BLOCK OF INFORMATION

For class
1. Neurosis, notion
2. Sensory disorders, types, pathogenesis.
3. Pain, types, pathogenesis.
4. Hyperkinetic states. Convulsive states, concept, etiology, pathogenesis. Etiology and pathogenesis of
epilepsy
5. Hypokinetic states. Paresis and paralysis, concept, types, etiology, pathogenesis
6. Etiology and pathogenesis of cerebral circulation disorders (ischemic and hemorrhagic stroke).

Neurosis
Neurosis is a class of functional mental disorders involving chronic distress but neither delusions nor
hallucinations. The term is no longer used by the professional psychiatric community in the United States.
There are many different neuroses: obsessive–compulsive disorder, anxiety disorder, hysteria, neurasthenia,
and a great variety of phobias.
Neurosis may be defined simply as a "poor ability to adapt to one's environment, an inability to change one's
life patterns, and the inability to develop a richer, more complex, more satisfying personality."
The symptoms of neurosis may involve:
... anxiety, sadness or depression, anger, irritability, mental confusion, low sense of self-worth, etc.,
behavioral symptoms such as phobic avoidance, vigilance, impulsive and compulsive acts, lethargy, etc.,
cognitive problems such as unpleasant or disturbing thoughts, repetition of thoughts and obsession, habitual
fantasizing, negativity and cynicism, etc. Interpersonally, neurosis involves dependency, aggressiveness,
perfectionism, schizoid isolation, socio-culturally inappropriate behaviors, etc.

2. Sensory disorders

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Causes of sensory disorders
Genetic anomalies, injury, intoxication by alcohol, salts of heavy metals, hypovitaminosis, autoimmune
processes, diabetes, circulatory disorders, tumors of the brain and spinal cord, encephalitis etc.,
damage to the structure and function of the sensory analyzer.

Types of sensation disorders according to pathogenesis

Mechanisms Pathogenesis
Receptor the change in the threshold of receptor sensitivity: hypo – and hypersensitivity of
receptors;

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 change in number of receptors (decrease or increase)
Conductor inhibition or blockade of impulses conduction
Central the change in the threshold of neuron sensitivity
disorders of conscious awareness of sensation.

Types of sensory disorders according to manifestations

Paresthesias - tingling or pins-and-needles sensations but may include a wide variety of other abnormal
sensations, except pain;
Dysesthesias - all types of abnormal sensations, including painful ones, regardless of whether a stimulus is
evident.
Hypesthesia or hypoesthesia refers to a reduction of cutaneous sensation to a specific type of testing such as
pressure, light touch, and warm or cold stimuli;
Anesthesia - complete absence of skin sensation to the same stimuli plus pinprick;
Hypalgesia or analgesia is reduced or absent pain perception (nociception), such as perception of the pricking
quality elicited by a pin.
Hyperesthesia means pain or increased sensitivity in response to touch.
Allodynia describes the situation in which a nonpainful stimulus, once perceived, is experienced as painful,
even excruciating. An example is elicitation of a painful sensation by application of a vibrating tuning fork.
Hyperalgesia denotes severe pain in response to a mildly noxious stimulus,
Hyperpathia, a broad term, encompasses all the phenomena described by hyperesthesia, allodynia, and
hyperalgesia. With hyperpathia, the threshold for a sensory stimulus is increased and perception is delayed,
but once felt, is unduly painful.
Discriminative Sensation
Primary sensory cortex provides awareness of somatosensory information and the ability to make sensory
discriminations. Touch, pain, temperature, and vibration sense are considered the primary modalities of
sensation and are relatively preserved in patients with damage to sensory cortex or its projections from the
thalamus. In contrast, complex tasks that require integration of multiple somatosensory stimuli and of
somatosensory stimuli with auditory or visual information are impaired. These include the ability to
distinguish two points from one when touched on the skin (two-point discrimination), localize tactile stimuli,
perceive the position of body parts in space, recognize letters or numbers drawn on the skin (graphesthesia),
and identify objects by their shape, size, and texture (stereognosis).

Anatomy of Sensory Loss

The patterns of sensory loss often indicate the level of nervous system involvement. Symmetric distal
sensory loss in the limbs, affecting the legs more than the arms, usually signifies a generalized disorder of
multiple peripheral nerves (polyneuropathy). Sensory symptoms and deficits may be restricted to the
distribution of a single peripheral nerve (mononeuropathy) or two or more peripheral nerves
(mononeuropathy multiplex). Symptoms limited to a dermatome indicate a spinal root lesion
(radiculopathy).
In the spinal cord, segregation of fiber tracts and the somatotopic arrangement of fibers give rise to
distinct patterns of sensory loss. Loss of pain and temperature sensation on one side of the body and of
proprioception on the opposite side occurs with lesions that involve one half of the cord on the side of the
proprioceptive deficit (Brown-Séquard's syndrome; ). Compression of the upper spinal cord causes loss of
pain, temperature, and touch sensation first in the legs, because the leg spinothalamic fibers are most
superficial. More severe cord compression compromises fibers from the trunk. In patients with spinal cord
compression, the lesion is often above the highest dermatome involved in the deficit. Thus, radiographic
studies should be tailored to visualize the cord at and above the level of the sensory deficit detected on
examination. Intrinsic cord lesions that involve the central portions of the cord often impair pain and
temperature sensation at the level of the lesion because the fibers crossing the anterior commissure and
entering the spinothalamic tracts are most centrally situated. Thus, enlargement of the central cervical canal
in syringomyelia typically causes loss of pain and temperature sensation across the shoulders and upper arms

Brainstem lesions involving the spinothalamic tract cause loss of pain and temperature sensation on
the opposite side of the body. In the medulla, such lesions can involve the neighboring spinal trigeminal
nucleus, resulting in a "crossed" sensory deficit involving the ipsilateral face and contralateral limbs. Above
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the medulla, the spinothalamic and trigeminothalamic tracts lie close together, and lesions there cause
contralateral sensory loss of the face and limbs. In the midbrain and thalamus, medial lemniscal fibers run
together with pain and temperature fibers, and lesions are more likely to impair all primary sensation
contralateral to the lesion. Because sensory fibers converge at the thalamus, lesions there tend to cause fairly
equal loss of pain, temperature, and proprioceptive sensation on the contralateral half of the face and body.
Lesions of the sensory cortex in the parietal lobe impair discriminative sensation on the opposite side of the
body, whereas detection of the primary modalities of sensation may remain relatively intact.

Brown-Séquard's syndrome with lesion at
left 10th thoracic level (motor deficits not
shown).
Syringomyelia (the presence of a cavity in the spinal cord
resulting from breakdown of gliomatous new formations,
presenting clinically with pain and paresthesias followed by
muscular atrophy of the hands) involving the cervicothoracic
portion of the cord.

Pain
Pain is an unpleasant sensation localized to a part of the body. World Health Organization:
“Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue
damage or described in terms of such damage.”
The function of the pain sensory system is to protect the body and maintain homeostasis. It does this
by detecting, localizing, and identifying tissue-damaging processes. The system associated with pain sensation
is called nociceptive system (Nociception – “pain sense” – from Latin nocere – to injure)

Nociceptive system
1. Nociceptors are free nerve endings in the afferent peripheral nervous system. Aδ fibers rapidly transmit
sharp, well-localized “fast” pain sensations. These fibers are responsible for causing reflex withdrawal of the
affected body part from the stimulus before a pain sensation is perceived. The smaller unmyelinated C fibers
are polymodal and are stimulated by mechanical, thermal, and chemical nociceptors. The unmyelinated C
fibers slowly transmit dull, aching, or burning sensations that are poorly localized and longer lasting. A-beta
(Aβ) fibers are large myelinated fibers that transmit touch and vibration sensations. They do not normally
transmit pain but play a role in pain modulation.

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2. Information from primary afferent fibers is relayed via sensory ganglia to the dorsal horn of the spinal cord
and then to the contralateral spinothalamic tract, which connects to thalamic neurons that project to the
somatosensory cortex.
Once the axons of the Aδ and C fibers enter the cord they synapse with interneurons. Two classes of
interneurons or second-order neurons are found in the dorsal horn:
(1) excitatory interneurons, which relay nociceptive transmissions to projection cells, to other interneu-
rons, or to motor cells concerned with local reflexes such as the pain withdrawal reflex;
(2) inhibitory interneurons, which modulate nociceptive transmission. The synaptic connections
between cells of primary and second-order neurons located in the substantia gelatinosa and other spinal
laminae function as a “pain gate.” The “gate” in the spinal cord regulates the transmission of pain impulses
that ascend to the brain for further processing and interpretation

Mediators of pain (biologically active substances that activate nociceptors, induce their hypersensitivity,
and conduct pain)

Inflammatory Mediators (Excitatory) Excitatory Transmitters

Bradykinin Glutamate (fast pain)
Leukotrienes NMDA
Prostaglandins AMPA
Serotonin Tachykinins
Substance P Neurokinin A
Interleukins Neurokinin B
Tumor necrosis factor-alpha Substance P
Nitric oxide Other receptors
ATP Calcitonin gene–related peptides
Neurokinins Somatostatins
Calcitonin gene–related peptide Bombesins
Cholecystokinins

Antinociceptive system
Neurogenous mechanisms
Integration of peripheral sensory axon terminals, spinal interneurons, and top-down control pathways that
converge on the spinal dorsal horns:
 Cells in the periaqueductal gray matter of the midbrain that receive afferents from frontal cortex and
hypothalamus and project to rostroventral medullary neurons.

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 These in turn project in the dorsolateral white matter of the spinal cord and terminate on dorsal horn
neurons of substantia gelatinosa.
Examples:
 Cognitive expectations (top-down pathways)
 Spinal-medullary-spinal pathways that are activated when peripheral pain stimulation remote from the pain
site relieves pain (counter-irritation). It may be the basis for pain relief with acupuncture or deep massage.
 Segmental inhibition of pain occurs when Aβ fibers close the pain gates through an inhibitory interneuron.
These afferent Aβ fibers carry non-noxious low-threshold mechanical information gained by touch,
vibration, and pressure. This is why rubbing a painful area may alleviate some of the discomfort.

Humoral mechanisms - Inhibitory Transmitters

Gamma-aminobutyric acid (GABA)
Glycine
Norepinephrine–α 2 –receptors, Serotonin (5-hydroxytryptamine)
Opioids (μ, δ, κ receptors): Endorphins, Enkephalins, Dynorphins

Types of pain
Pain can be classified according to location, site of referral, duration, pathogenesis, etiology etc.
 Cutaneous (epicritic) pain is sharp, localized burning pain that has its origin in the skin or subcutaneous
tissues, or mucous membranes. Latent period is short, Duration after cessation of irritation is short,
conducting fibers are myelinated A-delta fibers, threshold of sensation is low.
 Deep pain (protopathic) is a more diffuse and throbbing pain that originates in structures such as muscles,
bones, tendons, and radiates to surrounding tissues Latent period is long, Duration after cessation of
irritation is long, conducting fibers are unmyelinated C fibers, threshold of sensation is high.
 Visceral pain is a diffuse and poorly defined pain that results from stretching, distention, or ischemia of
tissues in a body organ
 Referred pain is pain that originates at a visceral site but perceived as originating in part of the body wall
that is innervated by neurons entering the same segment of the nervous system. The axon of each primary
afferent contacts many spinal neurons, and each spinal neuron receives convergent inputs from many
primary afferents. The convergence of sensory inputs to a single spinal pain-transmission neuron underlies
the referred pain. All spinal neurons that receive input from the viscera and deep musculoskeletal structures
also receive input from the skin

According to pathogenesis:
 Somatogenic pain syndromes
 Neurogenic pain syndromes
 Psychogenic pain syndromes

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 Pathogenesis of somatogenic pain syndromes
 Irritation of nociceptors due to tissue damage
 Releasing of algogens and sensitization of nociceptors
 Amplification of nociceptive afferent flow from the periphery
 Sensitization of nociceptive neurons at different levels of the CNS

Principles of treatment
 inhibition of inflammatory mediators synthesis
 limitation of nociceptive impulses from damaged areas to the CNS.
 activation of the antinociceptive system

Pathogenesis of neurogenic pain syndromes

Pathological pain of peripheral origin
Damage to nerves
(chronic inflammation, demyelination)

atrophy and loss of nerve fibers

+ regeneration of nerve fibers, with the formation of neuroma.
Nerve structure becomes inhomogeneous

sensitization of pain receptors, spontaneous ectopic activity in damaged axons, abnormal interactions of
peripheral sensory fibers

The overcoming the inhibitory neurons of substantia gelatinosa

The formation of GPEE in the posterior horns of the spinal cord

Pathological pain of Central origin

 Hyperactivation of nociceptive neurons (GPEE formation) in the spinal cord, thalamus, cortex
 Such hyperactive neurons are able to develop long-lasting self-sustaining pathological activity and
lead to the formation of a pathological system

Principles of treatment of neuropathic pain

 Suppression the abnormal activity of the peripheral pacemakers and hyperactive neurons
 Anticonvulsants and drugs that enhance the inhibitory reactions in the CNS— benzodiazepines,
agonists of the GABA receptors, calcium channel blockers, antagonists of excitatory amino acids,
peripheral and Central blockers of Na+ channels

Examples of Neuropathic pain

Thalamic pain syndrome -
severe and chronic pain that is not proportional to an environmental stimulus, with dysesthesia, (combination
of itching, tingling, burning, or searing experienced spontaneously or from stimuli) allodynia (pain from a
stimulus that would normally not cause pain) with vegetative disorders.
Pathogenesis: Formation of GPEE in thalamus

Phantom pain is the sensation that an amputated or missing limb is still attached. Approximately 60 to 80%
of individuals with an amputation experience phantom sensations in their amputated limb.
Phantom sensations may also occur after the removal of body parts other than the limbs, e.g. after amputation
of the breast, extraction of a tooth (phantom tooth pain) or removal of an eye
Pathogenesis:
neuroma or GPEE in spinal cord or brain cortex

Causalgia is severe burning pain in the region innervated by the nerve. Can be produced without obvious
nerve damage by a variety of injuries, including fractures of bone, soft tissue trauma, myocardial infarction,
and stroke
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 Pathogenesis:
 Pathologic high sensitivity of nociceptors in the region of damaged nerve endings
 GPEE formation in different regions of pathways

NEUROGENOUS DISORDERS OF MOVEMENT. PATHOGENESIS OF SEIZURES. EPILEPSY.

1. Neurogenous disorders of movement. Hypokinetic disorders.

2. Hyperkinetic disorders.
3. Etiology and pathogenesis of epilepsy.
3. Etiology and pathogenesis of meningitis.

1. Neurogenous disorders of movement. Hypokinetic disorders.

Movements are complex patterns of activity controlled by the cerebral cortex, the pyramidal system, the
extrapyramidal system, and the muscle motor units. Dysfunction in any of these areas can cause motor
dysfunction.

Types of movement disorders:

• Hypokinetic disorders
• Hyperkinetic disorders
• Ataxia
Hypokinetic disorders
Paralysis and the suffix "-plegia" is loss of motor function.
Paresis (weakness) is impairment of motor function, that is, partial paralysis with incomplete loss of
muscle power. The characteristics of paresis or paralysis are related to involvement of either the upper
or the lower motor neurons.
Types of paresis and paralysis according to localization
Monoplegia – is paralysis of a single limb
Paraplegia is paralysis of both legs or both hands
Hemiplegia – is paralysis of one side of a body.
Tetraplegia (quadriplegia)– is paralysis of all four limbs.

Depending on muscle tone:

SPASTIC (SPASTICITY)– increased tone of the muscles (i.e., upper limb flexors more than
extensors and lower limb extensors more than flexors). Observed in the lesion of the Central neurons
of the pyramidal system.
FLACCID PARALYSIS —weakness or loss of muscle tone
RIGID – long elevated tone of muscles – antagonists.
For example, while increased tone of both flexors and
extensors limbs retain any position into which they are
manipulated by another person, the so-called "waxy
rigidity“("waxy flexibility“), plastic resistance . Observed in
lesions of the extrapyramidal system.

According to the type of damaged neurons:

Central paralysis – damage to the Central (upper pyramidal) motor neurons (Upper motor
neuron syndrome). The injury may be in the cerebral cortex, the subcortical white matter, the internal
capsule, the brainstem, or the spinal cord.
Upper motor neuron paresis/paralysis is known also as spastic paresis/paralysis

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 Manifestations: hyperreflexia, increased muscle tone, pathologic segmentary reflexes
(observed in children in early postnatal period, such as Babinski's reflex (dorsification of the great toe
when the sole of the foot is stimulated.).

Peripheral paralysis– damage to peripheral (lower) motor neurons (alpha motor neurons of
the spinal cord motor and nuclei of the brainstem) –lower motor neuron syndrome. The paresis and
paralysis caused by a disorder of the lower motor neurons are called flaccid paresis/flaccid paralysis
Symptoms: loss of muscle tone and Hypo-or areflexia, Hypo - or atrophy.
Examples:
Spinal muscular atrophies (SMAs), a heterogeneous group of genetic diseases characterized
by selective degeneration of lower motor neurons.
Pathogenesis: deletions or mutations in the survival motor neuron 1 (SMN1) gene. The SMN
gene product is expressed in all tissues and appears to be involved in RNA metabolism. Loss of SMN
function promotes apoptosis of lower motor neurons..
The most common form of motor neuron disease in adults is amyotrophic lateral sclerosis
(ALS ). It is a worldwide degenerative disorder diffusely involving lower and upper motor neurons.
Death of the motor neuron results in axonal degeneration and secondary demyelination with glial
proliferation and sclerosis (scarring) along the corticospinal tract. The term amyotrophic (without
muscle nutrition or progressive muscle wasting) refers to the predominant lower motor neuron
component of the syndrome. Lateral sclerosis, or scarring of the corticospinal tract in the lateral
column of the spinal cord, refers to the upper motor neuron component of the syndrome.
Progressive muscle weakness leads to respiratory failure and death, usually 2 to 5 years from
symptom onset.
Pathogenesis:
 Disorders in Glutamate Signaling and RNA Processing
 missense mutations (SOD1) gene.
 neurofilament dysfunction
2. Hyperkinetic Movement Disorders

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Disorders Movement Characteristics
Athetosis Slow, distal, writhing, involuntary movements with a propensity to
affect the arms and hands. (The lesion of the striate system, the
caudate nucleus)

Chorea Rapid, semipurposeful, graceful, dancelike, involuntary movements involving distal or

proximal muscle groups.
Example: Huntington's Disease
HD is a progressive, fatal, autosomal dominant disorder characterized by motor,
behavioral, and cognitive dysfunction. HD is caused by an increase in the number of
polyglutamine (CAG) repeats (>40) in the coding sequence of the Huntington gene located
on the short arm of chromosome 4. The gene encodes the cytoplasmic protein huntingtin.
Abnormal huntingtin decreases production of brain-derived neurotrophic factor and
induces apoptosis
Sydenham's chorea (originally called Saint Vitus' dance) as a result of streptococcal
infection and autoimmune-mediated inflammatory disorder.
Chorea may recur in later life, particularly in association with pregnancy (chorea
gravidarum) or treatment with sex hormones or other drugs
Tics Brief, repeated, stereotyped muscle contractions. Can be simple and involve a single
muscle group or complex and affect a range of motor activities. (Damage to
extrapyramidal system)
Tremor Rhythmic oscillation of a body part due to intermittent muscle contractions. (Cerebellum
and inferior olives have been implicated as possible sites of a "tremor pacemaker").
Observed with organic brain lesions (multiple sclerosis, Wilson’s disease, encephalitis,
brain ischemia), exogenous intoxication (alcohol, mercury, morphine).
Parkinsonian tremor is usually the first motor symptom to appear in Parkinson disease.
It is a tremor at rest, disappearing briefly during the course of a voluntary movement and
reappearing when the limb is held in a stationary position. It appears to result from
instability of feedback from the basal ganglia to the cerebral cortex caused
by loss of the inhibitory influence of dopamine in the basal ganglia.
(Parkinsonism is a clinical syndrome of rigidity, bradykinesia, tremor, and postural
instability. Parkinson disease (PD) is disease with hereditary predisposition. In PD there
is selective degeneration of monoamine-containing cell populations in the brainstem and
basal ganglia, particularly of pigmented dopaminergic neurons of the substantia nigra. In
addition, scattered neurons in basal ganglia, brainstem, spinal cord, and sympathetic
ganglia contain eosinophilic, cytoplasmic inclusion bodies (Lewy bodies). These con-
tain filamentous aggregates of α-synuclein, along with parkin, synphilin, neurofilaments,
and synaptic vesicle proteins.

Findings Helpful for Localization Within the Nervous System

Signs
Cerebrum Abnormal mental status or cognitive impairment
Seizures
Unilateral weaknessa and sensory abnormalities including head and limbs
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 Visual field abnormalities
Movement abnormalities (e.g., diffuse incoordination, tremor, chorea)
Brainstem Isolated cranial nerve abnormalities (single or multiple)
"Crossed" weaknessa and sensory abnormalities of head and limbs, e.g., weakness of
right face and left arm and leg
Spinal cord Back pain or tenderness
Weaknessa and sensory abnormalities sparing the head
Mixed upper and lower motor neuron findings
Sensory level
Sphincter dysfunction
Spinal roots Radiating limb pain
Weaknessb or sensory abnormalities following root distribution (see Figs. 25-2 and
25-3)
Loss of reflexes
Peripheral nerve Mid or distal limb pain
Weaknessb or sensory abnormalities following nerve distribution
"Stocking or glove" distribution of sensory loss
Loss of reflexes
Neuromuscular Bilateral weakness including face (ptosis, diplopia, dysphagia) and proximal limbs
junction Increasing weakness with exertion
Sparing of sensation
Muscle Bilateral proximal or distal weakness
Sparing of sensation

3. Etiology and pathogenesis of epilepsy.

A seizure (from the Latin sacire, "to take possession of") is paroxysmal involuntary muscle contractions of
varying intensity, and duration due to abnormal, excessive, hypersynchronous discharges from an aggregate
of CNS neurons. Seizures are classified by behavioral and electrophysiologic data.
Clonic
short and irregular contraction of individual muscle groups (excessive excitation of the cerebral cortex or
lesions of the structures of the pyramidal system)

Tonic
Long-term muscle contractions that result in "freezing" of the trunk or
limbs in different positions internally.
(excessive excitation of subcortical structures)
Mixed

According to etiology seizures are classified:

1. Idiopathic (hereditary disorders)

2. Symptomatic (secondary) – acquired defects of SNS

Causes of seizures and epilepsy result from a dynamic interplay between

 endogenous factors (hereditary),
 epileptogenic factors (stroke, infections, and abnormalities of CNS development),
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 precipitating factors (psychological or physical stress, sleep deprivation, or hormonal changes associated
with the menstrual cycle).
Causes of seizures and epilepsy according to Age
Neonates (<1 month) Perinatal hypoxia and ischemia
Intracranial hemorrhage and trauma
Acute CNS infection
Metabolic disturbances (hypoglycemia, hypocalcemia,
hypomagnesemia, pyridoxine deficiency)
Drug withdrawal
Developmental disorders
Genetic disorders
Infants and children (>1 mo Febrile seizures
and <12 years) Genetic disorders (metabolic, degenerative, primary epilepsy
syndromes)
CNS infection
Developmental disorders
Trauma
Idiopathic
Adolescents (12–18 years) Trauma
Genetic disorders
Infection
Brain tumor
Illicit drug use
Idiopathic
Young adults (18–35 years) Trauma
Alcohol withdrawal
Illicit drug use
Brain tumor
Idiopathic

The causes of seizures in older adults include cerebrovascular disease, trauma (including subdural
hematoma), CNS tumors, and degenerative diseases.
Metabolic disturbances such as electrolyte imbalance, hypo- or hyperglycemia, renal failure, and hepatic
failure may cause seizures at any age.
Endocrine disorders, hematologic disorders, vasculitis, and many other systemic diseases
Medications and abused substances

Drugs and Other Substances that Can Cause Seizures

Alkylating agents (e.g., busulfan, chlorambucil) Psychotropics
Antimalarials (chloroquine, mefloquine) Antidepressants
Antimicrobials/antivirals Antipsychotics
-lactam and related compounds Lithium
Quinolones Radiographic contrast agents
Acyclovir Theophylline
Isoniazid
Ganciclovir
Sedative-hypnotic drug withdrawal
Alcohol
Anesthetics and analgesics Barbiturates (short-acting)
Meperidine Benzodiazepines (short-acting)
Tramadol
Local anesthetics
Drugs of abuse
Amphetamine
Dietary supplements Cocaine
Ephedra (ma huang) Phencyclidine
Gingko Methylphenidate
Immunomodulatory drugs
Cyclosporine
OKT3 (monoclonal antibodies to T cells)
Tacrolimus

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 Interferons

Pathogenesis of seizures
Partial seizure activity can begin in a very discrete region of cortex and then spread to neighboring regions.
There is a seizure initiation phase and a seizure propagation phase.
The initiation phase is characterized by two concurrent events in an aggregate of neurons:
(1) high-frequency bursts of action potentials (hyperexcitability of neurons)
(2) hypersynchronization.
Initiation phase
Factors increase neuronal excitability.
 changes in the ion channels - channelopathy (inherited or aquired) increased permeability for Ca++
 Disorders in response characteristics of membrane receptors decreased interaction with GABA
 Increased activity of excitatory neurotransmitters (aspartate, glutamate)
 modulation of receptors by extracellular ions and other molecules (increased extracellular K+ and other
metabolites)
 Decreased function of astrocytes and oligodendrocytes decreased metabolism of glutamate

Long-lasting depolarization of the neuronal membrane due to influx of extracellular calcium (Ca2+)
leads to the opening of voltage-dependent sodium (Na+) channels, and influx of Na+ , that leads to
hyperactivity of neurons and generation of repetitive action potentials.
Repetitive discharges lead to the following:
 an increase in extracellular K+, which blunts hyperpolarization and depolarizes neighboring neurons;
 accumulation of Ca2+ in presynaptic terminals, leading to enhanced neurotransmitter release;
 depolarization-induced activation of the aspartate subtype of the excitatory amino acid receptor, which
causes Ca2+ influx and neuronal activation.
 Decreased sensitivity of GABA receptors
 Accumulation of Ca2+ leads to expression of the genes c-fos, c-jun, participating in regulation of
membrane excitability.
Propagation phase
The recruitment of a sufficient number of neurons leads to a loss of the surrounding inhibition and
propagation of seizure activity into contiguous areas via local cortical connections, and to more distant areas
via long commissural pathways such as the corpus callosum.
Some forms of epileptogenesis are related to structural changes in neuronal networks. In response to
the loss of neurons, there is reorganization or "sprouting" of surviving neurons in a way that affects the
excitability of the network
Summary:
Traumas, strokes, intoxications, metabolic disorders - hypoglycemia, acid-base and electrolyte
balance disorders, inherited disorders of receptors and channels

disturbances of channel functions, increased Ca++ and Na+ influx;

increased extracellular K+ decreased Ca++ and Mg++ ;
increased activity of excitatory neurotransmitters, decreased activity of inhibitory neurotransmitters

neuron hyperactivation → GPEE→ seizures

Concept about the generator of pathologically excessive excitation (GPEE)

GENERATOR OF PATHOLPGICALLY EXCECIVE EXCITATION (GPEE) is a unit of hyperactive

neurons producing intensive, uncontrolled stream of impulses.
The mechanism of GPEE formation:
 steady significant depolarization of neurons (excitatory neurotransmitters, hypoxia, etc.)
 deficiency of neurons inhibition (reduction in synthesis of GABA or block of receptors)
 neurons deafferentation (absence of inhibitory effects from peripheral organs)
 damage to neurons and their microenvironment
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GPEE is the universal pathogenetic endogenous mechanism of development of pathological processes in
nervous system. The generator influences to other structures of CNS, and involves them in formation of a new
system with negative value for an organism. GPEE becomes the main part of this pathological system, its
determinant. An example of pathological system can be pathological scratch reflex which in experiment is
reproduced by creation of the generator in the spinal cord.

The pathological system underlies neuropathological syndromes – phantom pains, various phobias, epilepsy,
parkinson’s disease, etc.

GPEE  pathological determinant  pathological system  neuropathological syndromes

Etiology and pathogenesis of cerebral circulation disorders (ischemic and hemorrhagic stroke).
Cerebrovascular diseases. Stroke
Cerebrovascular diseases include some of the most common and devastating disorders: ischemic stroke,
hemorrhagic stroke, and cerebrovascular anomalies such as intracranial aneurysms and arteriovenous
malformations (AVMs).
Stroke is a clinical syndrome characterized by the sudden onset of a focal neurologic deficit that persists
for at least 24 h and is due to an abnormality of the cerebral circulation. The incidence of stroke increases with
age and is higher in men than in women. Significant risk factors include hypertension, hypercholesterolemia,
diabetes, smoking, heavy alcohol consumption, and oral contraceptive use.
Types of stroke:
1. Ischemic
2. Hemorrhagic
ISCHEMIC STROKE
Common causes:
Thrombosis Cardioembolic
Lacunar stroke (small vessel) Atrial fibrillation
Large vessel thrombosis Mural thrombus
Dehydration Myocardial infarction
Embolic occlusion Dilated cardiomyopathy
Artery-to-artery Valvular lesions
Carotid bifurcation Mitral stenosis
Aortic arch Mechanical valve
Arterial dissection Bacterial endocarditis
Paradoxical embolus
Atrial septal defect
Patent foramen ovale
Atrial septal aneurysm
Spontaneous echo contrast

Uncommon causes:
Hypercoagulable disorders Vasculitis
Protein C deficiency Systemic vasculitis
Protein S deficiency Primary CNS vasculitis
Antithrombin III deficiency Meningitis
Antiphospholipid syndrome Cardiogenic
Factor V Leiden mutationa Mitral valve calcification
Prothrombin G20210 mutationa Atrial myxoma
Systemic malignancy Intracardiac tumor
Sickle cell anemia Subarachnoid hemorrhage vasospasm
-Thalassemia Drugs: cocaine, amphetamine
Polycythemia vera Moyamoya disease
Systemic lupus erythematosus Eclampsia
Homocysteinemia
Thrombotic thrombocytopenic purpura
Disseminated intravascular coagulation
Dysproteinemias
Nephrotic syndrome

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 Inflammatory bowel disease
Oral contraceptives
Thrombosis usually involves the internal carotid, middle cerebral, or basilar arteries. Symptoms
typically evolve over several minutes and may be preceded by brief episodes of reversible focal deficits known
as transient ischemic attacks.
Emboli from the heart, aortic arch, or carotid arteries usually occlude the middle cerebral artery,
because it carries more than 80% of blood flow to the cerebral hemisphere. Emboli that travel in the vertebral
and basilar arteries commonly lodge at the apex of the basilar artery or in one or both posterior cerebral arteries.
Ischemic strokes involving occlusion of small arteries occur at select locations, where perfusion
depends on small vessels that are end arteries. Most result from a degenerative change in the vessel, caused
by chronic hypertension and predisposes to occlusion. The most common vessels involved are the
lenticulostriate arteries, which arise from the proximal middle cerebral artery and perfuse the basal ganglia
and internal capsule. Also commonly affected are small branches of the basilar and posterior cerebral arteries
that penetrate the brainstem and thalamus.
Clinical manifestations of thrombotic or ischemic stroke vary, depending on the artery obstructed.
Different sites of obstruction create different occlusion syndromes.

Vascular Territories and Clinical Features in Ischemic Stroke

Artery Territory Symptoms and Signs
Anterior Medial frontal and parietal cortex, Paresis and sensory loss of contralateral leg and
cerebral anterior corpus callosum foot
Middle Lateral frontal, parietal, occipital, Aphasia (dominant hemisphere), neglect
cerebral and temporal cortex and adjacent (nondominant hemisphere), contralateral
white matter, caudate, putamen, hemisensory loss,
internal capsule homonymous hemianopia
(Loss of vision for one half
of the visual field of one or
both eyes), hemiparesis

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Posterior Distal territory: medial occipital and Contralateral homonymous hemianopia,
cerebral temporal cortex and underlying white dyslexia without agraphia, visual
matter, posterior corpus callosum hallucinations and distortions, memory
defect, cortical blindness (bilateral occlusion)
Proximal territory: upper midbrain, Sensory loss, ataxia, third nerve palsy,
thalamus contralateral hemiparesis, vertical gaze palsy,
hemiballismus, choreoathetosis, impaired
consciousness
Vertebral Medulla, lower cerebellum Ipsilateral cerebellar ataxia, Horner's
(posterior syndrome, crossed sensory loss,
inferior nystagmus, vertigo, hiccup, dysarthria,
cerebellar) dysphagia
Basilar Lower midbrain, pons, upper and mid Nystagmus, vertigo, diplopia, skew
(including cerebellum deviation, gaze palsies, hemi- or crossed
anter. inferior sensory loss, dysarthria, hemi- or
cerebellar, quadriparesis, ipsilateral cerebellar ataxia,
superior Horner's syndrome, coma
cerebellar)

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 HEMORRHAGIC STROKE
Causes
1. Rapture of vessels
Spontaneous (nontraumatic) intraparenchymal hemorrhages occur most commonly (50%) in
hypertensive patients with a peak incidence at about age 60 years.
(accelerated atherosclerosis in larger arteries; hyaline arteriolosclerosis in smaller vessels,
proliferative changes and necrosis of arterioles. Arteriolar walls affected by hyaline change are presumably
weaker than are normal vessels and are therefore more vulnerable to rupture. In some instances, chronic
hypertension is associated with the development of minute aneurysms, termed Charcot-Bouchard
microaneurysms)
Primary hemorrhages within the epidural or subdural space are typically related to trauma.
Hemorrhages within the brain parenchyma and subarachnoid space, in contrast, are often a manifestation of
underlying cerebrovascular disease, although trauma may also cause hemorrhage in these sites
2.Systemic coagulation disorders, open heart surgery,
3.Neoplasms
4.Amyloid angiopathy
5.Vasculitis
6.Vascular malformations
6.Drug abuse. Cocaine and amphetamines cause rapid elevation of blood pressure and are common
causes of intraparenchymal hemorrhage in young adults.

Manifestations
The pattern of deficits resulting from hemorrhage is less predictable because it depends on the location of the
bleed and also on factors that affect the function of brain regions distant from the hemorrhage (eg, increased
intracranial pressure, brain edema, compression of neighboring brain tissue, and rupture of blood into
ventricles or subarachnoid space). Focal neurologic deficits are found in 80% of individuals
experiencing hemorrhagic strokes; altered consciousness occurs in 50%. Once a deep unresponsive state
occurs the immediate prognosis is grave, and the individual rarely survives. If the person survives, however,
recovery of function frequently is possible. Individuals experiencing intracranial hemorrhage from a ruptured
or leaking aneurysm have one of three sets of symptoms:
(1) onset of an excruciating generalized headache with an almost immediate lapse into an unresponsive state;
(2) headache, but with consciousness maintained;
(3) sudden lapse into unconsciousness.
Pathogenesis of brain hypoxic injury
Acute occlusion of an intracranial vessel causes reduction in blood flow to the brain region it supplies. The
magnitude of flow reduction is a function of collateral blood flow and this depends on individual vascular
anatomy and the site of occlusion. A fall in cerebral blood flow to zero causes death of brain tissue within 4–
10 min; values <16–18 mL/100 g tissue per min cause infarction within an hour; and values <20 mL/100 g
tissue per min cause ischemia without infarction unless prolonged for several hours or days. If blood flow is
restored prior to a significant amount of cell death, the patient may experience only transient symptoms, i.e.,
a TIA. Tissue surrounding the core region of infarction is ischemic but reversibly dysfunctional and is referred
to as the ischemic penumbra. The ischemic penumbra will eventually infarct if no change in flow occurs, and
hence saving the ischemic penumbra is the goal of revascularization therapies.
Focal cerebral infarction occurs via two distinct pathways:
(1) a necrotic pathway in which cellular cytoskeletal breakdown is rapid, due principally to energy failure
of the cell;
(2) an apoptotic pathway in which cells become programmed to die.

Ischemia produces necrosis by starving neurons of glucose, and oxygen which in turn results in failure of
mitochondria to produce ATP. Without ATP, membrane ion pumps stop functioning and neurons depolarize,
allowing intracellular calcium to rise. Cellular depolarization also causes glutamate release from synaptic
terminals; excess extracellular glutamate produces neurotoxicity (excitotoxicity) by activating postsynaptic
glutamate receptors that increase neuronal calcium influx. Free radicals are produced by membrane lipid
degradation and mitochondrial dysfunction. Free radicals cause catalytic destruction of membranes and likely
damage other vital functions of cells. Lesser degrees of ischemia, as are seen within the ischemic penumbra,
favor apoptotic cellular death causing cells to die days to weeks later. Fever dramatically worsens ischemia,
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as does hyperglycemia [glucose > 11.1 mmol/L (200 mg/dL)], so it is reasonable to suppress fever and prevent
hyperglycemia as much as possible. Induced moderate hypothermia to mitigate stroke is the subject of
continuing clinical research.

Excitotoxicity in neuronal ischemia. Depletion of energy supplies inhibits Na+ -K + ATPase, leading to accumulation of
extracellular K+ and a decline in extracellular Na + . The rise in extracellular K + depolarizes nerve terminals, causing release
of glutamate. The reduction in extracellular Na+ reduces Na + -dependent glutamate uptake, potentiating synaptic effects of
released glutamate. This generates a sustained increase in intracellular Ca2+ in the postsynaptic cell, leading to cell death. Bold
“X” denotes inhibition of Na + -K + ATPase ( left ),
glutamate transporters ( right ), and glutamine synthetase ( bottom ).

Principles of ischemic stroke treatment:

(1) restoring brain perfusion in a timeframe that does not contribute to reperfusion injury,
(2) counteracting the ischemic cascade pathways,

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(3) lowering cerebral metabolic demand so that the susceptible brain tissue is protected against impaired
perfusion,
(4) preventing recurrent ischemic events, and
(5) promoting tissue restoration.

Treatment of a hemorrhagic stroke

(1) stopping or reducing the bleeding,
(2) controlling increased ICP,
(3) preventing a rebleed,
(4) preventing vasospasm, and
(5) promoting tissue restoration.

The material for block of information is from:

1. V.Kumar, A.K. Abbas, J.C. Aster. Pathologic basis of disease, 9th edition, 2014, Ch. 28
2. Garry D Hammer, Stephen J.McPhee Pathophysiology of disease. An introduction to clinical
medicine 7rd edition, New York, 2014.- Ch.4 (Meningitis), Ch. 7.
3. K.L. McCance, S.E. Huether. The biologic basis for disease in adults and children.- 2014.- Unit V,
Ch. 15, 16, 17, 18
4. D.L. Kasper, S. Fauci, L. Longo et al. Harrison's Principles of Internal Medicine. 19th Edition, 2015,
Part 8, part 17
5. Porth Carol, Gaspard Kathryn J. Essentials of Pathophysiology.- 2010. -Unit 10, Ch. 36
6. Pathophysiology: A Textbook for med.univ. un / ed V.V. Nowicki and E.D. Goldberg, O.I. Urazova-
M .: GEOTAR-MED 2013 2 part, pp-528-593
7. P.F. Litvitski Pathophysiology: Tutorial: - M .: GEOTAR-MED, 2010, pp 456-470
8. Pathophysiology for students' independent work // Ed. Udartseva ETC. - Almaty KazNMU them. SD
Asfendiyarov 2006 -P.241-254.
9. Pathophysiology in diagrams and tables: Lectures: Textbook. Ed. A.N.Nurmuhambetov. - Almaty
Kitap, 2004. - P. 131-135.

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