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Purpose To demonstrate the ability of widefield en face swept source optical coherence tomography (OCT) imaging to monitor peri-venular fern-like patterns of paracentral acute middle maculopathy (PAMM) associated with retinal arterial occlusions. Observations The peri-venular fern-like pattern of PAMM was diagnosed on the 12 × 12 mm en face structural OCT images from three patients. Fluorescein angiography images were unremarkable. Over time, all three patients demonstrated significant improvement in visual acuity with resolution of their peri-venular PAMM. Conclusions The peri-venular fern-like pattern of PAMM is usually associated with retinal vein occlusions, but we identified three cases with this pattern in eyes with presumed incomplete retinal arterial occlusions. Our cases support the ischemic cascade theory that begins within the deep capillary plexus and ascends in the retina depending on the severity of the ischemic event. Using the 12 × 12 mm en face structural OCT images, we are able to demonstrate a wider area of ischemia in PAMM compared with the traditional 6 × 6 mm scans.

Purpose To report a case of paracentral acute middle maculopathy (PAMM) and evidence of the ischemic cascade documented with spectral domain optical coherence tomography (SD-OCT) following radiation treatment of a choroidal melanoma. Observations A healthy young patient was evaluated for an asymptomatic choroidal nevus in the left eye. Fundus examination was remarkable for a choroidal melanocytic lesion that measured 1.8 mm in thickness by initial B-scan ultrasound. Clinical examination 6 months later showed growth of the tumor at several margins with new subretinal fluid, and a B-scan measured thickness of 1.9 mm. The lesion was diagnosed as a small choroidal melanoma and treated with gamma knife radiation with a dose of 3000 cGy. Sixteen months later, examination showed signs of radiation retinopathy including cotton wool spots and PAMM via SD-OCT and OCT angiography and evidence of the ischemic cascade i.e. alternating zones of middle and combined middle and inner retinal layer infarction. Conclusions and Importance: Radiation retinopathy can include signs of microvascular damage and ischemia including lesions such as cotton wool spots and PAMM. A case is presented in this report of radiation retinopathy with OCT evidence of PAMM and the ischemic cascade.

Ischemic stroke is one of the leading causes of adult disability and cognitive impairment worldwide. Thrombolysis has been a standard treatment for ischemic stroke. However, due to the short time-window for thrombolytic agent administration, most patients cannot benefit from rt-PA treatment by missing this therapeutic time-window. Neuroprotection aims to improve the survival of brain tissues by impeding the devastating ischemic cascade events. Even though the neuroprotectant can be applied in the acute, subacute, and chronic stages of ischemic stroke, their therapeutic efficiencies are compromised by the blood-brain barrier (BBB) that restricts brain drug uptake. Therefore, specifically increasing neuroprotectant delivery in brain ischemia will improve the treatment efficiency. In this chapter, we first introduce the dynamics of structure, permeability, and transcytosis of BBB after the onset of ischemic stroke. Temporarily increasing para-endothelial diffusion, taking advantage of the up-regulated intra-endothelial transcytosis, and attenuating the pro-inflammatory response are summarized as the key issues to increase drug delivery efficiency in the acute, subacute, and chronic stages, respectively. Finally, recent reported strategies facilitating brain delivery of neuroprotectants by overcoming the BBB via intra-endothelial transcytosis or para-endothelial diffusion are introduced. Overall, elucidating BBB dynamics after ischemic attack helps to design new drug delivery vectors to maximize neuroprotective response, but minimize the potential side effects induced by the vascular leakage. Up-regulating neuroprotectant uptake in brain ischemia will benefit majority of ischemic stroke patients who lost the chance for thrombolytic treatment.

Ischemic stroke is a sudden loss of brain function due to the reduction of blood flow. Brain tissues cease to function with subsequent activation of the ischemic cascade. Metabolomics and lipidomics are modern disciplines that characterize the metabolites and lipid components of a biological system, respectively. Because the pathogenesis of ischemic stroke is heterogeneous and multifactorial, it is crucial to establish comprehensive metabolomic and lipidomic approaches to elucidate these alterations in this disease. Fortunately, metabolomic and lipidomic studies have the distinct advantages of identifying tissue/mechanism-specific biomarkers, predicting treatment and clinical outcome, and improving our understanding of the pathophysiologic basis of disease states. Therefore, recent applications of these analytical approaches in the early diagnosis of ischemic stroke were discussed. In addition, the emerging roles of metabolomics and lipidomics on ischemic stroke were summarized, in order to gain new insights into the mechanisms underlying ischemic stroke and in the search for novel metabolite biomarkers and their related pathways.

Therapeutic hypothermia (TH) is a potent neuroprotective therapy in experimental cerebral ischemia, with multiple effects at several stages of the ischemic cascade. In animals, TH is so powerful that all preclinical stroke studies require strict temperature control. In humans, multiple clinical studies documented powerful protection with TH after accidental neonatal hypoxic-ischemic injury and global cerebral ischemia with return of spontaneous circulation after cardiac arrest. National and international guidelines recommend TH for selected survivors of global ischemia, with profound benefits seen. Recently, a study comparing target temperature 33-36°C failed to demonstrate significant effects in cardiac arrest patients. Additionally, clinical trials of TH for head trauma and stroke have so far failed to confirm benefit in humans despite a vast preclinical literature. Therefore, it is now critical to understand the fundamental explanation for the success of TH in some, but famously not all, clinical trials. TH in animals appears to work when used soon after ischemia onset; for a short duration; and at a deep target temperature.

Several neuroprotection strategies shown to be effective in animal models have failed to demonstrate efficacy in human stroke. The complexity of the molecular ischemic cascade is perhaps one of the most important reasons for this failure. Pharmaceutical approaches aimed at blocking individual molecular pathways have proved to be insufficient for the task. Pleiotropic drugs, on the other hand, acting at different levels of the ischemic cascade, seem to provide a more comprehensive attack based on the pathophysiology of cerebral ischemia. The mammalian target of rapamycin (mTOR) has emerged as a new potential therapeutic target. Based on its ability to modulate different processes of the ischemic cascade, mTOR may acquire the capability to limit ischemic neuronal death and promote neurological recovery. However, further knowledge about the intricate cellular signaling pathways of mTOR in cerebral ischemia is required in order to develop mTOR-reliant clinical strategies.

The brain consumes an enormous amount of energy (20%) that is disproportionate to its small size (2%). It relies on the constant delivery of oxygen and glucose to produce adenosine triphosphate, the cellular energy unit required to maintain brain cells’ functioning. Even brief loss of blood flow as a result of blockage or rupture of a cerebral blood vessel, called ischemia, leads to a sudden appearance of neurological symptoms. Stroke usually affects only one side of the brain, and the perfusion field of the affected blood vessel defines the specific pattern of sensory or motor symptoms produced. In a minority of patients (10%) blood flow is disrupted because of a vessel rupture, causing a hemorrhagic stroke. The vast majority of patients have vessel blockage as a consequence of atherosclerotic plaque, narrowing cerebral blood vessels, or distant plaque, giving rise to floating fragments called emboli that can lodge in cerebral blood vessels. The most effective treatment for stroke involves the rapid opening of an occluded vessel either mechanically or using tissue plasminogen activator (tPA), a clot-busting chemical. Time is of the essence because neurons die quickly in the absence of blood flow and tPA becomes almost ineffective 3 h after a stroke. The cellular and molecular processes underlying the ischemic cascade that culminates in neuronal cell death are well understood, particularly the importance of the excitatory neurotransmitter glutamate (Glu), which is elevated to toxic concentrations after stroke. Its binding to neuronal Glu receptors triggers a process called excitotoxicity, which causes rapid necrotic and slow apoptotic neuronal death. Approximately 800,000 new stroke cases are diagnosed annually in the United States and 200,000 patients die from it. In spite of excellent poststroke physical and occupational therapy, many of the 4 million stroke survivors live with permanent disability at a huge cost to the individual, their families, and society.

Publisher Summary schemic stroke is caused by a transient or permanent reduction of blood flow restricted to the territory of a cerebral artery by embolic or thrombotic occlusion. Ischemic stroke results in death and dysfunction of brain cells. However, not all brain cells die immediately after an ischemic stroke. Ischemic penumbra is a perilesional area surrounding the ischemic core. Cell death occurs by a necrotic pathway characterized by ischemic or edematous cell changes, by an apoptotic pathway with a number of morphological, biochemical, pharmacological, and molecular characteristics, or by autophagocytosis. Brain depends upon oxidative phosphorylation for energy. It is sensitive to disturbances in oxygen and glucose supply. Following focal ischemia there is a profound deprivation of oxygen and glucose. Oxidative stress is linked to excitotoxicity, energy loss, and ionic imbalances and all these events contribute to tissue damage. In addition to reactive free oxygen species, nitrosative stress contributes to tissue damage. Early after the onset of ischemia, the expression of proinflammatory genes is triggered. Loss of membrane integrity, cell swelling, and organelle failure are the features of cell death following brain ischemia. The chapter discusses the stroke-induced endogenous neuroprotection. The failure to develop clinically effective neuroprotective strategies for stroke relate to the inattention to white matter injury and the failure to ameliorate ischemic damage to white matter. Recent developments in molecular and cell biology, plus neuroimaging, are tools for better translation of discoveries.

Publisher Summary This chapter elaborates mechanisms of antiplatelet agents and the prevention of stroke. The role of antiplatelet agents in cerebrovascular disease (stroke) is that of treatment for its acute and chronic phase. Treatment for stroke is based upon diagnosis and stroke diagnosis is based upon pathology and pathogenesis. Antiplatelet agents may have a role in the treatment of acute cerebral infarction, with the aim of treatment being limitation of tissue damage through interruption of the final ischemic cascade. At the no reflow stage of brain ischemia, platelet and erythrocyte aggregation, polymorphonuclear leukocyte-endothelial adhesion, and in situ thrombosis may cause microvascular occlusion. The use of antiplatelet therapy is defined by the white clot-red clot paradigm. If the clinician can determine that a particular patient is at risk for formation of white thrombi, then antiplatelet therapy can rationally be chosen for prevention of its occurrence. Both red and white thrombus potential may coexist in the same individual, and the presence of red thrombi may predispose to white thrombus. Recombinant leech antiplatelet protein blocks platelet deposition on collagen surfaces under flow conditions. Such therapy may be far more advantageous than therapy aimed uniquely at inhibiting the red or white clot formation specifically. Attention to common dietary substances and their potential effect on thrombosis may help the antithrombosis campaign.