easiest places to start is simple blood tests such as total white cell count and NLR. Systems biology approach point us towards simple tools such immune-inflammatory index (SII) and serial systemic immune inflammatory indices (SSIIi) which should pave the way for the stroke physician community address the challenges in systems biology approach in stroke care. These challenges include translating bench research to the bedside, managing big data (continuous pulse, blood pressure, sleep, oxygen saturation, progressive changes in NLR, SII, SSIIi, etc.). Working with an interdisciplinary team also provides a distinct advantage. Recent adoption of historic WHO-IGAP calls for immediate action. The 2022 World Brain Day campaign on Brain Health for All is the perfect opportunity to raise awareness and start the process.

Stroke warning syndrome.

Stroke Warning Syndrome (SWS) is a form of early recurrent transient ischemic attack (TIA) which carries a high risk of infarction. It is characterized by repeated stereotypical sensorimotor symptoms affecting the face, arm, and leg without associated cortical involvement occurring within a seven-day period after an index TIA. In this systematic review, we identified that 1.5-4.5% of TIAs present as SWS and despite this occurrence, little is known about management strategies and treatment outcomes. Various mechanisms including small vessel disease, artery to artery embolism, hemodynamic instability and periinfarct depolarization may account for its nature. There are no specific guidelines on treatment, but thrombolysis appears safe but does not necessarily provide an advantage over antiplatelet and/or anticoagulation in preventing recurrences. Regardless of treatment, SWS is associated with excellent clinical outcomes.

Happiness: A Novel Outcome Measure in Stroke?

In this narrated review, we draw attention to the use of happiness as a novel outcome measure in clinical research studies regarding patients with stroke. Commonly used outcome measures in clinical trials in stroke rehabilitation include the modified Rankin Score (mRS), Functional Impairment Measures (FIM), Barthel Index and quality of life (QoL). Despite being a part of QoL, happiness is arguably a significant construct on its own. While QoL assesses perceptions of various extrinsic aspects of life, happiness may be used as a measure of subjective enjoyment of life after an illness. We review the literature discussing the use of happiness as a formal outcome measure in stroke care and subacute and long-term stroke rehabilitation. Ultimately we recommend the wider use of happiness as an outcome measure where appropriate in these settings.

Understanding Why Post-Stroke Depression May Be the Norm Rather Than the Exception: The Anatomical and Neuroinflammatory Correlates of Post-Stroke Depression.

Ischemic Stroke precedes depression. Post-stroke depression (PSD) is a major driver for poor recovery, negative quality of life, poor rehabilitation outcomes and poor functional ability. In this systematic review, we analysed the inflammatory basis of post-stroke depression, which involves bioenergetic failure, deranged iron homeostasis (calcium influx, Na influx, potassium efflux etc), excitotoxicity, acidotoxicity, disruption of the blood brain barrier, cytokine-mediated cytotoxicity, reactive oxygen mediated toxicity, activation of cyclooxygenase pathway and generation of toxic products. This process subsequently results in cell death, maladapted, persistent neuro-inflammation and deranged neuronal networks in mood-related brain regions. Furthermore, an in-depth review likewise reveals that anatomic structures related to post-stroke depression may be localized to complex circuitries involving the cortical and subcortical regions.

Carotid artery stenosis and inflammatory biomarkers: the role of inflammation-induced immunological responses affecting the vascular systems.

The death, disability and economic cost of stroke are enormous. Indeed, among the 16 million people worldwide who suffer a stroke' annually, nearly six million die, and another five million are left permanently disabled making prevention of stroke one of the most important priorities in healthcare. Currently carotid artery stenosis (CS) or narrowing of the common carotid artery (CCA) or internal carotid artery (ICA) due to atherosclerotic plaque, accounts for 20-30% of all ischemic strokes. Atherosclerosis is now regarded as a chronic inflammatory disease in response to vascular compromise especially from hypertension. This has long been known to lead to inflammation and atherosclerotic plaque formation in the blood vessels. This mini-review aims to highlight the role of inflammation and neuro-immunological processes in carotid artery disease. Various cellular elements of inflammation and advanced imaging techniques have been identified as potential markers of plaque progression. Therapies related to decreasing and modulating immune-responsive inflammation in the carotid vessels have been shown to translate into decreased occurrence of acute neurologic events and improvement of clinical outcomes.

First Australian Case of Good Recovery of a COVID-19 Patient With Severe Neurological Symptoms Post Prolonged Hospitalization.

A case of a 75-year-old man with COVID-19, severe neurological symptoms (acute stroke-like symptoms and signs and full recovery after a prolonged hospital stay), and intracranial hypertension is discussed with an in-depth review of his clinical features, biochemistry, haematology, highlighting the relationship between changes in neutrophil-lymphocyte ratio, C-reactive protein level, D-dimer level, and the clinical onset of acute ischemic stroke-like symptoms in the setting of COVID-19 and major neurological manifestations. This is the first such case reported in Australia to date. This case also illustrates the recovery of a patient with COVID-19 complicated with severe neurological symptoms (acute ischemic stroke-like symptoms) during the prolonged intensive care unit stay (at day 26) followed by slow neurorehabilitation and normal recovery from both respiratory and neurological involvement. The onset of acute stroke-like symptoms appears to be closely associated with changes of neutrophil-lymphocyte ratio and in C-reactive protein, and D-dimer levels.

Acute Ischemic Stroke in COVID-19: A Case-Based Systematic Review.

Corona virus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) is recognized as a global pandemic by WHO 2020 with 5,934 936 infections, 367,166 deaths and affecting over 200 countries as of 30th May 2020. Acute Ischemic Stroke (AIS) in brain is also emerging as an important neurovascular/neurological complication of COVID-19, associated with extreme immune responses leading to dysregulated coagulation system and generalized thrombo-embolic status and increased risk of AIS especially among usually less vulnerable younger adults in this cohort. Thus, in early June 2020, we aimed to review the clinical data on all published cases of COVID-19 and concomitant AIS, with a view to understanding the pertinent clinical, laboratory and imaging features. The neutrophil-lymphocyte ratio (NLR) at time of hospital admission for COVID infection correlates positively with the duration of time before onset of clinical features of AIS. Higher NLR, C-Reactive protein, serum ferritin, D-dimer and fibrinogen levels are associated with poor prognosis of AIS in COVID-19 with 75% of patients dying or being severely disabled at present. Currently it is too early to comment on the long-term outcomes for survivors.

Acute Ischemic Stroke in SARS-CoV, MERS-CoV, SARS-CoV-2: Neurorehabilitation Implications of Inflammation Induced Immunological Responses Affecting Vascular Systems.

Coronaviruses (CoVs) are enveloped RNA viruses and have been shown to cause mild to severe respiratory infections in humans, with some severe cases inducing neurological manifestations. The lethality and Neurological effects of the Severe Acute Respiratory Syndrome (SARS-CoV), Middle-East Respiratory Syndrome (MERS-CoV), and recently the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) have been well documented though currently there is little literature regarding long term effects and the implications for neurorehabilitation. SARS-CoV-2 and MERS-CoV have been linked to the infection associated inflammatory cytokine storms and induced hypercoagulopathic states that affect the entire vascular system including that of the brain. This mini-review provides an overview of the commonalities among studies published on all three types of the coronavirus related to acute ischemic stroke (AIS). The aim was to elucidate the physiological mechanisms underpinning COVID-2 and to reflect the similarities with the chronic inflammation induced symptoms of AIS that are likely to prove a further challenge for neurorehabilitation clinicians post COVID. In terms of increased incidence of COVID and AIS, it is likely that in depth knowledge of increased thrombotic risk in this population will require appropriate anticoagulation treatment, and other therapeutic interventions as well as neurorehabilitation interventions. Lastly the risk of spreading the virus requires further balancing of the provision of neurorehabiliatation services useful to the patient.

Case Report: Posterior Reversible Leukoencephalopathy Syndrome (PRES) as a Biologically Predictable Neurological Association in Severe COVID-19. First Reported Case From Australia and Review of Internationally Published Cases.

Reports of different types of neurological manifestations of COVID-19 are rapidly increasing, including changes of posterior reversible leukoencephalopathy syndrome (PRES). Here we describe the first reported case of COVID-19 and PRES in Australia diagnosed on basis of MRI brain imaging and confirmed clinically by presence of confusion, delirium, headaches, also associated with hypertension and blood pressure variability and stable long-term kidney problems. He made full recovery as his blood pressure was controlled and clinical status was supported with appropriate supportive therapy. Although traditionally a rare condition, PRES is likely to be more common among patients with COVID-19 pathobiology there is Renin downregulation of ACE2 receptors, involvement of Renin-Angiotensin-Aldosterone system, endotheliitis, cytokine storm, and hyper-immune response. Thus we advocate clinical suspicion and early brain imaging with MRI brain among vulnerable patients with known co-morbidities, and diagnosed with COVID-19 given that hypertension and blood pressure variability are often exacerbated by acute SARS-CoV-2 immune reactions. Such acute hypertensive encephalopathy was able to be reversed with timely supportive therapy ensuring re-hydration and re-establishment of blood pressure control.

COVID-19 Pathophysiology Predicts That Ischemic Stroke Occurrence Is an Expectation, Not an Exception-A Systematic Review.

Clinical reports of neurological manifestations associated with severe coronavirus disease 2019 (COVID-19), such as acute ischemic stroke (AIS), encephalopathy, seizures, headaches, acute necrotizing encephalitis, cerebral microbleeds, posterior reversible leukoencephalopathy syndrome, hemophagocytic lymphohistiocytosis, peripheral neuropathy, cranial nerve palsies, transverse myelitis, and demyelinating disorders, are increasing rapidly. However, there are comparatively few studies investigating the potential impact of immunological responses secondary to hypoxia, oxidative stress, and excessive platelet-induced aggregation on the brain. This scoping review has focused on the pathophysiological mechanisms associated with peripheral and consequential neural (central) inflammation leading to COVID-19-related ischemic strokes. It also highlights the common biological processes shared between AIS and COVID-19 infection and the importance of the recognition that severe respiratory dysfunction and neurological impairments associated with COVID and chronic inflammation [post-COVID-19 neurological syndrome (PCNS)] may significantly impact recovery and ability to benefit from neurorehabilitation. This study provides a comprehensive review of the pathobiology of COVID-19 and ischemic stroke. It also affirms that the immunological contribution to the pathophysiology of COVID-19 is predictive of the neurological sequelae particularly ischemic stroke, which makes it the expectation rather than the exception. This work is of fundamental significance to the neurorehabilitation community given the increasing number of COVID-related ischemic strokes, the current limited knowledge regarding the risk of reinfection, and recent reports of a PCNS. It further highlights the need for global collaboration and research into new pathobiology-based neurorehabilitation treatment strategies and more integrated evidence-based care.