Eclampsia pathophysiology On the Web
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Eclampsia is severe form of pre-eclampsia and all the changes that happen in pre-eclampsia are further intensified. It is associated with abnormal or defective spiral artery remodelling, that is, high-resistance, low-flow blood vessels are unable to convert to low-resistance, high-flow blood vessels, hypoperfusion of the fetoplacental unit, and chronic placental ischemia which result in oxidative stress and formation of reactive oxygen species. There is an imbalance between vasodilator agents such as prostaglandins and nitric oxide and vasoconstrictor agents such as thromboxane-II (TXA-2) amd angiotensin II. Also there is increased production of endothelin-1 which also acts as a vasoconstrictor. Enhanced expression of antiangiogenic factors like sFlt-1 and soluble endoglin (sEng) are also responsible for deranged cell signalling and inhibition of VEGF and TGF-beta. The oxidative stress results in various organ system damages and can ultimately lead to cerebral edema, cerebral anoxia, cerebral autoregulation failure and excess of excitatory neurotransmitters, which can result in convulsions.
Anatomy and Physiology of placenta
The formation of the placenta commences with the development of trophoblast. After the fertilization of the ovum in the fallopian tubes, it travels towards the uterus and by the time it reaches the uterus it has already become a morula. The morula is still surrounded by the zona pellucida which prevents it from sticking to the walls of the tube. The zona pellucida disappears soon after the blastocyst reaches the uterine cavity. Now the cells lining the blastocyst constitute the trophoblast whose function is to invade the surrounding uterine tissues to provide nutrition to the developing blastocyst. When the trophoblast attaches to the endometrium, it is known as implantation, which begins on the sixth day after fertilization in humans. This process is additionally enhanced by the proteolytic enzymes produced by the trophoblast and the interaction between the receptors present uterine epithelium and L-selectin and integrins produced by the trophoblast cells. Hence, implantation is a result of mutual exchange between the endometrium of the uterine cavity and the trophoblastic cells surrounding the blastocyst.
After the implantation, the uterine endometrium is termed the Decidua. Once the implantation has occurred the stromal cells undergo a decidual reaction which consists of enlargement of the cells, vacuolisation and storage of glycogen and lipids.
- The area of the endometrium or decidua that is deep to the blastocyst, where the placenta is to be formed is inferred as decidua basalis. It consists of the terminally differentiated large stromal cells which encompass largely lipids and glycogen that acts as a source of nutrition for the embryo. It also comprises of maternal vascular cells and maternal blood cells inside and outside those vessels.
- This area is also known as the decidual plate and it is firmly united to the chorion.
- The stromal cells also produce a variety of humoral proteins such as insulin-like growth factor binding proteins and prolactin and its family proteins.
These consist of the fetal portion of the placenta. They are offshoots or very small finger-like processes, hence called the villi, from the surface of the trophoblast cells. Within the substance of these villi are fetal blood capillaries and fetal blood cells which arise from the extra-embryonic mesoderm. Since the trophoblast and the extra-embryonic mesoderm constitutes the chorion, these villi are also known as chorionic villi.
Originally the villi are formed all over the trophoblast and commence invading the surrounding decidua. Nevertheless gradually the villi related to the decidua capsularis degenerate and in contrast, those associated with the decidua basalis undergo further differentiation and substantial growth and helps form the placenta. This part is known as chorion fundosum. During the differentiation process, the trophoblast which is originally a single layer of cells multiplies into two distinct layers. The cells in the superficial layer, that is the layer which is in proximity with the decidua, lose their cell boundaries and mould into one consecutive layer of cytoplasm and several nuclei, known as the syncytiotrophoblast. The second layer cells, which rest on extra-embryonic mesoderm, however retain their cell walls and are known as the cytotrophoblast.
- The tissues of desidua basalis and chorion fundosum jointly form a disc-shaped structure called the placenta.
- Various septa start growing into the intervillous space from the maternal side and subdivide the placenta into 15-20 lobes known as the maternal cotyledons.
- Each lobe homes several anchoring villi and their branches. One such villus along with its branches constitute a fetal cotyledon.
- The maternal vessels empty into the intervillous space and the maternal blood circulates through the intervillous space and the fetal blood travels through the fetal blood vessels in the villi. At any given time, the maternal and fetal blood do not mix and all exchanges take place via the placental membrane or the placental barrier.
- The layers of the placental membrane(from the fetal side):
- The functions of the placenta include:
- The transport of water, electrolytes, oxygen, and nutrition from mother to the baby
- Excretion of waste products such as carbon dioxide, urea, etcetera produced by the fetus into the maternal blood
- Passage for the maternal IgG to reach the fetus and give immunity against some infections
- A barrier against many bacteria, certain viruses, and harmful substances
- Synthesis of several hormones such as oestrogen(estriol), progesterone, human chorionic gonadotropin (hCG), somatomammotropin (hCS)
- Spiral artery remodelling of the maternal blood vessels, one of the physiological changes of pregnancy, is a process that begins in the first few weeks of pregnancy and modifies the low-flow, high-resistant arteries to high-flow, low-resistance blood vessels which are capable of meeting the demands of the growing fetus.
- Spiral arteries develop from the radial arteries at the endometrial/myometrial border, and progressively remodel during the first 22 weeks of gestation. It correlates with extravillous trophoblast (EVT) invasion, which ultimately replaces the vascular endothelial cells and smooth muscle cells.
- It is also accompanied by fibrinoid deposition and loss of responsiveness to vasoconstrictors.
- The fetal trophoblast cells also synthesize a plethora of cytokines.
- All these changes result in increased blood flow to the intervillous spaces which ensures a proper supply of nutrition and oxygen for the growth of the fetus.
- Failure to properly remodel is a common feature seen in preeclampsia-eclampsia syndrome.
- Mechanisms responsible for the loss of vascular cells:
- Decidua-associated remodelling: Changes in the spiral artery structure before the arrival of the trophoblasts; may include, endothelial basophilia, vacuolation, and vessel dilation.
- The vascular effects of oestrogen: Stimulate nitric oxide synthesis, increase vessel permeability and endothelial cell proliferation via increased vascular endothelial growth factor (VEGF) release.
- Influence of progesterone: Enhanced recruitment of immune cells such as lymphocytes, macrophages and uterine natural killer cells to the endometrium, ability to up-regulate stromal cell chemokine expression.
- Trophoblast-dependent transformation: Cytotrophoblast stem cells differentiate along two pathways, Villous trophoblasts and Extravillous trophoblasts. Extravillous trophoblasts are responsible for spiral artery remodelling via various processes which could include: adherence, migration, dedifferentiation, medial necrosis and fibrinoid deposition, phagocytosis/autophagy and apoptosis. Although, the research on human spiral artery remodelling is insufficient due to unavailability of material at all phases of pregnancy it is known that spiral artery remodelling plays a central role in establishing and maintaining a normal pregnancy and failure for this remodelling to occur normally may result in preeclampsia among other pregnancy disorders.
- In pre-eclampsia there is an abnormal or defective invasion of the spiral arteries by trophoblast cells resulting in abnormal modelling of the fetal-maternal interface and hypoperfusion of the fetoplacental unit which in turn leads to chronic placental ischemia and oxidative stress.
- In normal pregnancy, following the remodelling and displacement of endothelial cells, the vascular system becomes refractory to the pressor agents such as Angiotensin-ΙΙ and there is increased production of vasodilator agents such as prostaglandin-12(PG12), nitric oxide(NO) but in preeclampsia, there is an imbalance of the components of prostaglandins. There is a deficiency of PG12 and increased synthesis of thromboxane-A2 (TXA2), a potent vasoconstrictor from the platelets.
- In normal pregnancy, Angiotensin-ΙΙ is destroyed by angiotensinase produced by the placenta, but in preeclampsia, the angiotensinase activity is decreased following its excretion in urine via proteinuria.
- There is a deficiency of nitric oxide, a significant vasodilator, which is normally synthesised from L-arginine in the vascular endothelium and syncytiotrophoblast. It normally relaxes smooth muscles, inhibits platelet aggregation, and prevents inter-villous thrombi formation; but its deficiency leads to the development of hypertension.
- Increased synthesis of Endothelin-Ι, a potent vasoconstrictor, from endothelial cells also contribute to hypertension.
- Increased production of inflammatory mediators such as tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), among others, from activated WBCs further cause endothelial injury.
- Placental hypoventilation and decreased oxygen leads to abnormal lipid metabolism, which further results in oxidative stress. It leads to the production of superoxide radicals such as reactive oxygen species (ROS), lipid peroxides, superoxide anion radicals, which further enhance endothelial dysfunction.
- Oxidative stress induces the release of substances such as free radicals, oxidized lipids, cytokines, and serum soluble vascular endothelial growth factor-1 (VEGF1) into the maternal circulation.
- These abnormalities are responsible for endothelial dysfunction with vascular hyperpermeability, thrombophilia, and hypertension, to compensate for the decreased flow in the uterine arteries due to peripheral vasoconstriction.
- Role of Angiogenic and antiangiogenic factors: Several studies have suggested the role of increased expression of Anti-angiogenic factors, such as sFlt1 and soluble Endoglin in the pathogenesis of preeclampsia and eclampsia.  
- sFlt1(Soluble fms-like tyrosine kinase-1): sFlt1 is produced as a result of deranged splicing of Flt1(fms-like tyrosine kinase-1) protein. SFlt1 differs from Flt1 protein in way that it retains the extracellular ligand binding domain but looses of transmembrane as well as intracellular signalling domain. Flt1 is an endothelial receptor for VEGF (Vascular Endothelial Growth Factor) and PlGF (Placental Growth Factor), and is essential for intracellular angiogenic signals. With the increased production of sFlt1 it binds to and antagonizes VEGF and PlGF .
- Soluble Endoglin (sEng): Endoglin (CD150), a transmembrane glycoprotein in vascular endothelium, is a cell surface receptor for transforming growth factor-beta (TGF-β) and plays a key role in angiogenesis. Soluble Endoglin is a deranged and truncated form of endoglin and when it binds to TGF-β, it antagonising its action and alters the cell signalling pathway.
- Hence, the secretion of Sflt1 and sEng antagonises VEGF and TGF-β1 signalling. Under normal circumstances, VEGF/PlGF and TFG-β1 are accountable for protecting endothelial health via their interaction with various receptors. But their inhibition ultimately results in endothelial cell dysfunction, declined NO production, reduced prostacyclin generation, and heightened procoagulant elements.  All these elements contribute to the various symptoms of preeclampsia and eclampsia.
Various mechanisms behind the convulsions in eclampsia
Several factors that cause cerebral irritation can provoke cerebral convulsion, and include:
- Cerebral edema:        Cerebral edema is a key characteristic of eclampsia, as numerous clinical measures such as CT findings, MRI findings, post-mortem etc have exhibited varying extents of edema and vasculopathy. Although both cytotoxic and vasogenic causes have been suggested, the reversibility of neurological symptoms and radiological lesions within few days to weeks postpartum points towards vasogenic edema. The increase in the extracellular space as a consequence of oedema takes up room within the closed cavity of the skull and results in progressive brain compression and the symptoms of eclampsia such as nausea, vomiting, headache, cortical blindness, and seizures.  
- Cerebrovascular autoregulation failure:   In a normotensive adult, if cerebral perfusion pressure is in the range of 60 to 150 mmHg, the Cerebral Blood Flow (CBF) is maintained at nearly 50 mL per 100 g of brain tissue per minute. Above 150 mmHg and below 60 mmHg, the autoregulation of blood flow is lost and a linear relationship between Cerebral Blood Flow (CBF) and Mean Arterial Pressure (MAP) begins. Above the autoregulation limit, the myogenic vasoconstriction of the blood vessels is overpowered by the increased intravascular pressure, resulting in forceful cerebral vessel dilation. This results in excessive cerebral blood flow, significant Blood-Brain Barrier destruction and vasogenic edema formation which contributes to eclampsia.   
- Cerebral anoxia
- Cerebral dysrhythmia: The numerous inflammatory cytokines and vasoconstrictor elements released as a result of uteroplacental ischemia can cause the stimulation of excitatory neuronal receptors and result in neuronal excitability and convulsions. 
- Excitatory neurotransmitters:  Preeclampsia is associated with the upregulation of a large number of proinflammatory cytokines in the blood, most notably tumor necrosis factor-alpha (TNF-α). Dissimilar to most cytokines, which do not easily traverse into the brain, circulating TNF-α can cross the Blood-Brain Barrier via receptor-mediated endocytosis. TNF-α then upregulates the expression of endothelial cell adhesion molecules such as E-selectin, VCAM-1, and ICAM-1 which facilitate the passage of White Blood cells into the brain. Leukocyte infiltration can trigger the microglia, which can then produce more TNF-α. TNF-α production in the brain can both decreases the seizure threshold and induce seizure itself via impacts on AMPA and GABA receptors.
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