Nina Simeonova

Pathologic Physiology

Part VI

Kyiv–2008

1
 CHAPTER 30

PATHOPHYSIOLOGY OF ENDOCRINE SYSTEM

Endocrine system plays important role in the regulation of basic physiological

processes. The specific function of endocrine glands realizes by hormones. Each
endocrine gland secrets not one, but several hormones with different biological effect.

Regulation of Endocrine Function

The function of endocrine system is regulated by nervous and endocrine mechanisms.

In spite of relative independence, endocrine glands are subordinated to the regulator
influences of nervous system. The disorder of the endocrine glands functions with the
emotional stress confirms the participation of brain in the regulation of endocrine
function. The nuclei of limbic system, reticulated formation and diencephalon influence
the secretion  of hormones.
The participation of vegetative nervous system in the regulation of physiological and
pathologic processes in endocrine system also takes place. The vagus excitation
strengthens the secretion of insulin; sympathetic nerves stimulate the adrenaline secretion
from the adrenal glands.
The central regulation of endocrine functions is achieved in two ways - nervous and
neurohumoral.
The main centers of the endocrine system regulation are located in hypothalamus. In
turn, hypothalamus function is connected with other divisions of brain. Neurosecretory
cells of the hypothalamus produce peptide neuropituitary hormones (vasopressin and
oxytocin), accumulating in the posterior lobe of the pituitary and coming into the blood
from there. They are addressed to the peripheral target cells. Hypothalamus regulates the
function of pituitary gland with the aid of the releasing-factors (stimulating oligopeptides
liberins and the inhibiting ones are statins).
The tropic hormones of pituitary gland are the important mechanism of the
regulation of peripheral endocrine glands.
Interrelations between the central (hypothalamus, pituitary gland) and peripheral
endocrine glands are characterized by important peculiarity – it is the regulated
mechanism of direct and reversed relations. Increased concentration of the hormone
inhibits stimulating effect on this hormone synthesis. Decreased concentration causes an
adverse effect.
Interglandular hormonal connections are the important mechanism of regulation.
Interrelations between the hormones are characterized as antagonism, synergism and
permissive function. The latter consists in the providing optimal conditions for the
physiological activity of one hormone by another.

2
 The regulated influences of hormones are achieved with the aid of the receptors,
which are located on the cellular membrane of endocrine cells. Intracellular messengers
provide the transmission of the regulated influences from the receptors to the cellular
nucleus.
The synthesis of any hormone requires specific substrates and enzymes and determines
by genetic mechanisms.
The predecessors of hormone are transformed into the final hormone.
The secretion of hormone from the glandular cells is an energy depending process.

Mechanisms of the Hormones Peripheral Effect

Released hormone is transported to the target cells by the blood with the aid of
transport proteins (albumins for estrogens, transferrin for insulin, transcortin for
glucocorticoids). Binding of hormone with the transport protein and its release from this
connection are the fermentative process.
The hormonal effect on a target cell is achieved with the participation of the cellular
receptors (for the peptide hormones), which determine cellular sensitivity to the hormone,
and the participation of intracellular messengers.
Hormones are destroyed in the liver.
The brief enumeration of the physiological aspects of the endocrine glands functions
helps to understand a numerous reasons, which lead to the endocrine pathology.

Participation of Hormones in the Development of Typical Pathologic Processes

and Leading Pathophysiological Syndromes

The participation of endocrine system in the development of different pathological

processes was mentioned in the previous chapters for many times.
The value of genetic factors in the endocrine pathology was mentioned. The majority
of chromosomal diseases is manifested by endocrinopathy and sterility. The role of
glucocorticoids and mineralocorticoids in the development of inflammation was
mentioned. Glucocorticoids were mentioned as the leading therapeutic means for allergy
treatment.
Hormones play important role in the development of all typical metabolic disorders –
the role of insulin in the development of diabetes mellitus, thyroxine - in the disturbance
of basal metabolism, aldosterone and vasopressin in the development of edema.
In the development of arterial hypertension catecholamines (adrenaline), aldosterone
and vasopressin play important role. The role of aldosterone and electrolyte disbalance in
the development of the myocardial necroses (infarct) was mentioned also.
It was mentioned, that in hepatic insufficiency the destruction of hormones is
depressed, and the picture of endocrine hyperfunction with the relative surplus of
hormones is observed. The kidney insufficiency, as it was mentioned, is accompanied
with arterial hypertension of nephritic origin and edema, in the development of which an

3
important role belongs to renin (hormone-like substance), aldosterone and vasopressin
(antidiuretic hormone).

ENDOCRINE INSUFFICIENCY

Endocrine insufficiency is an acquired and the genetically determined state of

organism, which is connected with disorder of the hormonal control on physiological
functions of organism.
It should be taken into consideration that the term insufficiency is not a synonym of a
term deficit, but reflects the disorder of function, which has the form hypofunction,
hyperfunction and disfunction.

TYPES
Classification

Several classifications of endocrine insufficiency are suggested depending on the

different principle, which are the basis of classification.
As to the participation of genetic mechanisms it is divided into acquired and
hereditary.
Monoglandular endocrine insufficiency is the pathology of one signal endocrine
gland. The polyglandular endocrine insufficiency is the pathology of several endocrine
glands.
The division of endocrine insufficiency into the glandular and extraglandular reflects
topographic aspect. In turn, extraglandular one is subdivided into preglandular and
postglandular.
Glandular endocrine insufficiency is subdivided into the partial and total depending on
that, the synthesis of all or one hormones of this gland is disrupted.
The division of endocrine insufficiency into the relative and absolute reflects the fact
that the production of hormone can be normal, however, metabolic dismetabolism is
similar to those that occur with the absolute deficit or surplus of hormone. The reasons
of relative endocrine insufficiency are located out of the endocrine gland. Relative
endocrine insufficiency can be complicated by absolute.
The division of endocrine insufficiency into the primary and secondary reflects the
sequence of disorders, namely, either it starts in the gland or it is a complication of
another illness.
As to the clinical current, endocrine insufficiency is divided into acute and chronic.
The age of patient has great significance in the endocrine pathology development.
Depending on this, endocrine pathology is divided into endocrinopathy of children's and
young age (growing organism) and endocrinopathy of adult or elderly patients. Sexual
differences in endocrine insufficiency also significant.
Each form of endocrine pathology is manifested in turn in the form of three syndromes
– hyperfunction, hypofunction or dysfunction. Dysfunction means the differently

4
directed changes of the production of different hormones in one gland or the formation of
atypical hormonal compounds.

METHODS OF EXPERIMENTAL STUDY

It is most easy to illustrate the role of experiment in the pathophysiology and its forms
by experimental study of the endocrine pathology.
The method of removal is the extirpation (ectomy) of endocrine gland.
The method of overload consists in the introduction of hormones or endocrine gland
extract into the animal.
Method of damage is the injury of endocrine gland by radioisotopes or immune
antibodies.

ETIOLOGY

Etiological factors, which lead to the endocrine insufficiency, are physical, chemical
and biological.
Among the physical factors the mechanical trauma and especially ionizing radiation
have the greatest value.
Among the chemical factors both deficit and surplus of microcells (iodine, cobalt),
poisons, radioactive nuclide and medicines have a value.
Biological factors include infectious, immune, genetic and psychogenic.
Endocrine glands can become an object of autoimmune aggression. The formation of
autoantibodies against the peptide hormones (releasing-factors of hypothalamus,  tropic
hormones of the hypophysis - somatotropic STH or of thyrotropic TTH, prolactin,
antidiuretic hormone of hypophysis - vasopressin, and insulin) is possible. The
production of autoantibodies against the cells of endocrine gland, and also against the
receptors on the membrane of endocrine cells or target cells is possible also. There is a
type of delayed type autoimmune reactions, so-called, stimulating, when antibodies
perform the stimulating role for the receptors similarly to tropic hormones.
The role of genetic factors is manifested in the form of genetic and chromosomal
mutations. Manifestations - enzymopathy, the genetic defect of hormones and protein
receptor, the defects of the endocrine glands genesis. Chromosomal and moleculo-genetic
diseases include the pathology of endocrine system. The patients with the syndromes of
Turner -Shereshevsky, Klinefelter are sterile.
Psychogenic overload and stress can be the factor of damage (cause thyrotoxicosis,
diabetes mellitus, disturbances of ovarian-menstrual cycle).

PATHOGENESIS

All typical pathologic processes can be developed in the endocrine glands, and also in
the organs, whose disease is secondarily manifested by the disturbance of the endocrine

5
glands function. These pathologic processes are the following - inflammation (including
allergic and infectious), tumor, thrombosis, the disturbance of hemostasis, atrophy,
dystrophy, genetic disorder, dismetabolism.

Preglandular Disregulatory Endocrine Insufficiency.

Disorder of the Central Mechanisms of the Endocrine System Regulation

In such cases the pathology develops in the organs, which regulate endocrine
functions. The following reasons and mechanisms are possible:
 Disorder of high nervous activity, for example, mental trauma frequently lead to the
endocrine diseases (diabetes mellitus, thyrotoxicosis, amenorrhea). It is the so-called
psychogenic endocrinopathy. Destruction or stimulation of limbic system, reticulate
formation, diencephalon together with irritation or blockade of the central and
peripheral mechanisms of vegetative innervation damage formation and secretion of
hormones.
 Disorder of the neuroendocrine regulation of endocrine system is caused by
pathology of hypothalamus or other part of the brain connected with it.
Hypothalamus pathology usually involves entire endocrine system. These diseases
are called neuroendocrine (hypothalamic syndrome). The damage of central regulatory
mechanisms are accompanied by pluriglandular endocrine insufficiency.
 Pathology of the hypophysis, which secretes the tropic regulated hormones for the
peripheral endocrine glands, causes diverse glandular pathology, most frequently
partial.
 Disorder of the so-called reversed connections is an important pathogenetic
mechanism of endocrine insufficiency. Reduction in hypothalamus sensitivity to the
effect of peripheral hormones leads to the more intensive production of releasing-
factors and tropic hormones of hypophysis. As a result, the peripheral gland activates
its function and results in exhaustion and insufficiency. Most frequently peripheral
gland answers not by activation of function, but the growth and the formation of
tumor (adenoma of prostate gland, the fibromyoma of utery). If patient uses some
hormone for the purpose of treatment (for example, prednisolone with the
rheumatism), the peripheral gland becomes less sensitive to the corresponding tropic
hormone of adenohypophysis. It creates a problem of cancellation of hormonal
therapy.
 All endocrine glands act as united system due to the interendocrine relations. It leads
to the situation, when the pathology of one gland causes another. For example, the
removal of the thyroid gland leads to the disturbance of the sexual glands and adrenal
cortex.
The disorder of the central regulation of endocrine functions usually leads to the
disorder of the hormone synthesis and an absolute deficit and hypofunction.

Glandular Type of Endocrine Insufficiency

6
 Glandular form of hormonal insufficiency appears as a result the disturbances of any
stage of formation and secretion of hormones. Inflammation, infection, autoimmune
aggression, vascular disorders (thrombosis), alimentary disturbances and the insufficient
entering of substrates and microcells can be the basis.
Glandular insufficiency can be total (formation of all hormones of a gland is disrupted)
and partial (formation of one hormone is disrupted).
Hypofunction, hyperfunction and dysfunction manifest this form of hormonal
insufficiency.
The following mechanisms are possible:
 Disorder of receptor system on the surface of endocrine cell, namely, the sensitivity
of these receptors and endocrine gland to regulatory signals. As a result, the
synthesis of hormone in response to the regulatory nervous and hormonal influences
stops.
 Disorder of intracellular messengers (adenylate cyclase system) which transfer signals
from the receptors to the genetic apparatus of cells. Damage of the Ca-ion entering
into the cell.
 Deficit of the substrates, microelements and ferments, which are necessary for the
hormone synthesis.
 Infectious damage of endocrine gland.
 Immune damage of gland (formation of antibodies against the gland).
 Destructive changes of gland (tumor, cirrhotic and inflammatory processes, a
sclerotic changes in the vessels).
 Cytotoxic damage of glandular cells by chemical (including medicinal) substances.
 Disorder of the prohormone transformation into the final hormone.
 Disorder of the hormone secretion.
 Genetic problems of the glandular cells functioning.
 Overproduction of hormones as a result of neoplasia (adenoma).

Postglandular Disorders.
Disorder of the Peripheral Hormone Effect

The postglandular disturbances of endocrine function lead to the relative hormonal

insufficiency. It is characterized by normal hormone production, however, the
dismetabolism is similar to absolute deficit or surplus of hormone. Clinical picture may
correspond to both the hypofunction and hyperfunction. Reason is located out of the
endocrine gland. The following reasons are possible:
 Disorder of the hormone transport in the blood (more strong or weak binding of
hormone with the transport proteins, the difficult or intensive release of hormone from
this connection).
 Increased or reduced production of the hormone antagonists.
 Activated or weakened hormone destruction.
 Increased need for the hormone (pregnancy).

7
 Pathology of receptors to the hormone on the target cells, which determine the
sensitivity of cells to the hormone effect. It is possible in
 decrease of a quantity of receptors,
 reduction in their affinity for the hormone,
 formation of antibodies against the receptors,
 genetic pathology of receptors.
Reduction in the sensitivity of the target cells to the hormone is called hormone
resistance. While aging, a quantity and sensitivity of receptors usually decreases. The
manifestations of hormonal insufficiency in elderly people are connected with it.
 Genetic pathology of the proteins, which participate in the endocrine function –
antagonists, transport proteins, receptor proteins, ferments that determine the hormone
synthesis, ferments that determine binding and release of hormones from the transport
blood proteins.

Compensatory-Adaptive Reactions

Endocrine system is a regulatory system of endocrine glands, transportation and

destruction of hormones. Both under the physiological conditions and in pathology,
endocrine system has the adaptive reactions, which balance organism with the external
and internal medium, which constantly change. They are the following:
 Presence of paired endocrine organs (the adrenal glands, ovaries).
 Hypertrophy of the pare organ during pathological process or removing one of them.
 Reverse connections between peripheral and central organs of endocrine system.
 Synergestic and permissive action of the hormones.
 Liability of the binding of hormone with the transport protein.
 Change in the quantity of receptors to the hormone on the target cells in dependence
with the content of hormone in the blood.
Concluding the account of the common concept of etiology and pathogenesis of
endocrine insufficiency, one should emphasize, that the common that is united all
endocrine glands was dismantled.
The points of hormone effect are the target cells. For each hormone they are specific.
The pathophysiological and clinical manifestations of endocrine insufficiency depend
on the endocrine gland and type of target cells, which function is disrupted.

PATHOLOGY OF PITUITARY GLANDS

The hormones of adenopituitary are thyrotropic, adrenocoritcotropic, gonadotropic

and prolactin. Hormones of neuropituitary are formed in hypothalamus, but are released
into the blood through the pituitary. They are vasopressin (antidiuretic hormone, which
influences revealing of water from the organism), oxytocin.

8
 Pituitary insufficiency may be total (panhypopituitarism) and partial in form of
separate pathology of adeno- or neuropituitary, hyper- and hypofunction.

Panhypopituitarism

Total insufficiency of the pituitary function may be congenital or acquired. The most
often causes of this disease are tumor, postnatal necrosis of the pituitary, inflammation,
thrombosis and viral infection. The affection of the glands in embryo leads to a dwarfism
(hypophysal nanism), hypogenitalism, and decrease of the function of the thyroid gland,
endocrine-methabolic disorders and decreases of the reactivity.
When more than 95% of the gland mass is destroyed, the adult people develop
hypophysial cachexia or Simmond's disease. It is characterized by severe cachexia and
atrophy of the thyroid, adrenal and sexual glands, the muscle tissue, visceral organs,
destruction of the bone tissue, hair and teeth falling, functional disorders of the vegetative
nervous system, hypoglycemia, increased sensitivity to insulin. Most of disorders are
connected with stopping of somatotropin and thyrotropin secretion.

Pathology of Neurohypophysis

The increased secretion of vasopressin (antidiuretic hormone) promotes the

accumulation of the liquids in the organism. It plays an important role in the
pathogenesis of reflex anuria (for example in pain shock) and edema, especially in cirrhosis
of the liver, when inactivation of the hormones is inhibited.

Deficiency of vasopressin disturbs the reabsorption of water in the tubules of the

nephron that results in polyuria and arterial hypotension. The patients excrete 3-8 liters of
urine with low relative density per day. Sometimes diuresis consists of 10-12 liters and
more.

Hyperfunction of Adenopituitary

The hyperfunction of adenohypophysis is more frequently partial. It is the

development of benign tumor (adenoma) from some cells.
If adenoma develops from the eosinophilic cells, hypersecretion of somatotropin
takes place.
The pathologic influence of excessive quantity of somatotripin on the organism is
determined by the ability of the hormone to increase the permeability of the cell membrane
to amine acids. Also it has an ability to accelerate their inclusion in synthesized proteins,
to stop disintegration proteolysis.
Increased lypolysis and inhibition of the lipid formation from the carbohydrates
increases the mobilization of fat from depot, contents of non-estherised fatty acids in

9
blood, their oxidation in the liver and formation of ketone bodies. It is due to the effect of
somatotropin on different links of the carbohydrate metabolism that hyperglycemia and
diminution of sensitivity to insulin are always observed (metasteroidal diabetes mellitus).
Pathologic effect of somatotropin on the connective tissue, bone and cartilage tissue is
stipulated by an ability of this hormone to stimulate pathologic formation of oxyproline (the
most important component of collagen) and chondroitine sulphate.
These and other effects of somatotropin are explained by the formation of a special
albuminous factor — somatomedin, which is formed in the liver under the influence of
somatotropin.
Hyperfunction of somatotropin in the human body is exhibited as pituitary gigantism
or acromegaly, depending on the age the pathology begins. Hypophysial gigantism
develops in excessive secretion of somatotropin in the young age, before the epiphysial
cartilages get closed. Later after closing the epiphysial sutures and completion of the
growth hormonal shifts cause acromegaly.
In this disease separate parts of the body are disproportionately enlarged, the features
of the face are enlarged. Simultaneously splanchnomegaly (enlargement of the liver, the
spleen and the heart) develops. These changes are stipulated by the growth of the soft
tissues. In acromegaly the concentration of the somatotropin in the blood can exceed
normal parameters 100 times and more.
If adenoma develops from basophilic cells which produce adrenocoritcotropin,
Itsenko-Cushing disease develops. The consequence of corticotropin hyperproduction is
a excessive secretion of cortizol and other glycocorticaids by the adrenal cortex glands.
Hypofunction of Adenohypophysis

Total hypofunction is more frequentl when all regions of adenohypophysis are

disrupted. Reason are inflammation of entire gland or its necrosis. It is manifasted by
severe fatal disease - Simonds, cachexia.
Partial hypofunction is a decreased production of any hormone of the pituitary.
Early falling out or depression of the somatotropic function of the pituitary leads to the
development of dwarfism or pituitary nanism. The diminution of the speed of synthesis of
proteins leads to atrophy of the muscular and connective tissue, which is externally
manifested by the flabbiness and aging of the skin. The sexual organs stay in the infantile
condition. Partial gonadotropic insufficiency leads to infantilism: in the girls it leads to the
absence of the menstruation, infertility; in boys it leads to the hypoplasia of the testis,
incomplete physical development and hypogenitalism.

PATHOLOGY OF THYROID GLAND

The basic hormone of the thyroid gland thyroxine influences metabolism.

There are five types of thyroid dysfunctions:
 hyperthyroidism (thyrotoxicosis), caused by an excess of thyroid hormone,
 hypothyroidism (myxedema), caused by a deficiency of thyroid hormone,

10
 goiter (Basedow's disease), a diffuse enlargement of the thyroid gland, caused by
promoted elevation of TSH,
 thyroid nodule, a focal enlargement of a portion of a gland, caused by a benign or
malignant neoplasm,
 abnormal thyroid functions tests in a clinically euthyroid patient.
The pathogenesis of the most common thyroid diseases involves an autoimmune
process with sensitization of the host's own lymphocytes by various thyroidal antigens.
Three major thyroidal antigens have been documented:
 thyroglobulin (Tg),
 thyroidal peroxidase (TPO),
 TSH receptor (TSH-R).
Both environmental factors (e.g. viral or bacterial infection or a high iodine intake) and
genetic factors (T- suppressor- lymphocytic immunodeficiency) may be responsible for
initiating of autoimmune thyroid disease.

HYPERFUNCTION ( HYPERTHYROIDISM )

These are many pathologic phenomena which are conditioned by the toxic action of
the exceeding quantity of thyroxin and thrijodtyronine.
The main mechanisms of increased effect of thyroid hormones which lead to
thyrotoxicosis development are:

 Increased thyroid hormones production ,

 weakening of thyroxin with thyroxin connected globulin,

 disorders of the metabolism of the thyroid gland hormones,

 increased sensitivity of the tissues targets to its influence.

Basedow Disease

Basedow disease is the most often manifestation is the diffuse toxic goiter.

Etiology. The most important etiological factor of thyrotoxicosis for the person is the
mental trauma. Infection and overcooling are considered to be predisposing factors.

Pathogenesis

In abundance of thyroxin and thrijodtyronine, the number of mitochondria in the cells

increases, they swell, increase the activity of oxidizing ferments
(succinatdehydrogenase, cytochromeoxidase, glycerophosphate-dehydrogenase), Na+,
ATP-ase, etc.

11
 Due to the high disintegration of glycogen in the liver and muscle tissue hyperglycemia
is marked. The utilization of glucose in the tissues is accelerated, the activity of
gexokinase is increased.
The abundance of the thyroid hormones inhibits the transformation of carbohydrates
in fats, accelerates disintegration of cholesterol and its utilization of the tissues,
intensifies oxidation of the fats in the liver and also increases the sensitivity of fatty
tissues to lipolytic action of adrenaline. Due to these changes mobilization of fats from
depot arises, explaining why the patients with thyrotoxicosis lose their weight and why
hyperchoiesterinemia and ketonemia occure.
Negative nitrogen balance gives evidence of the predominance of catabolism of
proteins.

Manifastations

Basedow's disease is characterized by typical syndrome: enlargement of the thyroid

gland, exophtalm, increase of heat production, tachycardia, arrhythmia, shivering of the
fingers, increase of the mental excitability, excitation, vibration, increase in the basal
metabolism, emaciation.
The thyroid hormones disturb the metabolism of the cardiac muscle. Dystrophic
changes in the myocardium, disorder of atrio-ventricular conductivity, overloading of the
left ventricle are revealed. The energetic and plastic maintenance of the cardiac activity
is disturbed. 'Thyrotoxic" heart reacts inadequately to cholinergic and adrenergic
influences.

HYPOFUNCTION (HYPOTHYROIDISM)

Etiology

Etiological factors of hypothyroidism in the people are:

 congenital defects of biosynthesis of the thyroid hormones, which are connected with
congenital hypoplasia or aplasia of the thyroid gland,
 autoimmune aggression against glandular epithelium,
 infectious processes,
 surgical intervention,
 damage of the gland by thyrostatic preparations,
 radioactive iodine due to overdosage,
 deficiency of iodine and cobalt coming into the organism.
Hypothyreoidism is manifested by reduction of basal metabolism, decrease of the
blood sugar level, tendency toward atherosclerosis, edema.
Autoimmune aggression has great significance in the development of hypothyroidism.

12
 In severe degree of the thyroid gland insufficiency, congenital or arisen in the early
childhood cretinism develops, in the adult people — myxedema.

Myxedema

Myxedema is a hypothyrosis with mucous edema.

Myxedema is characterized by decrease of metabolism and body temperature, obesity, and

immobility. As a result of the increased hydration of the skin and subcutaneous tissue and
the high accumulation of hydrophilic mucous substances in them the face becomes puffy
with poor mimics, the nose and the lips become thicker. Brittleness of the nails, hear falling
out and other trophic disorders are marked. The sexual function gradually subsides, the
intelligence decreases, memory is reduced, apathy and sleepiness appear, and in the late
period of the disease dementia appears.

Goiter

Goiter is an enlargment of the thyroid gland.

There are 3 types of goiter:
 thyrotoxic, with the increased function of thyroid gland (Basedow disease),
 hypothyroid, with reduced function of the thyroid gland,
 endemic with the normal function of the thyroid gland.
The first two types are observed above.
Endemic goiter is an enlargement of the thyroid gland due to iodine deficit in the
environment (in the water, in the food). In this case the production of the hormone of
thyroxine can be normal only because of an increase in the mass of gland.
This disease is widespread in Alp and other mountain regions of the world, where the
salt and water contain little amount of iodine. The deficiency of iodine stipulates decrease
of thyroxin and thryiodthyronine synthesis and due to this the production of thyrotropin
increases in the pituitary. In its turn it leads to hyperplasia of the thyroid glands, whose
mass sometimes reaches some kilograms.

Disorder of Calcitonin Secretion

Calcitonin interacts with receptors in kidneys and bones. This interaction stimulates
adenyl-cyclase activity and the generation of cAMP. Receptors for calcitonin are
localized in the cortical ascending limb of Henle's loop, while in bones, calcitonin
receptors are found on osteoclasts.
The main function of calcitonin is to lower serum calcium. This hormone is rapidly
released in response to hypercalcemia. Calcitonin inhibits osteoclastic bone resorption and
blocks the release of calcium and phosphate from bones. The latter effect is apparent
within minutes after the administration of calcitonin. This effect, along with the inhibition
of resorption, ultimately decreases the level of serum calcium and phosphate.

13
 Calcitonin accomplishes its antiresorptive effect acting directly on the osteoclast.
Calcitonin blocks bone resorption induced by a variety of hormones, including PTH and
vitamin D. The potency of calcitonin depends on the underlying rate of bone resorption.
Calcitonin also has a modest affect on the kidney to produce mild phosphaturia. With
prolonged administration of calcitonin, "escape" from its effects occurs.

PATHOPHYSIOLOGY OF PARATHYROID GLANDS

Primary hyperparathyroidism occurs due to excessive production and release of PTH
by the parathyroid gland. The main cause are:
 adenoma (80-85%),
 carcinoma (2-5%),
 diffuse hyperplasia (10% ) .
Secondary hyperparathyroidism occurs due to a defect outside the parathyroid gland. In
patients with chronic renal failure, there are many causative factors that contribute to the
enlargement of the parathyroid glands. They include
 decreased 1,25-(OH)2D production,
 reduced intestinal Ca absorption,
 skeletal resistance to PTH,
 renal phosphate retention.
In most cases of secondary hyperparathyroidism, parathyroid hyperplasia regresses
substantially with correcting underlying abnormality.

In animal with experimental chronic parathyrosis we observe osteoporosis,

accumulation of the calcium salts in the kidneys, lungs, heart and other intestinal organs.
The walls of the vessels become thick, and the blood pressure increases. The animals die
from anemia as a rule.

Hyperparathyrosis

The origin of hyperparathyrosis in the people is connected with adenoma or

hyperplasia of the parathyroid gland. General fibrosis, osteodystrophy develop and is
characterized by pain in the muscles, bones, osteomalacia, deformation of the skeleton.
Mineral components go out from the bones and accumulate in the muscles and the internal
organs. Nephrocalcinoses, constriction of the lumen of the tubules of the nephrons or their
occlusion by calculi (nephrolithiasis) develop that result in renal insufficiency. Due to
calcareous deposition in the wall of the magistral vessels, hemodynamics and blood supply
of the tissues are disturbed.

14
 The formation and the activity of the osteoclasts intensifies, their differentiation
into the osteoblasts inhibits. They participate in the formation of the bone tissue. The
absorsorption of calcium in the intestine increases, the reverse reabsorption of the
phosphate ions in the tubules of the nephrons gets decreased, the formation of the soluble
salts of calcium in the bone tissue and insoluble phosphate calcium in different organs
especially in the kidneys also increased.

Hypoparathyroidism

In the experiment hypoparathyroidism is reproduced by removal of the glands in dogs

and cats. In 1-2 days after the operation the animals become flaccid, refuse to take food,
have thirst, low body temperature, dyspnoe. There is a change of correlation of one-valent
(Na, K) and two-valent (Ca, Mg) ions due to reduction of calcium concentration in
blood from 2.25-2.99 to 1.0-1.25 mmol/1.
Feeding of parathyroectomized dogs by meat intensifies tetany due to insufficient
disintoxication of products of nitrous metabolism, in particular, weakened ability of the
liver to convert ammonium into urea.
Etiology
Causes of hypoparathyroidism in people are:
 complication of thyroid or parathyroid surgery,
 autoimmune aggression,
 post- I,31 therapy for Graves' disease or thyroid cancer,
 secondary to iron overload, Wilson's disease,
 DiGeorge syndrome: autosomal recessive disorder with congenital absence of the
parathyroid glands and thymic dysgenesis or agenesis,
 hereditary forms of hypoparathyroidism: autosomal dominant or recessive and X-
linked recessive.
 secondary to magnesium depletion,
 tumor invasion (very rare),
 hereditary nephrosis.
Relative hypofunction of the glands is marked in accelerated growth, pregnancy,
lactation and other conditions when the organism requires more calcium and salts of
calcium.

Pathogenesis

The main evidence of hypoparathyroidism is hypocalcemia, which eventuates in

different disorders.
Simultaneously with hypocalcemia blood has increased contents of non-organic
phosphorus. The mineral disbalance is conditioned by inhibition of resorption of the

15
bone tissue, absorption of the calcium in the intestines and increased reabsorption of
phosphates in the tubules of the nephrons.
A definite importance is attributed to the disorder of desintoxicating function of the
liver in the pathogenesis of parathyroprival tetany.
Pathogenesis and clinical picture of hypoparathyroidism in the human are close to those
observed in the experiment.
Increase of neuro-muscular excitability. There are multiple fibrillar convulsions of
the body muscles, which are then followed by episodes of clonic convulsions. Clonic
convulsions change into tonic ones, opisthotonus comes. Spasm contractions may spread
to the inner organs (pylorospasm, laryngospasm). The animals die during one of such
episodes.
Dysfunction of the parathyroid glands results in development of parathyroprival
tetany.
Children of 1st and 2nd year of life in have spasmophilia — periodic spasms of the
muscles, arising in the increase of the environmental temperature and other unfavorable
influences.
Laryngospasm is very dangerous as it may cause asphyxia and death.

PATHOLOGY OF ADRENAL GLANDS

There are 2 important parts of the adrenal glands – cortex and cerebral.
There are 3 groups of hormones produced in adrenal cortex – glucocorticoids
(hydrocortisone), mineralocorticoids (aldosterone) and sexual.

Hypofunction of the Cortical Substance of the Adrenal Glands

Acute Insufficiency
After adrenalectomy the depot of glycogen in the liver and muscles is exhausted. It is due
to a reduction of glucose-6-phosphatase activity. The speed of glycogenolysis in the cells of
the liver is reduced. The formation of glucose from amine acids is delayed si-
multaneously. All this leads to hypoglicemia, reduced sensitivity to insulin, increased
tolerance to glucose.
On the later stage of adrenal insufficiency blood pressure is decreased. Hypotension is
conditioned by reduction of the volume of the circulating blood, bradicardia and the
weakening of the vasoconstrictor action of catecholamins, for which corticosteroids are
permisive factor.
In the genesis of the acute adrenal gland insuffisiency the disorders of the water-
electrolyte metabolism play the main role. In physiological conditions aldosteron
supports sodium "pump", ensures the reabsorption of sodium ions in the distal parts of
the tubules of the nephron, but glucocorticoids increase the glomerular filtration.

16
 After removal of the adrenal glands the sodium ions go out of the body with the urine
and that's why the content of sodium in plasma of blood is reduced. At the beginning,
there is marked polyuria and than oliguria and anuria, "water poisoning" (high cells
hydration). It is explained by the fact that due to disorders of sodium pump the
intracellular concentration of soduim ions and the osmotic pressure are increased. The
acute increase of potasium ions concentration in plasma is the cause of bioelectric
processes disorders. Force and rhythm of cardiac contractions (up to ciliary arrhythmia),
weakening of the contractive ability of the striated muscle tissue take place.
In a terminal stage of acute adrenal gland insufficiency, the urination completely stops.
The pulse and the breathening are slowered down. The animal goes in coma and dies. The
life term of dogs and cats with ectomized adrenal gland ranges from 2-3 days up to 9-
11 days.
Acute adrenocortical insufficiency in a human can happen due to hemorrhage in the
adrenal glands.

Chronic Insufficiency

Chronic insufficiency of cortical substance of the adrenal gland in a human is known

as Addisson's disease (bronzed disease). It arises more often because of tuberculosis of
the adrenal glands, atrophy of the cortical substance after heavy infectious diseases or
prolonged treatment by corticosteroid preparations.
Chronic hypoadrenocorticism is characterized by emaciation, psychical tiredness, bad
appetite, dysfunction of the alimentary canal, arterial hypotension, progressive
hyperpegmentation of the skin. The mechanism of hyperpegmentation is connected with
intensification of melanostimulating activity of the pituitary gland, which is concomitant to
the increase of corticotropin secretion during hypoadrenocorticism. In the patient with
Addison's disease, different pathogenic effects such as trauma, infection, hemorrhages and
even tooth extraction can cause acute insufficiency of the cortical substance of the adrenal
glands.

Hyperfunction and Dysfunction of the Adrenal Cortex

The excessive secretion of cortisole, aldosteron (hyperaldosteronism), androgens
(adrenogenital syndrome) or estrogens (corticoestroma) are the leading pathogenic points,
determining the clinical picture of hyperfunction and dysfunction of the cortical
substance.
Itsenko-Cushing Syndrome

The reason for this disease is adenoma of the cells, which produce hydrocortisone.
Etiology of Itsenko-Cushing syndrome and Itsenko-Cushing disease is various, but the
clinical symptoms and the pathogenesis are very similar. The disease arises as a result of
the excessive secretion of corticotropin in adenopituitary tumors or diencephalic

17
regulation disorder. The syndrome is the result of the primary affection of the cortical
substance of the adrenal glands by tumor.

Medicamentous Synrome of Hypercorticism

Glucocorticoids (prednisolone) are used as immunodepressant while treatment of

different inflamatory and allergic diseases (bronchial asthma, rheumatism). The side
effects of this therapy resemble the picture of the hyperfunction of the adrenal cortex
(Itsenko- Cushing disease).
Clinical picture has the following manifestations:
 decreased synthesis of protein, the weakness of skeletal muscles,
 hyperglycemia can assume the form of diabetes mellitus (metasteroid),
 deposition of fat on face,
 increase of the arterial blood pressure,
 increase in the acidity of gastric juice and an increase in the risk of the stomach ulcer
formation.
The prolonged application of a hormonal therapy forms hormone-dependence. It
means that the production of own hormone is reduced. The exidental cancellation of
this hormonal therapy is accompanied by the development of the syndrome of
cancellation. Clinical picture is manifested as the acute hypofunction of the adrenal
cortex.
The clinical manifestations of the syndrome of cancellation are the following:
 hypoglycaemia,
 hypotension,
 reduction in the resistance of organism,
 muscular weakness,
 depression,
 disorder of growth and maturation of children.
Hyperaldosteronism

Under the influence of excessive aldosterone, sodium and water ions are retained in the
organism. The high concentration of sodium ions in the cells, especially in vessels walls,
increases their sensitivity to sympathetic mediators. In consequence, arterial hypertension
develops. Loss of considerable amount of potassium and chlorine ions causes myasthenia
and paresis, attack of the skeleton muscular cramps, disorders of myocardial contractive
function, non-gas alkaloids. The tubules of the nephrones are subject to dystrophic change
and lose ability to react to vasopressin. So, poliuria arises, which explains absence of
edemas in primary hyperaldosteronism.
In many pathologic conditions (cardiac insufficiency, cirrhosis of the liver, kidney
diseases with disorders of kidneys circulation, etc.), excessive production of aldosterone is
observed (secondary hyperaldosteronism). Decrease of blood pressure, hypovolemia, and

18
insufficiency of kidney depressor system and increased secretion of rennin by
juxtaglomerular cells with the following formation of angiotensin play the main role in
development of such sings. It is known that cells in the clustered zone of the adrenal glands
intensify production of aldosterone under the influence of angiotensin, ACTH (permissive
effect), abundance of K+ and Na+ deficit in blood plasma. Atrium natriuretical hormone
(antagonist of angiotensin), dopamine and high outcellular Na+ concentration inhibit
secretion of aldosterone.
Secondary hyperaldosteronism promotes retention of sodium and water in the
organism, loss of potassium and chlorine, development of edema, increase of blood
pressure.

Adrenogenital Syndrome

Adrenogenital syndrome in a child is a clinical manifestation of congenital hyperplasia

of the cortical substance of the adrenal glands.
Arising of the syndrome is connected with hereditary blockade of cortisol synthesis.
Secretion of corticotropin becomes disinhibited which stimulates secretion of androgens of
the adrenal glands. The latter has a virilizing effect — appearance and more evident signs of
the masculine sex in the intrauterine period. Consequences of hormonal disorders may be
different — from mild masculinisation to severe anatomic abnormalities of physical and
sexual development.
In boys this pathology cause premature development of the second sexual signs. Girls
often are born with pseudogermaphrodism. One of the androgenital syndrome variants in
children is characterized by deep disorder of ferments, which participate in biosynthesis of
steroid hormones and accompanied by severe disorders of water-electrolyte metabolism.
Without substitutional therapy with corticosteroids children die at early age.
If the hormone synthesis is blocked at the last stage, which is catalizated by 1.1-
hydroxilase, the excess of desoxicosterone is formed. In consequence, severe arterial
hypertension develops.
Adults and children can have hyperestrogenisation and hyper-androgenisation of the
organism in tumor of net (internal) zone of the adrenal glands cortical substance.
Depending on hormone secretion character, women can have development of virilisation,
men can have feminization (heterosexual syndrome) or person have premature sexual
development (isosexual syndrome).

Dysfunction of the Cerebral Part of the Adrenal Glands

Hypersecretion of catecholamines is observed in pheochromocytome. It is a tumor

originated from the cerebral substance of the adrenal glands with paroxysmal or stable

19
arterial hypertension or attack of tachycardia, acute pain in epigastrium, profuse
sweating. The attack is a result of massive throw out of adrenaline and noradrenaline into
the blood under the influence of psychical and physical loading and other provocatory
effects.

CONCEPT OF STRESS

Stress was mentioned in many chapters as a reason of a disease (arterial hypertension,

myocardial infarction, stomach ulcer, diabetes mellitus, thyrotoxicosis and others).
The study about the stress is connected with the physiological role and pathology of
the adrenal cortex. Canadian scientist Hans Selye is the author of this theory, which is
widely spread.
Selye noticed in experiment, that any harmful influence (trauma, infection,
overcooling, intoxication, muscular overloading) causes a complex of changes in the
thymus, adrenal glands, lymphatic nodes, blood composition and metabolism. He focused
special attention on the changes in the endocrine glands, in particular, the system of the
hypothalamic-adrenal system. He noticed, that any harmful influence is accompanied by
 activation of the adenopituitary (the role of ACTH secretion was revealed),
 hypertrophy of the cortical substance of the adrenal glands,
 increased content of the secretory granules in adrenal cortex.
Physiological role of glucocorticoids was revealed. It consists in
 activation of glyconeogenesis,
 increase of glucose blood level (hyperglycemia),
 increase of energy formation,
 reorganization of metabolism,
 protection of the membranes from damage,
 antipyretic effect,
 antiallergic effect,
 support of catecholamin effect.
Selye interpreted these changes as non-specific protective-adaptive reactions
developed at maximum. This group of symptoms he named as general (nonspecific)
adaptive syndrome. Selye drew the conclusion that precisely the hormones of
adenopituitary (corticotropin) and adrenal cortex (corticosteroids) play a significant role
in the development of adaptation. He called them as adaptive hormones.
Earlier W. Cannon and L. Orbelly studied the role of the sympathetic part of the
vegetative nervous system in the adaptive and trophic reactions. Selye added the concept
about the important role of endocrine system, especially, the hormones of pituitary and
adrenal cortex in the organism adaptation to the influence of pathogenic factors. Thus,
adaptation is a complex of nonspecific neuro-humoral reaction with participation of the
nervous system and endocrine glands.

20
 At the same time Selye revealed in experiments, that prolong tenseness of non-specific
adaptive reactions causes a typical complex of non-specific sighs of damage. They are:
 involution of the thymico-lymphatic apparatus,
 hemorrhage ulcers in the mucous membrane of the gastrointestinal tract.
Selye connected it with the prolong effect of adrenal cortex hormones. Really, in
experiment on rats, the prolong introduction of corticosteroids (combined with sodium
chloride) results in development of necrotic changes of the myocardium. Ulcers are
observed in pituitary ectomized animals.
It was Selye who introduced the term stress in medical science.
Stress is a condition of the nonspecific reactions of adaptation (developed at
maximum) and damage under the action of any strong influence (stressor).
So, we see the dual significance of stress. From one side, it is a tenseness of
adaptation, promoting life due to releasing of adaptive hormones, from another side
(with the prolonged duration) it is a damage.

Stages of Stress

Stress is manifested in three stages. They are :

 anxiety reaction (alarm reaction),
 the stage of resistance,
 the stage of exhaustion.
Alarm reaction means immediate mobilization. In turn, it is subdivided into shock and
antishock stages.
In the shock phase there are muscular and arterial hypotension, hypothermia,
hypoglycemia, eosinopenia, increased permeability of the capillaries, prevalence of
catabolic processes.
The phase of antishock is characterized by reverse changes - increase of blood
pressure, muscular tonus and blood glucose level. Increase of corticotropin and
corticosteroid secretion occurs with release of hormone reserves.
In the stage of resistance the cortical substance of the adrenal glands is hypertrophied
and secretes an additional amount of glucocorticoids. Anabolic processes prevale.
Glyconeogenesis is intensified.
At this stage not only the resistance toward the factor, causing stress, is increased, but
also to other different factors, even lethal agents. It is manifested in diminishing of
inflammation, prevention of the heart, kidneys and other organs impairment arising under
the additional influence of pathogenic factors. It is called as increase of nonspecific
organism resistance.
In prolonged effect of the injurious agent adaptation gets broken. The transition of
resistance stage into the stage of exhaustion is characterized by exhaustion of the
functional reserves. Atrophy of the cortical substance of the adrenal glands, exhaustion of
hormonal activity, involution of the thymus and lymphoid tissue, eosinopenia, negative
nitrous balance, decrease of the arterial blood pressure, activation of proteolysis,

21
development of hemorrhagic ulcers in the stomach and duodenum characterize the third
stage of stress.
In general, the stress outcome depends on the ratio of the force and duration of the
stressor effect and potential abilities of protective reactivity of the organism.

Diseases of Adaptation

Complex of adaptive reactions can be disturbed. According to Selye, endocrine

insufficiency (first of all hypo- and hyderfunction of pituitary and adrenal cortex) causes
adaptation insufficiency.
Introduction of glucocorticoids to the animals inhibits inflammation and immune re-
actions, cause impairment of the stomach and duodenum. Introduction of large doses of
desoxicorticosterone predisposes to the development of arterial hypertension,
nephrosclerosis, hyalinosis of the organs. Insufficiency of glucocorticoid secretion
promotes hyperergic course of inflammation and other pathogenic effects.
Selye considered rheumatism, bronchial asthma, some diseases of the kidneys, heart
and vessels, some skin diseases and others to be the diseases of adaptation. Any additional
influence of moderate force (overcooling, overheating, physical overstrain, excessive
intake of salt) is of a great significance in their arising.

Significance of Stress Concept

Stress concept has great influence on medicine development.

The study about the stress started the clinical use of hormones of the adrenal cortex in
medical practice. Selye gave theoretical groundation to corticosteroid therapy. It is used
in the gravest conditions in the departments of reanimation for increasing the resistance
of organism.
Use of the glucocorticoids, as immunodepressants, in allergy takes place. However, the
prolonged use of these hormones has sideline effect, which were named above.
Nonspecific therapy (autohemotherapy and acupuncture) was explained on its basis as
well as mechanisms of training with systematic influences of weak and moderate stimuli
(cold, physical exercises; muscular tension protects the animal from myocardial necrosis
caused by intravenous injection of proteolytic enzymes) on the organism, which support
the readiness of the endocrine system to adaptive reactions.

CHAPTER 31

PATHOPHYSIOLOGY OF NERVOUS SYSTEM

22
 The pathology of nervous system composes the separate branches of medicine –
neurology, psychiatry.
Functions of nervous system are –
 regulatory,
 sensitivity,
 motion,
 secretory,
 nervous trophicity,
 higher nervous activity,
 formation of constitution.
Nervous system performs its functions with the aid of the neuromediators and the
neurohormones.
The role of nervous system in the pathology was mentioned in all previous themes. It
was mentioned the role of nervous system in the development of inflammation, fever,
starvation, hypoxia, and also in insufficiency of all physiological systems (heart and
vascular insufficiency, respiratory, endocrine disturbances and so on).
This chapter deals with the disorder of nervous system functions.

ETIOLOGY

Disorder of the nervous system activity may appear as a result of the influence of
different factors affecting metabolism, structure and function of the nervous cells.
Etiological factors are exogenous and endogenous, and also physical, chemical and
biological.
Physical factors are mechanical trauma, barofactors, ionizing radiation (nervous form
of acute radiation disease), high and low temperature (thermal shock), electrical energy,
electromagnetic fields, noise, vibration.
As a result of its high sensitivity nervous system first of all reacts to a change in the
environment. The bones protect nervous system from trauma. Penetrating wounds of
head damages the brain and predispose to infection.
Chemical factors are cerebrotoxical substances. They are exogenous toxic substances
of natural and artificial origin, industrial poisons, alcohol, narcotics, psychotropic
medicines. They are a large group of the so-called neurotropic poisons which can
selectively disturb bioenergic processes in the nervous cells, formation, transportation,
excretion and metabolism of neuromediators, influence permeability of ionic canals in
neurons.
Clinical examples of endogenous intoxication are hepatic, diabetic coma and uremia.
Biological factors are infectious agents with the preferred neurotropic action –
neurotropic viruses (poliomielitis, meningoencephalitis and encephalitis),
meningococcus, pale spirochaeta, toxoplasma, causative factor of tuberculosis. They
cause pyogenic meningitis, cerebral abscess, fungal infection.

23
 Human immunodeficiency virus (HIV) can cause nervous system dysfunction,
may affect the brain, spinal cord, and peripheral nervous system by direct HIV
infection.
Psychogenic factors cause psychogenic shock. The pathology of internal organs
causes the disturbance of nervous activity by reflex under the influence of strong and
extraordinary actions upon external and internal receptors (in presence of concrements
in the bilious and urinary tubules, the pathology of uterus).
Social factors occupy an important place among the reactions which cause the
nervous system disturbances.
A man possesses the second signal system. With the help of images symbols and
notions a model of the surrounding world is created in his imaginatin. Prolonged or
frequent conflict situations which are connected with peculiarities of personality,
character of his social environment, organization of society on the whole, conditions of
work and mode of life may lead to an excessive stimulation of emotional centers and
disturbances of the higher nervous activity of a man, development of neurotic states,
psychic diseases and different psycho-somatic disturbances.
Immune damage of nerve tissue is possible as the autoimmune aggression in the case
of the disturbance of blood-brain barrier and loss of the physiological immunological
tolerance.
The genetic factors determine disturbances of nervous activity are described as
hereditary and chromosomal diseases. Affection of the nervous system in hereditary diseases
may have a secondary character (e.g. phenylketonuria).
Influence of aging on the structure and functions of the nervous system is beyond
doubt. With the age atrophy of neurons takes place that leads to the decrease of the brain
mass. During this process the decrease of mass of neurons occurs in different speed in
different parts of the brain and starts in different time.
Localization of damage is the important condition for the development of the
pathology of nervous system.

PATHOGENESIS

The development in the nervous system of all typical pathologic processes, which were
described – inflammation, tumor, hypoxia, the local disorders of blood circulation
(thrombosis, embolism, ischemia) is possible. Starvation, the vitamin deficiency in
particular, often causes disturbances of the nervous activity.
There are some peculiarities of the development of these pathologic processes in the
nervous system.
The special feature of inflammation and infections in the nervous system lies in the
fact that blood-brain barrier protects nerve tissue from the penetration of infection. It is
connected with the fact that, as a result of the microminiature structure of this organ,
neither phagocytosis nor antibodies production occur. From other side, precisely, the
presence of this barrier creates risk for the nervous system. If this barrier is disrupted,
own cells of nervous system become the object of autoimmune aggression.

24
 The tumors, which are developed in the nerve tissue, are benign and malignant, and
also primary and metastatic. Clinical picture depends on localization of tumor.
The disorder of blood circulation in the brain have very serious consequences. This
pathology is called stroke (insult). Specifically, it is very sensitive to the disturbance of
local (cerebral) and system blood circulation (decrease of the arterial blood pressure).
Reasons are - shock, collapse, thrombosis, embolism, ischemia, angiospasm.
Cerebrovascular disease is the most common group of the central nervous system
disorders. After heart disease and cancer it ranks the third major cause of death.
Infarction is caused by arterial occlusion from thrombosis, which is most often caused
by atherosclerosis, and embolism.
Hemorrhage (intracerebral, subarachnoidal) consists of bleeding into the brain
space or subarachnoidal space.
Transient ischemic attacks are brief episodes of impaired neurologic functions
caused by temporary disturbance of cerebral circulation.
It is necessary to mark that the nervous system (especially its central sections) is very
sensitive to hypoxia. The brain consumes about 20% of oxygen entering the organism. At
a sudden termination of oxygen supply of the brain (inhalation of oxygen-free gaseous
mixtures, disturbance of cerebral circulation) loss of consciousness comes, normal
bioelectric activity of the brain stops. Fool restoration of the brain function in such cases
is possible when the duration of circulation standstill does not exceed 5-6 min. If
ischemia of the brain continues, memory and intellect will be irreversibly disturbed. It
should be marked that different parts of the central nervous system possess different
sensitivity to oxygen deficiency. Phylogenetic old structures are more stable to hypoxia.
The typical systemic disturbances of metabolism also have manifestations in this
system. Nerve tissue consumes the greatest quantity of glucose. The brain is very
sensitive to hypoglycemia. Practically all oxygen consumed by the brain is used by
oxidation of glucose. An acute decrease of the level of glucose in the blood a
disturbance of biological currents of the brain takes place. And loss of consciousness may
occur. Prolonged hypoglycemia causes irreversible damages of the brain cortex. At
more marked hypoglycemia the functions regulated by the truncal mechanisms are
disturbed. Hypoglycemic coma is manifested by the loss of consciousness.
Atherosclerosis of cerebral vessels (disturbance of lipid metabolism) is the frequent
reason of the diseases of organism.
The deficit of vitamins of group B has neurologic manifestations.
Disorders of the nervous system activity are observed in the changes of concentration
of electrolytes and hydrogen ions in the blood.
Dystrophy and degenerative processes critically disturb the functional activity of
nervous tissue. Demyelinating diseases are characterized by destruction of
myelin with relative preservations of axons (multiple sclerosis).
Degenerative diseases are:
 Alzheimer's disease is the most important cause of dementia (progressive
dementia, decreased number of neurons in nucleus basalis, generalized

25
 cerebral atrophy, granulovascular degeneration), especially affecting temporal
and frontal lobes.
 Huntington's disease is autosomal dominant disorder with delay of onset of
clinical abnormalities to the age of 30-40. It causes chorea and athetoid
movements, progressive motor deterioration, motor deficits (bradykinesia,
akinesia) or abnormal activation of the motor system, resulting in rigidity, trem-
or, involuntary movements.
 Parkinsonism (paralysis of old age) usually occurs after the age of 50. There is
degeneration of nigral neurons. It leads to the loss of dopaminergic inhibition
and relative excess of cholinergic activity (dopamine is synthesized by neurons in
the substantia nigra).
Universal mechanisms of disturbances of all functions are the following: loss of
ability to maintain the definite quantity of membranous potential by the nervous
cell due to disturbance in passing excitation from one nervous cell to another one,
from one part of the nervous system to another one.
If nerves are damaged so much that its connection with the body of neuron is lost, it
degenerates and then the cessation of axoplasmatic flow and transportation of substances
of axoplasm occur.

Congenital Disorders

Neural tube defects are spina bifida (failure of posterior vertebra arches to close),
ancephalopathy.
Hydrocephalus is an increased volume of cerebrospinal fluid within the cranial
cavities (ventricles).
Fetal alcohol syndrome is associated with maternal alcohol abuse during pregnancy.
It is characterized by facial abnormalities and developmental defects such as
microcephaly, atrial septal defect and other anomalies.

MANIFESTATIONS

At the molecular level the disturbances are manifested in the disorder of the
formation of potentials, and also disturbance of the formation of neuromediators and
neurohormones.
The important links in pathogenesis of many disorders of the neuron functions are
the following:
 loss of ability to maintain the definite quantity of membranous potential by the
nervous cell, to generate potentials and pass excitation from one nervous cell to
another one,
 decrease of the quantity of interneuronal contacts,
 disorder of formation, excretion and disintegration of mediators.

26
 There are many facts that the activity of the nervous system and especially of its
higher sections is defined mainly by substances of the peptide nature (neuropeptides),
which are produced both by the nervous and other cells and carry out mediatory and
nonmediatory functions. Opiate brain systems, the work of which is regulated by
endorphins and encephalins, are the most studied. However in the brain of the man and
animals scores of other oligopeptides were discovered, injections of which into the
cerebral ventricles or directly into the nervous centers may cause different emotional
states and behaviour reactions, influence on elaboration of conditional reflexes, ability
to memorize, to study etc. Probably in pathogenesis of disorders of the nervous system
functions insufficiency of excessive formation of neuropeptides, change of sensitivity
of nervous cells to them may have significance.
At the tissue level the disturbance of the function of the highest and subcortical nerve
centers, and also the nervous conductors take place.
At the level of entire organism the pathology of the nervous system may be as
follows:
The disturbances of motor function are manifested by paralyses, parhesis and
convulsions.
Disorder of sensitivity depends on the disturbance of the ascending pathways. There
are two centripetal systems of sensitivity. One of them is called lemnisk and contains the
nervous fibers of large diameter which conduct stimuli from the proprioreceptors muscles,
sinews, joints and partially from cutaneous receptors of touch and pressure (tactile
receptors). The fibers of this system are included in the spinal cord and pass in the
structure of the posterior column into medulla oblongata. From nuclei of the medulla
oblongata the medial loop (lemnisk pathway) begins which passes on the opposite side
and ends in the posterio-lateral ventral nuclei of thalamus, neuron of which transmit the
obtained information of the somatosensory zone of the cortex of the brain. The second
ascending system in the spinothalamic (anterior and lateral) pathway carrying pain,
temperature and partially tactile sensitivity. Its fibers go up in the structure of the anterior
and lateral funiculi of the spinal cord and terminate in the cells of nuclei of the thalamus
(anterolateral system).
Changes of sensitivity are observed at cutting of the right or left half of the spinal
cord (Brown- Sequard's syndrome). On the side of cutting the deep sensitivity
disappears while temperature and pain ones disappear on the opposite side, as the
conductive pathways relating to the anterolateral system intersect in the spinal cord. The
tactile sensitivity is partially disturbed on both sides. The disorder of the lemnisk system is
possible in damage of the peripheral nerves (thick myelinic fibers) and also in various
pathologic processes in the spinal cord (disturbance of blood circulation, traumas,
inflammation).
The isolated damage of the posterior funiculi of the spinal cord occurs seldom, but like
other conductive pathways they can be damaged by tumor or during trauma. The
disturbance of conductivity in the fibers of the medial loop causes various disorders of
sensitivity, manifestation of which depends on the degree of the damage of the system.
Thus the ability to determinate speed and direction of motion of the limbs may be lost. The

27
feeling of separate perception of touch simultaneously in two places and also the ability to
feel vibration and to evaluate the weight of lifted load are considerably disturbed. The
sensation of pain and temperature sensitivity is preserved.
The disorder of sensitivity is manifested in the form of following symptoms -
hyperesthesia (increase of it), hypoesthesia (decrease of it) and anesthesia (lack of
sensitivity).
Depending on the character of the lost sensitivity there are tactile anesthesia, analgesia,
thermanesthesia and loss of deep or proprioceptive sensitivity.
An important sing of sensitivity disorder is a pain.

PAIN

Pain is a leading symptom of any disease.

Pain is a negative sensation and the negative reaction of organism to it.
The pain signals cause an adaptive effect. There is also a pathologic pain. The
pathologic pain conditions the development of the structural and functional changes
and impairments in the cardiovascular system, in the inner organs, in the system of
microcirculation, tissue dystrophy, disturbance of the vegetative reactions, changes in
the activity of the nervous, endocrine, immune and other systems. The main biological
criterion of distinguishing the pathologic pain from the physiological one is its
disadaptive and pathologic meaning for the organism.

PATHOGENESIS

Pain is unpleasant sensation realizing by a special system of the pain sensitivity and the
highest sections of the brain related to the psychoemotional sphere.
The system of perception and transfer of the pain signal is called nociceptive
(nociperceptive) system. The physiological system of reduction of pain exists in the
organism is. Its name is an antinociceptive system.
In the development of pain painful receptors, central painful centers (in
hypothalamus), and also mediators of pain (serotonin, bradykinin, prostaglandins) have a
value.

28
 According to the "gate control" theory of pain, there is a control mechanism for
passing of nociceptive impulsation by the afferent system into the spinal cord. Their
control represents "gate" which regulates the activity of T-cells and flow of imputations
produced by them, ascending by the pain tracts to the highest of the pain sensitivity.
From the point of view of this theory the pathologic pain occurs in insufficiency of the in-
hibitory mechanisms of the gate control when the uninhibited T-cells may be activated by
different stimuli from the periphery and other sources. Constant flow of stimuli from
different sources to T-cells with disturbed inhibitory control is a condition of the path-
ologic pain.

According to the generator theory the pathologic pain is caused by formation of

generators of the pathologically intensified excitation in the nociceptive system. The
generator is a formation of hyperactive neuron, which may develop self-supporting
activity without any additional stimulation from periphery or other sources. Generator
is formed in the nociceptive system and represents a new pathodynamic organization
with abnormal character of producing the pathological pain. It is a pathological algic
system (PAS) which is the base for the pain syndrome. The character of activity of the
generator and PAS allows understanding the peculiarities of the pathologic pain, in
particular, its attacks and character, preservation and intensification of pain after
provocation by single stimulus, spontaneous pain attack without afferent stimulation.
Peripheral sources of the pathologic pain may be tissue receptors (nociceptors) in
their intensified constant-stimulation, chronically damaged and regenerating sensitive
nerves (neuroma), demyelized fibers, etc. The damaged nerves are quite sensitive to
different humoral effects and therefore become an ectopic focus of nociceptive
stimulation. Neuroma plays an especially significant role. Neuroma is a formation of
chaotically grown sensitive nervous fibers, which is formed in unregulated regeneration.
Neuroma is quite sensitive to different effects. Different factors and changes of the
organism may provoke pain attacks (causalgia) in neuroma as well as in the damaged
nerve. Pains associated with the nerve damage are called neuropathic.
Central mechanisms of the pathologic pain are formation and activity of the
generation of the pathologically intensified excitation in some parts of the nociceptive
system and PAS, involving different parts of the pain sensitivity system.
The cause of the generator in the dorsal cornua of the spinal cord and nuclei of the
trigeminal nerve may be intensified from the periphery. Under these conditions the pain
initially of the peripheral character may acquire the character of the central pain
syndrome. The generator may appear in significant and stable depolarization of the
nociceptive neuron.
The inhibitory insufficiency of the neuron is an obligatory condition for the formation
and activity of the generator in any part of the pain sensitivity system.
The cause of the formation of the generator may be partial deafferentiation of the
neuron, for example, after cutting the ischiadic nerve or dorsal root. The epileptiformal
signals are registered at first at the deafferented dorsal cornua and then in the nuclei of the
thalamus and somatosensory zone of the cortex. The generator may be formed in the

29
dorsal cornua of the spinal cord under the local influence of different convulsants, their
nature is of no importance. In all cases there is a pain syndrome with characteristic
features.
The inhibition of the generator in the dorsal cornua or the caudal nucleus of the
trigeminal nerve by the inhibitory mediators leads to disappearance of the pain syndrome
for the time of their action when they are introduced in the area of the generator.
Anticonvulsants, inhibiting the generator, cause disappearance of the pain syndrome.
Under the influence of the primary generator, the functional state of other parts of the pain
sensitivity system is changed, the excitability of their neuron increases and there is a
tendency to formation of the neuron population with stable pathologic activity. Secondary,
generators may be formed in different parts of the pain sensitivity system. PAS also includes
structures of the emotional sphere and vegetative nervous system. Stable active PAS is a
pathophysiological mechanism of severe polymorphic pain syndromes.
Antinociceptive System. Nociceptive system has its physiological, functional antipode
— antinociceptive system that controls the activity of the nociceptive system structures.
Antinociceptive system consists of various nervous formations related to different parts
and levels of the central nervous system, beginning from the afferent entrance in the
spinal cord and ending with the brain cortex.
Antinociceptive system plays a significant role in mechanisms of prevention and
elimination of the pathologic pain. In excessive nociceptive stimuli, it joins the response
and lessens the flow of nociceptive stimulation and intensity of the pain sensation.
Thanks to it the pain remains under control and does not become pathologic.
The antinociceptive system requires additional and special activation.
Neurochemical Mechanisms of Pain. Neurochemical processes at different levels of
the nociceptive and antinociceptive systems realize neurochemical mechanisms of the
pain sensitivity.
The peripheral nociceptors are activated under the influence of many endogenic
biological active substances — histamine, substance P, kinines, prostaglandins, etc. The
substance P plays an important role in excitability conduction in the primary nocicep-
tive neuron. It is conditioned to be a pain mediator. The direct effect to the stimulating
substances causing depolarization or disturbance of neuron inhibition on the dorsal
cornua brings about the formation of the generator and the pain syndrome.
Effective endogenic analgetics are opioid neuropeptides. They inhibit the transmitting
of nociceptive neurons and activate the neurons of the antinociceptive system,
changing the activity of the neuron of the highest section of the brain. The substance
P may also cause analgesia and inhibition even of the pathologic pain, activating
antinociceptive structures, for example, the dorsal nucleus of the suture.
The analgetic effect has serotonin, noradrenaline, dopamine, and gamma aminobutyric
acid. Serotonin is a mediator of the antinociceptive system at the spinal level.
Noradrenalin is also a mediator of the descending antinociceptive system, it inhibits the
activity of the nociceptive neuron of the posterior cornua of the spinal cord and nuclei of

30
the trigeminal nerve. Gamma aminobutyric acid takes part in inhibition of the activity
if the nociceptive neurons are at the spinal level.

Significance

The value of pain is dual. From one side, the pain brings to patient large sufferings.
From other side, the pain is the defensive reaction of organism and signals about the
presence of pathology.

Treatment Principles in the Pathologic Pain

First of all, it is necessary to eliminate the etiologic factor maintaining the

pathologic changes in the nociceptive system.
As the nociceptive and antinociceptive effects are realized at different levels and by
several mechanisms, it is necessary to use complex pathogenetic therapy. It influences in
combination on different parts of the pathologic algic system.
The main principle of treatment of the pathologic pain is to inhibit the hyperactivity of
the nociceptive neuron and generators formed by them and to liquidate PAS, which is the
base of the pain syndrome.
Correction of the hyperactivity of the neuron and generator formation may be done
with the help of anticonvulsants. The main importance belongs to the blockers of Ca 2+
entry into the nociceptive neuron. It is accomplished with the help of Ca-antagonists.
Besides, it is important to effect psychoemotional, vascular and other vegetative and
tissue components of the pathologic pain.

DISORDER OF NERVOUS TROPHICITY

NEURODYSTROPHIC PROCESS

Nervous trophicity is a nervous control upon metabolism. The disturbance of nervous

trophicity bears the name of neurodystrophic process.

Mechanisms of Nervous Trophicity

Nervous trophicity is achieved by two mechanisms: impulsive (nervous mediators) and

unimpulsive (axoplasmatic flow). The substances of trophiciti accomplish the later.
Nervous trophicity is realised in such action of the nerves on the tissue which results
in metabolism changes according to the needs at each given moment. It means that the
trophic action of the nerves is closely connected with their other functions (sensitive,
motor, secretory) and together with them provides an optimum function of each organ.
The first proofs of the nervous influence on trophicity of the tissues were obtained by a

31
French scientist Majandy. In experiments on the rabbits he has cut the trigeminal nerve
and revealed ulcer in the zone of sensitive denervation (the eye, lip). The trophic
disorders develop in any organ if its innervation is disturbed by the intervention of the
nerves (afferent, efferent, vegetative) or nervous centers. A.D. Speransky with selective
damage of centers of hypothalamus revealed appearance of trophic ulcers in various
organs.
The medical practice can give a number of facts which also give evidence that the
damage of the nervous system (trauma, inflammation) may cause a damage in the
appropriate zone.
Today nobody doubts that the nerves influence on trophicity. But how is this process
accomplished? There are two points of view. Some consider that trophicity isn't an
independent nervous function. The nervous stimulus which sets an organ in motion (for
example, muscle) changes metabolism in the cell (acetylcholine activates metabolism and
ferments, which stimulate increasing permeability). Others think, that it is impossible to
reduce trophicity to impulsive (mediator) action of the nerve. The researches have shown
that the nerve has a second function, named unimpulsive. Axoplasmic flow occurs in
both sides, and the substances move via neuron, penetrate through synapses and appear in
the innervated cells. These substances exert a specific action on the effectory cell. The
surgical operation, when the nerve intended for the red muscle, grows into the white,
radical changes occur in its metabolism.
The question is, if special trophic nerves exist?
F. Majandy assumed that together with sensitive, motor and secretory nerves there are
also the special trophic ones, which regulate the tissue nutrition, i. e. assimilating of
nutritious materials.
I. P Pavlov in the experiment on animals among the nerves, coming to the heart, found
such a branch, which increases the power of systole without any influence on blood
circulation. I. P. Pavlov called this nerve "amplifying" and purely trophic. I. P. Pavlov
saw the complete and harmonious heart innervation in the triple nervous provision: the
functional nerves, vasomotor nerves, which regulate the supply of the nutritious material
and trophic nerves, defining the final utilization of these substances.
L. Orbelli had the same opinion.
However, it doesn't mean, that the sympathetic nerves have no other influence on
the tissue or that the motor (secretory) ones have no influence on metabolism. A. D.
Speransky said that all nerves influence metabolism, and there are no nontrophic
nerves — "the nerve is functional just because it is trophic".

Pathogenesis of Neurogenic Dystrophy

The trophic function performs by a principle of reflex. It means that in the analysis of
dystrophic process it is necessary to evaluate the value of each link of the reflex.
Neurodystrophic process is reproduced in the experiment by cutting of different nerves –
motor, sensitive, mixed.

32
 The sensitive (afferent) nerves play a special role. After cutting a sensitive nerve, the
information of the nervous center about events in the zone of denervation is interrupted. In
addition, the damaged sensitive nerve is a source of the pathologic information including
pain. Centrifuged influences on the tissue are proceeded from it. The special substance P
disturbing metabolism and microcirculation spreads through the sensitive nerves with
axocurrent in the tissue.
After cutting a efferent nerve, its normal functions disappear and pathological ones
occur. The impulsive activity and axonic transport of "substances of trophicity" are
disturbed. The functions of motility and secretion are ceased or perverted. The process
involves genome. The synthesis of ferments is disturbed, and metabolism acquires more
primitive character. The output of macroergs decreases. The membranes and their
transport functions are disturbed. The organ with disturbed innervation can become a
source of autoantigen. Process is complicated because of neurotrophic changes involve
the disturbance of blood, lympho- and microcirculation. Hypoxia appears as a result.
So, pathogenesis of neurogenic dystrophy is presented as a complex multifactor process:
the nervous system ceases "to control metabolism" in the tissues and after that disorders
of metabolism, structure and function occur.

Biochemical, Structural and Functional Changes in the Denervated Tissue

Changes of metabolism take place in the denervated organ. They concern

carbohydrates, lipids, proteins, nucleic acids, etc. There are observed not only quantitative
but also qualitative changes. So, myosin in the denervated muscle loses its ATPase
properties and glycogen in its structure becomes simple.
The reorganization of the fermentative process is observed. Thus, isofermentative
spectrum of lactate dehydrogenase varies for the benefit of LDG4 and LDG5, i. e. those
ferments, which are adapted to the anaerobic conditions. The activity of such ferments as
succinic dehydrogenase decreases. The common tendency is such, that metabolism
acquires an embryonal character i.e. glycolytic process predominates while the oxidizing
one is inhibited. The Krebs cycle is weakened, the output of macroergs decreases, the
energy potential is lowered.
In disorder of innervation there are essential morphological changes in tissues. In
denervated cornea, skin or mucosa all stages of inflammation develop. The prevention of
trauma, infection and drying doesn't prevent the process but delay its development.
Finally, ulcer appears which has no tendency to healing. The investigation of cells shows
the changes of the organelles. Mitochondrias are decreased in quantity, their matrix is
destroyed. The disorder of oxidizing phosphorilation and Ca-accumulating ability of
mitochondria together with energy production are connected with this. The mitotic
activity is reduced in the denervated tissues.
The development of the neurodystrophic process is associated with the functional
disorders.

33
 The skeletal muscles after denervation loss their main function – an ability to contract
(the cordial muscle contracts even in cutting of all extracordial nerves). The skeletal
muscles without sympathetic innervation react on adrenaline more than in norm. The
muscles separated from the motor (cholinergic) nerves react on acetylcholine more than in
the norm. It is a Cannon’s law of denervation, which means the increased sensitivity of
denervated structures. It is connected with a state of cholinoreceptors, which in the normal
muscles are concentrated only in the area of myoneural synapses, but after denervation
appear on the entire surface of myocyte membrane.
So, the response of denervated muscles consists not only in increase but also in perver-
sion of function when instead of relaxation they contract. It is easy to imagine what it
means, for example, for blood vessels.
The saliva glands secrete saliva, but its character does not depend on a kind of food.

Manifestations

Together with biochemical, structural and functional changes in the denervated tissue, the
heaviest manifestation of neurodystrophic process is a trophic ulcer.

PATHOPHYSIOLOGY
OF THE HIGHER NERVOUS SYSTEM

Types of Higher Nervous Activity

According to I. P. Pavlov there are 4 types of the nervous system:

 strong unbalanced type with predominance of excitation over inhibition;
 strong balanced type with high mobility of the nervous processes;
 strong unbalanced type with low mobility of the nervous processes and
predominance of inhibition over excitation;
 weak type with low development of excitation and inhibition.

NEUROSIS

Neurosis is a typical form of the functions of the nervous system disorder. It arises as a
result of overstrains and breakdown of higher nervous activity. The pathogenetic base of
the neurosis is a disorder of the main nervous processes - excitation and inhibition,
namely, their force and balance.

Etiology

34
 The pathology of the higher nervous activity is defined by some factors.
There are 3 groups of the causes in the etiology of pathology of higher nervous
activity. They are:
 environmental factors,
 genetic causes,
 their combination.
Posttraumatic pathology of higher nervous activity is the disturbance, which appear
as a result of direct action of pathogenic agent on the brain, for example, in its injury,
blood accumulation in the cerebral tissue and tumor of the brain.
Combined (functional and traumatic) pathology is the disturbances, which appear as
a result of action both on the receptor system of the organism and on the brain (for
example, in radioactive and thermal injury of the head, its mechanical injury, etc.).
The Role of the Negative Emotions. They appear under the influence of the pathogenic
irritants and can have a long stagnant character. They are promoted by the long delay of
external manifestation of negative emotion (the so-called unreactive emotions)
accompanied by hormonal and other chemical deviations in the blood. They decrease the
resistance of the nervous system to the pathogenic agent and thus independent self-main-
lined pathologic system is formed (vicious circle), which disorganizes the activity of other
systems. But such pathogenic influence of the negative emotions appears in their long
course. At early stages the negative emotions play the biologically positive role and have
characteristics of factor of extreme mobilization of the organism.
The functional disorders may occur as a result of long limitation of the inflow of the
ophthalmic, sound, tactile proprioceptive and other stimuli into the brain, changes of the
geographical regions, in long hypodynamia. The steadiness of higher nervous activity
decreases.
Due to the secondary signal system the functional pathology of higher nervous
activity can be stipulated by the verbal action. It means that pathologic agent can
influence on the higher parts of the brain through the second (verbal) signal system.

Pathogenesis

Pathophysiology of higher nervous activity studies the mechanisms of appearance

and development of the pathologic deviation of the higher nervous functions. The
mechanisms of pathology of higher nervous activity are based on emotions, memory and
humoral factors. Functional pathology is the disturbances of behavior, which are
conditioned by the action of the pathogenic irritants on internal and external receptors.
There are two causes for appearance of functional pathology of higher nervous
activity. They are:
 pathogenic agent acts on the receptors by the unconditioned reflex mechanism,
 pathogenic agent has a signal meaning and acts through the receptors of the brain by
the conditioned reflex mechanism.

35
 The action of pathologic agent induces the primary affection of the brain. Such
disturbances are called primary. The disturbances of higher nervous activity induced by
another pathology of the organism (infectious disease, non-cerebral localization of
tumor, cardiovascular disease) are secondary ones. As a rule, secondary pathology of
higher nervous activity results from astenisation of the nervous system, decrease of a force
of reaction to the psychogenic and other actions.
The method of electron microscopia established that the experimental neurosis has the
destructive changes in the neuronal and glial elements of the neocortex with parallel
reparative processes (a compensation of these disturbed functions).
The biological investigations of the neocortex in animals determined the reversible and
irreversible disturbances of the neuromediator system. The determination of
ultrastructural and neurochemical changes in the animal brain in experimental neurosis
leads to supposition that neuroses have structural basic. Any pathology has the
structural changes, which we can determine by the adequate methods of its
investigation.
The pathologic conditioned reflexes can be formed as a result of fixation of the
conditions, which appear in the brain under influence of pathogenic agent in the long-
term memory. Another mechanism of arising and maintaining of the pathologic higher
nervous activity consists in the formation of the pathologic time connections, which are
easily formed under functional disorders in the brain.

Manifestations

The manifestations of the functional pathology of higher nervous activity are various
but first of all they include the psychic functions. They are the weakness of analitycal-
synthetical activity of the brain, disturbance of the long- and short-term memory,
regulation of the emotions and motivations, regulation of general functional condition of
the brain, intersemifunctional condition of the brain and interhemispherical relations.
As a rule these disturbances are manifested in behavior. The frequent manifestation of
pathology of higher nervous activity is disturbance of cycles of sleep, regulation of the
vegetative and somatic functions, frequency of the cardiac contractions, regulation of the
arterial blood pressure and trophicity of the skin. The neuroses have such characteristics
as the disturbance of vegetative regulation, movements, nervous trophicity as well as a
decrease of the organism resistance.
The typical disturbances of the higher nervous activity for humans and animals are
noted in the organic injure of the frontal lobes of the brain cortex. The frontal lobe takes
part in the management of the congenital behavior reactions from positions of
accumulated experience as well as in concordance of the internal and external
motivations. We can see such changes in the patient with pathology of the frontal lobe as
absence of motivation, steadfast plans and intentions based on the prognosing with
preservation of intellect. The patient becomes rude, tactless, frivolous and irritable.
There is so-called information pathology as a form of functional pathology of the
higher nervous activity and behavior.

36
 The information pathology represents the different disturbances of the course of the
higher functions of the nervous system, and the disturbance of life activity of other
systems of the organism which appear under quite long of the unpleasant conditions of
combination of such factors as:
 volume of information which must be considered for making
an important decision,
 factor of time for making an important decision,
 level of motivation which determines the importance for making a decision.
The unpleasant combination of these factors is a large volume of information (with
making a decision), long deficit of time, high level of behavior motivations.
In information neurosis we can see such changes of the higher nervous activity as:
 frequent or constant mistakes in signal differentiation,
 decrease of time of keeping the stop reactions and short-time memory,
 inert processes in the brain determining activity with non-adequate meaning with
motor hyperkinetic reactions.

Experimental Modeling

The modeling of some symptoms and syndromes of pathology of the higher functions
of human brain on animals was studied by the objective methods of investigation, first of
all, by the method of the conditioned reflexes. The theoretical theses of pathophysiology
of higher nervous activity are based on I. P. Pavlov's doctrine about the conditioned
reflexes. Pathophysiology of higher nervous activity includes the studying of the
type of higher nervous activity, the speed of arising of the pathology, its
manifestations, level of activation of the protective mechanisms are determined by
the individual peculiarities of the nervous system.
The Principles and Methods of Neurosis Reproduction. The overstrain of the
excitation process can be realized by the using of very strong unconditioned stimulus (an
intensive pain, strong sound), long or repeated action of the stimulus, simultaneous action
of some different and strong stimuli (conditioned and unconditioned), difficult positive
conditioned and non-ordinary stimuli. Neurosis with predominance of the excitation
process (weakness of inhibition) has continuous, non-adequate agitation, aggressiveness
and anger of the animal. It can be transformed in neurosis of the inhibitive type as a result
of level-out inhibition.
The overstrain of the inhibition process is caused by acute increase of the time of
elaborated dynamic stereotype differentiation. Development of passive protective
reactions, depression and drowsiness of the animal characterize neurosis with
predominance of the inhibition process (weakness of excitation).

The overstrain of movement of the nervous process is achieved in the experiment by the
transformation of the signal meaning of the conditioned stimuli, disturbance of the
dynamic stereotype, "wrong" work of the reflexes (the electric current at the moment of

37
eating). The experimental reproductions of neuroses are directed at the maximal approach
of the model with the human neuroses. These methods are: the limitation of "reflex of
freedom" (forced fixation of the animal in the apparatus), disturbances of daily meal reg-
imen, light rhythm due to the changes of day and night, sexual relations in monkeys,
preliminary astenisation of the nervous system under the action of chronic noise,
radiation, etc.
The kinds of neurosis with pathologic movement of the nervous process are the
following:
 neurosis in men with pathologic inertion with development of the
phobia (from Greek phobos — fear),
 neurosis with pathologic liability (the animal makes fuss, convolutions actions,
increased movement activity).
Circular (cycle) neurosis is characterized by alteration of different above-
mentioned types of neuroses.
The pathology of the higher nervous activity appears in animals with the weak
type of the nervous system and such animals are the providers of the neuroses. The
character of reaction of the nervous system to the pathogenic agent is determined also
by the peculiarities, which were acquired in the process of the individual life.
Such process appears in the animals with the weak and strong type of higher
nervous activity - the weak type has frustration in the protective inhibition with the
development of the passive protective reactions and strong nonsteady type has
excitation with the formation of the active searching reactions.
The modeling of information pathology is memorizing a great number of the conditioned
stimuli and reacting on them in deficit of time and in high food motivation (strong feeling
of hunger). So in the behavior of animal we can see the development of the compensation
reactions, so under the action of many conditioned stimuli the animals make their problem
easier and stop reacting to one of the signals. But in the conditions of a long deficit of time
the decrease of the number of the stimuli stops the development of the higher nervous
activity pathology. Another mechanism is the development of more common inhibition
processes, which protect the central nervous system from further action of the pathogenic
factors. The protective inhibition is followed by the phase of excitation (intensive animal
movement). It is a compensation of factor of time deficit. It is the time of compensative
mechanism and under an influence of the pathogenic actions the information pathology
develops.

38
 CHAPTER 31

PATHOPHYSIOLOGY OF NERVOUS SYSTEM

The pathology of nervous system composes the separate branches of medicine –

neurology, psychiatry.
Functions of nervous system are –
 regulatory,
 sensitivity,
 motion,
 secretory,
 nervous trophicity,
 higher nervous activity,
 formation of constitution.
Nervous system performs its functions with the aid of the neuromediators and the
neurohormones.
The role of nervous system in the pathology was mentioned in all previous themes. It
was mentioned the role of nervous system in the development of inflammation, fever,
starvation, hypoxia, and also in insufficiency of all physiological systems (heart and
vascular insufficiency, respiratory, endocrine disturbances and so on).
This chapter deals with the disorder of nervous system functions.

ETIOLOGY

Disorder of the nervous system activity may appear as a result of the influence of
different factors affecting metabolism, structure and function of the nervous cells.
Etiological factors are exogenous and endogenous, and also physical, chemical and
biological.
Physical factors are mechanical trauma, barofactors, ionizing radiation (nervous form
of acute radiation disease), high and low temperature (thermal shock), electrical energy,
electromagnetic fields, noise, vibration.
As a result of its high sensitivity nervous system first of all reacts to a change in the
environment. The bones protect nervous system from trauma. Penetrating wounds of
head damages the brain and predispose to infection.
Chemical factors are cerebrotoxical substances. They are exogenous toxic substances
of natural and artificial origin, industrial poisons, alcohol, narcotics, psychotropic
medicines. They are a large group of the so-called neurotropic poisons which can
selectively disturb bioenergic processes in the nervous cells, formation, transportation,
excretion and metabolism of neuromediators, influence permeability of ionic canals in
neurons.

39
 Clinical examples of endogenous intoxication are hepatic, diabetic coma and uremia.
Biological factors are infectious agents with the preferred neurotropic action –
neurotropic viruses (poliomielitis, meningoencephalitis and encephalitis),
meningococcus, pale spirochaeta, toxoplasma, causative factor of tuberculosis. They
cause pyogenic meningitis, cerebral abscess, fungal infection.
Human immunodeficiency virus (HIV) can cause nervous system dysfunction,
may affect the brain, spinal cord, and peripheral nervous system by direct HIV
infection.
Psychogenic factors cause psychogenic shock. The pathology of internal organs
causes the disturbance of nervous activity by reflex under the influence of strong and
extraordinary actions upon external and internal receptors (in presence of concrements
in the bilious and urinary tubules, the pathology of uterus).
Social factors occupy an important place among the reactions which cause the
nervous system disturbances.
A man possesses the second signal system. With the help of images symbols and
notions a model of the surrounding world is created in his imaginatin. Prolonged or
frequent conflict situations which are connected with peculiarities of personality,
character of his social environment, organization of society on the whole, conditions of
work and mode of life may lead to an excessive stimulation of emotional centers and
disturbances of the higher nervous activity of a man, development of neurotic states,
psychic diseases and different psycho-somatic disturbances.
Immune damage of nerve tissue is possible as the autoimmune aggression in the case
of the disturbance of blood-brain barrier and loss of the physiological immunological
tolerance.
The genetic factors determine disturbances of nervous activity are described as
hereditary and chromosomal diseases. Affection of the nervous system in hereditary diseases
may have a secondary character (e.g. phenylketonuria).
Influence of aging on the structure and functions of the nervous system is beyond
doubt. With the age atrophy of neurons takes place that leads to the decrease of the brain
mass. During this process the decrease of mass of neurons occurs in different speed in
different parts of the brain and starts in different time.
Localization of damage is the important condition for the development of the
pathology of nervous system.

PATHOGENESIS

The development in the nervous system of all typical pathologic processes, which were
described – inflammation, tumor, hypoxia, the local disorders of blood circulation
(thrombosis, embolism, ischemia) is possible. Starvation, the vitamin deficiency in
particular, often causes disturbances of the nervous activity.
There are some peculiarities of the development of these pathologic processes in the
nervous system.

40
 The special feature of inflammation and infections in the nervous system lies in the
fact that blood-brain barrier protects nerve tissue from the penetration of infection. It is
connected with the fact that, as a result of the microminiature structure of this organ,
neither phagocytosis nor antibodies production occur. From other side, precisely, the
presence of this barrier creates risk for the nervous system. If this barrier is disrupted,
own cells of nervous system become the object of autoimmune aggression.
The tumors, which are developed in the nerve tissue, are benign and malignant, and
also primary and metastatic. Clinical picture depends on localization of tumor.
The disorder of blood circulation in the brain have very serious consequences. This
pathology is called stroke (insult). Specifically, it is very sensitive to the disturbance of
local (cerebral) and system blood circulation (decrease of the arterial blood pressure).
Reasons are - shock, collapse, thrombosis, embolism, ischemia, angiospasm.
Cerebrovascular disease is the most common group of the central nervous system
disorders. After heart disease and cancer it ranks the third major cause of death.
Infarction is caused by arterial occlusion from thrombosis, which is most often caused
by atherosclerosis, and embolism.
Hemorrhage (intracerebral, subarachnoidal) consists of bleeding into the brain
space or subarachnoidal space.
Transient ischemic attacks are brief episodes of impaired neurologic functions
caused by temporary disturbance of cerebral circulation.
It is necessary to mark that the nervous system (especially its central sections) is very
sensitive to hypoxia. The brain consumes about 20% of oxygen entering the organism. At
a sudden termination of oxygen supply of the brain (inhalation of oxygen-free gaseous
mixtures, disturbance of cerebral circulation) loss of consciousness comes, normal
bioelectric activity of the brain stops. Fool restoration of the brain function in such cases
is possible when the duration of circulation standstill does not exceed 5-6 min. If
ischemia of the brain continues, memory and intellect will be irreversibly disturbed. It
should be marked that different parts of the central nervous system possess different
sensitivity to oxygen deficiency. Phylogenetic old structures are more stable to hypoxia.
The typical systemic disturbances of metabolism also have manifestations in this
system. Nerve tissue consumes the greatest quantity of glucose. The brain is very
sensitive to hypoglycemia. Practically all oxygen consumed by the brain is used by
oxidation of glucose. An acute decrease of the level of glucose in the blood a
disturbance of biological currents of the brain takes place. And loss of consciousness may
occur. Prolonged hypoglycemia causes irreversible damages of the brain cortex. At
more marked hypoglycemia the functions regulated by the truncal mechanisms are
disturbed. Hypoglycemic coma is manifested by the loss of consciousness.
Atherosclerosis of cerebral vessels (disturbance of lipid metabolism) is the frequent
reason of the diseases of organism.
The deficit of vitamins of group B has neurologic manifestations.
Disorders of the nervous system activity are observed in the changes of concentration
of electrolytes and hydrogen ions in the blood.

41
 Dystrophy and degenerative processes critically disturb the functional activity of
nervous tissue. Demyelinating diseases are characterized by destruction of
myelin with relative preservations of axons (multiple sclerosis).
Degenerative diseases are:
 Alzheimer's disease is the most important cause of dementia (progressive
dementia, decreased number of neurons in nucleus basalis, generalized
cerebral atrophy, granulovascular degeneration), especially affecting temporal
and frontal lobes.
 Huntington's disease is autosomal dominant disorder with delay of onset of
clinical abnormalities to the age of 30-40. It causes chorea and athetoid
movements, progressive motor deterioration, motor deficits (bradykinesia,
akinesia) or abnormal activation of the motor system, resulting in rigidity, trem-
or, involuntary movements.
 Parkinsonism (paralysis of old age) usually occurs after the age of 50. There is
degeneration of nigral neurons. It leads to the loss of dopaminergic inhibition
and relative excess of cholinergic activity (dopamine is synthesized by neurons in
the substantia nigra).
Universal mechanisms of disturbances of all functions are the following: loss of
ability to maintain the definite quantity of membranous potential by the nervous
cell due to disturbance in passing excitation from one nervous cell to another one,
from one part of the nervous system to another one.
If nerves are damaged so much that its connection with the body of neuron is lost, it
degenerates and then the cessation of axoplasmatic flow and transportation of substances
of axoplasm occur.

Congenital Disorders

Neural tube defects are spina bifida (failure of posterior vertebra arches to close),
ancephalopathy.
Hydrocephalus is an increased volume of cerebrospinal fluid within the cranial
cavities (ventricles).
Fetal alcohol syndrome is associated with maternal alcohol abuse during pregnancy.
It is characterized by facial abnormalities and developmental defects such as
microcephaly, atrial septal defect and other anomalies.

MANIFESTATIONS

At the molecular level the disturbances are manifested in the disorder of the
formation of potentials, and also disturbance of the formation of neuromediators and
neurohormones.
The important links in pathogenesis of many disorders of the neuron functions are
the following:

42
 loss of ability to maintain the definite quantity of membranous potential by the
nervous cell, to generate potentials and pass excitation from one nervous cell to
another one,
 decrease of the quantity of interneuronal contacts,
 disorder of formation, excretion and disintegration of mediators.
There are many facts that the activity of the nervous system and especially of its
higher sections is defined mainly by substances of the peptide nature (neuropeptides),
which are produced both by the nervous and other cells and carry out mediatory and
nonmediatory functions. Opiate brain systems, the work of which is regulated by
endorphins and encephalins, are the most studied. However in the brain of the man and
animals scores of other oligopeptides were discovered, injections of which into the
cerebral ventricles or directly into the nervous centers may cause different emotional
states and behaviour reactions, influence on elaboration of conditional reflexes, ability
to memorize, to study etc. Probably in pathogenesis of disorders of the nervous system
functions insufficiency of excessive formation of neuropeptides, change of sensitivity
of nervous cells to them may have significance.
At the tissue level the disturbance of the function of the highest and subcortical nerve
centers, and also the nervous conductors take place.
At the level of entire organism the pathology of the nervous system may be as
follows:
The disturbances of motor function are manifested by paralyses, parhesis and
convulsions.
Disorder of sensitivity depends on the disturbance of the ascending pathways. There
are two centripetal systems of sensitivity. One of them is called lemnisk and contains the
nervous fibers of large diameter which conduct stimuli from the proprioreceptors muscles,
sinews, joints and partially from cutaneous receptors of touch and pressure (tactile
receptors). The fibers of this system are included in the spinal cord and pass in the
structure of the posterior column into medulla oblongata. From nuclei of the medulla
oblongata the medial loop (lemnisk pathway) begins which passes on the opposite side
and ends in the posterio-lateral ventral nuclei of thalamus, neuron of which transmit the
obtained information of the somatosensory zone of the cortex of the brain. The second
ascending system in the spinothalamic (anterior and lateral) pathway carrying pain,
temperature and partially tactile sensitivity. Its fibers go up in the structure of the anterior
and lateral funiculi of the spinal cord and terminate in the cells of nuclei of the thalamus
(anterolateral system).
Changes of sensitivity are observed at cutting of the right or left half of the spinal
cord (Brown- Sequard's syndrome). On the side of cutting the deep sensitivity
disappears while temperature and pain ones disappear on the opposite side, as the
conductive pathways relating to the anterolateral system intersect in the spinal cord. The
tactile sensitivity is partially disturbed on both sides. The disorder of the lemnisk system is
possible in damage of the peripheral nerves (thick myelinic fibers) and also in various
pathologic processes in the spinal cord (disturbance of blood circulation, traumas,
inflammation).

43
 The isolated damage of the posterior funiculi of the spinal cord occurs seldom, but like
other conductive pathways they can be damaged by tumor or during trauma. The
disturbance of conductivity in the fibers of the medial loop causes various disorders of
sensitivity, manifestation of which depends on the degree of the damage of the system.
Thus the ability to determinate speed and direction of motion of the limbs may be lost. The
feeling of separate perception of touch simultaneously in two places and also the ability to
feel vibration and to evaluate the weight of lifted load are considerably disturbed. The
sensation of pain and temperature sensitivity is preserved.
The disorder of sensitivity is manifested in the form of following symptoms -
hyperesthesia (increase of it), hypoesthesia (decrease of it) and anesthesia (lack of
sensitivity).
Depending on the character of the lost sensitivity there are tactile anesthesia, analgesia,
thermanesthesia and loss of deep or proprioceptive sensitivity.
An important sing of sensitivity disorder is a pain.

PAIN

Pain is a leading symptom of any disease.

Pain is a negative sensation and the negative reaction of organism to it.
The pain signals cause an adaptive effect. There is also a pathologic pain. The
pathologic pain conditions the development of the structural and functional changes
and impairments in the cardiovascular system, in the inner organs, in the system of
microcirculation, tissue dystrophy, disturbance of the vegetative reactions, changes in
the activity of the nervous, endocrine, immune and other systems. The main biological
criterion of distinguishing the pathologic pain from the physiological one is its
disadaptive and pathologic meaning for the organism.

PATHOGENESIS

Pain is unpleasant sensation realizing by a special system of the pain sensitivity and the
highest sections of the brain related to the psychoemotional sphere.
The system of perception and transfer of the pain signal is called nociceptive
(nociperceptive) system. The physiological system of reduction of pain exists in the
organism is. Its name is an antinociceptive system.
In the development of pain painful receptors, central painful centers (in
hypothalamus), and also mediators of pain (serotonin, bradykinin, prostaglandins) have a
value.

44
 According to the "gate control" theory of pain, there is a control mechanism for
passing of nociceptive impulsation by the afferent system into the spinal cord. Their
control represents "gate" which regulates the activity of T-cells and flow of imputations
produced by them, ascending by the pain tracts to the highest of the pain sensitivity.
From the point of view of this theory the pathologic pain occurs in insufficiency of the in-
hibitory mechanisms of the gate control when the uninhibited T-cells may be activated by
different stimuli from the periphery and other sources. Constant flow of stimuli from
different sources to T-cells with disturbed inhibitory control is a condition of the path-
ologic pain.

According to the generator theory the pathologic pain is caused by formation of

generators of the pathologically intensified excitation in the nociceptive system. The
generator is a formation of hyperactive neuron, which may develop self-supporting
activity without any additional stimulation from periphery or other sources. Generator is
formed in the nociceptive system and represents a new pathodynamic organization with
abnormal character of producing the pathological pain. It is a pathological algic system
(PAS) which is the base for the pain syndrome. The character of activity of the generator
and PAS allows understanding the peculiarities of the pathologic pain, in particular, its
attacks and character, preservation and intensification of pain after provocation by single
stimulus, spontaneous pain attack without afferent stimulation.
Peripheral sources of the pathologic pain may be tissue receptors (nociceptors) in their
intensified constant-stimulation, chronically damaged and regenerating sensitive nerves
(neuroma), demyelized fibers, etc. The damaged nerves are quite sensitive to different
humoral effects and therefore become an ectopic focus of nociceptive stimulation.
Neuroma plays an especially significant role. Neuroma is a formation of chaotically
grown sensitive nervous fibers, which is formed in unregulated regeneration. Neuroma is
quite sensitive to different effects. Different factors and changes of the organism may
provoke pain attacks (causalgia) in neuroma as well as in the damaged nerve. Pains
associated with the nerve damage are called neuropathic.
Central mechanisms of the pathologic pain are formation and activity of the
generation of the pathologically intensified excitation in some parts of the nociceptive
system and PAS, involving different parts of the pain sensitivity system.
The cause of the generator in the dorsal cornua of the spinal cord and nuclei of the
trigeminal nerve may be intensified from the periphery. Under these conditions the pain
initially of the peripheral character may acquire the character of the central pain
syndrome. The generator may appear in significant and stable depolarization of the
nociceptive neuron.
The inhibitory insufficiency of the neuron is an obligatory condition for the formation
and activity of the generator in any part of the pain sensitivity system.
The cause of the formation of the generator may be partial deafferentiation of the
neuron, for example, after cutting the ischiadic nerve or dorsal root. The epileptiformal
signals are registered at first at the deafferented dorsal cornua and then in the nuclei of the
thalamus and somatosensory zone of the cortex. The generator may be formed in the

45
dorsal cornua of the spinal cord under the local influence of different convulsants, their
nature is of no importance. In all cases there is a pain syndrome with characteristic
features.
The inhibition of the generator in the dorsal cornua or the caudal nucleus of the
trigeminal nerve by the inhibitory mediators leads to disappearance of the pain syndrome
for the time of their action when they are introduced in the area of the generator.
Anticonvulsants, inhibiting the generator, cause disappearance of the pain syndrome.
Under the influence of the primary generator, the functional state of other parts of the pain
sensitivity system is changed, the excitability of their neuron increases and there is a
tendency to formation of the neuron population with stable pathologic activity. Secondary,
generators may be formed in different parts of the pain sensitivity system. PAS also includes
structures of the emotional sphere and vegetative nervous system. Stable active PAS is a
pathophysiological mechanism of severe polymorphic pain syndromes.
Antinociceptive System. Nociceptive system has its physiological, functional antipode
— antinociceptive system that controls the activity of the nociceptive system structures.
Antinociceptive system consists of various nervous formations related to different parts
and levels of the central nervous system, beginning from the afferent entrance in the
spinal cord and ending with the brain cortex.
Antinociceptive system plays a significant role in mechanisms of prevention and
elimination of the pathologic pain. In excessive nociceptive stimuli, it joins the response
and lessens the flow of nociceptive stimulation and intensity of the pain sensation.
Thanks to it the pain remains under control and does not become pathologic.
The antinociceptive system requires additional and special activation.
Neurochemical Mechanisms of Pain. Neurochemical processes at different levels of
the nociceptive and antinociceptive systems realize neurochemical mechanisms of the
pain sensitivity.
The peripheral nociceptors are activated under the influence of many endogenic
biological active substances — histamine, substance P, kinines, prostaglandins, etc. The
substance P plays an important role in excitability conduction in the primary nocicep-
tive neuron. It is conditioned to be a pain mediator. The direct effect to the stimulating
substances causing depolarization or disturbance of neuron inhibition on the dorsal
cornua brings about the formation of the generator and the pain syndrome.
Effective endogenic analgetics are opioid neuropeptides. They inhibit the transmitting
of nociceptive neurons and activate the neurons of the antinociceptive system,
changing the activity of the neuron of the highest section of the brain. The substance
P may also cause analgesia and inhibition even of the pathologic pain, activating
antinociceptive structures, for example, the dorsal nucleus of the suture.
The analgetic effect has serotonin, noradrenaline, dopamine, and gamma aminobutyric
acid. Serotonin is a mediator of the antinociceptive system at the spinal level.
Noradrenalin is also a mediator of the descending antinociceptive system, it inhibits the
activity of the nociceptive neuron of the posterior cornua of the spinal cord and nuclei of

46
the trigeminal nerve. Gamma aminobutyric acid takes part in inhibition of the activity
if the nociceptive neurons are at the spinal level.

Significance

The value of pain is dual. From one side, the pain brings to patient large sufferings.
From other side, the pain is the defensive reaction of organism and signals about the
presence of pathology.

Treatment Principles in the Pathologic Pain

First of all, it is necessary to eliminate the etiologic factor maintaining the

pathologic changes in the nociceptive system.
As the nociceptive and antinociceptive effects are realized at different levels and by
several mechanisms, it is necessary to use complex pathogenetic therapy. It influences in
combination on different parts of the pathologic algic system.
The main principle of treatment of the pathologic pain is to inhibit the hyperactivity of
the nociceptive neuron and generators formed by them and to liquidate PAS, which is the
base of the pain syndrome.
Correction of the hyperactivity of the neuron and generator formation may be done
with the help of anticonvulsants. The main importance belongs to the blockers of Ca 2+
entry into the nociceptive neuron. It is accomplished with the help of Ca-antagonists.
Besides, it is important to effect psychoemotional, vascular and other vegetative and
tissue components of the pathologic pain.

DISORDER OF NERVOUS TROPHICITY

NEURODYSTROPHIC PROCESS

Nervous trophicity is a nervous control upon metabolism. The disturbance of nervous

trophicity bears the name of neurodystrophic process.

Mechanisms of Nervous Trophicity

Nervous trophicity is achieved by two mechanisms: impulsive (nervous mediators) and

unimpulsive (axoplasmatic flow). The substances of trophiciti accomplish the later.
Nervous trophicity is realised in such action of the nerves on the tissue which results
in metabolism changes according to the needs at each given moment. It means that the
trophic action of the nerves is closely connected with their other functions (sensitive,
motor, secretory) and together with them provides an optimum function of each organ.
The first proofs of the nervous influence on trophicity of the tissues were obtained by a

47
French scientist Majandy. In experiments on the rabbits he has cut the trigeminal nerve
and revealed ulcer in the zone of sensitive denervation (the eye, lip). The trophic
disorders develop in any organ if its innervation is disturbed by the intervention of the
nerves (afferent, efferent, vegetative) or nervous centers. A.D. Speransky with selective
damage of centers of hypothalamus revealed appearance of trophic ulcers in various
organs.
The medical practice can give a number of facts which also give evidence that the
damage of the nervous system (trauma, inflammation) may cause a damage in the
appropriate zone.
Today nobody doubts that the nerves influence on trophicity. But how is this process
accomplished? There are two points of view. Some consider that trophicity isn't an
independent nervous function. The nervous stimulus which sets an organ in motion (for
example, muscle) changes metabolism in the cell (acetylcholine activates metabolism and
ferments, which stimulate increasing permeability). Others think, that it is impossible to
reduce trophicity to impulsive (mediator) action of the nerve. The researches have shown
that the nerve has a second function, named unimpulsive. Axoplasmic flow occurs in
both sides, and the substances move via neuron, penetrate through synapses and appear in
the innervated cells. These substances exert a specific action on the effectory cell. The
surgical operation, when the nerve intended for the red muscle, grows into the white,
radical changes occur in its metabolism.
The question is, if special trophic nerves exist?
F. Majandy assumed that together with sensitive, motor and secretory nerves there are
also the special trophic ones, which regulate the tissue nutrition, i. e. assimilating of
nutritious materials.
I. P Pavlov in the experiment on animals among the nerves, coming to the heart, found
such a branch, which increases the power of systole without any influence on blood
circulation. I. P. Pavlov called this nerve "amplifying" and purely trophic. I. P. Pavlov
saw the complete and harmonious heart innervation in the triple nervous provision: the
functional nerves, vasomotor nerves, which regulate the supply of the nutritious material
and trophic nerves, defining the final utilization of these substances.
L. Orbelli had the same opinion.
However, it doesn't mean, that the sympathetic nerves have no other influence on
the tissue or that the motor (secretory) ones have no influence on metabolism. A. D.
Speransky said that all nerves influence metabolism, and there are no nontrophic
nerves — "the nerve is functional just because it is trophic".

Pathogenesis of Neurogenic Dystrophy

The trophic function performs by a principle of reflex. It means that in the analysis of
dystrophic process it is necessary to evaluate the value of each link of the reflex.
Neurodystrophic process is reproduced in the experiment by cutting of different nerves –
motor, sensitive, mixed.

48
 The sensitive (afferent) nerves play a special role. After cutting a sensitive nerve, the
information of the nervous center about events in the zone of denervation is interrupted. In
addition, the damaged sensitive nerve is a source of the pathologic information including
pain. Centrifuged influences on the tissue are proceeded from it. The special substance P
disturbing metabolism and microcirculation spreads through the sensitive nerves with
axocurrent in the tissue.
After cutting a efferent nerve, its normal functions disappear and pathological ones
occur. The impulsive activity and axonic transport of "substances of trophicity" are
disturbed. The functions of motility and secretion are ceased or perverted. The process
involves genome. The synthesis of ferments is disturbed, and metabolism acquires more
primitive character. The output of macroergs decreases. The membranes and their
transport functions are disturbed. The organ with disturbed innervation can become a
source of autoantigen. Process is complicated because of neurotrophic changes involve
the disturbance of blood, lympho- and microcirculation. Hypoxia appears as a result.
So, pathogenesis of neurogenic dystrophy is presented as a complex multifactor process:
the nervous system ceases "to control metabolism" in the tissues and after that disorders
of metabolism, structure and function occur.

Biochemical, Structural and Functional Changes in the Denervated Tissue

Changes of metabolism take place in the denervated organ. They concern

carbohydrates, lipids, proteins, nucleic acids, etc. There are observed not only quantitative
but also qualitative changes. So, myosin in the denervated muscle loses its ATPase
properties and glycogen in its structure becomes simple.
The reorganization of the fermentative process is observed. Thus, isofermentative
spectrum of lactate dehydrogenase varies for the benefit of LDG4 and LDG5, i. e. those
ferments, which are adapted to the anaerobic conditions. The activity of such ferments as
succinic dehydrogenase decreases. The common tendency is such, that metabolism
acquires an embryonal character i.e. glycolytic process predominates while the oxidizing
one is inhibited. The Krebs cycle is weakened, the output of macroergs decreases, the
energy potential is lowered.
In disorder of innervation there are essential morphological changes in tissues. In
denervated cornea, skin or mucosa all stages of inflammation develop. The prevention of
trauma, infection and drying doesn't prevent the process but delay its development.
Finally, ulcer appears which has no tendency to healing. The investigation of cells shows
the changes of the organelles. Mitochondrias are decreased in quantity, their matrix is
destroyed. The disorder of oxidizing phosphorilation and Ca-accumulating ability of
mitochondria together with energy production are connected with this. The mitotic
activity is reduced in the denervated tissues.
The development of the neurodystrophic process is associated with the functional
disorders.

49
 The skeletal muscles after denervation loss their main function – an ability to contract
(the cordial muscle contracts even in cutting of all extracordial nerves). The skeletal
muscles without sympathetic innervation react on adrenaline more than in norm. The
muscles separated from the motor (cholinergic) nerves react on acetylcholine more than in
the norm. It is a Cannon’s law of denervation, which means the increased sensitivity of
denervated structures. It is connected with a state of cholinoreceptors, which in the normal
muscles are concentrated only in the area of myoneural synapses, but after denervation
appear on the entire surface of myocyte membrane.
So, the response of denervated muscles consists not only in increase but also in perver-
sion of function when instead of relaxation they contract. It is easy to imagine what it
means, for example, for blood vessels.
The saliva glands secrete saliva, but its character does not depend on a kind of food.

Manifestations

Together with biochemical, structural and functional changes in the denervated tissue, the
heaviest manifestation of neurodystrophic process is a trophic ulcer.

PATHOPHYSIOLOGY
OF THE HIGHER NERVOUS SYSTEM

Types of Higher Nervous Activity

According to I. P. Pavlov there are 4 types of the nervous system:

 strong unbalanced type with predominance of excitation over inhibition;
 strong balanced type with high mobility of the nervous processes;
 strong unbalanced type with low mobility of the nervous processes and
predominance of inhibition over excitation;
 weak type with low development of excitation and inhibition.

NEUROSIS

Neurosis is a typical form of the functions of the nervous system disorder. It arises as a
result of overstrains and breakdown of higher nervous activity. The pathogenetic base of
the neurosis is a disorder of the main nervous processes - excitation and inhibition,
namely, their force and balance.

Etiology

50
 The pathology of the higher nervous activity is defined by some factors.
There are 3 groups of the causes in the etiology of pathology of higher nervous
activity. They are:
 environmental factors,
 genetic causes,
 their combination.
Posttraumatic pathology of higher nervous activity is the disturbance, which appear
as a result of direct action of pathogenic agent on the brain, for example, in its injury,
blood accumulation in the cerebral tissue and tumor of the brain.
Combined (functional and traumatic) pathology is the disturbances, which appear as
a result of action both on the receptor system of the organism and on the brain (for
example, in radioactive and thermal injury of the head, its mechanical injury, etc.).
The Role of the Negative Emotions. They appear under the influence of the pathogenic
irritants and can have a long stagnant character. They are promoted by the long delay of
external manifestation of negative emotion (the so-called unreactive emotions)
accompanied by hormonal and other chemical deviations in the blood. They decrease the
resistance of the nervous system to the pathogenic agent and thus independent self-main-
lined pathologic system is formed (vicious circle), which disorganizes the activity of other
systems. But such pathogenic influence of the negative emotions appears in their long
course. At early stages the negative emotions play the biologically positive role and have
characteristics of factor of extreme mobilization of the organism.
The functional disorders may occur as a result of long limitation of the inflow of the
ophthalmic, sound, tactile proprioceptive and other stimuli into the brain, changes of the
geographical regions, in long hypodynamia. The steadiness of higher nervous activity
decreases.
Due to the secondary signal system the functional pathology of higher nervous
activity can be stipulated by the verbal action. It means that pathologic agent can
influence on the higher parts of the brain through the second (verbal) signal system.

Pathogenesis

Pathophysiology of higher nervous activity studies the mechanisms of appearance

and development of the pathologic deviation of the higher nervous functions. The
mechanisms of pathology of higher nervous activity are based on emotions, memory and
humoral factors. Functional pathology is the disturbances of behavior, which are
conditioned by the action of the pathogenic irritants on internal and external receptors.
There are two causes for appearance of functional pathology of higher nervous
activity. They are:
 pathogenic agent acts on the receptors by the unconditioned reflex mechanism,
 pathogenic agent has a signal meaning and acts through the receptors of the brain by
the conditioned reflex mechanism.

51
 The action of pathologic agent induces the primary affection of the brain. Such
disturbances are called primary. The disturbances of higher nervous activity induced by
another pathology of the organism (infectious disease, non-cerebral localization of
tumor, cardiovascular disease) are secondary ones. As a rule, secondary pathology of
higher nervous activity results from astenisation of the nervous system, decrease of a force
of reaction to the psychogenic and other actions.
The method of electron microscopia established that the experimental neurosis has the
destructive changes in the neuronal and glial elements of the neocortex with parallel
reparative processes (a compensation of these disturbed functions).
The biological investigations of the neocortex in animals determined the reversible and
irreversible disturbances of the neuromediator system. The determination of
ultrastructural and neurochemical changes in the animal brain in experimental neurosis
leads to supposition that neuroses have structural basic. Any pathology has the
structural changes, which we can determine by the adequate methods of its
investigation.
The pathologic conditioned reflexes can be formed as a result of fixation of the
conditions, which appear in the brain under influence of pathogenic agent in the long-
term memory. Another mechanism of arising and maintaining of the pathologic higher
nervous activity consists in the formation of the pathologic time connections, which are
easily formed under functional disorders in the brain.

Manifestations

The manifestations of the functional pathology of higher nervous activity are various
but first of all they include the psychic functions. They are the weakness of analitycal-
synthetical activity of the brain, disturbance of the long- and short-term memory,
regulation of the emotions and motivations, regulation of general functional condition of
the brain, intersemifunctional condition of the brain and interhemispherical relations.
As a rule these disturbances are manifested in behavior. The frequent manifestation of
pathology of higher nervous activity is disturbance of cycles of sleep, regulation of the
vegetative and somatic functions, frequency of the cardiac contractions, regulation of the
arterial blood pressure and trophicity of the skin. The neuroses have such characteristics
as the disturbance of vegetative regulation, movements, nervous trophicity as well as a
decrease of the organism resistance.
The typical disturbances of the higher nervous activity for humans and animals are
noted in the organic injure of the frontal lobes of the brain cortex. The frontal lobe takes
part in the management of the congenital behavior reactions from positions of
accumulated experience as well as in concordance of the internal and external
motivations. We can see such changes in the patient with pathology of the frontal lobe as
absence of motivation, steadfast plans and intentions based on the prognosing with
preservation of intellect. The patient becomes rude, tactless, frivolous and irritable.
There is so-called information pathology as a form of functional pathology of the
higher nervous activity and behavior.

52
 The information pathology represents the different disturbances of the course of the
higher functions of the nervous system, and the disturbance of life activity of other
systems of the organism which appear under quite long of the unpleasant conditions of
combination of such factors as:
 volume of information which must be considered for making
an important decision,
 factor of time for making an important decision,
 level of motivation which determines the importance for making a decision.
The unpleasant combination of these factors is a large volume of information (with
making a decision), long deficit of time, high level of behavior motivations.
In information neurosis we can see such changes of the higher nervous activity as:
 frequent or constant mistakes in signal differentiation,
 decrease of time of keeping the stop reactions and short-time memory,
 inert processes in the brain determining activity with non-adequate meaning with
motor hyperkinetic reactions.

Experimental Modeling

The modeling of some symptoms and syndromes of pathology of the higher functions
of human brain on animals was studied by the objective methods of investigation, first of
all, by the method of the conditioned reflexes. The theoretical theses of pathophysiology
of higher nervous activity are based on I. P. Pavlov's doctrine about the conditioned
reflexes. Pathophysiology of higher nervous activity includes the studying of the
type of higher nervous activity, the speed of arising of the pathology, its
manifestations, level of activation of the protective mechanisms are determined by
the individual peculiarities of the nervous system.
The Principles and Methods of Neurosis Reproduction. The overstrain of the
excitation process can be realized by the using of very strong unconditioned stimulus (an
intensive pain, strong sound), long or repeated action of the stimulus, simultaneous action
of some different and strong stimuli (conditioned and unconditioned), difficult positive
conditioned and non-ordinary stimuli. Neurosis with predominance of the excitation
process (weakness of inhibition) has continuous, non-adequate agitation, aggressiveness
and anger of the animal. It can be transformed in neurosis of the inhibitive type as a result
of level-out inhibition.
The overstrain of the inhibition process is caused by acute increase of the time of
elaborated dynamic stereotype differentiation. Development of passive protective
reactions, depression and drowsiness of the animal characterize neurosis with
predominance of the inhibition process (weakness of excitation).

The overstrain of movement of the nervous process is achieved in the experiment by the
transformation of the signal meaning of the conditioned stimuli, disturbance of the
dynamic stereotype, "wrong" work of the reflexes (the electric current at the moment of

53
eating). The experimental reproductions of neuroses are directed at the maximal approach
of the model with the human neuroses. These methods are: the limitation of "reflex of
freedom" (forced fixation of the animal in the apparatus), disturbances of daily meal reg-
imen, light rhythm due to the changes of day and night, sexual relations in monkeys,
preliminary astenisation of the nervous system under the action of chronic noise,
radiation, etc.
The kinds of neurosis with pathologic movement of the nervous process are the
following:
 neurosis in men with pathologic inertion with development of the
phobia (from Greek phobos — fear),
 neurosis with pathologic liability (the animal makes fuss, convolutions actions,
increased movement activity).
Circular (cycle) neurosis is characterized by alteration of different above-
mentioned types of neuroses.
The pathology of the higher nervous activity appears in animals with the weak
type of the nervous system and such animals are the providers of the neuroses. The
character of reaction of the nervous system to the pathogenic agent is determined also
by the peculiarities, which were acquired in the process of the individual life.
Such process appears in the animals with the weak and strong type of higher
nervous activity - the weak type has frustration in the protective inhibition with the
development of the passive protective reactions and strong nonsteady type has
excitation with the formation of the active searching reactions.
The modeling of information pathology is memorizing a great number of the conditioned
stimuli and reacting on them in deficit of time and in high food motivation (strong feeling
of hunger). So in the behavior of animal we can see the development of the compensation
reactions, so under the action of many conditioned stimuli the animals make their problem
easier and stop reacting to one of the signals. But in the conditions of a long deficit of time
the decrease of the number of the stimuli stops the development of the higher nervous
activity pathology. Another mechanism is the development of more common inhibition
processes, which protect the central nervous system from further action of the pathogenic
factors. The protective inhibition is followed by the phase of excitation (intensive animal
movement). It is a compensation of factor of time deficit. It is the time of compensative
mechanism and under an influence of the pathogenic actions the information pathology
develops.

54
55