Transcript PATHOPHYSIOLOGY OF NERVOUS SYSTEM DISEASES

PATHOPHYSIOLOGY OF
NERVOUS SYSTEM
DISEASES
Mehtap KAÇAR KOÇAK MD PhD
Yeditepe University
Medicine School
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OVERWIEV
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1- Alterations in Cognitive Networks
2- Seizures and Epilepsy
3- Cerebrovascular Diseases (Ischemic stroke)
4- Dementias (Alzheimer’s Disease)
5- Movement Disorders (Parkinson’s Disease)
6- Motor Neuron Diseases (ALS)
7- Demyelinating Diseases (Multiple Sclerosis)
8- Neuromuscular Junction Diseases (Myasthenia
Gravis)
9- Meningitis (Acute Bacterial Meningitis)
10- Stress
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Alterations in Cognitive Networks
 Full consciousness: awareness of self and the
environment
 Arousal:
state of awakeness
 Mediated by the reticular activating
system
 Content of Thought: all cognitive
functions
 Awareness of self, environment and
affective states (moods)
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Alterations in Arousal
 Causes:
 Structural
 Divided
by location above or
below tentorial plate
 Metabolic
 Psychogenic
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Alterations in Arousal
 Pathological processes
 Infectious,
vascular, neoplastic,
traumatic, congenital, degenerative,
polygenic
 Metabolic
 Hypoxia, electrolyte disturbances,
hypoglycemia, drugs and toxins
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Alterations in Arousal
“range from slight drowsiness to
coma”
 Coma – produced by either
 Bilateral cerebral
hemisphere damage or
suppression
 Brain stem* lesions or
metabolic derangement that
damages and suppresses
the reticular activating
system
 *midbrain, medulla, Pons
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Alterations in Arousal
• Clinical manifestations
“extent of brain dysfunction”
“index for identifying ↑ or ↓ CNS function”
1)
2)
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Level of consciousness
Pattern of breathing
- Post hyperventilation apnea (PHVA)
- Cheyne–Stokes respiration (CSR)
Pupillary changes (size and reactivity)
Oculomotor response (position and reflexes)
Motor response (skeletal muscle)
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Clinical Manifestations
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Test for oculocephalic reflex response
A:Normal response, B:Abnormal response C:Absent response
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Clinical Manifestations
Normal response
Conjugate eye movements
Abnormal response
dysconjugate eye movements
Absent response
no eye movements
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A: Decorticate response: flexion of arms, wrists, and fingers with adduction in upper
extremities. Extension, internal rotation, and plantar flexion in lower extremities.
B: Decerebrate response: all four extremities in rigid extension, with hyperpronation of
forearms and plantar extension of feet.
C: Decorticate response on right side of body and Decerebrate response on left side of
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body.
Brain Death
“never recover nor maintain internal homeostasis”
 Brain stem death – criteria (5)
 Completion of all appropriate and therapeutic
procedures
 Unresponsive coma (absence of motor and
reflex responses)
 No spontaneous respirations (apnea)
 No ocular responses
 Isoelectric EEG: 6 to 12 hours without
hypothermia/depressant drugs
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Cerebral Death
“death exclusive of brain stem and cerebellum”
 No
behavioral or environmental responses
 Brain continues to maintain internal
homeostasis
 Survivors
Coma
 Vegetative state (“wakeful unconscious state”)
 Minimal conscious state
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 Locked-in
syndrome
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SEIZURES AND EPILEPSY
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Seizure is and abnormal discharge of
electrical activity within the brain.
It is a rapidly evolving disturbance of brain
function that may produce impaired
consciousness, abnormalities of sensation or
mental function or convulsive movements.
Convulsions are episodes of widespread
and intense motor activity
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Epilepsy, a recurrent disorder of cerebral
function marked by sudden, brief attacks of
altered consciousness, motor activity or
sensory phenomenon.
Convulsive seizures are the most common
form.
Using the definition of epilepsy as two or
more unprovoked seizures the incidence of
epilepsy is 0.3 to 0.5 % in different
populations throughout the world.
Incidence increases with age, with 30%
initially occurring before 4 years and 75 -80
% before 20 years.
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great majority of cases are idiopathic.
Signs and symptoms vary:
petit mal – almost imperceptible alterations
in consciousness
grand mal – generalized tonic-clonic
seizures – dramatic loss of consciousness,
falling, generalized tonic-clonic convulsions of
all extremities, incontinence, and amnesia for
the event.
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Epileptogenic focus
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Group of brain neurons susceptible to
activation.
Plasma membranes may be more permeable
to ion movement.
Firing of these neurons may be greater in
frequency and amplitude.
Electrical activity can spread to other
hemisphere and then to the spinal cord.
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Eliciting stimuli:
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Hypoglycemia
Fatigue
Emotional or physical stress
Fever
Hyperventilation
Environmental stimuli
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MECHANISM OF SEIZURE
INITIATION AND PROPAGATION
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Partial seizure activity can begin in avery discrete
region of cortex and then spread to neighboring
regions; i.e. There are two phases:
1- the seizure initiation phase
2- the seizure propagation phase.
The seizure initiation phase is characterized by two
concurrent events in an aggregate of neurons:
1- high-frequency burst of action potentials,
2- hypersynchronization.
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The bursting activity is caused by a relatively
long-lasting depolarization of the neuronal
membrane due to influx of extracellular calcium.
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The influx of extracellular calcium leads to
1- the opening of voltage-dependent sodium channels,
2- influx of sodium,
3- Generation of repetetive action potentials.
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This is followed by a hyperpolarizing
afterpotential mediated by GABA receptors or
potassium channels, depending on the cell type.
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Repetitive discharges leads to the following:
1- an increase in extracellular potassium
which blunts hyperpolarization and
depolarization and depolarizes neighboring
neurons,
2- accumulation of calcium in presynaptic
terminals, leading to enhanced
neurotransmitter release,
3- depolarization-induced activation of the Nmethyl-D-aspartate (NMDA) subtype of the
excitatory aminoacid receptor, which causes
calcium influx and neuronal activation.
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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 corpus
callosum.
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Seizures
 Partial
(focal/local)
 Simple,
complex, secondary,
generalized
 Generalized
(bilateral/symmetric)
 Unclassified
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CEREBROVASCULAR
DISEASES
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Most frequent of all neurological problems
Due to blood vessel pathology:
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Lesions on walls of vessels leading to brain
Occlusions of vessel lumen by thrombus or embolus
Vessel rupture
Alterations of blood quality
CV disease leads to two types of brain abnormalities :
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Ischemia (with or without infarct)
Hemorrhage
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Cerebrovascular Accident
(Stroke)
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Clinical expression of cerebrovascular disease: a
sudden, nonconvulsive focal neurological deficit
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Incidence:
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third leading cause of death in U.S. – half a million
people a year – one third will die from it
Highest risk > 65 years of age
But about 1/3 (28%) are < 65 years old
Tends to run in families
More often seen in females
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Stroke
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Classification based on underlying
pathophysiologic findings;
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1- Oclussive stroke
(Ischemia – thrombotic and embolic)
2- Hemorrhagic stroke
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Major Types of Stroke
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Risk Factors
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Arterial hypertension
Heart disease
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Myocardial infarction or endocarditis
Atrial fibrillation
Elevated plasma cholesterol
Diabetes mellitus
Oral contraceptives
Smoking
Polycythemia and thrombocythemia
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Occlusive strokes
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Occurs with blockage of blood vessel by a thrombus
or embolus
Atherosclerosis is a major cause of stroke
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Can lead to thrombus formation and contribute to emboli
May be temporary or permanent
Thrombotic stroke:
3 clinical types:
 TIAs
 Stroke-in-evolution
 Completed stroke
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Sites for Atherosclerosis
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Transient Ischemic Attacks
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Last for only a few minutes, always less than
24 hours
All neurological deficits resolve
Symptom of developing thrombosis
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Causes of TIA:
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Thrombus formation
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Atherosclerosis
Arteritis
Hypertension
Vasospasm
Other:
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Hypotension
Anemia
Polycythemia
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Symptoms depend on location
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Ophthalmic branch of internal carotid artery –
amaurosis fugax – fleeting blindness
Anterior or middle cerebral arteries –
contralateral monoparesis, hemiparesis,
localized, tingling numbness in one arm, loss
of right or left visual field or aphasia
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Stroke-in-evolution
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Can have abrupt onset, but develop in a stepby-step fashion over minutes to hours,
occasionally, from days to weeks
Characteristic of thrombotic stroke or slow
hemorrhage
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Thrombotic Stroke
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Involves permanent damage to brain due to
ischemia, hypoxia and necrosis of neurons
Most common form of CVA
Causes:
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Atherosclerosis associated with hypertension
Diabetes mellitus, and vascular disease
Trauma
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May take years to develop, often asymptomatic
until major narrowing of arterial lumen
Anything that lowers systemic B.P. will
exacerbate symptoms (60 % during sleep)
Area affected depends on artery and presence
of anastomoses
Area affected initially is greater than damage
due to edema
Infarcted tissue undergoes liquifaction necrosis
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Embolic stroke
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Second most common CVA
Fragments that break from a thrombus outside the
brain, or occasionally air, fat, clumps of bacteria, or
tumors
Impact is the same for thrombotic stroke
Rapid onset of symptoms
Often have a second stroke
Common causes:
Atrial fibrillation
Myocardial infarction
Endocarditis
Rheumatic heart disease and other defects
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Hemorrhagic Stroke
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Third most common, but most lethal
Bleeding into cerebrum or subarachnoid space
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Common causes:
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Ruptured aneurysms
Vascular malformations
Hypertension
Bleeding into tumors
Bleeding disorders
Head trauma
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Often a history of physical or emotional exertion
immediately prior to event
Causes infarction by interrupting blood flow to region
downstream from hemorrhage
Further damage by hematoma or ICP
Onset less rapid than embolic CVA, evolving over
an hour or two
Usually chronic hypertension, and B.P. may continue
to rise
About half report severe headache
In about 70 % hematoma expands, destroying vital
brain centers, shifts of brain tissue, and death
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Pathophysiology of stroke
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Brain requires continuous supply of O2 and
glucose for neurons to function
If blood flow is interrupted
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Neurologic metabolism is altered in 30 seconds
Metabolism stops in 2 minutes
Cell death occurs in 5 minutes
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Around the core area of ischemia is a border
zone of reduced blood flow where ischemia is
potentially reversible
If adequate blood flow can be restored early
(<3 hours) and the ischemic cascade can be
interrupted
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less brain damage and less neurologic function
lost
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Necrosis
Pneumbra
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Two kinds of ischemic insult
1. Cell damage  cell death (acute cell necrosis,
delayed cell degeneration)
2. Vascular (endothelial) damage 
(1) vasogenic edema  pressure effect
(2) reperfusion bleeding
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Clinical Manifestations of
Stroke
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Affects many body functions
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Motor activity
Elimination
Intellectual function
Spatial-perceptual alterations
Personality
Affect
Sensation
Communication
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Manifestations of Right-Brain and Left-Brain Stroke
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Neurodegenerative Disorders
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Definition
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Neurodegenerative disease is a condition which affects
brain function. Neurodegenerative diseases result from
deterioration of neurons.
They are divided into two groups:
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conditions affecting memory and conditions related
to dementia
conditions causing problems with movements.
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Examples:
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Alzheimer’s
Parkinson’s
Huntington’s
Creutzfeldt-Jakob disease
Multiple Sclerosis
Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease)
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DEMENTIAS
Learning
= a change of behaviour based on previous
experience, an entry to memory
Memory
= storage of information for further utilization
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Process of memory
1)
2)
3)
4)
creation of the memory trace
consolidation of the memory trace
retention
evocation - evocation based on stimuli (reminder)
- recall
- recognition
trace creation
trace consolidation
retention
evocation
forgetting
„warming“ of the trace: extends retention, decreases probability of forgetting
new exposition
to the stimulus
or evocation
trace reconsolidation
retention
Processes of trace consolidation and reconsolidation are sensitive to
disruptive effects.
brain commotion, electroshock, hypoglycaemia, hypothermia, intoxication (alcohol)
In the phase of retention the memory trace is more stable.
amnesia
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Classification of memory according to persistance
1) short-term
-seconds - minutes
-restricted capacity, older information are overlapped with new one
-information is then shifted into medium-term memory or forgotten
2) medium-term
-minutes - hours
-important information shifted into long-term memory, other forgotten
3) long-term
-hours, days, years, permanently
Working memory – information is stored until it is used, then it is forgotten,
belongs to medium-term memory
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Declarative memory
- information can be expressed verbally or as
visual
image
- evocation is wilful
1) semantic – abstract information
2) episodic - events
3) recognition – recognition of objects)
Non-declarative memory
- information can not be expressed verbally
- evocation is unaware
1) motor patterns
2) conditioned reflexes
3) perceptive a cognitive patterns
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Structures involved in processes of learning and
memory
1- Hippocampus
- Necessary for declarative memory
- Emotional component and motivation in the learning
process
2- Associative cortical areas
3- Septum
4- Corpus amygdaloideum ( emotional memory)
5- Entorhinal cortex
6- Cerebellum
- motor learning, role in other types of learning
7- Striatum (motor learning)
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Injury and changes of these regions -structural, metabolic, changes of
neuromediator systems (namely acetylcholine, glutamate, dopamine,
noradrenalin)
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→ Learning and memory defects
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Learning and memory can be also influenced by changes of
attention, motivation and emotions, sensory systems.
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Learned behaviour depends also function of motor system.
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MEMORY DISORDERS
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Amnesia = complete loss of memory
-retrograde = loss of information acquired before
the genesis of the amnesia
- anterograde = defect of storing new information
Hypomnesia = decrease of memory capacity
Hypermnesia = excessive and inadequate
remembering of some facts
Paramnesia = distortion of stored information, the
patient is confident at it is correct
Memory delusion = conviction about reality of an
event, which did not happen, a kind of paramnesia
Ekmnesia = inaccurate time localisation of an event
(which is memorized correctly)
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DISORDERS OF MIND AND INTELLIGENCE
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Dementia – acquired disorder of cognitive functions, including
memory
Causes of dementia:
Alzheimer‘s disease, vascular dementia, alcoholic dementia
Pick‘s disease, Parkinson‘s disease, Huntington‘s chorea,
infections, brain tumours, hydrocephalus, brain trauma,
endocrinopathy
temporary (reversible) disorders of cognitive functions (e.g.
circulatory decompensation, dehydratation, hypothyroidism)
Mental retardation – developmental disorder of cognitive
functions
-slight – independence, possibility of simple job
-middle – partial independence
-severe – limited self-service, speech limited to single words
- deep – inability of self-service, inability to speak
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Dementia is a loss of ordered
neural function
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Discrimination and attending to stimuli
Storing new memories and retrieving old
Planning and delay of gratification
Abstraction and problem solving
Judgement and reasoning
Orientation in time and space
Language processing
Appropriate use of objects
Planning and execution of voluntary movements
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Course : slow progression
(5years or more)
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At first affects only short term memory, but
gradually extends to long term
Many experience restlessness
Many patients retain insight, which leads to
anxiety and depression
Personality may be lost
Ultimately, mute and paralyzed
Death comes from infection
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ALZHEIMER’S DISEASE
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Onset may be as young as 50, and Alois
incidence increases with age:
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6 % of people over 65 years have AD
Almost half over 85 have AD
Alzheimer
1907
Diagnosis is by ruling out all other
causes –specific diagnosis only by
biopsy or autopsy
Pathology restricted to cerebral
cortex, hippocampus, amygdala,
and another basal nucleus called
nucleus of Meynert
Nucleus of Meynert produces
Acetylcholine. Its loss results in
impaired neural function.
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ALZHEIMER’S DISEASE
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The exact cause of AD is unknown.
Several possible theroies being investigated
include:
Loss of neurotransmitter stimulation by
acetlytransferase,
Mutation for encoding amyloid precursor
protein (APP),
Alteration in Apolipoprotein E, which binds βamyloid,
Pathologic activation of N-methly-D-aspartate
receptors resulting in an influx of excess
calcium.
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Genetic and Environmental Factors in
Alzheimer’s Disease
Environment
Genes
Susceptibility
Susceptibility
APOE-E 4
Alzheimer’s
Disease
Head trauma
Vascular factors
HSV-1
Total cholesterol
Hypertension
Probabilistic
-amyloid
precursor
Presenilin – 1
Presenilin – 2
Protective
N.S.A.I.D.’s
Estrogen
Education
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ALZHEIMER’S DISEASE
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Early-onset familial AD includes at least three gene
defects:
APP (Chromosome 21)
PSEN-1 (Presenilin-1) (Chromosome 14)
PSEN-2 (Presenilin-2) (Chromosome 1).
Late-onset FAD is linked to a defect in the
Apolipoprotein E-4.
[ApoE helps carry cholesterol and fat in bloodstream
3 common forms:
 ε2, ε3, ε4
 Apo ε4 most linked to leading to Alzheimers (1/3 of cases?)
 Apo ε2 may have protective effect]
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Pathophysiology of AD:
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Each of these mechanisms linked to
aggregation and precipitation of insoluble
amyloid in brain tissue and blood vessels.
Insoluble amyloid (abnormal amyloidal beta
proteins) is called senile plaques, amyloid
plaques, and neuritic plaques.
Microscopically the Tau protein that normally
stabilizes the microtubular transport system in
the neurons detaches from the microtubule and
forms insoluble helical filaments called a
neurofibrillary tangle.
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Pathophysiology of AD:
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Tangles are flame shaped.
Cortical nerve cell processes become twisted
and dilated because of accumulation of the
same filaments that form tangles.
Amyloid also is deposited in cerebral arteries,
causing an amyloid angiopathy.
Groups of nerve cells, especially terminal
axons, degenerate and coalesce around an
amyloid core.
Microscopic examination of these areas of
degeneration reveals plaquelike material known
as senile plaques.
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Pathophysiology of AD:
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These plaques disrupt nerve-impulse
transmission.
β-amyloid binds to the seven nicotinic Ach
receptors on cholinergic neurons. (Degeneration
of cholinergic neurons)
This binding induces phospate groups to attach
to Tau protein.
Senile plaques and neurofibrillary tangles are
more concentrated in the cerebral cortex and
hippocampus.
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Normal
Alzheimer’s Brain
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Alzheimer’s Brain
Control Brain
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Alzheimer’s Disease
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Clinical manifestations:
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Insidious onset
Forgetfulness increasing over time
Memory loss
Deteriorating ability for problem solving
Judgment deteriorates
Behavioral changes
Labile
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PARKINSON’S DISEASE
1817
James Parkinson
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Epidemiology
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Its peak age of onset is in the 60s.
Familial clusters of autosomal dominant and
recessive forms of PD comprise ~5% of
cases.
Although most patients with PD appear to
have no strong genetic determinant,
epidemiologic evidence points to complex
interaction between genetic vulnerability and
environmental factors.
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Locus
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Gene
PARK1
α-Synuclein
PARK2
Parkin
PARK4
α-Synuclein
PARK5
UCHL1
PARK7
DJ-1
PARK3,4,6,8,9 Unknown
PARK10
Unknown
Inheritance
AD
AR
AD
AD
AR
AD and AR
Late onset
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Risk Factors (Why)
Rural living
Family history
Pesticide exposure
Gender (♂)
Diet (bad food)
Age
Head injury
Race (Caucasian)
Non-smoking
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Etiologic Classification:
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PD is a commonly occuring
degenerative disorder of the basal
ganglia (corpus striatum) involving
the dopaminergic nigrostriatal
pathway.
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Gross pathologic examination of the
brain in PD reveals mild frontal atrophy
with loss of the normal dark melanin
pigment of the midbrain.
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Nigrostriatal disorders produce a
syndrome of abnormal movement
called parkinsonism.
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Etiologic classification of parkinsonism
includes:
primary (idiopathic) PD and
secondary parkinsonism.
Primary PD is characterized by the loss of
pigmented neurons in the substansia
nigra, mainly in the ventral and medial
portions asociated with reactive gliosis.
Secondary Parkinsonism is caused by
disorders other than PD (i.e.
Trauma,infection, neoplasm,
atherosclerosis, toxins, drug intoxication).
Drug induced parkinsonism is usually
reversible.
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Pathophysiology of PD
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The pathogenesis of PD is unknown.
There is mutation in the α-synuclein gene (AD
form) and the parkin gene (AR form).
Atrophy and neuronal loss are found in the
cerebral cortex.
The principle pathologic feature of PD is
degeneration of the dopaminergic nigrostriatal
pathway, which is composed of neurons of the
SN (black substance) with fibers synapsing in
the caudate and putamen basal ganglia.
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In primary PD, Lewy bodies are found in
remaining neurons of the SN.
Lewy bodies are generated by
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intracytoplasmic eosinofilic inclusions composed of
neurofilaments,
Tuberculin components,
Synuclein,
Ubiquitin,
Pale bodies.
The mechanism of Lewy bodies formation is
not known.
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Halo
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LBs have a high concentration of
a-synuclein and are the
pathologic hallmark of the
disorder.
There is a neuronal accumulation
of the presynaptic protein αsynuclein.
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Cytoplasmic
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LBs are presented in neurones
and glia cells.
Core
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The another pathologic feature is significant
reduction in certain dopamine receptors (D1) in
basal ganglia.
Nigral and basal ganglial depletion of
dopamine, an inhibitory neurotransmitter is the
principal biochemical alteration in PD.
There is a imbalance of dopaminergic
(inhibitory) and cholinergic (excitatory) activity
in the caudate nucleus and putamen of the
basal ganglia in PD.
Dopaminergic-cholinergic balance produces
normal motor functions.
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In PD, degeneration of the dopaminergic
nigrostriatal pathway causes dopamine
depletion, and a relative excess of cholinergic
activity in the feedback circuit involving the
cerebral cortex, basal ganglia, and thalamus.
A relative excess of cholinergic activity in this
circuit as in PD is manifested by hypertonia
(tremor, rigidity) and akinesia.
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Basics
Normal brain
Substantia
Nigra
Dopamine
Striatum
Motor cortex
via
globus pallidus
and thalamus
Movement
Striatum
M
Motor
to ccortex
r x
Movement
Movement
Parkinson’s Disease
Substantia
Nigra
Dopamine
85
In PD dopaminergic and other cells die due
to a combination of factors including:




1- Genetic vulnerability,
2- Oxidative stress,
3- Proteosomal dysfunction,
4- Environmental factors: MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine) and
rotenone)
86
What is synuclein?

Synuclein
 Expressed in neuronal & non-neuronal cells

Little is known about function
 May regulates enzymes
 transporters,
 vesicles (inc. DA)

α-synuclein self-aggregates
Linear
Protofibril
Fibril
87
How is α-synuclein toxic?
Linear
Cyt C
Protofibril
Fibril/Lewy Body
Forms pores
e.g. in DA vesicle
Initiates inflammatory
response
Increases cytosolic DA
Microglia activated
DA is metabolised
Apoptosis
ROS
Abnormal DA trafficking
ROS
Removes syn from
normal function
88
89
Clinical Manifestations:


Primary symptoms:
Rigidity - increased tone or
stiffness in the muscles

Tremor - 25% of patients
experience very slight tremor or
none at all

Bradykinesia - slowness of
movement

Akinesia - impaired movement
initiation and poverty of movement
90









Secondary symptoms:
Poor balance
Depression
Sleep disturbances
Dizziness
Stooped posture
Constipation
Dementia
Problems with speech,
breathing, swallowing, and
sexual function
91
Hoehn and Yahr Staging of PD
Stage one
Signs/symptoms unilateral
Symptoms mild
Symptoms inconvenient but not disabling
Usually presents with tremor of one limb
Changes in posture, locomotion and facial expression
Stage five
Invalidism complete
Cannot stand or walk
Requires constant nursing care
Stage four
Severe symptoms
Walking limited
Rigidity and bradykinesia
Not self sufficient
Tremor may decrease
Stage two
Symptoms are bilateral
Minimal disability
Posture and gait affected
Stage three
Bradykinesia
Impaired balance
Moderately severe dysfunction
92
MOTOR NEURON DİSEASES
(Amyotrophic Lateral Sclerosis)
93
Amyotrophic Lateral Sclerosis

Degenerative motor
neuron disease that
affects UMN & LMN
lying within the brain,
spinal cord and
peripheral nerves

Lou Gehrig
94
ALS

Definition: rare,
progressive neurological
disorder characterized by
loss of motor neurons



Motor neurons in brain and
spinal cord gradually
degenerate
Leads to death within 26yrs of diagnosis
More common in men than
women by ratio of 2:1
95


The myelin sheaths are
destroyed and
replaced with scar
tissue
Does not affect CN




The patient is therefore
able to



3
4
6
Blink
Move eye
Cognition is left intact!
96
Etiology
 Unknown
 Men > Women
Clinical manifestations
 Progressive muscle
weakness
 Atrophy
 Spasity
 Dysphagia
 Dysarthria
 Jaw Clonus
 Tongue fasciculation
97
Pathophysiology of ALS



Glutamate is the most abundant excitatory
neurotransmitter in the CNS. Glutamate is
removed from synapses by transport proteins
on surrounding astrocytes and nerve terminals.
In astrocytes, it is metabolized to glutamine.
ALS associated with a loss of the astrocytic
glutamate transporter protein excitatory amino
acid transporter 2(EAAT2) and GluR2 receptor
subunit.
Thus, selective loss of glutamate transporter
may cause excitotoxicity in ALS by increasing
extracellular levels of glutamate.
98
Pathophysiology of ALS

ALS associated with mutant SOD1 (cytosolic
Cu-Zn SOD).

Thus, the levels of carbonyl proteins in the brain
and the levels of free nitrotyrosine in the spinal
cord elevate.
ALS associated with neurofilament
dysfunctions. (mutant heavy chain neurofilament
subunit, increased peripherin expression)

99
Demyelinating Diseases
(Multiple Sclerosis)
100
Multiple Sclerosis



Focal, chronic, progressive, usually
exacerbating and remitting demyelination of
CNS tracts.
Lesions can occur in a wide variety of
locations and give rise to complex symptoms
Areas of demyelination are called plaques,
and can occur anywhere oligodendrocytes
provide myelin sheath
101
Onset

Onset is between 20 and
40 years, rarely before 15
or after 50

Females: Males 2:1
102
ETIOLOGY


Cause is still unknown
Identified factors:

Autoimmune causes


Human Leukocyte Antigens
Viral causes

Roseola virus
103
Multiple Sclerosis



Pathophysiology
Autoimmune disease
Demyelination of the
myelin covering that
protects the neurons of
the brain and spinal
cord
104

Demyelination




Demyelinated axons



Destruction of the myelin
sheath 
Impaired transmission of nerve
impulses
Both the axon & myelin are
attacked
Do not conduct normal
action potentials
Hyperexcitable (generate
action potentials with
minimal stimuli)
Lesions are “scattered in
space and time”
105



Multiple scarred areas
visible on macroscopic
examination of the brain
(plaques)
Plaques vary in size from
1-2mm to several cm
Lesions evolve over time:



Initially, contain T
lymphocytes and
macrophages which
infiltrate areas of
demyelination.
As lesion evolves,
macrophages scavenge
myelin debris. Then scar
tissue forms.
MS lesions are typically
more numerous than
anticipated based on
clinical symptoms.

Correspondence between
number and size of
plaques and severity of
clinical symptoms is not
precise.
106
Immunology

Autoimmune disease modulated by T lymphocytes



Etiology





Etiology not completely understood
much of what we know comes from animal models of experimental
allergic encephalomyelitis (another dymelinating disease)
Neural antigens are processed by antigen presenting cells in
lymph nodes and presented to T cells
Sensitized memory T cells migrate to the CNS, where they are
reactivated by antigen presenting macrophages
Proinflammatory cytokines are secreted. Enhance expression of
adhesion molecules by vascular endothelium, alter permeability of
the blood-brain barrier, and induce a second wave of inflammatory
cell recruitment
Inflammatory response leads to localized demyelination
Auto-antigen is most likely a myelin protein
107
108
109
Immunologic features:




Myelin basic protein (MBP) is probably an
important T cell antigen in MS.
Activated MBP-reactive T cells are often
found in bloods or CSF of MS patients.
There are autoantibodies which directed
against myelin oligodendrocyte glycoprotein
(MOG).
Cytokines: IL-2, TNF-α and IFN-γ
110
111
112
Presenting Symptoms








Visual disorders (optic neuritis – blurring of central
visual field, loss of brightness in one eye, eye pain)
Movement coordination and balance problems
Numbness and tingling (paresthesia and dyesthesia)
Spacticitiy
Tremors
Weakness and fatigue
Bladder and bowel disorders
Diagnosis by exclusion
113
114
115
Neuromuscular Junction Diseases
(Myasthenia Gravis)
116
Myasthenia Gravis (MG)



Autoimmune disorder
Antibody destruction of Ach
receptors
Skeletal muscle weakness


Eye muscles
Facial, speech, mastication

Exacerbations

Frequently associated with hyperplasia
of thymus or thymoma
Association with other autoimmune
diseases

117
Neuromuscular Junction (NMJ)

Components:





Presynaptic membrane
Postsynaptic membrane
Synaptic cleft
Presynaptic membrane contains vesicles with
Acetylcholine (ACh) which are released into
synaptic cleft in a calcium dependent manner
ACh attaches to ACh receptors (AChR) on
postsynaptic membrane
118
Neuromuscular Junction (NMJ)

Neuromuscular Junction (NMJ)

The Acetylcholine receptor (AChR) is a sodium
channel that opens when bound by ACh


There is a partial depolarization of the postsynaptic
membrane and this causes an excitatory postsynaptic
potential (EPSP)
If enough sodium channels open and a threshold
potential is reached, a muscle action potential is
generated in the postsynaptic membrane
119
Pathophysiology


In MG, antibodies are directed toward the
acetylcholine receptor at the neuromuscular
junction of skeletal muscles
Results in:



Decreased number of nicotinic acetylcholine
receptors at the motor end-plate
Reduced postsynaptic membrane folds
Widened synaptic cleft
120
Immunology

It is the prototype autoimmune disease mediated by
blocking auto-antibodies

A patient withthis disease produces autoAbs to the Ach
receptors on the motor end-plates of muscles

Binding of these AutoAbs to the receptors blocks the
normal binding of Ach and also induces complementmediated degradation of the receptors, resulting in
progressive weakening of the skeletal muscles
121
122
123
Epidemiology



Frequency
 Annual incidence in US- 2/1,000,000 (E)
 Worldwide prevalence 1/10,000 (D)
Mortality/morbidity
 Recent decrease in mortality rate due to advances in treatment
 3-4% (as high as 30-40%)
 Risk factors
 Age > 40
 Short history of disease
 Thymoma
Sex
 F-M (6:4)
 Mean age of onset (M-42, F-28)
 Incidence peaks- M- 6-7th decade F- 3rd decade
124
Clinical presentation

Muscle strength





Facial muscle weakness
Bulbar muscle weakness
Limb muscle weakness
Respiratory weakness
Ocular muscle weakness
125
Clinical presentation

Facial muscle weakness is almost always present



Ptosis and bilateral facial muscle weakness
Sclera below limbus may be exposed due to weak
lower lids
Occular muscle weakness

Asymmetric


Usually affects more than one extraocular muscle and is not
limited to muscles innervated by one cranial nerve
Weakness of lateral and medial recti may produce a
pseudointernuclear opthalmoplegia



Limited adduction of one eye with nystagmus of the abducting eye
on attempted lateral gaze
Ptosis caused by eyelid weakness
Diplopia is very common
126
Meningitis
(Acute Bacterial Meningitis)
127
Definition










Meningitis: inflammation of the
leptomeninges (the tissues
surrounding the brain and spinal
cord)
Bacterial meningitis
Aseptic meningits: infectious or
noninfectious
Viral Rickettsiae
Mycoplasma, Fungal
Spirochetes: syphilis, Lyme
Protozoa: malaria
Malignancy
Lupus erythematous
Lead or mercury poisoning
128
Meningitis


The most common bacterial pathogens are:
Haemophili influenzai



Streptococcus pneumoniae


Affected kids < 5 yrs
H influenzae vaccine (Hib)
Affects age 19-59
Neisseria meningitides


Easily transmitted to others
Least lethal
129
Pathophysiology


Once in CSF, the absence of antibodies &
complement components allows bacterial infection
to flourish
Cascade of events:




Mortality: 3 to 13%



Cell wall and membrane products of organism disrupt
capillary endothelium of CNS (BBB)
Margination and transmigration of PMNs across endothelia
in CSF
 Release of cytokines and chemokines into the CNS
Inflammation of subarachnoid space
Rate varies with organism
Higher with gram negative organism
Neurologic Sequelae: 10 % of surviving patients
130
131
Meningitis


Clinical manifestations
S&S of I-ICP





H/A
↓LOC
Vomiting
Papilledema
Hydrocephalus
132
Meningitis


Clinical manifestations
Onset:


Abrupt
General S&S




Nuchal rigidity
Positive Kernig's
Positive Brudzinski’s
Photophobia
133
Physical Findings
Kernig’s sign
Brudzinski’s sign
134
Opisthotonus
135
Stress and Disease
136
Stress



A person experiences stress when a demand exceeds a person’s
coping abilities, resulting in reactions such as disturbances of
cognition, emotion, and behavior that can adversely affect wellbeing
General Adaptation Syndrome (GAS)-response to stressors
Three stages
 Alarm stage


Stage of resistance or adaptation


Arousal of body defenses
Mobilization contributes to fight or flight
Stage of exhaustion

Progressive breakdown of compensatory mechanisms
137
GAS Activation

Alarm stage

Stressor triggers the hypothalamic-pituitaryadrenal (HPA) axis


Resistance stage


Activates sympathetic nervous system
Begins with the actions of adrenal hormones
Exhaustion stage

Occurs only if stress continues and adaptation is
not successful
138
Psychoneuroimmunologic
Mediators




Interactions of consciousness, the brain and spinal
cord, and the body’s defense mechanisms
Corticotropin-releasing hormone (CRH) is released
from the hypothalamus
CRH is also released peripherally at inflammatory
sites
Immune modulation by psychosocial stressors leads
directly to health outcomes
139
Central Stress Response

Catecholamines

Released from chromaffin cells of the adrenal
medulla


α-adrenergic receptors


α1 and α2
β-adrenergic receptors


Large amounts of epinephrine; small amounts of
norepinephrine
β1 and β2
Mimic direct sympathetic stimulation
140
Central Stress Response

Cortisol (hydrocortisone)






Activated by adrenocorticotropic hormone (ACTH)
Stimulates gluconeogenesis
Elevates the blood glucose level
Protein anabolic effect in the liver; catabolic effect
in other tissues
Lipolytic in some areas of the body, lipogenic in
others
Powerful anti-inflammatory/immunosuppressive
agent
141
Central Stress Response
142
143
Central Stress Response
144
Stress-Induced Hormone
Alterations

Female reproductive system



Cortisol exerts inhibiting effects by suppressing
the release of luteinizing hormone, estradiol, and
progesterone
Stress suppresses hypothalamic gonadotropinreleasing hormone
Estrogen stimulates the HPA axis
145
Stress-Induced Hormone
Alterations

Endorphins and enkephalins


Proteins found in the brain that have painrelieving capabilities
In a number of conditions, individuals not only
experience insensitivity to pain but also increased
feelings of excitement, positive well-being, and
euphoria
146
Stress-Induced Hormone
Alterations

Growth hormone (somatotropin)



Produced by the anterior pituitary and by
lymphocytes and mononuclear phagocytic cells
Affects protein, lipid, and carbohydrate
metabolism and counters the effects of insulin
Enhances immune function
147
Stress-Induced Hormone
Alterations

Prolactin




Released from the anterior pituitary
Necessary for lactation and breast development
Prolactin levels in the plasma increase as a result
of stressful stimuli
Oxytocin



Produced by the hypothalamus
Produced during orgasm in both sexes
May promote reduced anxiety
148
Stress-Induced Hormone
Alterations

Testosterone



Secreted by Leydig cells
Regulates male secondary sex characteristics
and libido
Testosterone levels decrease due to stressful
stimuli
149
Stress
Response




Amygdala is the brains ‘alarm system’- it scans sensory
In developing brains these stress neuro-hormones also
inhibit neural development
It can act independently of the neo-cortex
Stores memories and initiate response repertoires without
conscious involvement & can initiate secretion of
adrenaline/cortisol
Massive secretion of neuro-hormones at time of trauma
leads to long term potentiation of traumatic memories
150
Anxiety Bell Curve



Anxiety increases to
a level where
performance
decreases
Speech centres shut
down, increased
blood flow motor
areas
Over-arousal can
quickly lead to
aggression
151
Stress, Personality, Coping,
and Illness


A stressor for one person may not be a stressor for
another
Psychologic distress


General state of unpleasant arousal after life events that
manifests as physiologic, emotional, cognitive, and
behavior changes
Coping

Managing stressful demands and challenges that are
appraised as taxing or exceeding the resources of the
person
152
Stress
Personality
Coping
Illness
153
Aging and Stress

Stress-age syndrome








Excitability changes in the limbic system and hypothalamus
Increased catecholamines, ADH, ACTH, and cortisol
Decreased testosterone, thyroxine, and other hormones
Alterations of opioid peptides
Immunodepression
Alterations in lipoproteins
Hypercoagulation of the blood
Free radical damage of cells
154