Paj 5103 clinical neuropahtophys ii hn10

Lecture IINg, Hoikee PA-C, MPASNova Southeastern University

Learning Objectives

Understand the mechanisms of brain injury Understand how the brain components affect

intracranial pressure Define different types of tramatic brain injury Understand different types of intracranial

hematomas Understand the epidemiology and etiology of

cerebrovascular disease Understand the epidemiology and etiology of

different type of central nervous system infections

Acute brain injury

Brain trauma Cerebrovascular disease Brain hemorrhage Central nervous infections

Mechanisms of Brain Injury

Primary brain injury occurs as a direct result of the initial insult (trauma, stroke)

Secondary injury refers to progressive damage resulting from the body’s physiologic response to the primary insult, (from days to weeks)

A critical factor in determining the neuronal cell fate after injury is the degree of adenosine triphosphate (ATP) depletion

Sequence of neuronal cell injury following acute ischemia

Ischemia

Cell hypoxia

Mitochondrial failure

Decreased ATP production

Decreased Ca++ pumping

Calcium overload

Increased Glutamate

release

Open NMDA

channelsFree-radical production Reperfusion

Immune cellsCell death

Mechanisms of Brain Injury (Cont.)Ischemia and Hypoxia Ischemia is a contributing factor as the

primary insult Ischemia results in immediate

neurologic dysfunction due to the inability of neurons to generate the ATP needed for energy-requiring processes

Ischemia sets the stage for secondary injury by oxygen free radicals, excitatory amino acids, and inflammatory cells.

Mechanisms of Brain Injury (Cont.)

Cellular Energy Failure Neuronal tissue is highly sensitive to oxygen

deprivation because it has great ATP requirement Lack of cellular oxygen results in mitochondrial

dysfunction; anaerobic glycotic pathways are initiated; pyruvate converted to lactate; hydrogen ions lead to cellular acidosis, which affects neuronal integrity; inadequate energy supply leads to deterioration of ion gradients (Calcium overload)

Calcium overload is thought to be a critical factor leading to activation of enzyme cascades, which disrupt function and cause irreversible damage to cell membranes


Excitatory Amino Acids Excessive glutamate may be released because of impaired

membrane integrity Reuptake mechanisms fail to remove excess glutamate

because they are energy-dependent processes Excess glutamate stimulates nearby neurons that then take

up large amounts of injurious calcium ions; calcium overload , which results in cytotoxic edema, a rapid swelling of neurons

Gluatmate binds to NMDA receptors, stimulates nitric oxide production in neurons; in excess it may increase the production of reactive nitrogen species that function as free radicals to damage cellular components

Mechanisms of Brain Injury (Cont.)Reperfusion Injury Is the secondary injury that occurs after re-

establishing blood flow When oxygen reenters cells, erratic transfer of

electrons to oxygen can produce reactive oxygen products that behave as free radicals (hydroxyl radicals, superoxide, peroxide)

Cell membranes may undergo lipid peroxidation in response to free radical damage with subsequent formation of arachidonic acid

Arachidonic acid cascade yields more oxygen free radicals and immune cells (interleukin, tumor necrosis factor, neurophils)

All this contributes to brain inflammation


Abnormal Autoregulation Autoregulation is normally influenced by

the partial pressures of carbon dioxide and oxygen in the arterial blood

PaCO2 decreased: cerebral vessels constrict

PaCO2 increased: cerebral vessels dilate Excessive cerebral blood volume can

exacebrate cerebral edema Hyperventilation low PaCO2

vasoconstriction reduction of ICP

Mechanisms of Brain Injury (Cont.) Injury can cause local or global

impairment of autoregulation Loss of matching between oxygen

supply and demand occurs when autoregulatory mechanisms fail

Sequence of neuronal cell injury following acute ischemia

Ischemia

Cell hypoxia

Mitochondrial failure

Decreased ATP production

Decreased Ca++ pumping

Calcium overload

Increased Glutamate

release

Open NMDA

channelsFree-radical production Reperfusion

Immune cellsCell death

Calcium overload is a key event in producing cellular damage


Consequence of the mechanisms of brain injury

A. Increased Intracranial Pressure (ICP)

Volume of cranium composed of three elements: brain tissue, cerebrospinal fluid (CSF), blood

Monro-Kellie hypothesis: compensatory responses to change in volume in any of these components

Increased ICP can occur with space-occupying lesions, vasogenic or cytotoxic edema, or with obstruction or excessive production of CSF


Cytotoxic edema (intracellular edema) Ischemic tissue swells because of cellular

energy (ATP) failure. Calcium overload, Na inflow to the cell, creating an osmotic force to draw in water

Vasogenic edema Increase capillary pressure damage to

the capillary endothelium extravasation of electrolytes, proteins and fluid into the intracellular space disrupt the blood brain barrier brain swells cerebral edema



Consequence of the mechanisms of brain injury

B. Brain Compression and Herniation• As intracranial pressure rises, it can compress

neural tissue and blood vessels• Herniation: the protrusion of brain tissue

through an opening in the supporting dura of the brain

• Types of herniation syndromes include:– Subfalcine – Tentorial– Uncal– Tonsillar


Mechanisms of Brain Injury (Cont.) From the ischemia injury, if not treat

promptly, will result in focal cell death, cascade event causes cerebral edema, increase ICP, brain herniation, result in permanent neurologic damage

Traumatic Brain Injury

TBI is a major cause of death and a leading cause of disability among young adults

Most head injuries are incurred in motor vehicle accidents, falls, and sports accidents

The severity of TBI is classified by the GCS (Glasgow Coma Scale) score as: Mild GCS score 13-15 Moderate GCS score 9-12 Severe GCS score 8 or below

Epidemiology

1.5 million cases of TBI diagnosed annually; 50,000 result in death

Males are more likely to sustain a TBI and have a higher risk of death from TBI than females

Those at lowest socioeconomic levels have the highest per capita rate of TBI

Types of Brain Injury

Tramatic brain injury: Primary injury Focal Polar Diffuse

Intracranial hematomas Epidural Subdural Subarachnoid

Primary Injury

Focal injuries localized to site of impact Polar injuries are due to acceleration-

deceleration movement of the brain within the skull, resulting in double injury

Diffuse injury is due to movement of the brain within the skull, resulting in widespread axonal injury

Types of Tramatic Brain Injury Concussion

Head injury produces an alternation on consciousness, but no evidence of brain damage is found on physical and radiologic exam

Common consequence of sports related head injury

Contusion When CT or MRI reveals an area of brain

tissue damage (necrosis, laceration, bruising)

Primary Injury (Cont.)

Intracranial Hematomas• Disruption of the vasculature can result

in intracranial hemorrhage• May expand slowly or rapidly,

progressively compressing brain structures and increasing ICP

• Three types of hematoma can develop:– Epidural– Subdural– Subarachnoid


04/12/23


Epidural Hematoma Collection of blood between dura and

skull Typically involves arterial injury thus

rapid onset of symptoms Often involves a fracture of the

temporal bone with disruption of the middle meningeal artery


Subdural Hematoma Collection of blood between dura and

outer layer of the arachnoid membrane Typically involves bridging veins, thus

symptom onset may be slower Bridging veins drain venous blood from the

surface of the brain, crossing the arachnoid and subdural spaces before emptying into the venous sinuses

Chronic subdural hematomas may be prone to rebleeding


Subarachnoid Hemorrhage Collection of blood between arachnoid

membrane and the pia mater Due to rupture of bridging veins

(tramatic brain injury) that pass through the subarachnoid space

Can also be caused by rupture of cerebral aneurysm, arteriovenous malformations

Blood spreads throughout CSF, causing meningeal irritation


Cerebral Aneurysm and Arteriovenous Malformation Structural abnormalities of the cerebral

arteries predispose to intracerebral bleeding and hemorrhage

Cerebral aneurysms and AVMs are the most common causes of subarachnoid hemorrhage


Cerebral Aneurysm Lesion of an artery that results in dilation and

ballooning of a segment of the vessel Congenital defect of the medial layer of the artery

weakens to arterial pressure, allowing the dilated portion to fill with blood and eventually burst causing SAH

90%of cerebral aneurysms are located in the circle of Willis

Typical presentation is severe HA with meningismus: worst headache in his/her life

Treatment involves surgical stabilization with aneurysm clipping or embolization


Arteriovenous Malformation Capillary system fails to develop appropriately

with arterial blood shunted directly into the venous system; causes the vessels to progressively enlarge; becomes a congested mass of enlarged vessels that can burst

The majority of AVMs are diagnosed in 20-40 yrs of age

90% of AVMs are found in the cerebral hemispheres

Patients typically present with seizure and neurologic dysfunction

Secondary Injury

Ischemic and hypoxic events, subsequent vasogenic/ cytotoxic edema and other processes that lead to increased ICP, and altered vascular regulation may affect patient outcomes to a greater extent than the primary injury Vasogenic, cytotoxic edema may increase

for 48 to 72 hrs after injury

Cerebrovascular Disease and Stroke

Stroke is a sudden onset of neurologic dysfunction due to cardiovascular disease that results in an area of brain infarction

Stroke is the third leading cause of death in the United States

Most common form of stroke is ischemic

Epidemiology

Females affected more often than males

Most stroke victims are >65 years of age

Risk factors are similar to those for other atherosclerotic vascular diseases (hypertension, DM, hyperlipidemia, smoking)

Ischemic Stroke Result from sudden occlusion of cerebral artery

secondary to thrombus formation or emboli Thrombotic strokes associated with

atherosclerosis and coagulopathies Embolic strokes associated with cardiac

dysfunction or dysrhythmias (atrial fibrillation) Penumbra: a much larger area of ischemic but

viable cells that is surrounding the infarct. The penumbra receives some partial or collateral flow and may recover if the ischemia is mild or perfusion is restored in a timely manner.

Salvaging the penumbra is the aim of early thrombotic therapy; however, treatment must be instituted within 3 hours of symptom onset to be maximally effective

Ischemic Stroke Transient ischemic attack (TIA)

Neurologic symptoms typically last only minutes, but may last as long as 24 hrs. Symptoms resolve completely without evidence of neurologic dysunction

Lacunar infarcts Occlusion of the small penetrating

arterioles can produce small lesions. The basal ganglia, pons, cerebellum and internal capsule are common sites for lacunar infarcts

Hemorrhagic Stroke

Hemorrhage within the brain parenchyma

Usually occurs secondary to severe, chronic, hypertension

Most occur in basal ganglia or thalamus Degree of secondary injury and

associated morbidity and mortality is much higher in hemorrhagic stroke than ischemic stroke

Central Nervous System Infections

Organisms may gain access to the CNS through the bloodstream, direct extension from a primary site or along peripheral and cranial nerves, or through maternal-fetal exchange

Meningitis and cerebral abscess commonly associated with bacterial infections; encephalitis is usually viral

A frequent consequence of bacterial infections is hydrocephalus, as the bacterial, WBCs block CSF resorption in the arachnoid villi

Meningitis

Bacteria usually reach the CNS via the bloodstream or extension from cranial structures

Most common bacteria are Streptococcus pneumoniae and Neisseria meningitidis

Bacteria invade leptomeninges (pia mater & the arachnoid space) accumulation of inflammatory exudate can result in hydrocephalus

Encephalitis

Inflammation of the brain commonly caused by West Nile virus, western equine encephalitis, and herpes simplex

Typical presentation includes fever, HA, malaise, muscle pain, and/or rash

Brain Abscess

Localized collection of pus within the brain parenchyma

Pyogenic (pus-producing) pathogens reach the brain by Penetrating wounds Direct extension or retrograde

thrombophlebitis of an infected neighboring structure (mastoiditis)

Blood borne dissemination for a distant infected site (lungs)

Brain Abscess Most common infective organisms:

streptococci, staphylococci, and anaerobes The abscess has a focal infected core:

central portion contains neurtrophils and pus

The peripheral portion of the abscess: made up of inflammatory granulation tissue

Around the brain abscess is perifocal edema with proliferation of surviving astrocytes.

In chronic phase, the core is liquefied & the peripheral portion forms a collagenous capsule & is surrounded by fibrous gliosis

Brain Abscess

Chronic Disorders of Neurologic Function

Learning objectives Understand the etiology and

pathogenesis of cerebral and cerebellar disorder: Seizure disorder, Dementia, Parkinson disease, Cerebral Palsy, hydrocephalus, cerebellar disorders.

Understand the etiology and pathogenesis of certain spinal cord and peripheral nerve disorders: Multiple Sclerosis, Spina Bifida, Amyotrophic Lateral Sclerosis, Spinal Cord Injury, Guillain-Barre Syndrome

Brain and cerebellar disorders Seizure Disorder Dementia Parkinson Disease Cerebral Palsy Hydrocephalus Cerebellar Disorders

Seizure Disorder

Transient neurologic event of paroxysmal abnormal or excessive cortical electrical discharges that are manifested by disturbances of skeletal motor function, sensation, autonomic visceral function, behavior, or consciousness

Epilepsy or seizure disorder refers to recurrent seizures

Seizures are a component of many diseases

Seizure Disorder

Etiology Acquired event as a consequence of

cerebral injury or other pathologic process such as tumors, blood clots, infection, metabolic disorders, head injury, stroke, medication overdose, medication adverse effect, exposure to toxins

In some cases, no explanation for the seizure disorder: idiopathic seizures.

Seizure Disorder Pathogenesis

Due to an alteration in membrane potential that makes certain neurons abnormally hyperactive and hypersensitive to changes in their environment

Abnormal neurons form an epileptogenic focus. This focus functions autonomously, emitting excessively large numbers of paroxysmal electrical discharges. Nerve cells can recruit neurons in adjacent areas and synaptically related neurons in distant areas of the brain; thus, greatly increasing the number of neurons involved in seizure activity

Seizure Disorder

Seizure Disorder (Cont.)

Generalized seizures involve the entire brain from the onset of the seizure

Partial seizures are those in which abnormal electrical activity is restricted to one brain hemisphere

Status epilepticus is a continuing series of seizures without a period of recovery between seizure episodes and can be life-threatening

Dementia A syndrome associated with many

pathologic processes and characterized by progressive deterioration and continuing decline of memory and other cognitive changes

Patients may initially appear uninterested or lacking initiative, many have agnosia (lack of ability to interpret sensory stimulation) or lack of insight into their cognitive deficiencies

Important to first rule out manageable causes of dementia; often cause unknown

Dementia

Etiology 50-60% Alzhemier ‘sdisease 15-20% vascular dementia Dementia-causing illness:

alcoholism, intracranial tumor, normal pressure hydrocephalus, Parkinson disease, Lewy Body disease, Huntington disease, multiple sclerosis, Creutzfeldt-Jakob disease

Dementia

Delirium A global mental dysfunction includes

disturbed consciousness, decreased awareness of the environment, inability to maintain attention, disrupted sleep wake cycles, drowsiness, restlessness, emotional lability, incoherence, hallucinations

Abrupt onset, fluctuate often, worse at night Causes: polypharmacy, metabolic

abnormalities, nutritional deficiencies, infection

Dementia

Pathogenesis of Alzheimer’s disease 1. Intracellular neurofibrillary tangles 2. Extracellular amyloid (senile) plaques diffuse neuronal damage & brain

atrophy occurs The brain of Alzheimer disease often

weighs less than a normal person The temporoparietal and anterior frontal

regions of the brain are affected the most

Dementia

Pathogenesis of Alzheimer’s Disease 3. Neurotransmitter system:

abnormalities in cholinergic system Reduced activity of choline

acetyltransferase(the enzyme necessary for acetylcholine synthesis), and decreased ACH synthesis

Dementia

Conclusion: The dementia of Alzheimer disease is

characterized by degeneration of neurons in temporal and frontal lobes, brain atrophy, amyloid plaques, and neurofibrillary tangles

Cause remains unknown, although genetic and environmental triggers are suggested

Synthesis of brain acetylcholine is deficient and treatment is aimed at increasing acetylcholine levels by reducing acetylcholine reuptake

Parkinson’s disease

The basal ganglia includes the caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra.

Parkinson disease

The basal ganglia and the cerebellum transmit information via the thalamus to the cerebral cortex in order to regulate movement. In a healthy brain, the neurons based in the substantia nigra extend into the putamen and caudate (which both comprise the striatum). These cells release dopamine in the striatum, which modulates neuronal activity. As a result, this affects the performance of movement.

Basal Ganglia

Parkinson disease

In Parkinson’s disease, there is a breakdown in the connection between the neuron in the substantia nigra and the putamen portion of the striatum. Symptoms of Parkinson’s disease appear after 60-80% of these cells become impaired or die. It is not specifically the loss of the cells that causes the disease, but rather the decrease in the dopamine, which occurs with the decreased number of substantia nigra neurons.

Parkinson disease

Typically, symptoms appear after striatal dopamine levels have decreased by 20-50% of normal levels.

When Substantia nigra projections to the putamen have been impaired, the globus pallidus interna and subthalamic nucleus begin to function abnormally. The result is that the brain is no longer able to sufficiently control motor function.

Parkinson Disease (Cont.)

These signals could overly excite many of the muscles of the body, leading to rigidity. Symptoms include lead-pipe rigidity, tremor, pill-rolling movements, and reduced voluntary movement, loss of facial expression, drooling, propulsive gait, and absent arm swing

Parkinson Disease (Cont.)

Cerebral Palsy

Diverse group of crippling syndromes that appear during childhood and involve permanent, nonprogressive damage to motor control areas of the brain

Classified on the basis of neurologic signs and symptoms, with the major types involving spasticity, ataxia, dyskinesia, or a mix of one or more of the three

Cerebral Palsy (Cont.)

Etiology may include prenatal infections, or diseases of the mother; mechanical trauma to the head before, during, or after birth; exposure to nerve-damaging poisons or reduced oxygen supply to the brain

Hydrocephalus

Characterized by abnormal accumulation of fluid in the cerebroventricular system

1. Normal pressure hydrocephalus is due to an increased volume of CSF without change in ICP Ventricles become distended,

compressing brain tissue & cerebral vessels

NPH triad of symptoms: gait instability, urinary incontience, dementia

Hydrocephalus

2. Obstructive hydrocephalus is due to an obstruction to the flow of CSF There is an obstruction at some point in

either the intraventricular or extraventricular pathways of the ventricular system.

Usually congential abnormality, such as stenosis of the foramina of the 4th ventricle, aqueduct stenosis or spina bifida cystica

Hydrocephalus

3. Communicating hydrocephalus occurs due to abnormal absorption of CSF Also called acquired communicating

hydrocephalus Abnormality in CSF absorption from the

subarachnoid space. There is no obstruction to the flow of the fluid between the ventricles and subarachnoid space

Causes: Infections, trauma, tumors

Hydrocephalus (Cont.)

Hydrocephalus

Medical treatment is limited Obstructions may be corrected

surgically The most effective treatment for

management of hydrocephalus is surgical correction employing a shunt

Hydrocephalus (Cont.)

Cerebellar Disorders

Cerebellum is responsible for coordinated control of muscle action, excitation and inhibition of postural reflexes, and maintenance of balance

Etiology of cerebellar disorders includes abscess, hemorrhage, tumors, trauma, viral infection, or chronic alcoholism

Clinical manifestations include ataxia, hypotonia, intention tremors, and disturbances in gait and balance

Spinal cord & peripheral nerve disorders Multiple sclerosis Spina bifida Amyotrophic lateral sclerosis Spinal cord injury Guillain barre syndrome

Multiple Sclerosis

Chronic inflammation, demyelination, & gliosis (scarring) “Disseminated in time & space”

Affects 400,000 Americans Most frequent cause of neurologic disability

early/middle adulthood (excluding trauma) ? autoimmune etiology

environmental trigger in genetically susceptible

Name from plaques in white matter Occasionally - gray matter

Multiple Sclerosis

Epidemiology: Female:Male = 2:1 Onset of age: 20-50 yrs Orkney islands - Scandinavia - northern

European descent US - Caucasians > other races Rare in Japan; unknown in black Africans;

Japanese Americans/African Americans risk

Disease of temperate climates

Multiple Sclerosis

Etiology A viral infection or environmental toxin

intitates the autoimmune attack in a genetrically predisposed individual

Both humoral and cellular immune factors have been implicated in demyelination

T-cell lymphocyte-mediated damage to the myelin has also been implicated in causing the autoimmune damage and sustaining inflammation

Multiple Sclerosis

Pathogenosis Demyelination can occur throughout the

CNS but often affects the optic and oculomotor nerves, the corticospinal, cerebellar, and posterior column systems

Myelin facilitates nerve conduction, inflammation and scarring of the myelin slows or interrupts the conduction of nerves impulses

Spinal Cord and Peripheral Nerve Disorders

Spina Bifida

Developmental anomaly characterized by defective closure of the bony encasement of the spinal cord (neural tube) through which the spinal cord and meninges may or may not protrude

If anomaly not visible, condition is called spina bifida occulta

If there is an external protrusion of the saclike structure, the condition is called spina bifida cystica, and further classified according to the extent of neural involvement

Amyotrophic Lateral Sclerosis ALS is a progressive degenerative disease

affecting both the upper and lower motor neurons

Cause remains unknown, environmental factors, and genetic predisposition

Weakness and wasting of the upper extremities usually occur, followed by impaired speech, swallowing, and respiration

Typically occurs between the ages of 40-60 years and affects men more than women

Amyotrophic Lateral Sclerosis Pathologic changes in the spinal cord

include degeneration of the lateral columns where the corticospinal tracts are located

ALS is also known as Lou Gehrigh disease

Spinal Cord Injury

Etiology Usually traumatic, a result of motor vehicle

accidents, falls, penetrating wounds, or sports injuries

Spinal Cord Injury

Pathogenesis The major mechanisms of injury:

hyperflexion, hyperextension, and compression

Primary injury: The cord may be compressed, transected, or contused

Secondary injury: edema, ischemia, excitotoxicity, inflammation (neutrophils, macrophages, pro-inflammatory cytokines, T-lymphocytes), causing increased cell death, disruption of blood brain barrier, and demyelination

Spinal Cord Injury (Cont.)

Spinal Cord Injury (Cont.)

Spinal shock occurs immediately following SCI and is characterized by temporary loss of reflexes below the level of injury Muscles are flaccid; skeletal and autonomic

reflexes are lost Neurogenic shock may occur after SCI

due to peripheral vasodilation Hypotension and circulatory collapse can

occur; high spinal cord injuries can affect respiratory muscles, leading to ventilatory failure

Guillain-Barré Syndrome

Acute Inflammatory Demyelinating Polyneuropathy (AIDP) Axonal degeneration

Disease of the peripheral nervous system or a lower motor neuron disorder

Immune-mediated - ? immunopathogenesis

~ 75% - antecedent infection (prior 1-3 wks acute infection process) CMV& EBV, Campylobacter jejuni

gastroenteritis, herpesvirus, mycoplasma, surgical procedure

Guillain-Barré Syndrome (GBS) Occurs: 0.6-1.9 cases/100,000/yr All parts of world; all seasons;

children & adults; both sexes; all ages (d 50-81 yoa)

Life-threatening respiratory insufficiency, swallowing

difficulties, & autonomic dysregulation Mortality < 5% in optimal settings Ascending, primarily motor paralysis

References

Pathophysiology by Copstead & Banasik Ch 44, 45

Education

Paj 5103 clinical neuropahtophys ii hn10