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The mechanisms underlying poor outcome following subarachnoid haemorrhage (SAH) are complex and multifactorial. They include early brain injury, spreading depolarisation, inflammation, oxidative stress, macroscopic cerebral vasospasm, and microcirculatory disturbances. Nrf2 is a global promoter of the antioxidant and anti-inflammatory response and has potential protective effects against all of these mechanisms. It has been shown to be upregulated after SAH, and Nrf2 knockout animals have poorer functional and behavioural outcomes after SAH. There are many agents known to activate the Nrf2 pathway. Of these, the actions of sulforaphane, curcumin, astaxanthin, lycopene, tert-butylhydroquinone, dimethyl fumarate, melatonin, and erythropoietin have been studied in SAH models. This review details the different mechanisms of injury after SAH including the contribution of haemoglobin (Hb) and its breakdown products. It then summarises the evidence that the Nrf2 pathway is active and protective after SAH and finally examines the evidence supporting Nrf2 upregulation as a therapy after SAH.

Haemoglobin is released into the CNS during the breakdown of red blood cells after intracranial bleeding. Extracellular free haemoglobin is directly neurotoxic. Haemoglobin scavenging mechanisms clear haemoglobin and reduce toxicity; these mechanisms include erythrophagocytosis, haptoglobin binding of haemoglobin, haemopexin binding of haem and haem oxygenase breakdown of haem. However, the capacity of these mechanisms is limited in the CNS, and they easily become overwhelmed. Targeting of haemoglobin toxicity and scavenging is, therefore, a rational therapeutic strategy. In this Review, we summarize the neurotoxic mechanisms of extracellular haemoglobin and the peculiarities of haemoglobin scavenging pathways in the brain. Evidence for a role of haemoglobin toxicity in neurological disorders is discussed, with a focus on subarachnoid haemorrhage and intracerebral haemorrhage, and emerging treatment strategies based on the molecular pathways involved are considered. By focusing on a fundamental biological commonality between diverse neurological conditions, we aim to encourage the application of knowledge of haemoglobin toxicity and scavenging across various conditions. We also hope that the principles highlighted will stimulate research to explore the potential of the pathways discussed. Finally, we present a consensus opinion on the research priorities that will help to bring about clinical benefits.

Haptoglobin is the body’s first line of defence against the toxicity of extracellular haemoglobin released following a subarachnoid haemorrhage (SAH). We investigated the haptoglobin response after SAH in cerebrospinal fluid (CSF) and serum. Paired CSF and serum samples from 19 controls and 92 SAH patients were assayed as follows: ultra-performance liquid chromatography for CSF haemoglobin and haptoglobin, immunoassay for serum haptoglobin and multiplexed CSF cytokines, and colorimetry for albumin. There was marked CSF haptoglobin deficiency: 99% of extracellular haemoglobin was unbound. The quotients for both CSF/serum albumin (qAlb) and haptoglobin (qHp) were used to compute the CSF haptoglobin index (qHp/qAlb). CSF from SAH patients had a significantly lower haptoglobin index compared to controls, especially in Haptoglobin-1 allele carriers. Serum haptoglobin levels increased after SAH and were correlated with CSF cytokine levels. Haptoglobin variables were not associated with long-term clinical outcomes post-SAH. We conclude that: (1) intrathecal haptoglobin consumption occurs after SAH, more so in haptoglobin-1 allele carriers; (2) serum haptoglobin is upregulated after SAH, in keeping with the liver acute phase response to central inflammation; (3) haptoglobin in the CSF is so low that any variation is too small for this to affect long-term outcomes, emphasising the potential for therapeutic haptoglobin supplementation.

IntroductionSubarachnoid haemorrhage (SAH) from a ruptured cerebral aneurysm carries high morbidity and mortality. Despite huge advances in techniques to secure the aneurysm, there has been little progress in the treatment of the deleterious effects of the haemorrhage.Sulforaphane is an Nrf2 inducer with anti-oxidant and anti-inflammatory properties. It has been shown to improve clinical outcome in experimental models of SAH, but is unstable. SFX-01 (Evgen Pharma) is a novel composition comprised of synthetic sulforaphane stabilised within an α-cyclodextrin complex. On ingestion, the complex releases sulforaphane making SFX-01 an ideal vehicle for delivery of sulforaphane.Methods and analysisThe objective of the study is to assess the safety, pharmacokinetics and efficacy of SFX-01. This is a prospective, multicentre, randomised, double-blind placebo-controlled trial in patients aged 18–80 years with aneurysmal subarachnoid haemorrhage in the previous 48 hours. 90 patients will be randomised to receive SFX-01 (300 mg) or placebo two times per day for up to 28 days.Safety will be assessed using blood tests and adverse event reporting.Pharmacokinetics will be assessed based on paired blood and cerebrospinal fluid (CSF) sulforaphane levels on day 7. A subgroup will have hourly samples taken during 6 hours post-dosing on days 1 and 7. Pharmacodynamics will be assessed by haptoglobin and malondialdehyde levels, and maximum flow velocity of middle cerebral artery will be measured by transcranial Doppler ultrasound.Clinical outcomes will be assessed at days 28, 90 and 180 with modified Rankin Scale, Glasgow Outcome Score, SAH Outcome Tool, Short Form-36, Brain Injury Community Rehabilitation Outcome Scales and Check List for Cognitive and Emotional consequences following stroke. MRI at 6 months including quantitative susceptibility mapping and volumetric T1 will measure iron deposition and cortical volume.Safety, CSF sulforaphane concentration and middle cerebral artery flow velocity will be primary outcomes and all others secondary.Ethics and disseminationEthical approval was obtained from South Central Hampshire A committee. Outcomes of the trial will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT02614742.

BackgroundThe best predictor of clinical outcome after aneurysmal subarachnoid haemorrhage (aSAH) is the World Federation of Neurological Surgeons (WFNS) score. Yet, this marker of early brain injury only explains 12% of the variance in outcome. Prolonged neurotoxicity via extracellular haemoglobin (Hb) may play a role. Neurofilament light chain (NFL) is released during neuronal damage. We hypothesize that CSF NFL predicts clinical outcome after aSAH and reflects Hb-induced neurotoxicity.MethodsCSF was collected via an external ventricular drain from 44 high-grade aSAH patients over 14 days post-ictus, and via lumbar puncture from 11 non-haemorrhagic, non-inflammatory neurologi- cal control patients. NFL and Hb were measured using enzyme-linked immunosorbent assay and ultra- performance liquid chromatography respectively. Clinical outcome after aSAH was assessed using the modified Rankin Score (mRS).ResultsNFL was higher in aSAH versus control CSF. High CSF NFL and high WFNS independently predicted worse mRS. CSF NFL was a stronger predictor than WFNS. Post-ictus, NFL and Hb CSF concentration gradually increased over two weeks. Maximum CSF NFL was correlated with maximum preceding CSF Hb, but not WFNS.ConclusionThe biomarker NFL is a predictor of clinical outcome after aSAH. NFL concentration likely reflects delayed Hb-induced neurotoxicity rather than early brain injury.pg1p07@soton.ac.uk

Peri-mesencephalic subarachnoid haemorrhage (PMSAH) is considered to be a clinically benign subset of subarachnoid haemorrhage (SAH). Cranial nerve palsies have been previously reported as rare sequelae of PMSAH. Herein, we report an unusual case of multiple cranial nerve palsies as a presenting feature of PMSAH and a review of the literature for cranial nerve palsies post-PMSAH. A 60-year-old gentleman was admitted with a sudden onset headache, bilateral oculomotor nerve, and unilateral abducens nerve palsies. CT demonstrated PMSAH, and angiography excluded a structural cause. On longer-term follow-up, he had persistent left-sided oculomotor nerve palsy. To the best of our knowledge, this is the first report of multiple cranial nerve palsies as a presenting feature of PMSAH and demonstrates the possibility of persistent neurological deficit following PMSAH.

ObjectiveAfter aneurysmal subarachnoid haemorrhage (aSAH), extracellular haemoglobin (Hb) in the subarachnoid space is bound by haptoglobin, neutralising Hb toxicity and helping its clearance. Two exons in the HP gene (encoding haptoglobin) exhibit copy number variation (CNV), giving rise to HP1 and HP2 alleles, which influence haptoglobin expression level and possibly haptoglobin function. We hypothesised that the HP CNV associates with long-term outcome beyond the first year after aSAH.MethodsThe HP CNV was typed using quantitative PCR in 1299 aSAH survivors in the Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study, a retrospective multicentre cohort study with a median follow-up of 18 months. To investigate mediation of the HP CNV effect by haptoglobin expression level, as opposed to functional differences, we used rs2000999, a single nucleotide polymorphism associated with haptoglobin expression independent of the HP CNV. Outcome was assessed using modified Rankin and Glasgow Outcome Scores. SAH volume was dichotomised on the Fisher grade. Haemoglobin-haptoglobin complexes were measured in cerebrospinal fluid (CSF) of 44 patients with aSAH and related to the HP CNV.ResultsThe HP2 allele associated with a favourable long-term outcome after high-volume but not low-volume aSAH (multivariable logistic regression). However rs2000999 did not predict outcome. The HP2 allele associated with lower CSF haemoglobin-haptoglobin complex levels. The CSF Hb concentration after high-volume and low-volume aSAH was, respectively, higher and lower than the Hb-binding capacity of CSF haptoglobin.ConclusionThe HP2 allele carries a favourable long-term prognosis after high-volume aSAH. Haptoglobin and the Hb clearance pathway are therapeutic targets after aSAH.

The work presented in this paper is focused on the use of spectroscopy to identify the type of tissue of human brain samples employing support vector machine classifiers. Two different spectrometers were used to acquire infrared spectroscopic signatures in the wavenumber range between 1200–3500 cm−1. An extensive analysis was performed to find the optimal configuration for a support vector machine classifier and determine the most relevant regions of the spectra for this particular application. The results demonstrate that the developed algorithm is robust enough to classify the infrared spectroscopic data of human brain tissue at three different discrimination levels.

Spontaneous intraorbital hematoma is an uncommon clinical entity seen in ophthalmology practice. It is poorly represented in the literature. Current evidence attributes it to orbital trauma, neoplasm, vascular malformations, acute sinusitis, and systemic abnormalities. A 65-year-old female presented with spontaneous intraorbital hematoma manifesting as severe ocular pains, eyelid edema, proptosis, and diplopia, without a history of trauma. Computer tomography demonstrated a fairly well defined extraconal lesion with opacification of the paranasal sinuses. The principal differential based on all findings was that of a spreading sinus infection and an extraconal tumor. An unprecedented finding of a spontaneous orbital hematoma was discovered when the patient was taken to theater. We discuss the rarity of this condition and its management.

In a trial that compared a 2-week course of dexamethasone with placebo in patients with a chronic subdural hematoma, a favorable outcome on the modified Rankin scale at 6 months was more common in the placebo group than in the dexamethasone group, but repeat surgery to evacuate a hematoma was performed more frequently in the placebo group.