Transcript Neurological Pathophysiology

Neurological Pathophysiology
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Edema in the CNS
• Increase in tissue mass that results from
the excess movement of body fluid from
the vascular compartment or its abnormal
retention in the tissue.
• Why is this a special problem in the brain
and spinal cord?
• Enclosed space
• Lack of lymphatics
• Lack of anastomoses in venous drainage
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Vasogenic edema
• Occurs when the blood-brain barrier is upset
– Inflammation due to infection
– Toxic agents that damage capillary
endothelium
– Abnormal capillaries associated with
malignant neoplasm
• Leakage of proteins fluid into interstitium →
swelling
• Plasma filtrate accumulation alters ionic balance
and impairs function
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Cytotoxic edema
• Intracellular phenomenon
• Hypoxia
– Cardiac arrest
– Near drowning
– Strangulation
– Focal edema due to blockage of an end artery
• Toxic substances that:
– Impair sodium/potassium pump
– Impair production of ATP
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• In practice, swelling often caused by both
• Treatment is different
• If swelling is due to cytotoxicity, can give
I.V. bolus of a hypertonic solution such as
mannitol to draw water into the
vasculature and out of the brain
• If the cause is vasogenic would this help?
• No! would draw fluid into interstitial space
and increase swelling!!
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Increased intracranial pressure (IICP)
• Normal intracranial pressure is 5-15 mm Hg
• May be due to:
– Tumor growth
– Edema
– Excess cerebrospinal fluid
– Hemorrhage
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Contents of cranium
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Tissue of the Central Nervous System
Cerebrospinal Fluid (CSF)
Blood
An increase in any one of these increases
intracranial pressure.
• Clinical hallmarks of IICP:
– Headache
– Vomiting
– Papilledema – swelling of the optic discs
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Since the brain is encased in the cranium,
the only way pressure can be relieved is by
decreasing cranial contents.
• Most readily displaced is CSF
•If ICP still high, cerebral blood volume is
altered:
•Stage 1 – vasoconstriction and external
compression of the venous system
•Compensating, so few symptoms
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If ICP continues to increase, may exceed
brain’s ability to adjust.
• Stage 2:
•IICP (gradually rising) causes a decrease of
oxygenation of neural tissue
•Systemic vasoconstriction occurs to
increase blood pressure to get blood to brain
•Clinical manifestations transient: episodes
of confusion, restlessness, drowsiness, and
slight pupillary and breathing changes
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When ICP begins to = arterial pressure, there is
a lack of compensation- beginning
decompensation Stage 3
•Hypoxia and hypercapnia → cytotoxic edema
•Decreasing levels of arousal
•Widened pulse pressure
•May begin Cheynes-Stokes respirations
•Bradycardia – due to increased pressure in carotid
arteries
•Pupils small and sluggish
•Surgical or medical intervention needed
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When all compensatory mechanisms have
been exhausted:
•Stage 4:
•Dramatic rise in ICP in a short time
•Autoregulation is lost, and get vasodilation,
further increasing intracranial volume
•↓ cerebral perfusion = severe hypoxia and
acidosis
•Brain contents shift (herniate) from area of
high pressure to areas of lower pressure ↓
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blood flow
•Small hemorrhages develop
•Ipsilateral pupil dilation and fixation,
progressing to bilateral fixed and dilated pupils
•When mean systolic arterial pressure equal
ICP, cerebral blood flow ceases
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Treatment
• Remove the cause of the IICP
• Mechanical hyperventilation to medicated
and comatose patient
• Reduce blood pressure through diuretics,
which slows production of CSF and
decreases blood-brain volume
• Drugs, us. Barbiturates to slow brain
metabolism and ↓ effects of hypoxia
• Emergency craniotomy to relieve pressure
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Brain Trauma
• Highest risk:
– 15 to 30 years of age
– Infants 6 mo. to two years
– Young school age children
– Elderly persons
• Male: female = 3:1
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Most likely causes of head injury:
• Transportation accidents
• Falls
• Sports related events
• Violence
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Two major categories of head trauma:
closed (blunt) trauma
open (penetrating) trauma
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Open (penetrating) trauma
Break in dura results in exposure of brain
tissues to environment.
Results in focal (localized) injury
May be due to skull fracture or wound –
intracerebral hematoma
Traumatic pneumocephalus - injury to a
nasal sinus that allows air into brain or
ventricles - cerebrospinal rhinorrhea
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Blunt Head Trauma
More common than open trauma.
Involves head hitting hard surface or rapidly
moving object strikes head
Dura is intact – no brain tissue exposed
May cause focal or diffuse axonal injury (DAI)
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Serious injury decrease due to :
Seat belt use
Improved management
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Mild cerebral concussion
• 75- 90 % of all head injuries
• Not severe
• Diffuse axonal injury – no visible signs on
brain
• May see transient dizziness, paralysis,
unconsciousness, unequal pupils and
shock.
• Reactive period: vomiting, Temp 99 -100o,
rapid pulse, headache, and cerebral
irritation lasting 12 -24 hours.
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Contusions (bruise) : impacts which lead to
hemorrhage and possibly hematoma
Coup (strike) – head strikes against object
shearing forces cause small tears in
blood vessels (subdural vessels)
edema
severity = force
smaller area = greater force
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Contrecoup (rebound) – brain hits opposite
side of skull
shearing forces
and damage opposite to site of impact
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Extradural (Epidural) Hematomas
• 1-2% of major head injuries
• Most common in 20-40 year olds
• Often caused by temporal skull fracture or
injury
• Artery is often the source of bleeding
• Get herniation (shift) of temporal lobe of
brain through tentorial notch
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Subdural hematomas
• 10 - 20 % of persons with traumatic brain
injury
• Develop rapidly (within hours)
• Typically on top of skull
• Often due to tearing of veins or dural
sinuses
• Acts as an expanding mass → IICP→
herniation of brain
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Intracerebral hematomas
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2-3% of head injuries
Single or multiple
Usually frontal and temporal lobes
May occur in deep white matter
Small blood vessels injured by shearing
forces
• Acts as expanding mass, compresses
tissue, and causes edema
• May appear 3- 10 days after head injury
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Clinical manifestations of
contusions
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Loss of consciousness, loss of reflexes
Transient cessation of breathing
Brief bradycardia
Decreased blood pressure
As hematoma enlarges:
headache, vomiting, drowsiness,
confusion, seizure, hemiparesis
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Treatment
• Contusions:
– Control intracranial pressure
• Drugs can relieve fluid pressures; may
alter Na+ conc. in brain fluids
– Manage symptoms
• hematomas:
– Surgical ligation
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Cerebrovascular Disease
• Most frequent of all neurological problems
• Due to blood vessel pathology:
– Lesions on walls of vessels leading to brain
– Occlusions of vessel lumen by thrombus or
embolus
– Vessel rupture
– Alterations of blood quality
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CV disease leads to two types of brain
abnormalities :
Ischemia (with or without infarct)
Hemorrhage
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Cerebrovascular Accident
(Stroke)
• Clinical expression of cerebrovascular
disease: a sudden, nonconvulsive focal
neurological deficit
• Incidence: third leading cause of death in
U.S. – half a million people a year – one
third will die from it
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Incidence
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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
More often seen in Blacks, perhaps due to
increased incidence of hypertension
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Three types :
• Global hypoperfusion – shock
• Ischemia – thrombotic and embolic
• Hemorrhagic
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Risk Factors
• Arterial hypertension
• Heart disease
– Myocardial infarction or endocarditis
– Atrial fibrillation
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Elevated plasma cholesterol
Diabetes mellitus
Oral contraceptives
Smoking
Polycythemia and thrombocythemia
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Occlusive strokes
• Occurs with blockage of blood vessel by a
thrombus or embolus
• May be temporary or permanent
• Thrombotic stroke:
– 3 clinical types:
• TIAs
• Stroke-in-evolution
• Completed stroke
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Transient Ischemic Attacks
• Last for only a few minutes, always less
than 24 hours
• All neurological deficits resolve
• Symptom of developing thrombosis
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Causes:
• Thrombus formation
– Atherosclerosis
– Arteritis
– Hypertension
• Vasospasm
• Other:
– Hypotension
– Anemia
– Polycythemia
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Symptoms depend on location
• 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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Treatment
• Without Tx 80% have a recurrence in
symptoms, and 1/3 go on to have a full
stroke within 5 years
• Give anticoagulants prophylactically ,
usually ½ to 1 aspirin / day
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Stroke-in-evolution
• Can have abrupt onset, but develop in a
step-by-step fashion over minutes to
hours, occasionally, from days to weeks
• Characteristic of thrombotic stroke or slow
hemorrhage
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Thrombotic CVA
• Involves permanent damage to brain due
to ischemia, hypoxia and necrosis of
neurons
• Most common form of CVA
• Causes:
– Atherosclerosis assoc. 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
• Second most common CVA
• Fragments that break from a thrombus
outside the brain, or occasionally air, fat,
clumps of bacteria, or tumors
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Common causes
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Atrial fibrillation
Myocardial infarction
Endocarditis
Rheumatic heart disease and other
defects
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• Impact is the same for thrombotic stroke
• Rapid onset of symptoms
• Often have a second stroke
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Hemorrhagic Stroke
• Third most common, but most lethal
• Bleeding into cerebrum or subarachnoid
space
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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 IICP
• Onset less rapid than embolic CVA,
evolving over an hour or two
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• 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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Degenerative Disorders
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Progressive neurodisorders
Long-lasting
Permanent effects
Many present as syndromes
No cure, but much research
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Alzheimer Disease (Dementia of
Alzheimer Type)
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Dementia is a loss of ordered
neural function
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)
• 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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• Onset may be as young as 50, and
incidence increases with age:
– 6 % of people over 65 years have AD
– Almost half over 85 have AD
• Diagnosis is by ruling out all other causes
–specific diagnosis only by biopsy or
autopsy
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• Pathology restricted to cerebral cortex,
hippocampus, amygdala, and another
basal nucleus called nucleus of Meynert
• Nucleus of Meynert produces
Acetylcholine – loss results in impaired
neural function
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Pathology
• Pyramidal cells die; loss of white matter
• Gyri shrink and and ventricles and sulci
expand – walnut like appearance
• Neurofibrillary tangles
• Neuritic (senile) plaques : filaments,
microglia, astrocytes around core of
amyloid
• Amyloid angiopathy
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http://www.ahaf.org/alzdis/about/plaques_tanglesBorder.jpg
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www.infoaging.org/ d-alz-8-r-tangles.html
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http://homepage.psy.utexas.edu/homepage/class/Psy332/Salinas/Disorders%20/61
Disorders.html
• About 10 % of cases are familial, usually
early onset
• Gene on chromosome 21 – carries gene
for amyloid protein
• Almost all people with Down syndrome
who live beyond 45 years develop AD
• Also linked to mutations on chromosomes
14 and 19
• Prions have been isolated
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Treatment
• So far resistant
• May revolve around amyloid protein
• See high levels of aluminum – chelating agents
temporarily arrest or reverse some symptoms
• THA(tetrahydroaminoacridine) used
experimentally – liver toxicity
• Arthritics have lower incidence of AD
• Therapy centers on problems of failing cognitive
skills
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Parkinson Disease – movement
disorder
• Described over 180 years ago by James
Parkinson
• Combination of slowed, reduced
movements and restless tremoring
• Paralysis agitans
• Slowly degenerative CNS disorder
affecting 80,000 adults in North America
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Parkinson Disease
• Degenerative disease of the basal ganglia
involving the failure of dopamine-secreting
neurons (substantia nigra)
• Can be primary or secondary
• Secondary caused by trauma, infection,
neoplasm, atherosclerosis, toxins and
drug intoxication
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Primary Parkinson Disease
• Begins after the age of 40, with peak age of
onset between 58 – 62
• Course of 10- 20 years – slowly progressive
• More prevalent in males (slightly to 2X)
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• Substantia nigra – two nuclei in midbrain
• Outflow pathway from basal nuclei to
cortex via thalamus
• Damage impairs flow of motor programs
• Expressed as difficulty initiating
movements, general lack and slowing of
movement (bradykinesia)
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• Loss of feedback loop impairs flow of
programs and expresses as resting tremor
• Most disabling symptoms are muscle
rigidity and bradykinesia
• Muscle strength is more or less normal
• Poor balance
• Face becomes immobile and inexpressive
• Autonomic function is decreased:
– orthostatic hypotension, excess sweating,
constipation, etc.
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• Some patients suffer dementia similar to
Alzheimer Disease
• Not fatal, but shortens life expectancy
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Treatment
• Active exercise and good nutrition
• Strategies to overcome bradykinesia
• Only when symptoms are severe are
drugs given – levodopa
• Side effects: cardiac arrhythmias,
gastrointestinal hemorrhage, psychiatric
problems, unpredictable involuntary
movement disorders
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Possible therapies
• Foreign or autograft of tissue still
experimental
• Lesions in the subthalamic nucleus,
thalamus or internal segment of globus
pallidus promising
• Stem cell research?
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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
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Onset
• Onset is between 20
and 40 years, rarely
before 15 or after 50
• Females: Males 2:1
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• Clinical presentation depends on site of
lesion
• Involvement of optic nerve produces
monocular visual disturbances – first
symptom in ¼ of patients
• Half of people with optic neuritis are
diagnosed with MS
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Common symptoms:
• Double vision
• Tingling in the back and anterior thigh
upon neck flexion – Lhermitte’s sign
• Symptoms worsen when patient becomes
heated – Uhthoff’s sign
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Diagnosis
• CSF obtained by lumbar puncture shows
slight increase in protein; on
electrophoresis shows specific banding
pattern – antibodies within CSF suggest
immune reaction
• Changes in velocities of visual and
auditory pathways
• Plaques visible on MRI
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Cause
• Myelin undergoes breakdown and
phagocytic destruction – antibodies may
play a role
• Decreased signal conduction due to
edema and demyelination that exposes
potassium channels that short-circuit
signal (edema resolves and have partial
remyelination)
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• Epidemiology hints at interaction between
a viral illness in the teen years and a
genetic predisposition
• Growing up in northern temperate climates
increases rise
• Non Asian heritage increases risk
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Course
• Pattern of exacerbation and remission
• Stresses can trigger exacerbation:
infection, medication, stress, fatigue
• Course is unstable and unpredictable
• 10 % undergo severe, rapid progressive
deterioration
• Some have died with 7 months of first
symptom due to acute brain inflammation
and infection
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• A significant number never severely
incapacitated
• Some experience only a single episode
• Death is usually attributable to
complications of MS (infections due to
decreased function)
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Symptoms
• Increased urinary frequency
• Lesions in frontal or temporal lobes can
cause emotional outbursts
• Depression and euphoria can be problems
• Unpredictable progression taxes ability to
cope
• Occasionally, plaques can cause
paraplegia or quadriplegia
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Therapies
• Only corticosteroids and ACTH appear to
have effects – reduce the duration of
exacrerbation, but have no impact on long
term outcome
• Interferon β
• Maintaining a healthy lifestyle and outlook
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Acute encephalopathies:
• Reye’s Syndrome
• First recognized in 1963
• Characterized by encephalopathy and
fatty changes in several organs, esp. liver
• Incidence has declined in past 20 years
due to awareness of ingestion of aspirin
during illness and development of Reye’s
syndrome.
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Reye’s syndrome
• Typically develops in a healthy child of 6
mo. to 15 years recovering from varicella,
influenza B, upper respiratory tract
infection, or gastroenteritis.
• Stage I: vomiting, lethargy, drowsiness
• Stage II: disorientation, delirium,
aggressiveness and combativeness,
central neurological hyperventilation,
shallow breathing, hyperactive reflexes,
stupor
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Reye’s syndrome
• Stage III: Insensitivity to pain, coma,
hyperventilation, rigidity
• Stage IV: deepening coma, loss of ocular
reflexes; large, fixed pupils; divergent eye
movements
• Stage V: seizures, loss of deep tendon
reflex, flaccidity, respiratory arrest
• Mortality is 10 or more
• Formerly 40 to as high as 80%
• In a few cases death is due to liver failure
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Reye’s syndrome
• Cause:
– May have a genetic predisposition
– May be due in part to exhaustion of glycogen
stores and use of fatty acids -Mitochondrial
injury
• Treatment:
– Aggressive intensive care
– Treatment for brain edema and IICP
– Fluids I.V. and control of blood electrolytes
– Prevent hyperthermia
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Seizure disorders
• 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
• Some, but not all, recurrent seizures are
due to epilepsy
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Epilepsy
• Second most common neurological
disorder
• Incidence increases with age, with 30%
initially occurring before 4 years and 75 80 % before 20 years.
• Causes: brain tumor, scar tissue,
neurological disease, great majority of
cases are idiopathic.
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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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• Some attacks are proceeded by a
prodrome – a set of symptoms that warn
of a seizure
• As the seizure begins, the patient may
experience an aura – mental, sensory or
motor phenomena
• Others have no warning
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Phases of a grand mal seizure
1. Tonic phase ( 10 -20 seconds) – muscle
contraction
Epileptic cry – respiration stops
2. Clonic phase – (1/2 -2 minutes) muscle
spasms; respiration is ineffective;
autonomic nervous system active
3. Terminal phase (about 5 minutes) –limp
and quiet, EEG flat lines
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• 5-8 % are at risk of status epilepticus –
a series of GTCS without regaining
consciousness – medical emergency
• Seizure activity lasts more than 30
minutes
– Acidosis
– Elevated pCO2
– Hypoglycemia
– Fall in blood pressure
• Can lead to severe brain damage or
death
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Epileptogenic focus
• 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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Treatment
• Treat any underlying metabolic disorders,
or tumors
• Most cases can be controlled through
routine use of antiepileptic medications –
usually only one drug to minimize side
effects
• Surgical intervention if drugs ineffective
• Supportive therapy – patients learn to
cope effectively with stress, eat well, and
get sufficient rest and avoid triggers.
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Eliciting stimuli:
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Hypoglycemia
Fatigue
Emotional or physical stress
Fever
Hyperventilation
Environmental stimuli
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• Patients are normal between attacks
• Can participate in sports, drive a car (if no
seizures for 6 mo – 1 year)
• Should not drink alcohol
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