Pathophysiology of Main Clinical Syndromes in Diseases of the Nervous System PDF

MINISTRY OF HEALTHCARE OF THE REPUBLIC OF KAZAKHSTAN Np JSC «Astana Medical University» Tazhibayeva D.S., Kabdualiyeva N.B., Aitbayeva Zh.B., Suiindik K.B. PATHOPHYSIOLOGY OF MAIN CLINICAL SYNDROMES IN DISEASES OF THE NERVOUS SYSTEM Training manual for students Nur-Sultan 2021 UDC 616.8-092-02(075.8) LBC 52. 5я73 P 32 REVIEWERS: S.B.Zhautikova - Doctor of Medical Sciences, Professor, Head of the Department of Pathological Physiology named after Zh.A.Lazaris of the NpJSC "Karaganda Medical University". T.M.Omarov - Associate Professor of the Department of Pathological Anatomy of the NpJSC "Astana Medical University", Candidate of Medical Sciences. L.S.Kolyayeva- Senior teacher of English of the NpJSC "Astana Medical University", Master of Education Sciences. Authors: Tazhibayeva D.S., Kabdualieva N.B., Aitbaeva Zh.B, Suiindik K.B Р 32. Pathophysiology of main clinical syndromes in diseases of the nervous system. Тraining manual for students./ Tazhibayeva D.S., Kabdualieva N.B., Aitbaeva Zh.B. - Nur-Sultan, 2021.- 88 р. ISBN The training manual covers the issues of etiology and pathogenesis of the main clinical syndromes that occur in the pathology of the nervous system. The material on the pathophysiology of strokes, epilepsy and meningitis is presented. The manual contains a glossary, test items with a standard of answers, a list of recommended literature; illustrated with drawings, diagrams, and photos. The training manual is intended for students studying in institutions of higher professional education in the specialty 6В10107 "General Medicine". UDC 616.8-092-02(075.8) LBC 52. 5я73 Approved and recommended for publication by the Quality Assurance Committee of educational programs of NJSC “Astana Medical University” as additional educational literature. Protocol number ___from “ ”, 20 y. @ Tazhibayeva D.S., Kabdualieva N.B., Aitbaeva Zh.B., Suiindik K.B., 2021 ISBN CONTENT Chapters Pages List of abbreviations 3 Introduction 4 Glossary 5 Pathophysiology of cerebral 21 circulation Features of cerebral circulation 21 Pathophysiology of stroke 24 Pathophysiology of convulsive 56 syndrome. Epilepsy 58 Pathophysiology of the syndrome 69 of irritation of the meninges Conclusion 78 Test items 82 Standards of answers to the test 87 items References 88 LIST OF ABBREVIATIONS ACCD – acute cerebral circulatory disorder AH - arterial hypertension AP – arterial pressure ATP – adenosinetriphosphate AVM - arteriovenous malformation BBB – blood- brain barrier BC – brain circulation CCD – cerebral circulatory disorder CNS – central nervous system EEG – electroencephalogram GABA – gamma amino butyric acid GPIE – generator of the pathologically increased excitation HNA – Higher nervous activity HS – hemorrhagic stroke ICB – intracerebral bleeding IL – interleukins IS – ischemic stroke LPO – lipid peroxidation Nm – Neisseria meningitides, meningoccoccus ROS – reactive oxygen species TCCD – transient cerebral circulatory disorder TIA – transient ischemic attack TNF – tumor necrosis factor 3 INTRODUCTION Relevance. The importance of studying the pathophysiological foundations of neuropathology is primarily due to the high level of mortality, morbidity and disability of diseases of the nervous system. Thus, in the structure of the general morbidity of the population, the share of nervous diseases accounts for from 10 to 35%. Moreover, in recent decades, there has been a widespread increase in their incidence. This is due to the intensive influence of risk factors for the development of diseases of the nervous system on the population of the country: aging, arterial hypertension( AH), diabetes mellitus, inactivity, obesity, chronic stress, unfavorable environmental situation, increasing prevalence of infectious, viral and autoimmune diseases, etc. The main medical and social problem of neurology is cerebrovascular disease and strokes. Vascular diseases of the brain account for 18-20% of all diseases of the nervous system and occupy the 2nd place in the structure of total mortality, second only to cardiac pathology. Disability after acute cerebral circulatory disorders (ACCD), ranks 1st among all causes of primary disability. Another urgent problem is epilepsy and convulsive syndromes, which occupy the 3rd place in the structure of neurological morbidity (19.9%). The high frequency of epilepsy with a tendency to increase due to symptomatic forms, etiological, pathogenetic and clinical heterogeneity, as well as a significant percentage of socio-mental maladaptation and disability of patients (20%) determine the importance of studying the processes of formation of the epileptic and antiepileptic systems, understanding the mechanisms of seizures. Particular interest are also infectious lesions of the nervous system, the specific weight of which in the structure of neuropathology is about 40%. At the same time, meningitis and meningoencephalitis are the most common clinical forms of neuroinfectious diseases. Among the causes of death from infectious diseases, they occupy the 10th place and the 2nd (after AIDS) in the structure of mortality in infectious hospitals. These facts indicate the importance of studying the etiological and pathogenetic factors of meningococcal infection. Purpose: to present up-to-date data on the main causes, mechanisms of development and manifestations of acute and chronic disorders of cerebral circulation, convulsive syndrome, and irritation of the meninges. Tasks: 1. To describe the etiology and pathogenesis of ischemic and hemorrhagic strokes. 2. Present the material on the pathophysiology of convulsive syndromes and epilepsy. 3. To form general ideas about the causes and mechanisms of meningitis development. 4 GLOSSARY Theme: "Typical pathological processes in the nervous system" Trophogenes (from the Greek trophe - food) are macromolecular substances (mostly proteins) that are extracted from the axon endings and enter the synaptic cleft, from which they move to the innervated cell and carry out trophic effects therein. Trophogenes determine the functional properties of innervated cells, the features of metabolism and ultrastructure, the degree of their differentiation. Pathotrophogens (from the Greek pathos - disease, suffering + trophe - nutrition) – substances formed in conditions of pathology in cells, including nerves, and inducing stable pathological changes in recipient cells. Neurodystrophic process (from the Greek neuron - nerve + dys - disorder, frustration + trophe - nutrition) - a complex of trophic disorders in organs and tissues (including in the nervous system itself) that occurs as a result of the loss or violation of various nervous influences from the afferent, associative and efferent neurons (their bodies and processes) of the somatic and autonomous nervous system. The neurodystrophic process is manifested by changes in the functional activity of organs, deviations in their structure (atrophy, erosion, ulceration, malignancy). In a typical case, it develops with denervation syndrome. Denervation syndrome (from Latin de - absence, abolition, elimination + from the Greek neuron - nerve) - a set of changes that occur in postsynaptic neurons, organs and tissues after the loss of nerve influences on these structures. It is characteristic to increase the sensitivity of denervated structures to mediators, biologically active substances, and pharmacological agents. During denervation, the properties inherent in the early, in particular, embryonic stages of development appear in the tissues. This phenomenon occurs as a result of pathological disinhibition of normally suppressed genes. Denervation reduces the resistance of the denervated organ or tissue to damaging factors.. Spinal shock - transient inhibition of the reflex activity of the spinal cord below the level of trauma with complete loss of motor, sensitive and autonomic functions, development of flaccid paralysis, anesthesia, urinary retention and feces. The duration of spinal shock can range from a few weeks to several months. Pathological parabiosis (from the Greek para - near, near + bios- life) - the state of a stable, stationary, non-oscillating, localized at the place of its origin of excitation, leading to a disruption of conductivity in this or that nervous structure of the organism. The development of parabiosis is associated with the blockade of the sodium channels of the neuron membrane, accompanied by a partial or complete loss of the ability of the nervous structure to restore impaired functions. Generator of pathologically intensified excitation (GPIE) (from the Latin generator - producer) is an aggregate of hyperactive interacting neurons, producing an excessive and uncontrolled flow of impulses. A necessary condition for the formation and activity of the GPIE is the inadequacy of the 5 braking mechanisms in a certain group of neurons. GPIEs can be formed in all departments of the central nervous system. Neuron deafferentation (from Latin de - absence + afferentis - bringing) - stopping sensory impulses from the periphery to the center as a result of a violation of the anatomical or physiological integrity of the sensory nerves. With deafferentation, there is an increase in the excitability of neurons and disruption of the inhibitory mechanisms, so a group of neurons can acquire the properties of a GPIE. Hysteresis (from the Greek hystera - uterus) is a pathological state of sharply increased excitability in the central nervous system, caused by prolonged rhythmic stimulation of an afferent nerve. As a result, even a slight irritation of another sensitive nerve gives a generalized reaction. Hysteriasis can occur with tetanus, rabies, strychnine poisoning, etc. The pathological determinant (from Latin determino - I define) is the altered formation of the central nervous system, which becomes hyperactive as a result of the occurrence of GPIE. The pathological determinant is realized at the system level, is the principle and mechanism of intrasystemic relations. This is the most resistant part of the pathological system, which determines the leading pathogenetic changes in the body. Pathological dominant (from Latin dominans - dominant) is the functional structure of the central nervous system that dominates at the moment, directing the functions of other nerve centers through the weakening of their activity by "attracting" impulses addressed to them. The pathological dominant is the principle and mechanism of intersystem relations. Pathological system - a new integration (the pathodynamic organization) of neurons of primary and/or secondary altered formations of the central nervous system, which is caused by a pathological determinant caused by a variety of intense and/or long-acting pathogenic factors. The activity of the pathological system is clinically expressed as a neuropathological syndrome. Antisystems – regulatory mechanisms aimed at limiting development and suppressing the activity of pathological systems Examples: antinociceptive, antiepileptic and antiemotional antisystem. The pathological reflex (from Latin reflexus - turned back, inverted, reflected) is a reflex reaction limiting the adaptation of the organism to changes in the external and / or internal environment. Pathological reflexes are distinguished by strenght, inertness, can be formed on the basis of protective adaptive reflexes (vomiting, coughing, sneezing, diarrhea). In a clinic is used in the diagnosis of nervous diseases (for example, the reflex of Babinsky, the reflex Rassolimo, the pathological sucking reflex, etc.). Theme: "Pathophysiology of cerebral circulation. Strokes.» Autoregulation of cerebral blood flow is a phenomenon of the independence of blood flow through the brain from changes in systemic arterial pressure (BP) in the range from 50 to 180 mm Hg. due to the ability of the vessels to respond 6 to the increase in systemic BP - spasm, to decrease - by dilatation. Disruption of autoregulation is the most important link in the pathogenesis of acute and chronic disorders of cerebral hemodynamics. Cerebrovascular diseases (from Latin cerebrum - brain + vas - vessel) - a group of brain diseases caused by pathological changes in cerebral vessels that cause impaired cerebral circulation. Transitory disturbance of cerebral circulation (TDCC) - acute disorders of cerebral circulation, manifested by focal, cerebral or mixed symptoms and lasting not more than 24 hours. Usually, in the base is transient ischemia in the basin of a cerebral vessel. The most important criterion of TDCC is the complete reversibility of focal or diffuse neurologic symptoms within 24 hours. Transient ischemic attacks (TIA) (from Latin transire - to pass) is one of the forms of TDCC, representing transient episodes of neurological dysfunction caused by regional ischemia of brain tissue, spinal cord or retina, but not leading to the development of a myocardial infarction. The occurrence of repeated TIA can lead to the development of diffuse atrophic changes in the brain tissue. Stroke, insult (from the Latin insilio - to jump in, attack) - an acute disorder of cerebral circulation (ADCC), characterized by sudden (within a few minutes, hours) appearance of focal (motor, speech, sensory, coordination, visual and other disorders) and/or cerebral (changes in consciousness, headache, vomiting) of neurological symptoms that persists for more than 24 hours or leads to the patient's death in a shorter period of time due to cerebrovascular pathology. Threshold ischemic blood flow is a critically low level of cerebral blood flow, in which insufficient intake of oxygen and nutrient substrates in the brain leads to the development of local ischemia, up to a cerebral infarction. Irreversible damage to neurons and neuroglia cells occurs when the cerebral blood flow decreases to 10 ml / 100 g / min-1 or less. Ischemic stroke (cerebral infarction) (from Latin infarcire - stuffing) - a clinical syndrome, represented by focal and/or cerebral infringements, which develops suddenly due to the cessation of blood supply of a certain part of it as a result of occlusion of the arteries of the head or neck with the death of the brain tissue. The nuclear zone of ischemia in stroke ("core", "infarct nucleus") is the region of the brain with the most pronounced decrease in blood flow (less than 10 ml/100 g/min-1) and irreversible cell damage that develop within 6-8 minutes from the time of development acute disturbance of cerebral blood flow. This is the central zone of the stroke, the necrosis zone, which is surrounded by a potentially more viable zone of "ischemic penumbra" that is larger in volume. 7 Picture 1. A. Nuclear zone (Structural changes) B. Ischemic penumbra = mitochondrial dysfunction (functional changes) (Klocheva E.G. Application cytoflavin drug in Neurology - A Handbook for Physicians - St. Petersburg, 2008). Penumbra ("ischemic penumbra") (from Latin paene - almost + umbra - shadow) is the area of ischemic but viable brain tissue that surrounds the area of the infarcted nucleus. The blood supply in the penumbra is below the level necessary for normal functioning, but above the critical threshold of irreversible changes. In the penumbra region, energy metabolism is generally preserved and there are only functional but not structural changes. Diaschisis (from the Greek diaschisis - division, splitting) - a disturbance of the function of nerve structures located at a distance from the lesion, but related to it anatomically and functionally. As a result, the volume of the nonfunctioning part of the central nervous system significantly exceeds the size of the anatomical lesion. Hemorrhagic transformation of cerebral infarction is a secondary hemorrhage into necrotic tissue, which is considered as a complication of severe ischemic brain damage and is a marker of reperfusion of cerebral tissue. A special predisposition to hemorrhagic transformation has a cardioembolic stroke. Glutamate (from Latin glut - glue + from English ammonia - ammonia) - the main exciting neurotransmitter in the brain, is found in all departments of the central nervous system, stimulates postsynaptic receptors (NMDA, AMPA, kainate). In cerebral ischemia, a massive release of glutamate into the extracellular space occurs, which leads to the hyperactivation of glutamate receptors, especially NMDA. The consequence of this is an increased current of calcium into the cell and its death (excitotoxicity of glutamate). Exceeding the concentration of glutamate in the synapse more than 1 mM triggers the processes of apoptosis. Aspartate (from the Greek asparagos - asparagus) is an exciting neurotransmitter that stimulates NMDA receptors, although not as strongly as glutamate, and therefore has a weaker excitotoxicity. NMDAreceptors are ionotropic glutamate receptors that selectively bind N- methyl-D-aspartate (NMDA) and control calcium channels. NMDA-mediated hyperactivity is one of the important components of the pathogenesis of ischemic stroke. Excessive stimulation of the NMDA receptors in the beginning leads to a rapid sodium-dependent response with the development of the edema 8 of the cell, and then to a slow calcium-dependent response that causes delayed excitotoxic damage to the cell. Picture 2. NMDA-receptor (http://ru.wikipedia.org) Note: 1. The cell membrane. 2. The channel blockable magnesium Mg2 +. 3. Lock Site Mg2 +. 4. The binding site of hallucinogens. 5. The zinc binding site (Zn2 +). 6. The binding site agonist (glutamate) and \ or antagonists (APV). 7. The glycosylation sites. 8. The binding sites of protons. 9. glycine binding sites. 10. The binding site of polyamines. 11. Intracellular Extracellular space 12. The space. 13. subunit complex. AMPA receptors are ionotropic glutamate receptors that selectively bind alpha- amino-methyl-isoxazole-propionic acid (AMPA). The hyperactivation of AMPA receptors in the ischemic brain increases the incoming current of Na +, Cl-, H2O, causes osmotic swelling of cells and removes the magnesium block of NMDA receptors. As a result, there is a short-term depolarization of the postsynaptic membrane and an increase in the influx of Ca2+ into the cell through agonist- dependent channels (NMDA receptors). Excitotoxicity (from English to excite - to activate, activate) - the trigger mechanism of necrotic and apoptotic death of nerve cells under the influence of neurotransmitters capable of hyperactivating NMDA receptors and AMPA receptors. As a result of the hyperactivation of ionotropic glutamate receptors, ion channels are opened for calcium, sodium, and potassium. The toxicity of glutamate is a key link in the pathobiochemical cascade of cerebral ischemia. 9 Reperfusion (from Latin re - resumption + perfusio - pouring) - restore blood flow to organs or tissues that were previously devoid of blood supply. Reperfusion is one of the main directions of pathogenetic treatment of ischemic stroke, the purpose of which is to eliminate the obstruction to blood supply to brain tissue. Reperfusion methods: thrombolytic, anticoagulant, antiaggregant therapy; surgical methods - the application of microanastomoses, thrombectomy, reconstructive surgery on the arteries. Neuroprotection (from Latin protectio - protection) is one of the main directions of pathogenetic treatment of ischemic stroke, the purpose of which is to prevent the death of neurons affected by the damaging effect. Neuroprotective therapy is aimed at the main stages of ischemic brain damage. The main target of neuroprotection is penumbra. Primary neuroprotection is a complex of measures aimed at interrupting the earliest processes of the ischemic cascade, unfolding within the "therapeutic window" and underlying the rapid necrotic damage to brain tissue. Therapeutic effects, in the first place, are aimed at interrupting the rapid reactions of the glutamate-calcium cascade. Primary neuroprotection begins from the first minutes to 2-3 days after injury, especially actively in the first 12 hours. Secondary neuroprotection is a complex of measures, which purpose is to interrupt the delayed mechanisms of cell death: excessive synthesis of NO and the development of oxidative stress; activation of microglia and associated imbalance of cytokines, immune shifts, local inflammation, microcirculatory disturbances and blood-brain barrier; trophic dysfunction and apoptosis. The most intensive is carried out during the first 7 days. Secondary neuroprotection has not only therapeutic, but also preventive significance. Hemorrhagic stroke (from Greek haima - blood + rhegnymi - breakthrough) is a type of stroke in which hemorrhages in brain tissue, subshell spaces or into the ventricles are observed. Intracerebral haemorrhage is a clinical form of ADCC caused by rupture of the intracerebral vessel or increased permeability of its wall and penetration of blood into the parenchyma of the brain. Subarachnoid hemorrhage (from Latin sub - from + from Greek arachne - spider + eidos - species) is one of the forms of ADCC, in which there is a hemorrhage into the subarachnoid space (the cavity between the arachnoid and mild membranes). Usually occurs due to rupture of arterial saccular aneurysm (70-85% of cases) or arteriovenous malformation. Arteriovenous malformations of the brain (from the Latin malus - bad + formatio - formation) - congenital anomalies in the development of the cerebral vascular system, which are different shapes and sizes of the coils, formed as a result of the disorderly interlacing of pathological vessels. In arteriovenous malformations, most often there is no capillary network, as a result of which a direct shunting of blood from the arterial basin to the system of superficial and deep veins takes place. In 40-70% of patients with AMB manifest intracerebral hemorrhage. 10 Chronic insufficiency of cerebral circulation (discirculatory encephalopathy) is a progressive form of cerebrovascular pathology with a gradual development of a complex of neurological and neuropsychological disorders, based on chronic brain hypoperfusion. The main forms (according to ICD-10): chronic cerebral ischemia, chronic hypertensive encephalopathy, subcortical arteriosclerotic encephalopathy, vascular dementia. Picture 3. Node of arteriovenous malphormation of the brain (http://www.dr- sitnikov.ru) Theme: “Disturbances of the motor and sensory function of the nervous system. Pathogenesis of neuropathies” Ataxia (from Greek a - denial and taxis - order) - impaired coordination of movements. There are static ataxia (disequilibrium when standing) and dynamic ataxia (discoordination when moving). Asynergia (from Greek a - negation + synergia - interaction) - disturbance of friendly work of muscles, manifested by a disorder of movements that require simultaneous reduction of several muscle groups; loss of smoothness of movements. It is observed when the cerebellum is affected. Hyperkinesia (from Greek hyper - over + kinesis - movement) - strengthening of auxiliary movements with a complex motor act. Hypokinesia (from Greek hypo - below + kinesis - movement) - restriction of the volume and speed of arbitrary movements. Decerebrate rigidity (from Latin de - elimination + cerebrum - brain + rigidus - numb) - a sharp increase in the tone of the extensor muscles and the relative relaxation of the flexor muscles resulting from the transection of the brain stem (between the lower and upper hills of the midbrain). At the same time, reflexes are lost that preserve the balance of the body and its ability to move. The reason: the release of the tonic centers of the medulla oblongata and spinal cord from the restraining control of the reticular formation of the medulla oblongata and midbrain. Decerebration rigidity most often occurs in severe damage to the midbrain with the involvement of red nuclei in the pathological process. Catalepsy (from the Greek katalepsia - grasping) - numbness, congestion of the whole body or limbs in an artificially attached to them posture ("waxy 11 flexibility"), pathologically prolonged retention of the attached posture. Muscle tone increased. In a restricted state, patients may stay for several weeks or even months. Оpisthotonus (From the Greek opisten -. Rear, back + tonos - voltage) - convulsive posture with sharp arching of the back, tilting the head back (arc posture relying only on the back of the head and heels), leg stretching, bending the arms, hands, feet and fingers as a result of the tonic contraction of muscles, back and neck (Picture 4). It is an extreme expression of decerebrate rigidity. Picture 4. patient posture in a state of opisthotonos (http://dic.academic.ru ) Severe myasthenia gravis (myasthenia gravis, from Greek myos - muscle + asthenia - weakness) is an autoimmune neuromuscular disease manifested by weakness and pathological fatigue (up to states like paralysis) of different groups of striated muscles. This disease affects the cholinergic receptors of postsynaptic membranes, and the pathology of neuromuscular transmission arises as a result of the development of antibodies against the a-subunit of cholinergic receptors. Picture 5. Right century ptosis in myasthenia (http://www.medicalj.ru) Paresis (from Greek paresis - weakening) - weakening of the contractile function of the muscles, caused by a disturbance of their innervation. 12 Paralysis (from the Greek paralyo- relax) is the complete absence of voluntary movements due to a disturbance of the innervation of the corresponding muscles. Central (spastic) paralysis (pyramidal failure) is a consequence of the destruction of the motor cortex of the brain or any part of the nervous system that connects it with peripheral motor neurons. Characteristic increase in muscle tone, strengthening tendon and periosteal reflexes, the appearance of pathological reflexes. The spread of paralysis is usually diffuse. Peripheral (flaccid, atonic) paralysis is a paralysis that develops when the peripheral neuron is damaged in any part: the anterior horns of the spinal cord, the roots, plexuses, peripheral nerves, and the motor cranial nerves and / or their nuclei. Characteristic decrease in muscle tone and reflexes, development of hypotrophy or atrophy, accompanied by the reaction of degeneration. The spread of paralysis is usually limited. Hemiplegia (from the Greek hemi - half + plege - stroke, defeat) - complete loss of arbitrary movements in the arm and leg on one side. Paraplegia (from the Greek para - about + plege - stroke, defeat) - paralysis of either lower or upper extremities. Tetraplegia (from the Greek tetra - four + plege - stroke, defeat) - paralysis of all four limbs. Brown-Sequard syndrome (lateral hemisection of the spinal cord) is a symptom complex, which is observed when a half of the diameter of the spinal cord is affected. On the side of the lesion, central paralysis (or paresis) is noted and the loss of muscle-joint and vibration sensitivity, on the opposite side - loss of pain and temperature sensitivity. It occurs with injuries and penetrating injuries of the spinal cord, circulatory disorders of the spinal cord, infectious myelopathy, tumors of the spinal cord, multiple sclerosis. Picture 6. Area of spinal cord injury in Brown-Sequard syndrome (http://www.owoman.ru) Pain is a complex psycho-emotional unpleasant sensation, realized by a special system of pain sensitivity and higher parts of the brain. It signals the effects of tissue damage, or of existing damage. Pathological pain is a changed perception of pain impulses as a result of disorders in the cortical and subcortical areas of the central nervous system. Disturbances can occur at any level of the nociceptive system, as well as in 13 disturbance of the connection between nociceptive ascending structures and the antinociceptive system Nociceptive system (from the Latin pose - to damage + to the earring - to perceive) - the system of perception and transmission of the pain signal. The central apparatus of the painful reception includes the nuclei of the thalamus, hypothalamus, reticular formation, central gray matter, cerebral cortex (somatosensory zone). Antinociceptive system (analgesic system) (Latin anti - against + sowge - damage + earring - perceive) - a system that controls the activity of the nociceptive system and provides a reduction in pain. The main components are neuronal and hormonal opiate analgesic systems, as well as neuronal and hormonal neo-opiate analgesic systems. Anesthesia (from the Greek an - negation + aisthesis - sensation, feeling) - loss of sensitivity, which occurs with certain diseases of the nervous system; can be induced artificially by the administration of medicinal substances for anesthesia during surgical operations. Hypoesthesia (from the Greek hypo - below + aisthesis - sensation, feeling) - a decrease in surface sensitivity. Hyperesthesia (from the Greek hyper - over + aisthesis - feeling, sensation) - increased sensitivity to the physical stimuli acting on the sense organs, manifested in the appearance of excessively strong subjective sensations without changing their modality. Paresthesia (from the Greek para - next to, about + aistesis-sensation) - a false sensation; spontaneously arising unpleasant sensation of numbness, burning, crawling creepy, not caused by external irritation. Paresthesias can be a manifestation of diseases of peripheral nerves, vessels, rarely - sensory centers of the spinal cord or brain. Causalgia (from the Greek kausis - burning + algos - pain) - paroxysmal intensifying burning pains that occur after damage to large mixed nerves, rich in sympathetic fibers. Phantom pain (from the Greek phantasma - a ghost, a representation) is a pain localized to patients in an absent limb. The mechanism is associated with the formation of a pathologically enhanced excitation generator at the level of the spinal cord, the reticular formation, the trunk or medial structures of the brain with the simultaneous weakening of descending antinociceptive influences. Neuropathy (from the Greek neuron - nerve + pathos - suffering) - non- inflammatory lesions of peripheral nerves, which are based on degenerative- dystrophic processes, caused by various causes (metabolic disorders, traumas, intoxications, vitamin deficiency, autoimmune processes, tumors...). The clinical picture is polymorphic, depending on the type of damaged nerves (motor, sensory or vegetative neuropathies). Motor neuropathy is a kind of neuropathy, in which the bodies of motor neurons of the anterior horns of the spinal cord, their axons or neuromuscular synapses are predominantly damaged, which leads to motor disorders without 14 sensitivity disorders. Manifestations - muscle weakness, muscle atrophy, hyporeflexia or areflexia... Sensory neuropathy is a type of neuropathy in which the primary sensory lesions of sensory neurons of spinal ganglia are observed. With damage to thick fibers, there are disturbances in vibration and proprioceptive sensitivity, sensory ataxia; with damage to fine fibers - numbness, decreased pain and temperature sensitivity, diesesia in the form of burning; when both types of fibers are damaged, a disturbance of all types of sensitivity. Vegetative neuropathies are a kind of neuropathy, in which visceral, vegetative-vasomotor and vegetative-trophic disorders appear as a result of the defeat of vegetative fibers. Among visceral symptoms, cardiac, urogenital, gastrointestinal, respiratory disorders, etc. are distinguished. Vegetative-trophic disorders include deformation of the nails, thinning of the skin, ulceration. Vegetative-vasomotor symptoms are characterized by changes in the temperature of the skin of the hands and feet, their swelling, and marble color. Polyneuropathy is a group of diseases of the peripheral nervous system characterized by diffuse lesions of peripheral nerve fibers that form part of various nerves, mainly in the distal regions. In the pathological process, either the myelin sheath or the axial cylinder is involved. Development is associated with: 1) a disturbance of the allocation of neurotransmitters, blockade of carrying out the action potential; 2) alteration of the synthesis, secretion or action of comedians and trophogens, as well as impairment of axonal transport. Theme: "Pathophysiology of convulsive syndrome and syndrome of affecting meninges" Seizures (from Greek spasmos - spasm, spasm) - sudden, paroxysmal or persistent involuntary contractions of muscles of varying intensity, duration and prevalence, usually accompanied by sharp pain; one of the forms of rapid hyperkinesis. Clonic convulsions (from Greek klonos - movement) are successive contractions of flexor and extensor muscles, which is manifested by rapid involuntary movements of limbs and trunk. They arise most often as a result of excessive excitation of the cortex of the cerebral hemispheres or damage to the structure of the pyramidal system; occur usually without concomitant phenomena, therefore less dangerous than tonic convulsions. Tonic convulsions (from Greek tonikos - tension, force) - prolonged contractions of the muscles, as a result of which the limbs "freeze" in the position of flexion or extension, the patient's body stretches, the head tilts back or is brought to the chest. Develop with excessive excitation of subcortical structures and certain types of intoxication (eg, alcoholic, tetanus). Opistotonus (from Greek opisten - from behind + tonos - tension) - convulsive posture with sharp arching of the back, tipping the head back, stretching the legs, bending hands, hands, feet and fingers due to tonic contraction of the muscles of the extremities, back and neck. 15 Fasciculations (from the Latin fasciculus - a bundle of muscle fibers) - visible involuntary twitching of individual parts of the muscle in the absence of its general contraction, due to a spontaneous contraction of a group of muscle fibers of one beam. Fibrillation (from Latin fibrilla - fiber) - spontaneously arising constant contractions of individual muscle fibers (myofibrils). Unlike fasciculations, fibrillation can not be detected visually. They are recorded only with electromyography in the form of involuntary contractions of individual muscle fibers. Tick (from French tic - support) - rapid, involuntary, stereotyped, clonic jerking of an individual muscle or muscle group. They are observed mainly in the defeat of the extrapyramidal system as a result of encephalitis, intoxications, including under the influence of drugs, with certain mental disorders. Tremor (from Latin tremor) is a hyperkinesis of a trembling type in the form of rhythmic involuntary trembling of limbs, eyelids, fingers or torso caused by muscle contractions. Chorea (from the Greek choreia - dance) is a rapid hyperkinesia characterized by random, fast, irregular, violent contractions of various muscle groups. Athetosis (Greek athetos - devoid of a certain position) - involuntary stereotyped, slow wormlike pretentious movements, resulting from simultaneous prolonged activation of agonist muscles and antagonists. The distal parts of the extremities of the fingers and toes are most often affected; is a manifestation of slow hyperkinesis. Epilepsy (from the Greek epilepsia - seizure) is a chronic brain disease characterized by repeated convulsive seizures, which are manifested by disorders of motor, sensitive, autonomic, mental and mental functions arising from excessive neuronal discharges. The pathogenesis is based on spontaneous membrane instability of neurons of the cortex of the cerebral hemispheres, which leads to a paroxysmal depolarization shift on the cell membrane. The epileptogenic focus is a region of local brain damage that is the source of pathological excitation of surrounding neurons, as a result of which they generate focal amplified and synchronous discharges, and can also lead to the formation of a functionally active epileptic focus. The epileptic focus is a group of interconnected neurons with abnormal electrogenesis that generates excessive neuronal discharges, leading to hypersynchronization of the surrounding neurons. The generation (generation) of epileptic activity is mainly associated with neuronal bodies, and propagation (generalization) with dendrites and membranes. At the heart of the development of the epileptic focus is the emergence of generators of pathologically enhanced excitation. The epileptic system is a pathological system formed by an epileptic focus that has become a determinant structure and, consequently, the imposition of its activity on other entities. The epileptic system includes the structures that activate the epileptic focus, the ways of spreading the epileptic discharge and the formation that promote its generalization. 16 Antiepileptic system - a set of mechanisms that prevent the spread and generalization of epileptic activity. It includes the caudate nucleus, the cerebellum, the lateral nucleus of the hypothalamus, the caudal reticular nucleus of the bridge and the front-orbital cortex, which have an inhibitory function. Kindling phenomenon - from the phenomenon of "swinging", which occurs in response to the application of multiple epileptogenic stimulations of subthreshold intensity, initially not causing convulsive reactions. Gradually occurring progressive convulsive activity is accompanied by focal convulsive post-discharge, behavioral automatisms and generalized convulsive seizures. The state of increased convulsive readiness formed at the Kindling can be maintained for a long time, perhaps, for the whole life. Absence (from French absence - absence) is a type of generalized non- convulsive seizures characterized by high frequency and short duration of paroxysms with impaired consciousness. At typical absences on an electroencephalogram, a specific pattern is observed in the form of generalized spike-wave activity with a frequency of 3-4 Hz. Aura (from the Greek aura - a gentle breeze, a whiff) - different states or sensations preceding an epileptic attack or an independent seizure (an isolated aura). Types: somatosensory, visual, auditory, olfactory, psychic, etc. Aura is a clinical manifestation of activity of a convulsive focus. Epileptic status is a condition in which epileptic seizures follow one after another (usually more than 30 minutes), and in the intervals between seizures the patient does not regain consciousness. At the heart of the epistatus is the continuous (or intermittent, but often recurring) paroxysmal electrical activity of the neurons of the brain. Neuroinfections are the common name of infectious diseases affecting the human nervous system and possessing both specific manifestations due to the action of a specific infectious agent and non-specific syndromes associated with the general reactions of the body to the disease. Types of neuroinfections: meningitis, encephalitis, myelitis, brain abscess, poliomyelitis, rabies, neurotuberculosis, neurosyphilis, nervous system disorders in AIDS and parasitic diseases, prion diseases, etc. Meningitis (from Latin meninx - cerebral membrane + itis - suffix meaning inflammatory process) - purulent or serous inflammation of the brain and / or spinal cord, caused by bacteria, viruses, fungi and other agents. In the clinic, the term "meningitis" usually refers to the inflammation of the pia mater. Meningitis is characterized by a combination of meningeal symptoms and inflammatory changes in the cerebrospinal fluid. Meningism is a state of irritation of the membranes of the brain or spinal cord, in which there are meningeal symptoms in the absence of liquorological signs of inflammation. Meningococcus (Neisseria meningitidis) is an aerobic gram-negative diplococcus that causes a meningococcal infection that can occur with nasopharyngeal mucosa (nasopharyngitis), cerebral membranes (meningitis), 17 and septicemia. The main path of spread of the pathogen in the body is hematogenous. Meningococcal infection refers to anthroponosis. Meningococcemia is a generalized form of meningococcal infection, characterized by bacteremia with massive death of meningococci and manifested by the symptoms of acute septicemia with the development of an infectious - toxic shock and thrombohemorrhagic syndrome. Theme: "Pathophysiology of neurodegenerative diseases" Neurodegenerative diseases (from the Greek neuron - nerves + from the Latin degerener - degenerate) - a group of different in the etiology and pathogenesis of hereditary or acquired slowly progressing diseases, which are based on the degeneration and death of nerve cells entering into certain structures of the central nervous system. Characteristic is the severance of connections between the departments of the central nervous system, imbalance in the synthesis / isolation of neurotransmitters and, as a consequence, memory impairment, coordination of movements and thinking abilities of a person. Dementia (from Latin dementia - dementia) - acquired dementia, persistent decline in cognitive activity with a loss to varying degrees of previously acquired knowledge and practical skills and the difficulty or inability to acquire new ones. Up to 60% of all cases of dementia occur in Alzheimer's disease. Alzheimer's disease is the most common form of primary neurodegenerative dementia, which is characterized by a gradual onset in presenile or old age, a steady progression of memory disorders and higher cortical functions. Characteristic are atrophy of the cerebral cortex, narrowing of the gyri, deepening of the furrows, diminution of the volume and mass of the brain. Morphological features are senile plaques and neurofibrillary tangles. The neurons of temporomandibular divisions of the cerebral cortex, parts of the frontal cortex and the cingulate gyrus are mostly affected. Senile (amyloid) plaques are dense, in most cases insoluble, extracellular deposits of beta-amyloid. Plaque formation may be associated with a mutation of the β-amyloid precursor protein APP (Amyloid Precursor Protein); with a disturbance of APP processing under the influence of altered secretase enzymes with the formation of longer forms of ß-amyloid prone to fibrillation aggregation; with disturbance of the microglia digestion function. Senile plaques contribute to the degeneration of synaptic structures, disrupt the metabolism of neurons, stimulate the development of the inflammatory process, and also increase the concentration of calcium ions in neurons. As a result, the affected neurons die by both necrosis and apoptosis. Presenilins1, 2 (from Latin prae- prefix, meaning in front + senilis - senile, PS1 and PS2) - membrane proteins that perform secretarial functions with respect to the membrane protein of APP, processing it to the level of ß-amyloid. Mutations in the genes of presenelins provide the formation of elongated forms of ß- amyloid, which have increased aggregation properties, which leads to the appearance of perineuronal senile plaques. 18 Tau protein is a protein designed to stabilize microtubules, the main function of which is to transport the trophogens to the innervated cellular structures and back to the cytoplasm of neurons. When pathology occurs, hyperphosphorylation of protein-tau, rupture of its connection with microtubules, the union of protein strands among themselves, which contributes to the formation of neurofibrillary tangles. Neurofibrillary tangles - inner neuron plexuses, consisting of aggregates of hyperphosphorylated protein - tau protein. The formation of coils causes disintegration of microtubules and the collapse of the transport system of neurons. Neurofibrillary tangles are characteristic of Alzheimer's and other neurodegenerative diseases. Parkinsonism is a group of chronic neurodegenerative diseases that are characterized by progressive destruction and death of dopamine neurons in the central nervous system. There are primary Parkinsonism (idiopathic, Parkinson's disease), which occurs in 75-80% of cases, and secondary Parkinsonism (drug, metabolic, vascular, toxic, tumor, etc.). Characteristic trembling of hands decreased motor activity, slowed movements, increased muscle tone, stiffness, gait disturbances and postures, dementia. Parkinson's disease is a slowly progressing disease, in which degenerative changes and the death of dopaminergic cells in the structures of the striopallidal system (black matter, blue spot, and striatum) occur first. As the disease develops, dopaminergic neurons are destroyed in other areas of the brain. The key process leading to the death of neurons is the accumulation of alpha- sinuclein protein, the formation of neurotoxic aggregates and Levi bodies from it. Picture 7. Parkinson's Disease (http://www.parkinsonizm.ru) Picture A shows a portion of the brain of a healthy person with a good black pigmented substance. In Picture B - portion of the brain of the patient suffering from Parkinson's disease, a noticeable lack of pigmentation of the substantia nigra. 19 Alpha-synuclein is a small neuronal protein that is present in the bodies and processes of dopaminergic neurons and provides interaction between various intracellular proteins in the process of vital activity of neurons. Excess and disruption of the metabolism of this protein as a transition from monomeric and oligomeric forms to fibrillar, followed by aggregation of fibrils into conglomerates (Lewy body), leads to the death of nerve cells. Lewy bodies- pathological eosinophilic cytoplasmic inclusions inside damaged dopaminergic neurons. The formation of Levi bodies is associated with abnormal aggregation of alpha-synuclein, due to impaired metabolic degradation in the cell and the disorder of axonal transport. Another component of Lewy bodies is the phosphorylated and partially proteolytic proteins of neurofilaments, which normally form the cytoskeleton of axons. Multiple sclerosis is a chronic progressive neurodegenerative disease in which sclerosis is found scattered throughout the central nervous system, without definite localization. The basis is the formation of foci of myelin destruction (demyelination) of the white matter of the brain and spinal cord (plaques of multiple sclerosis). A variety of neurological symptoms are typical, consisting of a predominant lesion of the optic, cerebellar and pyramidal systems of the brain and spinal cord. Amyotrophic lateral sclerosis is a slowly progressive, incurable degenerative CNS disease in which both the upper (motor cortex of the brain) and the lower (anterior horns of the spinal cord and the nucleus of the cranial nerves) of motor neurons are affected, which leads to paralysis and subsequent muscle atrophy. In pathogenesis, a key role is played by the increased activity of the glutamatergic system, which leads to overexcitation and death of neurons (excitotoxicity). Prion neurodegenerative diseases are a group of neurodegenerative diseases of humans and animals with the formation of spongiform encephalopathy, which refers to slow infections and is characterized by CNS, muscle, lymphatic and other damage, with lethal outcome. The disease leads to the degradation of mental and physical abilities with the formation of a large number of holes in the cortex of the large hemispheres, in connection with which the brain under a microscope resembles a sponge during an autopsy. The causative agents of this group of diseases are prions. Prions (from English proteinaceous infectious particles) are a special class of infectious agents, represented by low molecular weight proteins with an abnormal tertiary structure and not containing nucleic acids. Prions cause the formation of amyloids. Prions are resistant to denaturation under the influence of chemical and physical agents. 20 PATHOPHYSIOLOGY OF CEREBRAL CIRCULATION Features of cerebral circulation The brain is characterized by continuous energy-intensive processes, but it does not have any substrates for oxidative processes, nor oxygen reserves, and, therefore, for normal functioning, a high intensity of its blood supply is necessary. In this regard, the brain, which has an average mass of 1400-1500 g, contains a network of more than 100 billion small vessels with a total length of about 600 km, through which about 600-800 ml of blood flows per minute. The volume rate of blood flow under these conditions corresponds to 55-60 ml/100g / min-1. At this level of blood flow, the total oxygen consumption of the brain, whose mass is only 2% of the body weight, is equal to 3.3-3.5 ml/100g / min-1 or 45 ml of oxygen/min-1, that is, 20 % of the total oxygen consumption of the body. In children of the first year of life, the amount of blood flow is 50-55% more, and in old age it is 20% less than in a person in adulthood. The main tasks of the cerebral circulation system are to minimize deviations of circulatory and chemical homeostasis of the brain in various functional States. This is due to the complex structural and functional organization of the process of autoregulation of cerebral blood flow (MC) through the interaction of three main mechanisms - myogenic, humoral-metabolic and neurogenic. Autoregulation of cerebral blood flow is characterized, first of all, by the ability of brain vessels to maintain a relatively constant volume rate of MK when perfusion pressure changes (the difference between systemic arterial and intracranial pressure) within a wide range - the Ostroumov-Bayliss effect. (Picture 8) Picture 8. Dependence of total cerebral blood flow (TCBF) on perfusion pressure (PP). 1, 2 – respectively the lower and upper limits of autoregulation of cerebral blood flow. (Semenyutin V. B., Aliev V. A. Modern methods of evaluating autoregulation of cerebral blood flow // Regional blood circulation and microcirculation, 2011.-№4) Myogenic regulation of cerebral circulation (CC) is carried out by the reaction of smooth muscles of the arterial vessels of the brain to changes in blood pressure (BP). An increase in blood pressure leads to an increase in the tone of myocytes, narrowing of the arteries and restricts blood flow to the brain. 21 A decrease in blood pressure , on the contrary, is accompanied by a decrease in tone, an expansion of the arteries and an increase in blood flow to the brain. As a result, brain perfusion remains unchanged when the system blood pressure fluctuates. However, when the blood pressure falls below the minimum limit of autoregulation (60-50 mm Hg.St.) CC decreases and the arterio-venous difference in oxygen increases. When blood pressure rises above the upper limit of autoregulation (more than 160-170 mm Hg.St.) intravascular pressure overcomes the resistance of arterioles, increases the volume speed of blood flow in the brain, the function of the blood-brain barrier (BBB) is disrupted, which may be accompanied by brain edema. Thus, if the blood pressure decreases less than 50 mm Hg.st or increases above 180 mm Hg.st then there is a passive dependence "AP-cerebral blood flow", that is, there is a failure of the reaction of autoregulation of cerebral circulation. Myogenic autoregulation is closely related to the level of venous pressure and cerebrospinal fluid pressure. Among humoral regulators of cerebral circulation, the voltage of carbon dioxide in arterial blood (PaCO2) is particularly important: when PaCO2 changes by 1 mm Hg.the average CC value changes by 4-6%. Hypercapnia, characterized by an increase in PaCO2, is accompanied by an expansion of the brain vessels and an increase in the cerebral circulation. The action of CO2 is mediated by a corresponding increase in the concentration of H+ formed during the dissociation of carbonic acid. In hypocapnia, on the contrary, there is a narrowing of the arteries and a decrease in the cerebral circulation. However, when the PaCO2 is reduced, it is less than 25 mmHg.however, there is no further decrease in the cerebral circulation. Cerebral circulation is also in strict accordance with the brain's oxygen consumption. However, the effect of P02 on vascular lumen is lower than that of PC02. Thus, the total brain blood flow begins to increase only when the P02 falls below 30 mm Hg.and decrease - with an increase in the oxygen content in the environment of the body more than 2-3 times. The metabolic component of CC regulation does not have a significant impact on the overall CC, but plays an important role in local blood redistributions between brain regions that have different levels of functional activity in each specific situation. Depending on the level of functional activity of the nervous tissue, its blood supply can vary from 30 to 180 ml/100 g/min-1. Local vasodilation and increased blood flow in them with the development of working arterial hyperemia is associated with a local increase in the concentration of hydrogen, adenosine and potassium ions in the intercellular environment. Acetylcholine and histamine (medium and large arteries) also have a vasodilating effect on brain vessels), bradykinin (small arteries). At the same time, vasopressin, angiotensin, prostaglandins of group F and catecholamines have a vasoconstrictor effect. Neurogenic regulation of brain vessels is less effective than metabolic regulation. Thus, with maximum stimulation of the sympathetic nerves, MK decreases by only 5-10%. The main area of application of adrenergic, cholinergic, serotonergic and peptidergic nerve fibers that regulate the tone of brain vessels are small arterial brain vessels with a diameter of up to 25-30 22 microns. Nerve effects on the brain vessel wall are mediated through α - and β - adrenergic receptors (norepinephrine), M-holinoreceptors (acetylcholine, vasointestinal peptide), D-receptors (serotonin). The role of the nervous system, especially its sympathetic link, is limited to modulating influences on other circuits of regulation of cerebral hemodynamics. Thus, the features of cerebral hemodynamics, which differ from the blood supply to other organs, include: high intensity of blood supply autoregulation of MC, high sensitivity of brain vessels to C02 and low susceptibility to neurogenic influences, the relationship between the state of regional blood flow and the functional activity of various brain formations, the arteries that feed the brain form a circle on its lower surface, from where they are directed to the surface of the brain and send probing branches inside (in other organs, the centrifuge blood circulation is carried out); in the cerebral arteries, the wall thickness is significantly lower with a more powerful development of the internal elastic membrane than in the arteries of other organs numerous bends (siphons) along the course of the vascular bed contribute to a significant pressure drop and smoothening of the pulsating blood flow; highly developed collateral circulation, which is due to blood (Villiziev) circle, underany anastomoses systems anastomoses on the surface and inside of the brain, dependency of perfusion pressure in the brain from the value of intracranial pressure the close relationship of the cerebral circulation with liquorosorption, the ability of large cerebral arteries to a significant change in tone and diameter, the pressure control in the microvasculature of the brain, which is a protective mechanism that prevents fluctuations in perfusion pressure in intracranial thin-walled vessels. Violations of cerebral circulation Pathological processes that cause CCD can affect the main and cerebral arteries (aorta, brachiocephalic trunk, common, internal and external carotid, subclavian, vertebral, basilar, spinal, root arteries and their branches), brain veins and venous sinuses, jugular veins. Classification of disorders of cerebral circulation 1. Initial manifestations of insufficient blood supply to the brain. These are early compensated dyscirculatory encephalopathies that are not accompanied by organic neurological symptoms and are a manifestation of general vascular pathology. Under normal conditions, patients feel normal, but 23 in situations that require increased blood supply to the brain (strenuous mental work, physical fatigue, stuffy room, etc.), there are complaints. 2. Chronic slowly progressive disorders of cerebral and spinal circulation. These include discirculatory encephalopathies( DE) and myelopathies. In the etiology of DE, the most important are atherosclerosis and primary hypertension, as well as diabetic cerebral angiopathy, cardiac pathology, blood diseases, and systemic vasculitis. DE is characterized by the development of diffuse small-focal changes in brain tissue that cause a gradual increase in brain function disorders, up to a decrease in intelligence and memory disorders, Parkinsonian syndrome, dementia, and strokes. The pathogenesis of DE is caused by insufficiency of cerebral circulation in a relatively stable form or in the form of repeated episodes of dyscirculation. As a result of pathological changes in the vascular wall, there is a violation of the regulation of cerebral circulation, there is a large dependence on the state of systemic hemodynamics, which also turns out to be unstable due to atherosclerosis and arterial hypertension. Lesions of small intracerebral arteries lead to the development of primary and secondary changes in the brain substance. Damage to the nerve fibers that pass through the white matter leads to the separation of the functions of the cortex and underlying structures, which causes the clinical manifestations of the disease. An important pathogenetic factor in the development of DE is hypoxia, which is an integral component of the disease-conductor and leads to further damage to the mechanisms of regulation of cerebral circulation. 3. Acute disorders of the cerebral circulation (ACCD) – transient disorders of the cerebral circulation (TIA and hypertensive cerebral crisis), ischemic stroke, hemorrhagic stroke. About 2/3 of circulatory disorders occur in the carotid artery basin and 1/3 in the vertebro-basilar basin. Pathophysiology of stroke Stroke is a clinical syndrome characterized by a sudden focal and / or general cerebral neurological deficit in the CNS that develops as a result of cerebral ischemia or hemorrhage. Stroke- ACCD with the development of persistent symptoms of Central nervous system damage, the nature of which depends on the location and volume of the damaged area of the brain (i.e., the area of the stroke itself). The main types of strokes are ischemic, hemorrhagic, and cryptogenic (Picture 9). 24 Stroke Criptogenic Hemorrhagic Ischemic (idiopathic) 17% 65% 18% Heterogenic stroke Atherothrombic Arterio- Cardio- Thrombosis Lacunar Hemodi- Hemo- arterial embolic of brain namyc rheologic 26% 14% embolias vessels micro- 21% 10% oсclusions 7% 20% 2% Picture 9. The main types of strokes (Evtushenko S. K. The relationship between cardioneurology and neurocardiology on the clinical model of cardioembolic stroke / / international neurological journal-2010, no. 6). Ischemic stroke Ischemic stroke (IS) is the most common form of ACCD , characterized by damage to the brain tissue, violation of its functions due to difficulty or cessation of blood flow to a particular area. Accompanied by the formation of a brain infarction. The most characteristic occurrence is during sleep or immediately after sleep. In IS, signs of focal symptoms prevail over General brain symptoms, and there is also a close relationship between focal symptoms and the basin of a certain vessel. Risk factors for ischemic stroke IS risk factors can be divided into two groups: 1) modifiable factors, including potential ones – factors that can be influenced and controlled; 2) non-modifiable factors that cannot be influenced, but must be taken into account. Modifiable (controlled, regulated) risk factors for ischemic stroke Arterial hypertension (the population risk of hypertension for IS is 70-80%; with blood pressure greater than 160/95 mm Hg.art. the risk of IS increases 4-5 times, with blood pressure above 200/115 mm Hg.art. - 10 times; increase in diastolic blood pressure by 7.5 mm Hg.art increases the risk of stroke by almost 2 times). 25 Cigarette Smoking (doubles the risk of developing IS; the risk of stroke is higher in women who smoke; secondhand smoke is a risk factor for the progression of cerebral atherosclerosis; complete tobacco cessation reduces the risk by 50%, and after 5 years, the risk is almost the same as in those who have never smoked). Heart disease (ischemic heart disease increases the risk of developing IS by 3-5 times, atrial fibrillation-by 2-4 times, left ventricular hypertrophy according to ECG data-by 3 times, heart failure-by 3-4 times). Diabetes mellitus (increased risk 2-4 times; 20-35% of IS patients are diagnosed with diabetes mellitus, which develops atherosclerotic cerebral macro-and microangiopathies). Hypercholesterolemia (an increase in total cholesterol greater than 5.2 mmol / l and low-density lipoprotein levels greater than 3.36 mmol / l is an indirect risk factor for IS). Suffered strokes, TIA (after the first stroke, the risk of repeated IS increases by 10 times; 1/3 of patients who have suffered TIA develop IS; the risk of IS in patients with TIA is 4-5% per year; about 2/3 of brain infarctions develop in the same vascular pool as those who have suffered TIA). Modifiable potential risk factors for ischemic stroke Lifestyle factors (increased body mass index ≥25 kg / m2, insufficient physical activity, eating disorders, mental and physical strain, etc.). These factors indirectly affect the risk of developing IS, as they are associated with high blood pressure, hyperglycemia, and hypercholesterolemia. Alcohol abuse (the role of alcohol in the development of stroke is controversial and depends on the dose of use and subtype of brain infarction, but it has been proven that taking more than 50 g of pure alcohol per day for men and 35 g for women increases the risk of IS by 2-3 times due to the development of a hypercoagulable state, arrhythmia, hypertension). Hyperhomocysteinemia (increases the risk of stroke by 3-4 times after endothelial damage, accelerated atherogenesis, thrombosis). Hypercoagulation disorders (antiphospholipid antibodies, Leiden factor V, prothrombin mutation, protein C, s deficiency, antithrombin III). Taking oral contraceptives (drugs containing estrogens greater than 50 mg significantly increase the risk of IS). Chronic infections and inflammatory processes. Infections, in features caused by Chlamydia pneumonia lead to damage endothelium and increase the risk of developing vascular diseases. Non-modifiable (uncontrolled, unregulated) risk factors for ischemic stroke 26 Heredity. People whose next of kin had stroke, have a higher risk of developing IS. Hereditary the tendency to stroke is more often transmitted through the maternal line.Genetic risk factors of IS play a significant role in its etiology especially in young people who do not have other the most common risk factors. Age - 2/3 of strokes occur in people over 60 years of age; for every 10 years after 55 years, the risk of stroke increases by 2 times (picture 10). 8 7 6 5 4 3 2 1 0 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70 and Age elder Ischemic stroke Hemorrhagic stroke Picture 10. Incidence of ischemic and hemorrhagic stroke in different age groups (Lutsky M. A. Main aspects of the problem of stroke in Russia //Journal of theoretical and practical medicine. -2004.- Vol. 2, no. 1) Gender- in men aged 45-65, IS is registered 30% more often, but as the age increases, this difference is leveled. Sexual differences are also noted in the subtypes of IS: men are more likely to have atherosclerotic and lacunar strokes, women – cardioembolic. Etiological factors of ischemic stroke Etiological factors of IS development are divided into two groups: 1) local factors; 2) system factors. The local causative factors in the development of ischemic stroke Atherosclerosis and thrombosis. Ischemic disorders of cerebral circulation in about 90-95% of cases are caused by vascular atherosclerosis. The pathogenesis of stroke in atherosclerosis is very diverse, which is due to the nature and duration of its course, the increase in the severity and prevalence of atherosclerotic changes in the vascular system of the brain. Atherosclerotic plaques affect the precerebral, large and medium-sized cerebral arteries, mainly 27 in the places of their division, tortuosity and fusion. In the precerebral arteries, they are formed mainly in the area of the proximal divisions of the internal carotid (Picture 11) and vertebral arteries. Cerebral artery most affected in the region Willize circle. Picture 11. Duplex scanning of the internal carotid artery. A- small atherosclerotic plaque, the vessel lumen is slightly narrowed; B - later stages of atherosclerosis the vessel lumen of the internal carotid artery partially blocked by a large metal buckle; C - occlusion - complete closure of the lumen vessel plaque; D- is the tortuosity of the artery (Manvelov L., Adam's Apple, A. Vascular diseases of the brain //Science and life – 2007, No. 2). Embolism of brain vessels. Most often, cardiogenic thromboembolism occurs, which is the cause of approximately 20 % of IS and TIA. Stenosis and compression of the precerebral and cerebral arteries. Vascular abnormalities in the craniovertebral region, in which blood pressure falls below the lower limit of autoregulation of cerebral circulation. Arteritis (infectious in meningitis or syphilis; non-infectious in collagenoses and systemic vasculitis). Rare causes: damage to the carotid artery, a complication of angiography, dissecting aneurysm of the aorta, closed scull-brain trauma, migraine etc. Systemic causative factors in the development of ischemic stroke 28 Blood diseases that develop hypercoagulation and increased blood viscosity, predisposing to the development of thrombosis in the cerebral arteries (erythremia, coagulopathy, etc.). Arterial hypertension. The main mechanisms of cerebral ischemia in hypertension: the development of changes in the brain arteries (lipogialinosis, fibrinoid necrosis); increased atherosclerosis in the precerebral large and medium-sized cerebral arteries; the development of heart diseases (atrial fibrillation, myocardial infarction, etc.), complicated by cerebral embolism and circulatory failure. Arterial hypotension. The decrease in cardiac output and stroke volume leads to a drop in blood flow in the arterial system of the brain, disruption of the mechanisms of autoregulation of cerebral circulation and formation of thrombotic stroke or the development of cerebral ischemia by the type of cerebrovascular insufficiency. Main pathogenetic subtypes of ischemic stroke Atherothromboembolic IS. The main mechanisms of cerebral ischemia in atherosclerosis: blockage of the cerebral and/or cerebral artery; hemodynamically significant artery stenosis (narrowing of 70-75% or more of the area of the artery lumen); thrombosis. A blood clot is usually formed on an ulcerated plaque. The formation of a blood clot is facilitated by a violation of the rheological and clotting properties of blood: increased aggregation (ability to glue) of platelets and red blood cells, hypercoagulation. The most frequent localization of blood clots is the mouth of the internal carotid or vertebral artery- the place of the greatest turbulence in the blood flow. Fragments of a blood clot and atherosclerotic plaque can be the source of embolism in the more distal part of the artery - arterio-arterial embolism, which accounts for 13% of all IS subtypes. In General, atherothrombosis and atheroembolism are the cause of about 50% of ischemic disorders of cerebral circulation. Cardioembolic IS. 2 pathological processes play a role I n the origin of cardioembolism: intrachamber thrombosis and valvular pathology. Most cases of intracameral thrombus formation are non-rheumatic atrial fibrillation, which is caused by IHD against the background of coronary artery atherosclerosis and hypertension. The most common causes of valvular pathology leading to cardioembolism are: rheumatism, bacterial endocarditis, mitral valve prolapse, prosthetic valves. Lacunar IS. Accounts for 15-30% of IS cases. The main cause is hypertension, which is characterized by changes in small arteries in the form of plasmorrhagia, fibrinoid necrosis, and obliterating hyalinosis. Lacunar strokes are small in size (up to 15 mm in diameter) infarcts of the brain, which in 80% of cases are localized in the periventricular region, the visual tubercle, basal ganglia (Picture 12), in 20% - the brain stem and cerebellum. In the process of organizing these infarcts, a small cavity is formed - a lacuna (from French. lacunarie-cavity). Their development is associated with the defeat of small (40- 29 80 microns in diameter) perforating branches of the middle, posterior and main cerebral artery. Picture 12. Bilateral lacunar infarcts in the basal ganglia (http://neuropathology-web.org) Hemodynamic IS (stroke developed on the mechanism of acute circulatory failure). It is 10-15% of all cases of IS. It can occur with stenosis or blockage of the cerebral and/or cerebral arteries, when blood pressure falls below the lower limit of autoregulation of the cerebral circulation, which causes hypoperfusion of the brain. A significant decrease in blood pressure is possible with deep sleep, orthostatic arterial hypotension, overdose of antihypertensive drugs, myocardial infarction, heart rhythm disorders, bleeding, hypovolemia, etc. Local ischemia is more often observed in areas of adjacent blood supply to the anterior, middle and posterior cerebral arteries or in the pool of the most narrowed precerebral or cerebral artery. Thus, in the development of hemodynamic stroke, a significant role belongs to changes in the main arteries of the neck or intracranial vessels and factors that cause instability of systemic hemodynamics with subsequent reduction of cerebral perfusion. Hemorheological vascular microoclusion.It is about 2-7 % of all cases of IS. It is based on hyperagregation of platelets and red blood cells, increased hematocrit, blood viscosity, and fibrinogen. Causes: decreased blood levels of natural anticoagulants-protein C and S, antithrombin III; polycythemia; hyperhomocysteinemia; antiphospholipid syndrome. Risk factors: Smoking, alcohol abuse, dehydration, overheating in the sun, contraceptives. Remember! 1. Ischemic stroke most often develops in elderly patients suffering from general and cerebral atherosclerosis. In this case, the combination of atherosclerosis, hypertension, and diabetes is important. 2. In accordance with the concept of heterogeneity, based on the variety of causes of acute disorders of cerebral circulation, there are five main subtypes of ischemic stroke: atherothromboembolic, cardioembolic, hemodynamic, lacunar, and hemorheological microocclusion. 30 Pathogenetic factors of ischemic stroke 1. Threshold ischemic blood flow - a critically low level of CC and insufficient supply of oxygen and nutrient substrates to the brain, leading to the development of local ischemia, up to a brain infarction. The dynamics of IS development and the nature of changes in the focus of ischemia depend on the level of decrease in cerebral blood flow (Picture 13). ✓ A decrease in CC below 50 ml / 100g / min-1 leads to primary disorders in the cell: inhibition of protein synthesis, dispersion of ribosomes, selective gene expression, but the function of neurons is still preserved. This is the so- called critical level I, the marginal zone of ischemia. ✓ Reducing the CC below 35 ml / 100g / min-1 stimulates anaerobic glycolysis, the development of lactate acidosis and edema of the brain, causes a short- term violation of the functions of nerve cells, but without morphological changes. This is the II critical level, the area of dynamic metabolic changes, the zone of "ischemic penumbra". Picture 13. Formation of a brain infarction against the background of a decrease in cerebral blood flow (Fisher M., Takano K. Ballierie's clinical neurology, cerebrovascular disease.- London, 1995) ✓ Decrease in CC less than 20 ml/100g / min-1 is characterized by a maximum increase in the fraction of oxygen extraction with a simultaneous drop in the rate of cerebral oxygen metabolism. A decrease in cerebral blood flow to 20 ml/100g / min-1 and below leads to the development of a complex cascade of pathobiochemical reactions in neurons - discoordination in the Krebs cycle, disruption of the respiratory chain of mitochondria, the appearance of energy 31 deficiency, the development of membrane depolarization, the release of excitatory production of reactive oxygen species of aminoacidergic neurotransmitters, especially glutamate. This degree of ischemia is considered the III critical level, the upper ischemic threshold, that is, the threshold for the loss of electrical function of neurons with the preservation of their membrane potential. ✓ Reduction of CC to 15 ml/100g / min-1 is accompanied by the disappearance of electroencephalographic and evoked potentials while maintaining the structural organization of nerve cells. ✓ Reduction of CC to 10 ml / 100g / min-1 is a critical threshold for irreversible cell damage. At this stage, severe oxygen deficiency suppresses metabolism in the mitochondria and stimulates an ineffective anaerobic pathway of glucose cleavage, which leads to an increase in the content of lactate, a decrease in pH, and the development of extracellular and intracellular acidosis. The function of energy-dependent cell membranes that support ionic homeostasis is disrupted: K+ ions exit the cells into the extracellular space, Na+ ions and water enter into the cells. CA++ also moves into cells, where it causes mitochondrial function insufficiency, cytotoxicity, and generalized membrane function insufficiency. This degree of ischemia is considered as a threshold for loss of cellular ion homeostasis or a lower ischemic threshold for energy damage. A decrease in CC less than 10 ml/100g / min-1 leads to absolute (complete) ischemia. Within 6-8 minutes after its onset, irreversible damage to neurons and neuroglia cells develops - cell death (necrosis), that is, the zone of the infarct nucleus-the Central zone of stroke-is formed. Remember! 1. The key point in the pathogenesis of ischemic stroke is local brain ischemia, which develops when the cerebral perfusion decreases below 15- 20 ml 100g / min-1. 2. The level of perfusion less than 8-10 ml per 100 g of brain tissue per minute is the threshold for the development of apoplexy depolarization of cell membranes and irreversible changes-the threshold of infarction. 3. There is a "hierarchy" of ischemic brain damage - first the function of neurons stops, and then, secondarily, the integrity of cells is lost It is important that in areas far from the focus of ischemia, secondary changes in the CC and energy metabolism of the brain are also detected. This is the result of the development of the Diashesis phenomenon, which is based on transsynaptic functional deactivation, which occurs at a distance from the lesion due to direct damage to the conductor pathways, the lack of pulse transmission, and violations of the modulating influence of various neurotransmitter systems. The deficit of excitatory impulses transfers structurally preserved nerve cells to a different level of reactivity, which is clinically manifested by various disorders of functions. As a result, the volume of the non-functioning part of the Central nervous system significantly exceeds the size of the anatomical lesion. For example, a cerebellar stroke causes metabolic disorders in the large hemispheres 32 of the brain when they are structurally intact. As a result, the clinical picture shows not only disorders of muscle tone and coordination of antagonist muscle functions characteristic of cerebellar lesions, but also hemiparesis, hemigipesthesia, cognitive, speech, and behavioral disorders. With dialysis, there is a proportional decrease in the speed of blood flow, the volume of blood circulating in the blood vessels, the level of exchange of acid and glucose. This indicates the preservation of the physiological correspondence of hemodynamics and metabolism in dialysis, but at a lower level. The number of zones of diathesis significantly affects the clinical outcome of stroke: patients with a large number of zones of distant hypometabolism have a more unfavorable outcome. Thus, despite the fact that Diashesis part of the process of structural reorganization associated with axonal sprouting and the formation of new cortical connections, it has a prognostically unfavorable value. The duration of dialysis depends on the size, nature, localization of the lesion and compensatory capabilities of the Central nervous system. 2."Ischemic penumbra". This is an area of ischemic but viable brain tissue that surrounds the infarct core area (Picture 14). Picture 14. Zones of ischemia 1-Nuclear zone - a zone that contains irreversible damage to neurons. 2-Penumbra-zone of ischemic penumbra, neurons that have functional disorders, not structural ones. 3-Marginal zone – areas of the brain whose neurons do not have structural and functional disorders, but in the unfavorable course of a stroke can be involved in the pathological process. Why is there an ischemic penumbra? The blood flow in the penumbra area is located between two ischemic thresholds and corresponds to scanty or critical perfusion, which does not provide metabolic requests for brain tissue. One critical level of blood flow is characteristic of the cell's bioelectric activity, it is 20ml/100 g / min-1. The second critical level relates to ion cell pumps and maintenance of cellular homeostasis and is equal to 15ml/100 g / min-1. Cells with volume blood flow located between these two levels form ischemic penumbra. The structural and morphological organization of neurons in this area is preserved, but there is a defect in its functional activity - the loss of electrical function of neurons. The zone of blood flow of ischemic penumbra has a mosaic character without a dense zonal difference. This is due to the peculiarities of microcirculation, local reduction of blood flow, and rheological properties of blood. In the first place are violations of microhemocirculation, blockage of 33 microthrombs, arteries, capillaries and other microvessels, which explains the features of the mosaic character of the penumbra. Cell death in the penumbra area leads to an increase in the size of the infarction. However, these cells can maintain their viability for a certain time, so the development of irreversible changes in them can be prevented by restoring blood flow. The duration of the period during which it is possible to restore nerve cells in the penumbra area is not precisely established. Although for most nerve cells, this time is limited to 3-6 hours (rarely 2-3 days). This period of time is called the "therapeutic window", during which you can have an effective therapeutic effect on the cells of the" ischemic penumbra " zone and prevent the development of necrosis. With an unfavorable course, after about 6 hours, the formation of most of the brain infarction is completed. In the penumbra zone, complex pathobiochemical and pathophysiological changes occur, leading to cell death. The main mechanisms of neuron death in the penumbra zone are: glutamate excitotoxicity, wave of perifocal depolarization, inflammation and reperfusion damage, apoptosis (Picture 15). Picture 15. The main mechanisms of death of neurons in the penumbra zone and the time of development of these mechanisms from the moment of injury (Moskowitz M. A., Lo E., Iadekola S. science of stroke: mechanisms in search of treatment methods. Neuron. - 2010) With further development of damage in the penumbra zone, mechanisms of secondary brain damage are triggered due to delayed neuronal losses. The activation of microglia, which is the only one immune compartment in the Central nervous system and therefore participates in all the reactions of brain tissue to ischemia. The ischemic process activates microglial cells, making them ready for phagocytosis. Activated microglia has a neurotoxic effect through the production of direct neurotoxic factors, the formation of microglial factors that trigger pathobiochemical cascades that lead to cell death, as well as through the induction of a local inflammatory response. At the same time, microglial cells 34 induce the synthesis of signaling molecules, cellular regulators, and trophic factors that contribute to the survival of neurons and reduce the processes of post-ischemic scarring. Remember! 1. The meaning of "ischemic penumbra" is that disorders of neuronal functions in it during, as a rule, the first 3-6 hours after the onset of stroke are reversible. Improved perfusion of the" ischemic penumbra " allows to restore the functioning of the nervous tissue of this area, and a decrease in perfusion leads to the death of cells of all types, including neurons and neuroglia cells. 2. In the penumbra area, glia cells are affected faster and to a greater extent than cortical neurons. Aggressive action of the neuroglia excited by ischemia on still viable cells of the peri-infarct area refers to the mechanisms of delayed neuron death 3.Ischemic brain edema. ATP deficiency and the development of lactate acidosis, accompanied by a violation of ionic homeostasis, lead to the development of cerebral edema, which refers to the manifestations of secondary brain damage caused by its ischemia. In this case, an important role is given to the flow of Na+ ions, which is accompanied by the entry of water and Ca-ions into the cells. This leads to swelling of the apical dendrites and lysis of neurons (the theory of "osmolytic damage of neurons"). Edema begins a few hours after the onset of the stroke and reaches a maximum on the 2nd-4th day. Brain edema is characterized not so much by the accumulation of extracellular fluid as by an increase in the volume of water inside cells, primarily glial cells. In this regard, the term "edema-swelling of the brain"is used. Intracellular edema-swelling of astrocytes is considered as the main form of cytotoxic edema of the brain, observed after ischemia, when a number of pathobiochemical reactions of secondary neuronal damage are triggered and cytotoxic and excitotoxic effects are realized. Cytotoxic edema is based on primary damage to cell membranes and cell cytoplasm. As a consequence of astrocytic edema, there is a more intense release of excitatory amino acids from swollen astrocytes. In addition to cytotoxic edema, vasogenic edema develops, in the formation of which vascular factors play an important role, as well as mediators – kinins, glutamate, free fatty acids, prostaglandins and thromboxanes. The resulting increase in the permeability of microvessel walls, as a result of which protein molecules and other components of blood plasma pass through the BBB into the tissue spaces of the brain, not only increases the osmolarity of the intercellular fluid, but also damages cell membranes, disrupting the function of neural elements of the brain. As a result of edema, the volume of the brain increases and intracranial pressure increases. With further progression, the process is complicated by dislocation, wedging of the brain and violation of vital functions. 4.Hemorrhagic transformation of a brain infarction (HT). The frequency and probability of HT development correlates with the pathogenetic 35 nature of stroke, localization and volume of brain damage. A special predisposition to HT is cardioembolic stroke, and strokes with extensive sizes of the ischemic damage zone. HT can also be a consequence of reperfusion therapy for stroke. The key point is the fibrinolysis of the embolus, which leads to the restoration of blood flow through the ischemic arteries and capillaries. As a result, there is an increased diapedesis in the infarction zone and secondary intracranial hemorrhages, which can be of two types: hemorrhagic infarction and infarction-hematoma or parenchymal hematoma. Hemorrhagic infarction is characterized by blood infiltration of ischemic brain tissue without displacement and mandatory destruction of brain cells. Infarction-hematoma manifests as a homogeneous focus of high density, shaped like a lake, and occupies a certain area of the brain infarction (Picture 16). Picture 16. Zone of hemorrhagic transformation of the brain lesion (indicated by an arrow) (Skvortsova V. I., Volynsky Yu. D., Kirillov M. G. the First experience of using selective intra-arterial thrombolysis in the treatment of stroke // Diagnostic and interventional radiology-2007, no. 1) 5. Changes in the physical and chemical properties of blood. Obstruction of capillary blood flow in the area of local brain ischemia may be associated with violations of the rheological properties of blood, protein and electrolyte composition. This is primarily due to increased red blood cell stiffness, increased platelet and red blood cell aggregation, increased blood viscosity, hyperprothrombinemia, and increased albumin content. 6. Violations of the nervous regulation of vascular tone. This mechanism is important in patients with hypertension. Expressed vasoconstriction and failure of self-regulation of brain vessels during the rise of blood pressure lead to severe ischemia and the development of a brain infarction. Hypoperfusion of the brain with the subsequent development of stroke is also possible with paresis or paralysis of the intracerebral arteries and arterioles. 7. Reduction of compensatory possibilities of collateral blood supply. A rich network of anastomoses between the arteries that carry out blood circulation in the brain, provides ample opportunities for blood redistribution between different areas and compensation for reduced blood flow. The most effective 36 collateral blood circulation in the gradually developing occluding process in the main extracranial vessels. The effectiveness of collateral blood circulation is also affected by the level of systemic blood pressure, the safety of metabolic and myogenic mechanisms of self-regulation of cerebral circulation, the level of vascular lumen obturation (main vessels of the head, main arterial trunks or smaller vascular branches). For example, when certain proximal branches of the aortic arch are affected (nameless and common carotid arteries, subclavian artery), "stealing syndromes" may occur to the detriment of the blood supply to the brain. In addition, the ability to switch a section of nerve tissue to blood supply via collaterals depends on the state of the vascular wall. The latter is of great importance for any fluctuations in blood pressure, since it is the state of the vessel wall that determines their ability to narrow and expand. Thus, the redistribution of blood flow when closing one of the cerebral arteries is accompanied by a sharp expansion of the arteries in the area of adjacent blood supply. This type of vasodilation is possible only if the vascular wall is not affected by the pathological process and has normal contractility. Otherwise, the collateral pathways will be the most vulnerable areas of the brain's vascular network, since they are the main load when moving large amounts of blood from one area of the brain to another. 8. Reperfusion injury to brain tissue. Recovery of blood flow after ischemia is not only positive, but also negative. This is primarily due to the fact that when restoring vascular patency, blood enters the area of the ischemic artery with increased vascular wall permeability. At the same time, there is a gradual change in arterial perfusion of the brain. First, post-ischemic hyperperfusion develops with the release of vasoactive and anti-inflammatory metabolites. In this case, the need of the brain does not correspond to the blood flow, oxygen and glucose are not absorbed by the brain tissue, so it is possible to increase the processes of lipid peroxidation ("oxygen paradox"), the accumulation of intracellular calcium ("calcium paradox") and the development of an ion imbalance ("ion paradox"). The next stage is post - ischemic hypoperfusion (restricted blood flow). If there is a violation of microcirculation, then there is a zone of not restored blood flow (the phenomenon of "no- reflow"). The main cause of "no-reflow" is damage to the vessels of the microcirculatory bed, both structural and functional. Microcirculation disorders can be caused by a number of pathological processes associated with ischemia in stroke - endothelial dysfunction in arterioles and capillaries, edema of pericapillary tissues, microembolization by atheromatous and thrombotic masses, inflammatory response to ischemia (free radical damage, activation of a cascade of proinflammatory mediators, local hypercoagulation). Of particular importance is microcirculatory microembolization, which can develop independently in IS (natural microembolization), but can also be caused or aggravated by medical intervention for the purpose of revascularization (pharmacological or mechanical). 37 9. Violation of reparative processes. After a stroke, the brain tissue is activated for recovery. In particular, the expression of various genes and related proteins indicates an increase in regenerative and reparative processes, the plasticity of neural tissue and the formation of new associative connections. In the activated state, angiogenesis, neurogenesis, and synaptogenesis are also observed. These reparative processes, which are essentially interdependent, remodel the brain and lead to improved neurological functions. The severity of recovery processes is strongly influenced by neurotrophic factors, modulators of the functional state of membranes and receptors (gangliosides), endogenous regulators (neuropeptides). It is the level and completeness of their formation that determines in many ways the growth and branching of the processes of neurons and synaptogenesis. When restoring functions after a brain infarction, reparative processes have a certain regularity. Next to the nuclear zone of irreversible brain damage, zones of plasticity and secondary replacement of lost functions are formed. In this case, similar zones of hypermetabolism are formed in symmetrical regions of the opposite hemisphere of the brain (Picture 17). Picture 17. Restoring of brain function after a stroke. 1-zone of irreversible tissue necrosis; 2-zone of possible brain plasticity; 3-secondary zone of replacement of lost functions; 4-activation of the "mirror" zone in the opposite hemisphere of the brain (Fedin A. Modern concept of pathogenesis and treatment of acute brain ischemia-Scientific and practical conference "Treatment of brain ischemia" - Moscow, 2011) Stages of the ischemic (pathobiochemical) cascade Violations of the energy supply of neurons. As a result of a decrease in CC, aerobic glycolysis is sharply reduced, which normally provides 95% of the brain's energy needs. Metabolic processes in the brain acquire the character of anaerobic glycolysis: in these conditions, only 2 molecules of adenosine triphosphate (ATP) are produced from 1 glucose molecule, that is, 19 times less than in normal brain oxygenation, when 38 ATP molecules are formed from 1 glucose molecule. In addition, ischemia blocks the inclusion of pyruvic acid (PVA) in the Krebs cycle. Accumulating, PVA is not 38 oxidized, but turns into lactic acid. A significant increase in lactate in the first minutes after the development of brain ischemia causes a decrease in pH to 6.4– 6.7, there is a lactate-dependent intracellular acidosis (scheme 1). The development of energy deficit and lactate acidosis inhibit metabolic reactions and ion transport, as the energy-dependent Na+/K+-ATP-azic enzyme system is disrupted. As a result, there is a passive outflow of K+ from the cell and an influx of Na+ and Cl-into it. This second time increases the entry of water into the cell and contributes to edema. The resulting membrane depolarization opens charge-sensitive calcium channels to enter the Ca2+into the cell. Acute focal cerebral ischemia Energy deficit _________________________ Lactic acidosis Active ion transport disorders____________________ Glutamate excitotoxicity____________________________ Accumulation of Ca2 + inside the cell_________________________ Activation of intracellular enzymes________________________ Excessive synthesis of nitric oxide____________________________ Activation of oxidative stress reactions ______________________

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