Ring Hemorrhages Research Articles

Malaria and hypertension. Another co-evolutionary adaptation?

Arterial hypertension is a complex multifactorial disease and a global public health concern. It is responsible for at least 45% of deaths due to heart disease and 51% of deaths due to stroke, adding up the tremendous number of 9.4 million deaths every year (Lim et al., 2012; World Health Organization, 2013). The renin-angiotensin-aldosterone system (RAAS) is one of the most important regulatory systems of blood volume, arterial pressure and cardiovascular homeostasis. Angiotensin II (Ang II) is the principal effector hormone of the RAAS in vascular biology, mediating effects via two main receptors: Angiotensin receptor type 1 (AT1) and type 2 (AT2) (Callera et al., 2007). When Ang II binds to AT1 on vascular smooth muscle cells, it mobilizes intracellular Ca2+, leading to cellular contraction. Sustained cellular contraction increases peripheral vascular resistance, resulting in high blood pressure (Touyz and Schiffrin, 2000). Among others, genetic factors are closely related with the development of hypertension. People with African American and South Asian genetic background have higher prevalence of hypertension compared to Caucasians, independently of their socioeconomic status (Cappuccio, 1997; Sampson et al., 2014). These differences in the ethnic background can increase the prevalence of hypertension by 2 fold until the age of 55, when the differences decline, presumably because of the interfering effect of age-related factors (Wolz et al., 2000). Several polymorphisms have been associated with higher prevalence of arterial hypertension; there are 2 polymorphisms in the Angiotensin Converting Enzyme (ACE) and Angiotensin Converting Enzyme 2 (ACE2) that lead to elevate circulating Ang II levels (Giner et al., 2000; Di Pasquale et al., 2004; Fan et al., 2007). Interestingly, these same genetic variations (the “D” allele of ACE I/D polymorphism and the ACE2 C→T substitution) have been associated with a lower incidence of cerebral malaria (CM) in Indian adults, although the later one only in women (Dhangadamajhi et al., 2010). Malaria is still a major public health problem world wide, causing approximately 600,000 deaths, mostly among African children (World Health Organization, 2012a). A high proportion of these deaths are caused by CM, a syndrome characterized by impaired consciousness, generalized convulsions, coma and neurological sequelae (Idro et al., 2005). CM is caused by the interaction between Plasmodium falciparum infected erythrocytes and host brain endothelial cells. Parasite proteins that are expressed on the surface of infected erythrocytes (PfEMP1), interact with host endothelial cell receptors (Protein C receptor, ICAM1; Newbold et al., 1997; Turner et al., 2013) leading to their sequestration within the brain microcirculation. Disruption of the blood-brain barrier is observed producing the characteristic petechiae and ring hemorrhages found on the brain of dead patients with CM (Rasti et al., 2004). Although it is still not well-established that Ang II has beneficial effects onmalaria and particularly on CM, different lines of evidence suggest a possible ‘protective’ effect that could be mediated by different, non-exclusive mechanisms that could affect parasite development and/or host susceptibility to Plasmodium-induced pathology. Recent reports have shown that angiotensin peptides can induce impairment of the erythrocytic cycle of Plasmodium, reducing the parasite growth in vitro (Maciel et al., 2008; Saraiva et al., 2011). Since the development of CM depends on the initial levels of parasitemia in mice (Amani et al., 1998) and possibly in humans (Bejon et al., 2005), this could be a potential explanation for Ang II protection from CM. Our unpublished results using mice infected with Plasmodium berghei seem to confirm that the elevation of Ang II levels results in modestly decreased parasitemias in this animal model. It is possible that Ang II could modulate malaria severity through additional mechanisms, specially, since the inhibitory effect observed in parasite growth is modest (Maciel et al., 2008; Saraiva et al., 2011). Sodium conservation could provide an alternative explanation to the protective effect of the polymorphisms associated with higher levels of Ang II. In this case, Ang II could be acting to counterbalance hyponatremia by stimulating the secretion of aldosterone from the adrenal cortex, the major regulator of Na+ reabsorption. Hyponatremia (serum sodium < 135mmol/L) is frequent in malaria patients and correlates with disease severity in imported malaria (van Wolfswinkel et al., 2010). However, other studies have shown that circulating Na+

The systemic pathology of cerebral malaria in African children.

Pediatric cerebral malaria carries a high mortality rate in sub-Saharan Africa. We present our systematic analysis of the descriptive and quantitative histopathology of all organs sampled from a series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi on pediatric cerebral malaria patients and control patients (without coma, or without malaria infection) who were clinically well characterized prior to death. We found brain swelling in all cerebral malaria patients and the majority of controls. The histopathology in patients with sequestration of parasites in the brain demonstrated two patterns: (a) the “classic” appearance (i.e., ring hemorrhages, dense sequestration, and extra-erythrocytic pigment) which was associated with evidence of systemic activation of coagulation and (b) the “sequestration only” appearance associated with shorter duration of illness and higher total burden of parasites in all organs including the spleen. Sequestration of parasites was most intense in the gastrointestinal tract in all parasitemic patients (those with cerebral malarial and those without).

Hemozoin impairs cell cycle progression and promotes chemokine release in human microvascular endothelial cells

Background Cerebral malaria (CM) is a fatal complication of P. falciparum infection caused by the cytoadherence of infected erythrocytes to brain endothelial cells followed by microcirculatory obstruction, blood-brain barrier (BBB) damage, ring hemorrhages, inflammatory response and neurological sequelae. The combination of both parasite and host factors are involved in the pathogenesis of CM. In particular, malarial pigment, hemozoin (HZ) was shown to interfere with monocytes and endothelial cell functions. Recently our group demonstrated that HZ enhanced total gelatinolytic activity in endothelial cells by inducing ex novo matrix metalloproteinases-9 (MMP9) and promoting proMMP-9 protein expression (Prato et al., 2011).

The Neuropathology of Fatal Cerebral Malaria in Malawian Children

We examined the brains of 50 Malawian children who satisfied the clinical definition of cerebral malaria (CM) during life; 37 children had sequestration of infected red blood cells (iRBCs) and no other cause of death, and 13 had a nonmalarial cause of death with no cerebral sequestration. For comparison, 18 patients with coma and no parasitemia were included. We subdivided the 37 CM cases into two groups based on the cerebral microvasculature pathology: iRBC sequestration only (CM1) or sequestration with intravascular and perivascular pathology (CM2). We characterized and quantified the axonal and myelin damage, blood-brain barrier (BBB) disruption, and cellular immune responses and correlated these changes with iRBC sequestration and microvascular pathology. Axonal and myelin damage was associated with ring hemorrhages and vascular thrombosis in the cerebral and cerebellar white matter and brainstem of the CM2 cases. Diffuse axonal and myelin damage were present in CM1 and CM2 cases in areas of prominent iRBC sequestration. Disruption of the BBB was associated with ring hemorrhages and vascular thrombosis in CM2 cases and with sequestration in both CM1 and CM2 groups. Monocytes with phagocytosed hemozoin accumulated within microvessels containing iRBCs in CM2 cases but were not present in the adjacent neuropil. These findings are consistent with a link between iRBC sequestration and intravascular and perivascular pathology in fatal pediatric CM, resulting in myelin damage, axonal injury, and breakdown of the BBB.

Stroke in central nervous system infections

Stroke subtypes and etiology may differ between developing and developed countries. Infections are a relatively common cause of stroke in tropical regions. To review the main infectious diseases associated with stroke. Prevalence of stroke in HIV patients is around 1%. Pathogenic mechanisms include HIV vasculopathy, vasculitis, cardioembolism, acquired hypercoagulability, and the effect of opportunistic infections. Treatment with protease inhibitors has been associated with premature atherosclerotic vascular disease. Emerging viral infections that are associated with stroke include viral hemorrhagic fevers, Japanese encephalitis, dengue, and West Nile virus. Vasculitis involving perforating vessels of the brain is a cerebrovascular complication of tuberculous meningitis. Small, medium, and large arteries of the anterior circulation can be involved. A progressive intracranial arteriopathy afterLeptospira interrogansinfection has been described, which involves the large intracranial arteries. Cerebrovascular complications of mycosis are associated with large vessel vasculitis, direct vessel damage by invasion or embolization, and subarachnoid hemorrhage due to mycotic aneurysm rupture. Pathological findings of cerebral malaria include diffuse cerebral edema, perivascular ring hemorrhages, white matter necrosis, parenchyma petechial hemorrhages, occlusion of brain vessels, and sequestration of infected erythrocytes in cortical and perforating arteries. Stroke can occur in subarachnoid neurocysticercosis and the lesions in such cases consist mostly of deep lacunar infarctions resulting from endarteritis of small penetrating arteries. Cardiac arrhythmias, congestive heart failure, apical aneurysm, and mural thrombus are the conditions that predispose patients with American trypanosomiasis to cardioembolism. Gnathostoma spinigerum infestation is a cause of hemorrhagic stroke in Asia. Infectious and tropical diseases should be included in the differential diagnoses of stroke.

West Nile Flavivirus Polioencephalomyelitis in a Harbor Seal (Phoca vitulina)

A 12-year-old male harbor seal presented with progressive signs of neurologic dysfunction including head tremors, muzzle twitching, clonic spasms, and weakness. Lesions included polioencephalomyelitis with glial nodules, spheroids, neuronophagia, ring hemorrhages, and a few neutrophils. Neurons, fibers, and glial nodules were multifocally colonized with intracytoplasmic West Nile flavivirus antigens that were demonstrated using indirect immunohistochemical analysis. Flavivirus on cultured cells also was isolated and was identified by use of monoclonal antibodies and reverse transcriptase-polymerase chain reaction analysis. Clinical signs of disease and lesion morphology and distribution were similar to those of equine West Nile virus infection. Similar to horses, alpacas, humans, dogs, and reptiles, seals can be dead-end hosts of West Nile virus.

Accumulation of endostatin/collagenXVIII in brains of patients who died with cerebral malaria

Endostatin is a 20 kDa C-terminal fragment of collagenXVIII that, when added exogenously, inhibits angiogenesis by inducing apoptosis of endothelial cells. In cerebral malaria (CM), blood–brain barrier dysfunction is a hallmark alteration in the formation of edema, inflammation, hemorrhage and Dürck's granulomas that are thought to represent the histopathological basis of neurological impairments observed in CM patients. We now analyzed endostatin/collagenXVIII expression in brains of seven patients who died with CM and in seven control patients by immunohistochemistry double-labeling experiments. Endostatin/collagenXVIII immunoreactive macrophages/microglial cells accumulated predominantly in Dürck's granulomas. Some immunoreactivity was observed in macrophages located in cerebral capillaries with deposition of malarial pigment and sequestration, but almost no immunoreactivity was detected in ring hemorrhages. Focal accumulation of endostatin/collagenXVIII in granulomas but not in ring hemorrhages of CM brains suggests a novel process that is involved in the destruction of endothelial cells at the time of Dürck's granuloma formation.

Differential cellular accumulation of transforming growth factor-beta1, -beta2, and -beta3 in brains of patients who died with cerebral malaria.

In cerebral malaria (CM), pathologic cytokine expression patterns are thought to contribute to disruption of the blood-brain barrier, inflammation, and astrocytic scar formation. Expression of transforming growth factor (TGF)-beta1, -beta2, and -beta3 was analyzed in the brains of 7 patients who died with CM and in 8 control patients. In the brains of patients with CM, there were significantly (P=.0003) more TGF-beta1-immunoreactive astrocytes adjacent to brain vessels with deposition of malarial pigment, significantly (P=.0081) more TGF-beta2-expressing macrophages/microglial cells in glioses of ring hemorrhages and Dürck's granulomas, and significantly (P=.0022) more TGF-beta3-expressing smooth-muscle cells and endothelial cells of brain vessels with sequestration. It is concluded that focal accumulation of TGF-beta1, -beta2, and -beta3 provides evidence for their involvement in the reorganization process of the brain parenchyma, immunologic dysfunction, and endothelial cell activation in patients with CM.

Differential Cellular Accumulation of Transforming Growth Factor–β1, –β2, and –β3 in Brains of Patients Who Died of Cerebral Malaria

In cerebral malaria (CM), pathologic cytokine expression patterns are thought to contribute to disruption of the blood-brain barrier, inflammation, and astrocytic scar formation. Expression of transforming growth factor (TGF)-β1, -β2, and -β3 was analyzed in the brains of 7 patients who died with CM and in 8 control patients. In the brains of patients with CM, there were significantly (P = .0003) more TGF-β1-immunoreactive astrocytes adjacent to brain vessels with deposition of malarial pigment, significantly (P = .0081) more TGF-β2-expressing macrophages/microglial cells in glioses of ring hemorrhages and Dürck's granulomas, and significantly (P= .0022) more TGF-β3-expressing smooth-muscle cells and endothelial cells of brain vessels with sequestration. It is concluded that focal accumulation of TGF-β1, -β2, and -β3 provides evidence for their involvement in the reorganization process of the brain parenchyma, immunologic dysfunction, and endothelial cell activation in patients with CM.

Cerebral malaria.

Malaria infection of the Central Nervous System (CNS) can cause a severe neurological syndrome termed Cerebral Malaria (CM). The central neuropathological feature of CM is the preferential sequestration of parasitised red blood cells (PRBC) in the cerebral microvasculature. The level of sequestration is related to the incidence of cerebral symptoms in severe malaria. Other neuropathological features of CM include petechial hemorrhages in the brain parenchyma, ring hemorrhages and Dürck's granuloma's. Immunohisto-chemical and electron microscopy studies have shown widespread cerebral endothelial cell activation and morphological changes occur in CM, as well as focal endothelial cell damage and necrosis. The immune cell response to intravascular sequestration appears to be limited, although activation of pigment-phagocytosing monocytes is a late feature. The mechanisms by which PRBC cause coma in malaria remain unclear. In vitro parasitised erythrocytes bind to endothelial cells by specific, receptor mediated interactions with host adhesion molecules such as ICAM-1, whose expression on cerebral endothelial cells is increased during CM as part of a systemic endothelial activation. Induction of local neuro-active mediators such as nitric oxide and systemic cytokines like TNF alpha may be responsible for the rapidly reversible symptoms of the coma of CM. The recent cloning of the parasite ligand PfEMP-1, thought to mediate binding to host sequestration receptors, promises further insight into the relationship between patterns of sequestration and the incidence and pathogenesis of coma in cerebral malaria.

Pathology of falciparum malaria in Vietnam.

Autopsy samples from the brains of 20 patients who died of falciparum malaria were examined by light microscopy and by an immunohistologic method. Particular attention was paid to a comparison of the pathologic features of the white matter and the cortex. In the high-sequestration (greater than 50%) group (n = 8), the mean +/- SD percentage of cerebral microvessels that showed parasitized red blood cell (PRBC) sequestration was 71.2 +/- 8.1% in the cortex and 84.0 +/- 6.7% in the white matter. The difference in the PRBC sequestration rate between cortex and white matter was statistically significant (P less than 0.01). Perivascular and ring hemorrhages were seen more frequently in the white matter than in the cortex. Deposition of IgG and Plasmodium falciparum antigen in the cerebral microvessels was more highly significant in the white matter than in the cortex (P less than 0.01). Our study demonstrated that the localized concentration of PRBC sequestration in the brain correlated with the marked immunohistologic differences in the microvessels of cortex and white matter.

Human cerebral malaria in Thailand: A clinico-pathological correlation

Based on the cerebral malaria coma scale, 39 falciparum malaria autopsy cases from the Hospital for Tropical Diseases, Mahidol University, Bangkok, Thailand were divided into two groups of patients that had either cerebral malaria or non-cerebral malaria. We then studied significant pathological differences, such as parasitized erythrocyte (PRBC) sequestration, ring hemorrhages and cerebral edema, between these two groups in order to investigate the correlation between the clinical coma scale and pathological findings. Patients with a coma grade of 2 and higher were designated as having cerebral malaria, and had erythrocyte PRBC sequestration in cerebral microvessels. Ninety four percent (94%) of cerebral microvessels showed PRBC sequestration when quantitatively analyzed. On the other hand, only 13% of cerebral microvessels showed sequestration in non-cerebral malaria patients with a coma grade of 1 and lower, although some degree of PRBC sequestration was found in 50% of these patients. Our study, therefore, clearly demonstrated that the degree of the PRBC sequestration in cerebral microvessels appeared to correlate closely with the clinical coma scale.

Human cerebral malaria: a pathological study.

The following report using light and electron microscopic and immunological techniques is based on a series of 19 Burmese patients who died of cerebral malaria. The principal change was blockage of cerebral capillaries by Plasmodium falciparum-infected erythrocytes. Ring hemorrhages and segmental necrosis of cerebral capillaries were common. Cerebral edema was variable in these cases. Electron-dense knobs, 40 X 80 nm in size, which protruded from the membrane of infected erythrocytes, formed focal junctions between endothelial cells and erythrocytes. These junctions resulted in the entrapment of erythrocytes and caused blockage in the capillary lumen. Immunoperoxidase study revealed that P. falciparum antigens and IgG deposits in the capillary basement membrane. This implies that damage to the cerebral capillary could be related to immune mechanisms.

Human cerebral malaria: a pathological study

The following report using light and electron microscopic and immunological techniques is based on a series of 19 Burmese patients who died of cerebral malaria. The principal change was blockage of cerebral capillaries by Plasmodium !alcipal'um-infected erythrocytes. Ring hemorrhages and segmental necrosis of cerebral capillaries were common. Cerebral edema was variable in these cases. Electrondense knobs, 40 x 80 nm in size, which protruded from the membrane of infected erythrocytes, formed focaljunctions between endothelial cellsand erythrocytes. These junctions resulted in the entrapment of erythrocytes and caused blockage in the capillary lumen. Immunoperoxidase study revealed that P. falciparum antigens and IgG deposits in the capillary basement membrane. This implies that damage to the cerebral capillary could be related to immune mechanisms.

Experimental lead paint poisoning in nonhuman primates. III. Pathologic findings.

Necropsies were performed on 25 rhesus monkeys, three cebus monkeys and three baboons which had been fed leaded paint or lead acetate at various doses up to 666 days. The 31 test primates and six controls ranged in age from five days to about eight years. In addition, the brains of 13 subadult squirrel monkeys fed lead oxide and two controls were studied grossly and microscopically. Lead content of liver, kidney and brain correlated with clinical outcome and typical histologic changes. Neuropathologic lesions, most severe in the young, occurred in 28 of 43 test primates despite a paucity of neurological signs. Brain lesions were similar to those occurring in human lead encephalopathy and included degenerative and proliferative changes of small vessels, ring hemorrhages, edema, perivascular hyalin droplets, rosette-like deposits of proteinaceous exudates, focal loss of myelin, astrogliosis and necrosis of hippocampal neurons.

Morphology and morphogenesis of cerebral ring hemorrhages in anemic monkeys.

Cerebral ring hemorrhages were observed in four species of monkeys with various forms of anemia. The lesions resembled those described in humans with a variety of diseases, including pernicious anemia. The pale centers of most lesions were surrounded by rings of erythrocytes. Also observed were petechiae, pale foci without hemorrhage, and glial nodules. Ultrastructural study revealed that the pale cores were foci of degenerating neurites associated with infiltration of fibrin into the finest interstitial spaces. Leakage of firbinogen and erythrocytes apparently occurred from capillary sized vessels. A few of these were thrombosed, some were normal and some had only small fibrin thrombi in apparent apposition to damaged endothelial tight junctions. These findings suggest that a primary effect of anemia and other insults associated with ring hemorrhages is damage to tight junctions. Consequent fibrinous exudation clogs the interstitium and results in neuritic degeneration.

Cerebral Malaria

Neuropathologic examination of 19 fatal cases of cerebral malaria and a review of the literature showed that the epidemiologic, clinical, and pathologic features of this entity suggest consideration of cerebral malaria as a form of disseminated vasculomyelinopathy, a hyperegic reaction of the CNS to the antigenic challenge of Plasmodium falciparum infection. Experimental evidence also substantiates this view The initial event seems to be vasculopathy, with alteration of the endothelial permeability, followed by brain edema, perivascular infiltrates and ring hemorrhages, perivascular demyelination, and gliosis (malarial granuloma) in the late stages. This chain of events could be interrupted early in its course by corticosteroids. Parenteral dexamethasone should then be seriously considered at the first signs of involvement of the CNS during P falciparum malaria along with the standard forms of antimalarial therapy.

Agonal nature of the cerebral ring hemorrhages.

CEREBRAL ring hemorrhages are seen in a variety of diseases, such as fat embolism, laceration of the brain, acute Plasmodium falciparum malaria, postvaccinial and parainfectious encephalitides, pernicious anemia, aplastic anemia and leukemia, and intoxications (barbiturates, neoarsphenamine, arsphenamine), as reviewed by Kirschbaum,1Dietrich,2Weimann,3Lindau,4Durck,5Wolff,6Winblad,7Sjovall,8and others. These hemorrhages may occur in such large numbers throughout the white matter that the hemorrhagic tendency is considered one of the important features of the disease process. This justifies the use of the term brain purpura (Schmidt9), acute hemorrhagic leucoencephalitis (Alexander and Putnam,10Hurst,11Henson and Russell12), and acute necrotizing hemorrhagic encephalopathy (Adams, Cammermeyer, and Denny-Brown13). The effusions of blood are thought to take place in diseases in which the nerves to the vessels have been paralyzed and stasis has thereby been furthered, with diapedesis hemorrhages, as

PETECHIAL HEMORRHAGES OF THE BRAIN

In a previous study 1 we investigated the nature of traumatic petechial hemorrhages in 11 human brains, the interval of survival after trauma varying from an unmeasurable period, designated for lack of a better term, perhaps improperly, as immediate death, to eight days. All brains, studied by careful histologic methods, showed perivascular petechiae. They were frequent about the arterioles. The different forms and states of petechiae, as well as their location in the brain substance, were described. A theory was advanced as to the formation of ring and ball hemorrhages from fresh petechiae. The data obtained led to the conclusion that multiple petechial hemorrhages are a characteristic finding in cases of severe concussion of the brain and are dependent on vasodilatation, vascular stasis (prestasis) and anoxemia, and that mild, reversible concussion effects on the parenchyma of the brain should be distinguished from severe, irreversible concussion effects. The possible relationship of