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Brain swelling, raised intracranial pressure and hypoxia-related brain injury
Published in Helen Whitwell, Christopher Milroy, Daniel du Plessis, Forensic Neuropathology, 2021
Appreciable brain swelling due to post-cardiac arrest hypoxic-ischaemic injury mandates a period of survival. Computerised tomography (CT) imaging may demonstrate sulcal effacement as soon as 20 minutes after restitution of spontaneous circulation in survivors of out-of-hospital cardiac arrest (Inamasu et al. 2010). Diffuse brain oedema early after cardiac arrest is often associated with poor neurology and outcome. The mechanisms of cardiac arrest-induced cerebral oedema are likely multifactorial with a possible significant role for the perivascular pool of aquaporin 4 (AQP4), which is rate limiting for water influx during cerebral oedema formation.
Cranial Neuropathies II, III, IV, and VI
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Tanyatuth Padungkiatsagul, Heather E. Moss
Inflammation can affect the optic nerve itself or the surrounding nerves, in which case it is called perineuritis. Optic neuritis is the most common cause of inflammatory optic neuropathy, typically causing acute, unilateral vision loss with retrobulbar pain that is worse during eye movement. This used to be categorized as demyelination (associated with multiple sclerosis [MS]) or idiopathic. However, during the past two decades, identification of novel immunologic markers, specifically anti-aquaporin-4-IgG (AQP4-IgG), associated with neuromyelitis optica spectrum disorder (NMOSD), and anti-myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) have expanded the classification.
Neuropathology
Published in Burkhard Madea, Asphyxiation, Suffocation,and Neck Pressure Deaths, 2020
Wolfgang Keil, Claire Delbridge
Oedema develops as a result of the rapid drop in oxidative metabolism in the neurons, the glia, the endothelial cells of the blood vessels and the choroid plexus. The abrupt lack of energy leads to the breakdown of homeostatic conditions. In the acute hypoxic−ischaemic phase, the ion pump of the neuroglia and neurons, in particular the activity of the Na+/K+−ATPase, quickly comes to a standstill. As a result, the Na+ concentration increases intracellularly and the K+ concentration decreases. The resulting membrane depolarization leads to Cl− influx into the cells. Due to osmosis, water reaches the intracellular space and the cells swell. The glial cells in particular absorb water in order to compensate for the intracellular increase in osmolarity. Aquaporin-4 obviously plays a role as a mediator. This intracellular oedema, called cytotoxic oedema, occurs first. The subsequent collapse of the blood−brain barrier causes the formation of vasogenic oedema. As a result, proteins are transported extravasally and draw water into the interstitial space through osmosis. As a result, the volume of the interstitial space increases [2, 4, 5].
Emerging drugs for the acute treatment of relapses in adult neuromyelitis optica spectrum disorder patients
Published in Expert Opinion on Emerging Drugs, 2022
Edgar Carnero Contentti, Pablo A. López, Juan I. Rojas
Neuromyelitis optica spectrum disorders (NMOSD) are rare but often devastating neuroinflammatory autoimmune diseases of the central nervous system (CNS) associated to pathogenic serum aquaporin-4 antibodies (AQP4-Ab) in the majority of patients [1,2]. NMOSD is characterized mainly by severe relapses of optic neuritis (ON), transverse myelitis (TM), brainstem and/or cerebral syndromes [3]. Phenotypically, 90% of NMOSD patients experience a relapsing course over time, while a progressive clinical course is uncommon [1–3]. Neurologic disability typically accumulates with each clinical relapse, resulting in short- and long-term impairment of motor and/or visual functions, as well as affecting other organ systems [1–4]. In this regard, 41% of patients remain blind in one eye after an ON, 17% severely paralyzed (bedridden) following a TM relapse and 25% remain significantly disabled (cane dependent) [5]. Importantly, NMOSD relapses have been associated with mortality when primary relapses involve the brainstem or cervical lesions extend and include the medulla, ultimately increasing the risk of respiratory failure, particularly in patients with African ancestry [6]. Long-term outcomes from relapses were strongly associated with the severity of the attack at disease onset, regardless of acute treatment timing [7,8] and the initial onset attack [5]. Thus, severity of the relapses before an initial treatment was an independent predictor for subsequent relapses after adjusting treatments [5,9].
CBF regulation in hypertension and Alzheimer’s disease
Published in Clinical and Experimental Hypertension, 2020
Noushin Yazdani, Mark S. Kindy, Saeid Taheri
Astrocytes, similar to pericytes, because of their unique anatomical position, are important in CBF autoregulation as well as in NVC. Astrocyte end-feet tightly ensheath the abluminal side of the capillaries. This enabled them to directly translate the neuronal activity to pericytes and VSMCs (20,35). There are some grounds for assuming that in response to neuronal activity, the calcium-dependent release of vasoactive substances by astrocytes results in arteriole dilation and CBF increase (mechanisms reviewed in (36)). However, astrocyte’s role in CBF autoregulation is not limited to induce vasoactivity of their adjacent vessels. Astrocytes are also capable to establish remote communications with VSMCs at further upstream of a cerebrovascular tree, as it is shown especially in pial arterioles (37). This ability puts astrocytes in a unique position in comprehensive CBF regulation. Important to note is that astrocytes also control the hydrostatic pressure of vessels extraluminal space to modulate vasoactivity. This happens by modulation of aquaporin-4 (AQP-4) located at the endfeet of pericapillary astrocytes that regulates pericapillary water pressure. For example, reduction of pericapillary water pressure elicits a negative balance between pericapillary and intraluminal capillary pressure, allowing for capillary caliber expansion (38). Another hypothesis which also attracted attention postulates that astrocytes respond to glutamate released from activated neurons and release cytochrome P-450-derived epoxyeicosatrienoic acid that induces vasodilation (35).
Further understanding of epigenetic dysfunction of the retinal pigment epithelium in AMD
Published in Expert Review of Ophthalmology, 2020
Sonali Nashine, Maria Cristina Kenney
Hypoxia-induced upregulation and accumulation of VEGF, iNOS (the inducible form of nitric oxide synthase), and NO (nitric oxide) contribute to retinal vascularization, pathological angiogenesis, and subsequent retinal damage in AMD. VEGF mRNA transcript and VEGF-A protein are upregulated in AMD RPE cells compared to normal control cells in vitro [11]. Upregulation of VEGF in AMD largely relies on the binding of HIF-1α to the HBS in the VEGF gene promoter. Aquaporin-4 (AQP4) which is a predominant integral membrane water channel protein in the retina, affects the physical interaction between HIF-1α and the HBS in the VEGF promoter. Absence of AQP4 prevents VEGF upregulation by hindering the hypoxia-induced HBS demethylation process [17]. Moreover, DAC-mediated demethylation results in the downregulation of VEGF thereby bringing the VEGF level back to normal in human RPE cells and human retinal endothelial cells [11,18]. Treatment of AMD RPE cells with Trichostatin-A (TSA), an HDAC inhibitor, significantly reduces the levels of VEGF-A and HIF-α proteins compared to their untreated counterparts. TSA-induced anti-angiogenic effects are mediated via downregulation of VEGF and HIF-1α under hypoxic conditions both in vitro and in vivo [19].