Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body's first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin's anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation.

The subarachnoid haemorrhage (SAH) outcome tool (SAHOT) is the first SAH-specific patient reported outcome measure, and was developed in the UK. We aimed to validate the SAHOT outside the UK, and therefore endeavored to adapt the SAHOT into German and to test its psychometric properties.

Sphingosine-1-phosphate (S1P) is generated intracellularly and, when transported to the extracellular compartment, predominantly signals through S1P receptors. The S1P signalling pathway has been implicated in the pathophysiology of neurological injury following aneurysmal subarachnoid haemorrhage (aSAH). In this review, we bring together all the available data regarding the role of S1P in neurological injury following aSAH. There is agreement in the literature that S1P increases in the cerebrospinal fluid following aSAH and leads to cerebral artery vasospasm. On the other hand, the role of S1P in the parenchyma is less clear cut, with different studies arguing for beneficial and deleterious effects. A parsimonious interpretation of this apparently conflicting data is presented. We discuss the potential of S1P receptor modulators, in clinical use for multiple sclerosis, to be repurposed for aSAH. Finally, we highlight the gaps in our knowledge of S1P signalling in humans, the clinical challenges of targeting the S1P pathway after aSAH and other research priorities.

It is estimated that 1 in 6 people are living with a long-term neurological condition (LTNC). Although it is likely that systemic infections are a common trigger for urgent tertiary care needs in LTNCs, there is a lack of data. Yet this is important since systemic infections are a modifiable risk factor, and hence the motivation for a formal evaluation. We undertook case note review of 155 consecutive unselected adult patients with LTNC receiving urgent care at a tertiary hospital between November and December 2019. Data were collected on presenting symptoms, diagnosis, length of stay, complications, and change in social needs. The most common LTNCs were neurocognitive disorders (n = 68, 44%), cerebrovascular disorders (n = 65, 42%), and epilepsy (n = 19, 12%). Respiratory infections were most common (n = 40, 62.5%), followed by urinary (n = 16, 25%), skin (n = 4, 6%), gastrointestinal (n = 3, 5%) and bone (n = 1, 1.5%). Systemic infection was the trigger for urgent care in 41.3% of patients and in multivariable regression was associated with an increased likelihood of admission (p < 10, OR = 7.8, Nagelkerke R = 0.37), longer length of stay (p = 0.03, β = 5.91, R = 0.06), and death (p = 0.045, OR = 4.3, Nagelkerke R = 0.22). Altered mental status was the presenting symptom most frequently associated with infection (p < 10, χ test). In conclusion, systemic infections are a major trigger of acute tertiary care needs in adults with LTNCs, and play a role in determining clinical outcome. Since systemic infections are preventable or can be treated if identified early, they may represent a modifiable target to improve quality of life, clinical outcomes and health service efficiency.

To assess the long-term frequency, prognosis, and phenotype of persistent headache following aneurysmal subarachnoid hemorrhage (aSAH).