Neurological Pathophysiology

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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

• 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 brains
  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 ? blood flow

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• 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 31

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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

• 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

• 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

• Highest risk gt 65 years of age
• But about 1/3 (28) are lt 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
• 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

• 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

• 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

• 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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• 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 21

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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 Lhermittes sign
• Symptoms worsen when patient becomes heated
  Uhthoffs 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 ß
• Maintaining a healthy lifestyle and outlook

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Acute encephalopathies

• Reyes 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 Reyes syndrome.

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Reyes 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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Reyes 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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Reyes 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

• Tonic phase ( 10 -20 seconds) muscle
  contraction
• Epileptic cry respiration stops
• Clonic phase (1/2 -2 minutes) muscle spasms
  respiration is ineffective autonomic nervous
  system active
• 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

• 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