WHAT IS NEUROPIL

Areas in which axons and dendrites synapse (2). More broadly described as

any area in the nervous system composed of mostly unmyelinated axons,

dendrites, and glial cell processes that forms a synaptically dense region

containing a relatively low number of cell bodies.

IS A NUCLEUS IN THE CNS MADE UP OF GRAY

MATTER OR WHITE MATTER?

Gray matter

Tracts are white matter

THE CEREBRAL HEMISPHERES CONSIST OF…

An outer cerebral cortex consisting of gray matter and composed of four lobes:

frontal, parietal, temporal and occipital

White matter

Three deep nuclei: Basal ganglia, Hippocampus, Amygdala

Gray matter

**In the spinal cord the gray matter is on the inside

WHAT ARE THE GENERAL FUNCTIONS OF THE

FRONTAL LOBE?

Planning behavior

Language production

WHAT ARE THE GENERAL FUNCTIONS OF THE

PARIETAL LOBE?

Spatial orientation

Language comprehension

WHAT ARE THE GENERAL FUNCTIONS OF THE

TEMPORAL LOBE?

Audition

Visual processing

Recognition of stimuli

Learning and memory

WHAT ARE THE GENERAL FUNCTIONS OF THE

OCCIPITAL LOBE?

Vision

WHAT IS THE GENERAL FUNCTION OF THE

LIMBIC SYSTEM?

Emotional expression

Regulation of visceral motor activity

WHAT IS THE INTERNAL CAPSULE?

White matter separating the caudate nucleus and thalamus from the globus

pallidus and putamen (Basal ganglia). Contains both ascending and

descending fibers.

WHAT IS THE GENERAL FUNCTION OF THE

CEREBELLUM

Coordination of motor activity

Posture

Equilibrium

WHAT ARE THE THREE REGIONS OF THE CNS

THAT ARE IMPORTANT FOR CONSCIOUSNESS?

Cortical

Thalamic

Rostral reticular

WHAT ARE THE CELL LAYERS OF THE

NEOCORTEX?

WHAT ARE THE FOUR STEPS TO EVALUATE A

NEUROLOGICAL DISEASE?

Localize lesion

Determine type

Focal/diffuse

Mass/non-mass

Assess time course

Develop differential

WHAT ARE THE 5 NEUROLOGICAL SYSTEMS TO

WHICH DISEASE CAN LOCALIZE

Conscious

Motor

Sensory

Autonomic

Visual

WHAT ARE THE FIVE DIFFERENT TIME COURSES

OF A NEUROLOGICAL DISEASE

Acute – minutes to hours

Subacute – hours to days

Chronic

Relapsing and remitting

Static

FOCAL AND ACUTE

Vascular - infarct

Traumatic - contusion

DIFFUSE AND ACUTE

Toxic/Metabolic

Traumatic – diffuse axonal injury

FOCAL AND SUBACUTE

Inflammatory

Infectious abscess

DIFFUSE AND SUBACUTE

Diffuse infection

Hepatic coma

CHRONIC AND FOCAL

Neoplasm

Neurosyphilis

CHRONIC AND DIFFUSE

Degenerative – Alzheimers

Metabolic – B12 deficiency

LIST 2 CONDITIONS UNDER WHICH A LUMBAR

PUNCTURE ARE RISKY

Underlying coagulopathy

Increased intracranial pressure herniation

WHAT IS GFAP AND HOW IS IT USED IN

HISTOLOGY?

Glial fibrillary acid protein (GFAP) is an intermediate filament type unique to

astrocytes.

This protein is concentrated in the astrocytic processes which contribute to the

fibrous intercellular network called the neuropil.

Staining with anti-GFAP antibodies (brown in image below) allows visualization

of astrocytes (A), especially astrocytic processes. Some astrocytic processes

terminate in perivascular feet (PF in image) which surround capillaries in the

CNS, contributing significantly to the blood-brain barrier.

DESCRIBE THE LOCATION AND FUNCTION OF

THE CHOROID PLEXUS AND THE EPENDYMAL

CELLS

Ependymal cells line the ventricles of the brain and the central canal of the

spinal cord in a single layer of columnar or cuboidal cells.

In some places, ependymal cilia project into the CSF to help circulate it.

Ependymal microvilli also project into the CSF to monitor its composition.

In the choroid plexus, modified ependymal cells produce CSF.

Unlike a true epithelium, the ependymal cell layer lacks a basal lamina. Instead,

it is anchored by processes that extend into the neuropil.

WHAT DO THE ARROWS POINT TO?

Thick arrow – arachnoid mater

Star – blood vessel

Thin arrow – pia mater

Gray matter vs.

White matter

DESCRIBE THE HISTOLOGICAL

CHARACTERISTICS OF THE CEREBELLUM

The cerebellar cortex is convoluted with many distinctive small folds, each

supported at its center by cerebellar medulla (M), which is white matter

consisting of large tracts of axons.

Immediately surrounding the white matter of the medulla is the granular layer

(GL) of the cortex, which is densely packed with very small, rounded neuronal

cell bodies.

The outer, "molecular layer" (ML) consists of neuropil with fewer, more

scattered small neurons.

At the interface between the granular and molecular layers is a single layer with

very large neuronal cell bodies of unique Purkinje cells (P), whose axons pass

through the granular layer (Gr) to join tracts in the medulla and whose multiple

branching dendrites ramify throughout the molecular layer

HIPPOCAMPUS: IDENTIFY AMMON’S HORN AND

DENTATE GYRUS

WHY DOES THE SUBSTANTIA APPEAR DARK?

Located within cerebral peduncles

Appear dark due to presence of neuromelanin in neurons

WHAT IS THE PRINCIPAL SIGN OF ACUTE

NEURONAL INJURY

“Red neurons” refers to a spectrum of changes that accompany acute CNS hypoxia/ischemia or other acute insults and reflect cell death, either necrosis or apoptosis

Red neurons” are evident with hematoxylin and eosin (H&E) preparations at about 12 to 24 hours after an irreversible hypoxic/ischemic insult.

The morphologic features consist of shrinkage of the cell body, pyknosis of the nucleus, disappearance of the nucleolus, and loss of Nissl substance, with intense eosinophilia of the cytoplasm.

1 hour: microvacuolation of cytoplasm (mitochondria swollen) & perineuronalvacuolation (astrocytic processes swollen)

4-12 hours: neuronal cytoplasm eosinophilia (nissl bodies disappear), nucleus pykinosis, nucleoli not visible; red neuron

15-24 hours: neutrophil leukocytes infiltration begins

WHAT ARE SIGNS OF SUBACUTE AND CHRONIC

NEURONAL INJURY?

Pathologic Inclusions

Hyperplasia and hypertrophy

Gliosis

Gemistocytic - acute

Fibrillary – chronic

Microglial proliferation/activation

2 days: macrophagic infiltration begins (may stay for months)

5 days: neutrophil infiltration ceases

around 1 week: proliferation of reactive astrocytes

around 10 days: area of infarction is characterized by the presence of

macrophages and surrounding reactive gliosis

DISTINGUISH BETWEEN PATHOLOGICAL

RESPONSES OF GEMISTOCYTIC ASTROCYTOSIS

AND FIBRILLARY ASTROCYTOSIS.

gemistocytic astrocytosis

nuclei of the astrocytes, which are typically round to oval with evenly

dispersed, pale chromatin, enlarge, become vesicular, and develop

prominent nucleoli

previously scant cytoplasm expands to a bright pink, somewhat irregular

swath around an eccentric nucleus, from which emerge numerous stout,

ramifying processes

short term

fibrillary astrocytosis

eosinophilic masses called rosenthal fibers can be seen within the

processes, especially when the lesion involves the white matter

long term

GLIOSIS

DESCRIBE THE HISTOLOGICAL DIFFERENCES

BETWEEN RESTING AND ACTIVATED MICROGLIA

Resting – banana shaped, difficult to see without staining

Active – large foamy macrophages

NAME THE “ANATOMICAL” SITE OF THE BLOOD

BRAIN BARRIER

Cerebral capillary

Endothelial cells and astrocytes

DISTINGUISH THE ENDOTHELIAL AND

ASTROCYTIC SIDES OF THE BBB

Endothelial side of the BBB has occluding intercellular (tight) junctions, low

pinocytotic (pinocytosis=cell uptake of fluid) activity, carrier facilitated & active

transport, and highly regulated cellular (monocytes) transfer

The Astrocyte side of the barrier has foot processes and is important in

secretion of proteases, growth factors, and receptors as well as has

connections with neuronal elements.

WHAT ARE THE AREAS OF THE BRAIN THAT ARE

SENSITIVE TO HYPOXIA IN INFANTS?

CA1 hippocampus

diencephalon gray nuclei, thalami

midbrain nucleus

WHAT ARE THE COMMON REACTIONS OF THE

CNS TO INJURY

Cerebral Edema

Hydrocephalus

Raised ICP

Herniation

WHAT ARE THE TWO TYPES OF CEREBRAL

EDEMA AND HOW ARE THEY CAUSED?

Vasogenic edema

caused by blood-brain barrier disruption and increased vascular permeability,

allowing fluid to shift from the intravascular compartment to the intercellular

spaces of the brain. The paucity of lymphatics greatly impairs the resorption

of excess extracellular fluid. Vasogenic edema may be either localized (e.g.,

adjacent to inflammation or neoplasms) or generalized.

Cytotoxic edema

increase in intracellular fluid secondary to neuronal, glial, or endothelial cell

membrane injury, as might be encountered in someone with a generalized

hypoxic/ischemic insult or with metabolic damage.

MOST CASES OF HYDROCEPHALUS OCCUR AS A

RESULT OF …

Impaired flow or resorption of CSF

NOT overproduction

WHAT IS THE

VIRCHOW ROBIN

SPACE

When entering the brain

parenchyma, the vessels are

initially surrounded by the

perivascular space (also

known as the Virchow–Robin

space), which is connected

to the subarachnoid space

WHAT IS THE MAIN POSTSYNAPTIC INHIBITORY

NEURON

GABA

Glycine is another

WHAT IS FACILITATION AT THE SYNAPSE?

Consistent influx of Ca++ in presynaptic neurons → higher level of

neurotransmitter release → progressively higher & higher EPSPs

Short term effect

DESCRIBE SYNAPTIC DEPRESSION

The presynaptic vesicles cannot keep up with the presynaptic electrical

stimulation → decrease in available neurotransmitter → progressively smaller

EPSPs

Short term

Generally occurs at synapses with high probability of release

WHAT IS POST-TETANIC POTENTIATION

Enhancement of synaptic strength following a brief train of strikes. Higher

concentration of Ca++ available in the presynaptic neuron, so next stimulus

leads to higher EPSPs than normal. Same mechanism behind facilitation, with

many back-to-back stimuli (tetanic), so Ca++ accumulation & potentiation is

greater and lasts longer.

Short term

LONG TERM POTENTIATION

Brief, High Frequency Stimulation → Fast Increase in Ca++ →

Phosphorylation→ EXOcytosis of AMPAR→ Increased AMPAR at synapse→

Overall strength is increased

LTP (Ca2+ comes in through NMDA channels)

Ca++ binds to calmodulin which activates CaMKII which:

Autophosphorylates

Phosphorylates AMPAR to make them more permeable: goal is to keep

depolarization going

Phosphorylates Ras-ERK signaling→ allows exocytosis of AMPAR contained

within vesicles

Phosphorylates Stargazin on newly exocytosed AMPAR→ immobilizes

AMPAR at synapse (thereby increasing amount of AMPARs at synapse)

HOW ARE NMDA RECEPTORS ACTIVATED TO

INITITATE LTP?

NMDA receptors (N-methyl-D-aspartate) are permeable to Na and Ca, but

have an Mg ion in pore that acts as a plug (blocking it at rest)

NDMARs require a strong depolarization to first remove Mg ion from pore (>-

50mV)

Therefore it needs (1) glutamate binding PLUS (2) strong depolarization to

dislodge the Mg and allow Ca++ and Na+ to flow through

At rest, NDMARs will bind glutamate released from pre-synaptic neuron but will

not open due to lack of strong depolarization. NDMARs depend on AMPARs

opening first.

DESCRIBE THE STEPS OF LONG TERM

DEPRESSION

Generated by prolonged (3-15min) low frequency (1-5Hz) stimulation, reduction

in sensitivity, small slow rises in the levels of Ca++ (not above threshold

though) in the postsynaptic cell; ultimately leads to endocytosis of AMPARs and

lower sensitivity to further stimuli.

During LTD, low levels of Ca++ ions enter via the NMDA receptors. Low levels

of Ca++ ion activates protein phosphatases→ dephosphorylation of AMPAR→

endocytosis of AMPAR

WHAT IS A SILENT SYNAPSE?

NMDA activation WITHOUT AMPA activation

These synapses are “silent” because normal AMPA receptor-mediated signaling

is not present, rendering the synapse inactive under normal conditions.

Remember that AMPAR are the only active receptors at rest

NMDAR require initial depolarization from AMPAR activation to move the Mg++

block

When an LTP is induced, there is a rapid expression of AMPA receptors at the

silent synapses accounts for the depression of "failure" rate of postsynaptic

action potentials where there's an LTP

DESCRIBE THE MECHANISM UNDERLYING

EXCITOTOXICITY.

Overactivation of NMDARs triggers excessive entry of Ca++ ions, which

activate a series of cytoplasmic and nuclear processes that promote neuronal

cell death

Activation of Ca++-activated proteolytic enzymes like calpains that degrade

essential proteins

·Ca++ ions enter mitochondria, which enhances mitochondrial electron

transport leading to more ROS and free radical damage

NMDA antagonist (memantine) given in Alzheimers in order to prevent further

cell death.

WHAT ARE THE MAJOR METABOLITES OF THE

MONOAMINES?

Dopamine – HVA –

↑ Psychosis

↓ Parkinson’s

Serotonin – 5-HIAA

↓ Severe depression and suicide, aggressiveness, impulsiveness

Norepinephrine – VMA/MHPG

↓ Severe depression and attempted suicide

WHAT ARE THE THREE AREAS OF MENTAL LIFE

THAT PSYCHIATRY CONSIDERS?

Thoughts

Moods

Behaviors

WHAT IS OPERATIONALISM IN PSYCHIATRY AND

WHAT ARE ITS LIMITATIONS?

Seeks to define mental events by their public expression

Limitations

Patient must be verbal

Patient must have insight into condition

WHAT ARE THE TWO EXPLANATORY METHODS

OF PSYCHIATRY

Form – descriptive – what?

Function – interpretive – why?

Looks at people as unique individuals

DISTINGUISH BETWEEN FLIGHT OF IDEAS,

CIRCUMSTANTIALITY, AND LOOSE

ASSOCIATIONS.

Flight of ideas Pressured and accelerated speech Goal directed with preserved associations Shifting goals, distractible *MANIA

Circumstantiality Unnecessary digressions, parenthetical clarifications Excessive detail *OBSESSIVE

Loose associations Loss of goal directed speech Derailments, word salad *SCHIZOPHRENIA

WHAT ARE THE COMPONENTS OF A MENTAL

STATUS EXAM?

Appearance

Speech

Mood

Hallucinations

Delusions

Obsessions/Compulsions

Phobias

Cognition

Insight and Judgment

WHAT IS THE DIFFERENCE BETWEEN MOOD

AND AFFECT?

Affect – observable

Mood – subjective patient reported

WHAT ARE THE PRIMARY SYMPTOMS OF A

CLINICAL MOOD DISORDER?

Sleep

Interest

Guilt

Energy

Concentration

Appetite

Psychomotor retardation

Suicidal thoughts

DIGFAST for Mania – distractibility, insomnia, grandiosity, flight of ideas,

activity, speech, thoughtlessness

WHAT IS A HALLUCINATION?

Hallucination: true perception in the absence of an external stimulus

Pseudohallucination: sensation is inside but foreign “voice inside my head”

Illusions: external stimulus misperceived

WHAT IS THE DEFINITION OF A DELUSION

A belief (not a perception) that is FIXED, FALSE or IDIOSYNCRATIC

DIFFERENTIATE OBSESSIONS FROM

HALLUCINATIONS, DELUSIONS AND

RUMINATIONS

Obsessions - persistent ideas, thoughts, impulses or images that are

experienced as intrusive or inappropriate and that cause marked anxiety or

distress

different from ruminations because the patient perceives them to be senseless.

different from hallucinations because they are thoughts, and not sensory

perceptions.

different from delusions because the patient acknowledges the irrationality in

his or her ideas.

LIST THREE COMMON

OBSESSIONS/COMPULSIONS

Fear of germs/dirt

Pathologic doubt

Aggressive or sexual thoughts

Excessive need for order/symmetry

LIST THE THREE GENERAL TYPES OF PHOBIAS

AND DESCRIBE THEM

Specific phobias

Fear of a clearly discernible circumscribed object/situation

Agoraphobia

Fear of situations/places that are difficult to escape

Social phobia

Fear of social situations where embarrassment may occur

WHY IS INSIGHT IMPORTANT AND WHAT ARE

ITS COMPONENTS?

Strong correlations with prognosis

Awareness of symptoms?

Attribution of symptoms?

Consider themselves ill?

Treatment required?

Medications required?

NAME FOUR PERSPECTIVES EMPLOYED IN

UNDERSTANDING MENTAL PHENOMENA

Disease – what a person has

Syndrome pathology etiology

Dimensions – what a person is

The trait is abnormal when it is excessive enough that the individual is

rendered vulnerable by it

Behaviors – what a person does

Pathological when object or strength of drive is socially unacceptable

Life Stories – meaning of thoughts and feelings

Emphasis on meaning of experience and emotions

DEFINE DELIRIUM AND EXPLAIN WHY IT IS

BEST APPROACHED USING A DISEASE

PERSPECTIVE.

Change in the level of consciousness and change in the ability to sustain

attention

Can wax and wane - ranges from normal (or even hypervigilant) through

drowsiness, stupor, or coma

Treatment depends on pathology and etiology

Can be tested

DEFINE DEMENTIA AND EXPLAIN WHY IT IS

BEST APPROACHED USING A DISEASE

PERSPECTIVE.

Global decline in cognition with clear consciousness

Use of disease perspective:

syndrome is validated through serologic studies, radiographic studies, and

rarely brain biopsies

treatment depends on the pathology and etiology of the illness

EXPLAIN WHY IT IS MORE DIFFICULT TO APPLY A

DISEASE PERSPECTIVE TO MOOD DISORDERS,

ANXIETY DISORDERS, AND SCHIZOPHRENIA

THAN TO DO SO FOR DELIRIUM AND DEMENTIA.

There is continued uncertainty about the underlying pathology and etiology of

these disorders, so there is no “gold standard” ancillary tests to confirm or

refute the presence of these conditions such as mood disorders, anxiety

disorders, and schizophrenia .

WHAT ARE THE THREE CLUSTERS OF THE DSM

IV PERSONALITY DISORDERS

Odd Paranoid Schizoid Schizotypal

Dramatic Antisocial Borderline Histrionic Narcissistic

Anxious Avoidant Dependent Obsessive-compulsive

WHAT ARE THE MATURE DEFENSE

MECHANISMS

Anticipation

Humor

Sublimation

Suppression

Affiliation

WHAT ARE THE NEUROTIC DEFENSES

Displacement – emotion placed elsewhere from source

Externalization – blame on situation around

Intellectualization

Dissociation – detachment

Repression – unconscious mechanism – emotion expressed in other ways

Reaction formation – replaces impulse with exact opposite

WHAT ARE THE IMMATURE DEFENSES

Denial – resistance in the face objective facts

Autistic/Schizoid fantasy – out of touch with reality

Passive aggressive behavior – insists that they are not angry but actions differ

Acting out – behavior grossly out of proportion

Splitting – everything is black and white, no gray area

Projection - projecting emotions on other

Projective identification – projection, and the person assumes that projection

DEFINE PERSONALITY

The sum of an individual’s abiding and consistent traits

DEFINE A TRAIT

Tendencies to react in circumstances in a particular fashion

DIFFERENTIATE THE CATEGORICAL FROM THE

DIMENSIONAL APPROACH IN DETERMINING AN

ABNORMAL TRAIT

Categorical – inflexible and causing suffering

Dimensional – excessive enough that the individual is vulnerable

AXIS I

State related disorders

Delirium

Depression

Schizophrenia

Substance abuse

Eating disorder

AXIS II

Trait related disorders

Personality disorders

Mental retardation

NAME TWO DISADVANTAGES AND TWO

ADVANTAGES OF TYPOLOGICAL REASONING

Disadvantages

Proposes categories that are usually awkward and disjunctive

Types are poorly tied to phenomena beyond themselves

Advantages

Important to understand why stressors affect people differently

PARANOID PERSONALITY DISORDER

0.5-2.5% of population

• Suspiciousness and distrust of others

• No hallucinations or delusions

• No “odd or magical” thinking as in Schizotypal Personality Disorder

• Genetic link to both Schizophrenia and Delusional Disorder

• Defense Mechanisms

- Externalization and projection

• Treatment

– Most are reluctant to engage in psychotherapy

– Need to avoid being overly confrontational but also overly friendly

– Low dose antipsychotic medication

SCHIZOTYPAL PERSONALITY DISORDER

3% of Population

• Social Withdrawal, impaired ability to form social relationships, “magical thinking”

– Thus resembles negative symptoms of Schizophrenia, or prodromal phase of

Schizophrenia

– Clear genetic link and about 10-20% go on to develop

Schizophrenia

– Often have biological markers of schizophrenia, e.g. smooth pursuit eye movement

abnormalities and enlarged ventricles on CT

•Defense Mechanisms

- Denial , projections

• Treatment

– May be brought in by family, or come in for depression, but little interest in

treatment; low dose antipsychotics

SCHIZOID PERSONALITY DISORDER

Detachment and social withdrawal as well as a restricted range of emotions

• Few friends but not bothered by this

• Often live at home with parents into adulthood

• Prevalence as high as 7% in community

• Defenses: Autistic Fantasy

• Score high on Introversion, likely with genetic basis

• Similar treatment limitations as for the other Cluster A disorders

ANTISOCIAL PERSONALITY DISORDER

DIAGNOSTIC CRITERIA

A. Pervasive pattern of disregard for and violation of the rights of others occurring since age 15 years, as indicated by three (or more) of the following: (1) Failure to conform to social norms with respect to lawful behaviors as indicated by

repeatedly performing acts that are grounds for arrest (2) Deceitfulness, as indicated by repeated lying, use of aliases, or conning others for

personal profit or pleasure (3) Impulsivity or failure to plan ahead (4) Irritability and aggressiveness, as indicated by repeated physical fights or assaults (5) Reckless disregard for safety of self or others (6) Consistent irresponsibility, as indicated by repeated failure to sustain consistent work

behavior or honor financial obligations (7) Lack of remorse, as indicated by being indifferent to or rationalizing having hurt,

mistreated, or stolen from another

B. The individual is at least age 18 years. C. There is evidence of Conduct Disorder (see p. 90) with onset before age 15 years. D. The occurrence of antisocial behavior is not exclusively during the course of

Schizophrenia or a Manic Episode.

ANTISOCIAL PERSONALITY DISORDER

Prevalence: 3% of men and 1% of women Not out of touch with reality Lack of conscience or empathy for others

Preceded by childhood Conduct Disorder with onset before age 15 50% of prison inmates Substance-abuse rehab setting: 20% of men and 10% of women May “burn out” in some after age 40

Genetic Factors clearly involved More common in 1st degree relatives Monozygotic concordance > Dizygotic concordance

Biological findings Violent individuals with more “soft” neurologic signs EEG with diminished response to novel stimuli Decreased galvanic skin response

May be influenced by erratic parenting, ADHD, poverty, early substance abuse Treatment: Requires motivation by patient (may not be in the patient role); treat

comorbidity; avoid being conned

BORDERLINE PERSONALITY DISORDER

DIAGNOSTIC CRITERIA

Pervasive pattern of instability of interpersonal relationships, self-image, and affects, and marked impulsivity beginning by early adulthood and present in a variety of contexts, as indicated by five (or more) of the following:

(1) Frantic efforts to avoid real or imagined abandonment. (2) A pattern of unstable and intense interpersonal relationships characterized by

alternating between extremes of idealization and devaluation (3) Identity disturbance: markedly and persistently unstable self-image or sense of

self (4) Impulsivity in at least two areas that are potentially self-damaging (e.g., spending,

sex, substance abuse, reckless driving, binge eating). (5) Recurrent suicidal behavior, gestures, or threats, or self-mutilating behavior (6) Affective instability due to a marked reactivity of mood (e.g., intense episodic

dysphoria, irritability, or anxiety usually lasting a few hours and only rarely more than a few days)

(7) Chronic feelings of emptiness (8) Inappropriate, intense anger or difficulty controlling anger (e.g., frequent displays

of temper, constant anger, recurrent physical fights) (9) Transient, stress-related paranoid ideation or severe dissociative symptoms

BORDERLINE PERSONALITY DISORDER

2-3% of Population, but 20% of Psychiatric Inpatients (the most common among inpatients)

Genetic Contribution

5X more common in 1st degree relatives

Family histories of Antisocial Personality Disorder, Substance Abuse, and Mood Disorder

Higher prevelence of neurologic “soft signs” in severe cases

Lower CSF serotonin in more severe cases

Developmental contributions

Historical: Mahler’s rapprochement phase

High rates of neglect and abuse, parental loss or separations/adoptions

Chaotic family environment; Mother often with Borderline features; father distant or absent

Defenses: Acting out, splitting, projective identification

TREATMENT FOR BORDERLINE PERSONALITY

DISORDER

Psychotherapy

Keep the patient alive

Keep the patient out of the hospital

Avoid having sex with the patient or other boundary violations

Avoid acting on countertransference

Make appropriate use of projective identification

Pharmacotherapy

To treat comorbid mood disorder

To treat features of the personality disorder

HISTRIONIC PERSONALITY DISORDER

DIAGNOSTIC CRITERIA

A pervasive pattern of excessive emotionality and attention seeking, beginning by

early adulthood and present in a variety of contexts, as indicated by five (or more)

of the following:

(1) is uncomfortable in situations in which he or she is not the center of attention

(2) interaction with others is often characterized by inappropriate sexually

seductive or provocative behavior

(3) displays rapidly shifting and shallow expression of emotions

(4) consistently uses physical appearance to draw attention to self

(5) has a style of speech that is excessively impressionistic and lacking in detail

(6) shows self-dramatization, theatricality, and exaggerated expression of emotion

(7) is suggestible, i.e., easily influenced by others or circumstances

(8) considers relationships to be more intimate than they actually are

HISTRIONIC PERSONALITY DISORDER

Prevalence: 2-3% in community, but 15% in clinic population

May have similar temperament to Borderline Personality Disorder but without

as much hostility and identity disturbance

Defense mechanisms of repression and dissociation

Treatment

Psychotherapy: Beware of splitting, overidealization, sexualization of

relationship

Antidepressants and anxiolytics depending on comorbidity

NARCISSISTIC PERSONALITY DISORDER

DIAGNOSTIC CRITERIAA pervasive pattern of grandiosity (in fantasy or behavior), need for admiration, and lack of empathy,

beginning by early adulthood and present in a variety of contexts, as indicated by five (or more) of the

following:

(1) has a grandiose sense of self-importance (e.g., exaggerates achievements and talents, expects to be

recognized as superior without commensurate achievements)

(2) is preoccupied with fantasies of unlimited success, power, brilliance, beauty, or ideal love

(3) believes that he or she is "special" and unique and can only be understood by, or should associate with,

other special or high-status people (or institutions)

(4) requires excessive admiration

(5) has a sense of entitlement, i.e., unreasonable expectations of especially favorable treatment or automatic

compliance with his or her expectations

(6) is interpersonally exploitative, i.e., takes advantage of others to achieve his or her own ends

(7) lacks empathy: is unwilling to recognize or identify with the feelings and needs of others

(8) is often envious of others or believes that others are envious of him or her

(9) shows arrogant, haughty behaviors or attitudes

NARCISSISTIC PERSONALITY DISORDER• 1% of General Population; 2-16% of clinic population

• 50-75% are male (gender bias?)

• May have fragile self-esteem, with “narcissistic bubble” and tendency toward suicidal despair or

severe rage when faced with failure

• Therefore may present for treatment of depression or “mood swings”

• Lack of acceptance in childhood

• Defenses:

• Same biological factors as other cluster B disorders (overlap with Antisocial, Borderline, and

Histrionic)

• Treatment

– Psychotherapy: Debate over whether to confront or support defenses, based on theory involved

– Medications for comorbid depression or anxiety

– Similar pharmacologic options to treat affective or impulsive element of temperament as with

Borderline Personality Disorder, although not well studied

AVOIDANT PERSONALITY DISORDER

Wish for social contact, but fear humiliation

– Distinguishes it from Schizoid Personality Disorder

• 1% in Community; 10% in clinic

• Overlap with Social Phobia

• Genetics

– Introversion and Behavioral Inhibition highly heritable

– May be reinforced behaviorally by teasing by peers as children

• Defenses: Displacement

• Treatment

– Supportive psychotherapy to help bolster fragile self-esteem, followed by encouragement to do more

– challenge expectations of failure

– SSRI’s, Benzodiazepines, Beta-blockers

DEPENDENT PERSONALITY DISORDER

• Excessive need to be cared for by others, with difficulty being alone, difficulty making

independent decisions, submissive behaviors, often taken advantage of in their

interpersonal relationships, often belittle themselves (e.g. “stupid”) and at higher risk for

depression and anxiety

• 15% in community, making it one of most common Personality Disorders. Diagnosed in 2-

3% in clinic, but 20% if using standardized interview (may be ignored due to more

prominent Axis I features)

• Genetics

– Submissiveness appears heritable

• Treatment

– Supportive Psychotherapy

– Assertiveness Training

– Avoid dependence on therapy by patient

– Treatment of comorbid Axis I

OBSESSIVE COMPULSIVE DISORDER

DIAGNOSTIC CRITERIA

A pervasive pattern of preoccupation with orderliness, perfectionism, and mental and interpersonal control, at

the expense of flexibility, openness, and efficiency, beginning by early adulthood and present in a variety of

contexts, as indicated by four (or more) of the following:

(1) is preoccupied with details, rules, lists, order, organization, or schedules to the extent that the major point

of the activity is lost

(2) shows perfectionism that interferes with task completion (e.g., is unable to complete a project because his

or her own overly strict standards are not met)

(3) is excessively devoted to work and productivity to the exclusion of leisure activities and friendships (not

accounted for by obvious economic necessity)

(4) is overconscientious, scrupulous, and inflexible about matters of morality, ethics, or values (not accounted

for by cultural or religious identification)

(5) is unable to discard worn-out or worthless objects even when they have no sentimental value

(6) is reluctant to delegate tasks or to work with others unless they submit to exactly his or her way of doing

things

(7) adopts a miserly spending style toward both self and others; money is viewed as something to be

hoarded for future catastrophes

(8) shows rigidity and stubbornness

OBSESSIVE COMPULSIVE DISORDER

Prevalence: 1% in Community; 3-10% in the clinic

• Twice as prevalent in men as in women

Bruce Cohen, M.D.- Personality Disorders, p. 13

• No higher risk of depression or OCD, but they often present for this

• Comorbidity includes Avoidant and Paranoid Personality Disorder

• Etiology uncertain

Defenses include externalization, isolation, rationalization,

displacement, and reaction formation

• Treatment is psychotherapy

– Help the patient learn to set priorities, to laugh at self, to deal with uncertainty, not

to set such high standard for self (and for others), to help patient get in touch with

emotions

THE TRAITS OF IMPULSIVITY AND AGGRESSION

HAVE BEEN LINKED TO…

Low CNS serotonin

Side effect of SSRIs can be loss of affect, flatness

GABA enhancement can decrease aggressiveness

Benzodiazepine

High dopamine and norepinpehrine – increased impulsivity and aggression

IN THE HOSPITAL, DESCRIBE: A) PREVALENCE

OF DELIRIUM B) MORBIDITY C) MORTALITY

a.) prevalence: Delirium is present in 15-25% of hospital pts at the time of

admission and it prolongs hospitalization.

b.) morbidity: Have longer hospital stays, have worse medical or surgical

recovery, hit nurses, pull out their NG tubes, IV's, arterial lines, central lines,

and aortic balloon pumps, have much higher risk of decubitus ulcers and

aspiration pneumonia, cost money (due to medical complications and longer

hospital stays)

c.) mortality: Highest mortality of any psychiatric diagnosis (25-75% of patients,

either in that hospital stay, or within the next 6 months)

LIST THE KEY SIGNS AND SYMPTOMS

OBSERVED CLINICALLY IN DELIRIUM

Delirium is change in level of consciousness; may have hallmarks of other

disease like cognitive change (dementia), mood change (depression), or

hallucinations/delusions (schizophrenia), but consciousness change is what

distinguishes it

Signs and symptoms of delirium from lecture: Rapid onset, fluctuating course,

reduced level of consciousness (EEG slowing), reversible (usually), impaired

attention, disturbance in cognition or perception

NAME FACTORS THAT CAN PREDISPOSE A

PATIENT TO DELIRIUM

Elderly

Decreased clearance of pharm (pharmacokinetic)

Decreased brain mass/ catecholamines (pharmacodynamic)

comorbidities

Post op

Burn

Brain Injury

Alcohol/Drug Withdrawal

LIST THE PNEUMONIC AND COMMON

ETIOLOGIES OF DELIRIUM

I WATCH DEATH

Infectious

Withdrawal

Acute Metabolic

Trauma

CNS Disease

Hypoxia

Deficiencies

Environmental

Acute vascular

Toxins/drugs

Heavy metals

DESCRIBE HOW AN EEG CAN BE USEFUL IN

VALIDATING THE DIAGNOSIS OF DELIRIUM AND

DESCRIBE THE MOST COMMON EEG FINDING IN

DELIRIUM

Most delirious patients have reduced cerebral metabolic activity

EEG studies show slowing of background brainwave activity

Not seen in patients with schizophrenia or major depression

HOW CAN DELIRIUM BEST BE APPROACHED

Symptomatic management

Keep the patient safe

Initial focus should be on diagnosing and treating those conditions which will

lead to increased morbidity/mortality

Discontinue all nonessential meds

Daily labs and physical exam if cause of delirium remains undetermined

Check vital signs frequently and check for clinical deterioration

Pulling out lines

Crawling over bedrails

Fluid input/output

oxygenation

WHAT IS THE BEST PHARMACOLOGICAL

MANAGEMENT OF DELIRIUM

Haloperidol or atypical antipsychotic

Benzodiazepines

NOT ANTIDEPRESSANTS – tricyclic are anticholinergic exacerbate sx

DESCRIBE THE PREVALENCE OF

SCHIZOPHRENIA IN THE GENERAL

POPULATION.

1%

SCHIZOPHRENIA

Schizophrenia: > 6 months of symptoms (> 1 month active), including

hallucinations, delusions, thought disorder, disorganized or catatonic behavior,

or "negative” symptoms; decline in functioning.

Mood Disorder excluded (treatment and prognostic implications).

SCHIZOPHRENIFORM DISORDER

Schizophreniform Disorder: Same criteria except for duration (1-6 months) and

no requirement for decline in functioning.

BRIEF PSYCHOTIC DISORDER

Brief Psychotic Disorder: Lasts from < 1 month

SCHIZOAFFECTIVE DISORDER

Schizoaffective Disorder: Meets criteria for both schizophrenia and Mood

Disorder.

Mood episode and active-phase symptoms of Schizophrenia occur together,

preceded or followed by at least 2 weeks of delusions or hallucinations without

prominent mood symptoms.

OTHERS

Delusional Disorder: Non-bizarre delusions in the absence of other active-phase symptoms of Schizophrenia, lasting > 1 month.

Shared Psychotic Disorder (folie a deux): Disturbance develops in an individual who is influenced by someone else who has an established delusion with similar content.

Psychotic Disorder Due to a General Medical Condition: Psychotic symptoms judged to be direct physiological consequence of a general medical condition.

Substance-Induced Psychotic Disorder: Psychotic symptoms are judged to be direct physiological consequence of a drug of abuse, a medication, or toxin exposure.

Psychotic Disorder Not Otherwise Specified: Psychotic presentations that do not meet the criteria for any of the specific Psychotic Disorders, or psychotic symptomatology about which there is inadequate or contradictory information

DISCUSS POSITIVE VS NEGATIVE SX IN

SCHIZOPHRENIA

Positive Symptoms: Phenomena that are present in Schizophrenia aren’t seen

in normals, i.e. psychotic symptoms (Hallucinations, Delusions, Formal Thought

Disorder and grossly disorganized behavior) – Mesolimbic Dopamine

Negative Symptoms: Also called “deficit” symptoms; areas of functioning where

patients with Schizophrenia are lacking normal abilities. (Apathy, Affective

blunting, Poverty of speech or thought content, Social withdrawal & inability to

relate, Attention problems, Dishevelment) – Mesocortical Dopamine

Negative symptoms are the major source of life disability, even for when

patients who are taking medication and responding to them to the extent that

they are no longer actively “psychotic”

DESCRIBE THE TYPICAL COURSE OF

SCHIZOPHRENIA AND LIST FACTORS

ASSOCIATED WITH A BETTER PROGNOSIS.

1. Prodromal Phase: Slow and gradual

development of negative symptoms

(often Schizotypal Personality Disorder

features

2. Active Phase: Development of positive

symptoms, often occurs abruptly with

“psychotic break.”

3. Residual Phase: Resembles

prodromal, but positive symptoms might

be present in attenuated form; need to

watch for harbingers of relapse

Better Prognostic Factors

- Good premorbid adjustment (rather than “odd”

personality)

- Acute onset (rather than gradual decline)

- Later age at onset

- Being female

- Precipitating events

- Associated mood disturbance

- Brief duration of active-phase symptoms

- Good interepisode functioning, minimal residual

symptoms

- Absence of structural brain abnormalities

- Normal neurological functioning

- A family history of Mood Disorder

- No family history of Schizophrenia

DESCRIBE THE DIFFERENCE BETWEEN A) FAMILY

STUDIES, B) TWIN STUDIES, C) ADOPTION

STUDIES, AND D) LINKAGE STUDIES.

DESCRIBE HOW DELUSIONAL DISORDER

DIFFERS FROM SCHIZOPHRENIA IN ITS

PHENOMENOLOGY AND IN ITS IMPACT ON THE

AFFECTED INDIVIDUAL’S FUNCTIONING.

Patients with delusional disorder will be have delusions (fixed, false,

idiosyncratic beliefs) without the “active-phase” symptoms of schizophrenia (i.e.

hallucinations, disorganized speech). Unlike patients with schizophrenia,

patients with delusional disorder do not have any functional impairment beyond

that due to delusions themselves.

Dr. Cohen gives the example in his PRL of a patient with delusional disorder

who was convinced he had syphilis despite repeat negative syphilis tests. The

guy had a high level of functioning, but was still sure he had syphilis.

DESCRIBE THE FOUR PRIMARY DOPAMINE

PATHWAYS IN THE BRAIN

Mesolimbic Tract: DA activity to nucleus accumbens is thought to be cause pleasurable sensations that reinforce motivated behaviors, including the euphoria associated with addictive drugs

Overstimulation might increase hallucinations and delusions

D2 blockers might work here to treat positive symptoms

Nigrostriatal tract: Degeneration increases Parkinson’s Disease (resting tremor, rigidity, bradykinesia, postural instability)

Increased dopaminergic activity increases choreoform, dyskinetic, and dystonic movements

D2-blockade of this pathway increases Parkinsonism

Increased D2 sensitivity with longer-term antipsychotic use causes Tardive Dyskinesia

Mesocortical tract: Believed to mediate effects of DA on attention and planning

Negative symptoms of Schizophrenia resemble frontal lobe injury

Evidence on functional neuroimaging of lower frontal lobe activity in Schizophrenia

Reciprocal connections between frontal lobes and basal ganglia traditional antipsychotics may worsen negative symptoms due to Nigrostriatal dopamine (Parkinsonism), OR Mesocortical dopamine

Tuberoinfundibular tract

DA inhibits prolactin release

D2 –blockade increased serum prolactin gynecomastia and galactorrhea.

Antipsychotics also suppress levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which can cause amenorrhea and anorgasmia in women

DISTINGUISH THE CNS MECHANISMS BY WHICH

AMPHETAMINES, LSD, AND PCP CAN CAUSE

PSYCHOTIC SYMPTOMS

Amphetamines: increase brain levels of dopamine. Causes a paranoid psychotic state resembling schizophrenia and also can exacerbate psychotic symptoms when they are taken by people with preexisting schizophrenia.

LSD: serotonin receptor agonist. More serotonin → less DA in nigrostriatal and mesocortical systems. Causes pseudo psychotic state. Effects are different than schizophrenia in that it produces visual illusions, rather than visual and auditory hallucinations, insight is often preserved and negative symptoms are absent. Take-away: 5HT is not as important as DA

PCP: glutamate antagonist. Less glutamate → more dopamine. Causes true psychotic state. Glutamate fibers from the cortex to subcortical limbic structures stimulate interneurons that modulate with inhibitory GABA. These same interneurons are inhibited by DA fibers as well. So maybe in schizophrenia the interneurons are inhibited by DA, and in PCP induced psychosis the interneurons are not inhibited by glutamate.

DESCRIBE HOW ANTICHOLINERGIC AGENTS

MINIMIZE EXTRAPYRAMIDAL SIDE EFFECTS OF

TYPICAL ANTIPSYCHOTIC MEDICATIONS.

DA neurons from the substantia nigra synapse on cholinergic neurons in the

basal ganglia, inhibiting ACh release. So, blocking DA receptors on these ACh

neurons with antipsychotics triggers excessive ACh release, triggering

excessive inhibition of motor behavior - parkinsonism.

Anticholinergic drugs combat this effect without affecting the drugs effects

along the mesolimbic pathway.

DESCRIBE HOW SEROTONIN RECEPTOR HELPS

TO MINIMIZE EXTRAPYRAMIDAL SIDE EFFECTS

BY SECOND GENERATION (“ATYPICAL”)

ANTIPSYCHOTIC AGENTS.

Serotonin fibers from the dorsal raphe area project to the substantia nigra,

where they synapse on somatodendritic 5HT2 receptors located on the DA

neurons that project to the striatum. Thus, serotonin has an inhibitory effect on

the nigrostriatal DA system. A serotonin antagonist counteracts D2-blocking

effects by antipsychotics, minimizing EPS

DESCRIBE THE DIFFERENCE BETWEEN A)

ANTIPSYCHOTIC-INDUCED PARKINSONISM, B)

AKATHISIA, C) DYSTONIA, AND D) TARDIVE

DYSKINESIA.

Parkinsonism: resting tremor, rigidity, bradykinesia, and postural instability →

decreased motor activation

Akathisia: severe motor restlessness

Dystonia: sustained, involuntary muscle spasms, most often of the face, neck,

and back

Tardive dyskinesia: abnormal, involuntary movements of the tongue and jaw,

limbs, and/or trunk. → increased motor activation

WHAT DOPAMINE PATHWAY CAUSES

PARKINSONISM

Nigrostriatal

DESCRIBE THE SX AND RX OF NEUROLEPTIC

MALIGNANT SYNDROME Symptoms: -Severe muscle rigidity & elevated temperature (mild: 99 F; severe 106 F) -Diaphoresis -Dysphagia -Tremor -Incontinence -Delirium (can progress to coma or death) -Mutism -Tachycardia, elevated or labile blood pressure -Leukocytosis (WBC or labile blood pressure) -Increased creatine phosphokinase (severe elevations can cause myoglobinuria & renal

failure)

Treatment: Sepsis workup + Immediate discontinuation of antipsychotic medication Antipyretics, IV fluids, cooling blankets, dopamine agonists/ peripheral muscle relaxants

(dantrolene) can be adjuncts Often resolves after approx. 2 weeks -

RECEPTOR PROFILE ASSOCIATED WITH EACH

OF THE FOLLOWING: A) SEDATION AND WEIGHT

GAIN, B) DRY MOUTH AND CONSTIPATION, C)

PROTECTION AGAINST DRUG-INDUCED

PARKINSONISM, D) HYPOTENSION, AND E)

PROLACTIN ELEVATION.

Sedation & Weight Gain: H1 histamine receptor

Dry Mouth & Constipation: M1 acetylcholine receptor

Protection from drug-induced Parkinsonism: D2 dopamine receptor

(nigrostriatal)

Hypotension: Alpha 1 Norepinephrine Receptor

Prolactin Elevation: D2 dopamine receptor (tuberoinfundibular)

LIST THE ADVANTAGES AND DISADVANTAGES

OF PRESCRIBING TYPICAL ANTIPSYCHOTIC

DRUGS

Advantages: good at treating the positive symptoms

Haloperidol & Fluphenazine in long acting (Decanoate) forms especially useful

in non-compliant patients (only need dosing once a month)

Disadvantages: antagonistic activity at many receptor types

Histamine – sedation & weight gain

NE – hypotension;

M1 ACh – blurred vision, dry mouth & constipation)

D2 antagonism in nigrostriatal system – parkinsonism and EPSs

ANTIPSYCHOTICS

IN WHICH DOPAMINE SYSTEM DOES 5-HT NOT

PLAY A ROLE?

Mesolimbic

STRESS DIATHESIS MODEL

Stress-Diathesis Model: environmental stressors act on a genetically vulnerable

individual, and the disease ultimately becomes independent of these

environmental stressors once it has taken hold.

Life stress likely plays an important role in precipitating “first-break” episodes as

well as later relapses

DISTINGUISH THE INHIBITORY AND EXCITATORY

SEROTONIN AND DOPAMINE RECEPTORS

5-HT1 – Inhibitory – presynaptic autoreceptors

5-HT2 – Excitatory

Acts on dopamine receptor

D1 – Excitatory

D2 – Inhibitory – presynaptic autoreceptor

Interacts with acetylcholine receptor

AGONISTS OF GABA TREAT _______ WHILE

ANTAGONISTS OF GABA CAN CAUSE _________

Agonist (Benzodiazepine) treat anxiety

Antagonists cause seizures

DISTINGUISH BETWEEN SEROTONIN RECEPTOR

1 AND 2 FAMILIES AND HOW THEY ARE

INVOLVED IN THE TREATMENT OF PSYCHIATRIC

ILLNESSES.

5-HT1 receptor family: -5HT1A is an autoreceptor in the limbic area that affects mood. Desensitization of 5HT1A

may help raise synaptic cleft 5-HT during chronic SSRI administration. If 5HT1A is postsynaptic, it exacerbates anxiety (anxiogenic). If presynaptic, it alleviates anxiety (anxiolytic).

-5HT1B and 5HT1D are both presynaptic autoreceptors that inhibit cell firing and 5HT release.

5-HT2 receptor family: -5HT2A is postsynaptic and the main excitatory receptor for serotonin. Psychedelic drugs

work as 5HT2A agonists, and new generation antipsychotics are 5HT2A antagonists (fewer side effects than previous generations).

-5HT2B is presynaptic and regulates serotonin release via the serotonin transporter. -5HT2C activation is responsible for side effects of SSRI and SNRI medications by

inhibiting dopamine and norepinephrine release.

EXPLAIN THE INTERACTION BETWEEN

DOPAMINE AND SEROTONIN NEURONS IN THE

BASAL GANGLIA AND HOW IT AFFECTS THE

SIDE EFFECT PROFILE OF CONVENTIONAL

ANTIPSYCHOTICS VERSUS THE SECOND

GENERATION ANTIPSYCHOTICS

Summary of Anti-Psychotics:

1st gen: D2 antagonists. Block dopamine everywhere, including basal ganglia

→ extrapyramidal symptoms.

2nd gen: D2 & 5HT2 antagonists: Block dopamine everywhere but increase

dopamine in basal ganglia (by blocking serotonin receptors which in turn block

dopamine thus resulting in more dopamine)→ less extrapyramidal symptoms.

EXPLAIN THE INTERACTION BETWEEN

DOPAMINE AND ACETYLCHOLINE NEURONS IN

THE NIGROSTRIATAL DOPAMINE PATHWAY AND

HOW D2 BLOCKADE BY ANTIPSYCHOTICS CAN

AFFECT MOVEMENT.

Dopamine signaling to cholinergic neurons inhibits ACh release. D2 blockade

by antipsychotics removes this inhibitory effect and increases ACh signaling,

which exacerbates extrapyramidal symptoms.

WHAT IS THE LOCATION OF DOPAMINE IN THE

BRAIN?

Midbrain

Substantia nigra

VTA

WHAT IS THE LOCATION OF SEROTONIN IN THE

BRAIN

Midbrain and pons

Raphe nuclei

WHAT IS THE LOCATION OF NE IN THE BRAIN

Locus ceruleus - pons

WHAT IS THE BEST WAY TO DISTINGUISH

BETWEEN T1 AND T2

On T1 water/CSF (the spaces in the brain) appear dark

On T2 water/CSF appears bright

DISCUSS CONTRAST AGENTS FOR CT AND MRI

In x-ray based studies, they are higher density materials (e.g., iodine, barium)

that absorb more x-rays and appear brighter

In MRIs, they are chelates of paramagnetic ions and exert an effect on protons

to alter their relaxation times

CT contrast agents = iodine compounds

Iohexol (Omnipaque)

Iodixanol (Visipaque)

MR contrast agents = gadolinium compounds

gadopentetate dimeglumine (Magnevist)

gadobutrol (Gadavist)

gadobenate (MultiHance)

CATHETER ANGIOGRAPHY

Small flexible catheter inserted into femoral artery

X-ray fluoroscopy used guide catheter tip into neck or head

Iodinated contrast injected through catheter into artery

X-rays taken simultaneously over 6-20 seconds

May be combined with endovascular treatment at same setting

CT ANGIOGRAPHY

Timed IV bolus contrast injected as neck and head are rapidly (< 1 min)

scanned with CT

Vasculature depicted at high resolution with white contrast opacification

Post-processed as 2D or 3D images

MRA AND MRV

Depends on moving hydrogen protons in blood

Detects fast moving flow of arterial blood

Detects slow moving venous blood in sinuses

May or may not use contrast

Typically used to identify sites of impeded or absent arterial blood flow due to

atherosclerosis, thrombosis, dissection, or aneurysm

DISTINGUISH BETWEEN CLOSED AND OPEN

HEAD INJURY.

Closed head injury = blunt trauma and is associated with acceleration and

deceleration forces. In other words, there is a traumatic force to the head but

the dura and skull remain intact.

Open head injury = penetrating trauma. This is when you actually get

penetration of the skull or brain by an object

DISTINGUISH BETWEEN LINEAR, DEPRESSED

AND CONTRECOUP FRACTURES. LIST THE

COMPLICATIONS OF SKULL FRACTURES.

Linear skull fractures: fractures in the skull that traverse the full thickness of the bone, are fairly straight, and do not displace bone. Linear skull fractures are of clinically little significance unless they occur close to or in a suture or if they involve a venous sinus or vascular channel. The resulting complications of a linear fracture is suture diastasis (separation in sutures), venous sinus thrombosis, and epidural hematoma.

Depressed skull fractures: These are comminuted fractures in which broken bones are displaced inwards. These fractures carry the risk of increasing pressure on the brain and hemorrhage. If the scalp and dura are lacerated, these types of fractures carry a risk of infection.

Contrecoup fractures: These fractures occur when there is an initial impact to the skull, but the injury occurs on the opposite side or far away from the site of impact. The example in the handout is occipital area impact leads to fracture of the roofs or orbits/ethmoid bone.

Complications of skull fractures: If you get a vascular tear- epidural hematomas. If trauma causes a dural tear and or depressed skull fractures- susceptible to infections. Contusions are another complication of skull fracture.

EXPLAIN THE PHYSIOLOGICAL CONSEQUENCES

OF BRAIN CONTUSIONS

Contusions are caused by rapid displacement of brain tissue, disruption of

vascular channels, and subsequent hemorrhage, tissue injury and edema. The

most susceptible structures for contusion are the crests of the gyri because

they are close to the surface.

The physiological consequence of brain contusions are focal subarachnoid

hemorrhages. To expand on this a little; Contusions are wedge-shaped, with

the widest aspect close to the point of impact. Within a few hours, blood

extravasates throughout the injury. The inflammatory response to the injury

follows, with neutrophil invasion and subsequent macrophage invasion. The

superficial layers of cortex are most severely affected

IDENTIFY THE MOST COMMON LOCATIONS OF

CONTUSIONS. DISTINGUISH BETWEEN COUP

LESIONS AND CONTRE-COUP CONTUSIONS.

The most common locations of contusions are regions of the brain overlying

rough and irregular inner skull surfaces, such as the orbitofrontal regions and

the temporal lobe tips.

A coup contusion occurs at the same site of injury. A contrecoup contusion is

when the contusion occurs on the other side of the brain (opposite the impact)

DISTINGUISH BETWEEN EPIDURAL HEMATOMA,

SUBDURAL HEMATOMA AND SUBARACHNOID

HEMORRHAGE IN TERMS OF THEIR TRAUMATIC

CAUSES AND LOCATIONS IN THE SKULL.

Epidural hematoma: Dural vessels, especially the MIDDLE MENINGEAL A., are vulnerable to traumatic

injury. In infants, traumatic displacement of the easily deformable skull may tear a vessel, even in the

absence of a skull fracture. In children and adults, by contrast, tears involving dural vessels almost always

stem from skull fractures. Once a vessel is torn, blood accumulating under arterial pressure can dissect

the tightly applied dura away from the inner skull surface, producing a hematoma that compresses the

brain surface. Clinically, patients can be lucid for several hours between the moment of trauma and the

development of neurologic signs

Subdural Hematoma: Rapid movement of the brain during trauma can tear the BRIDGING VEINS that

extend from the cerebral hemispheres through the subarachnoid and subdural space to the dural sinuses.

Their disruption produces bleeding into the subdural space. LESS ACUTE SYMPTOMS, SLOW

DEVELOPMENT

Subarachnoid hemorrhage: This is bleeding into the subarachnoid space, between the arachnoid and pia

mater. This can occur from a ruptured cerebral aneurysm or from head trauma. **often due to rupture of

CORTICOMENINGEAL A. in association with cerebral contusion.

EXPLAIN HOW EPIDURAL AND SUBDURAL

HEMATOMAS CAN BE DISTINGUISHED IN

NEURORADIOGRAPHIC IMAGES.

Epidural – lens shaped and well-circumscribed

Subdural – follows shape of brain

STATE THE CAUSE AND CONSEQUENCE OF

TRAUMATIC INTRAPARENCHYMAL

HEMORRHAGES.

Tend to be multiple

Commonly ‘delayed’ hemorrhages

> 24 hours following trauma

Common locations:

Cortex in association with contusion

Frontal and temporal lobes

Intraventricular extension

DEFINE DIFFUSE AXONAL INJURY. EXPLAIN

HOW ACUTE AND CHRONIC PHASES OF EACH

CAN BE RECOGNIZED HISTOPATHOLOGICALLY.

DIFFUSE AXONAL INJURY (DAI): widespread damage of axons resulting from severe

acceleration or deceleration of the head.

Common locations: Locations of long myelinated (white) axons in the brain

- corpus callosum

- cerebral hemisphere white matter

- subcortical fiber tracts (fornix, internal and external capsules)

- brain stem (long white tracts)

- cervico medullary junction

Histology:

Acute- Axonal retraction balls and swelling in acute phases

(these lesions are best seen by APP immunohistochemistry)

WHAT IS THE MAJOR CAUSE OF CNS TRAUMA IN

INFANTS AND THE ELDERLY?

Falls

MVA for adults

PENETRATING VS. PERFORATING INJURY

Perforating enters and exits

FACTORS OTHER THAN DIRECT LACERATION

THAT IMPACT BULLET WOUNDS

1) Explosive forces

- due to the exploding gases from the barrel of the gun causing expansive

forces on the head

-will result in a larger entrance wound than exit wound when the barrel is

held near the head

2) Expansive forces

- the wave of tissue compression and expansion as a result of the energy of

the bullet

-Will diminish as the energy of the bullet diminishes

3) Infectious elements:

-Bullets carry contaminated scalp and hair into the brain, increasing the risk

of infection

WHICH REGION OF THE SPINAL CORD IS MOST

VULNERABLE TO TRAUMATIC INJURY

Cervical

C1-C2

C4-C7

T11-L2

EXPLAIN THE COMBINATION OF ETIOLOGIES

THAT UNDERLIE ISCHEMIC/HYPOXIC BRAIN

DAMAGE SECONDARY TO TRAUMATIC INJURY.

Hypoxic-ischemic damage is common after head trauma and is highly likely in

patients that have had clinical evidence of hypoxia and/or hypotension for at least 15

minutes

Etiologies are:

1) Intracranial arterial spasm→ ischemia/hypoxia

2) Edema/hematomas→ increased intracranial pressure→ decreased blood flow

3) Increased metabolic activity due to post-trauma status epilepticus (epilepsy

following head trauma leading to increased metabolic activity and subsequent

ischemia)

Secondary brain damage often leads to diffuse brain edema leading to a buildup of

fluid in the brain. This can be the result of both vasogenic (leakage of fluid from the

capillaries) or cytotoxic (leakage of contents from cells) edema. This buildup of fluid

in the brain is what can cause increases in inracranial pressure.

WHAT IS KERNOHAN’S NOTCH?

The Kernohan's notch is an imaging finding resulting from extensive midline

shift due to mass effect.

Indentation of the Crus against the cerebellar tentorium secondary to

transtentorial herniation due to mass effect (tumor, etc)

Contrecoup injury: injury to right brain results in left Kernohan’s Notch, which

then affects the right side of the body (freakin CNS mind games).

source: http://radiopaedia.org/articles/kernohans-phenomenon

WHAT IS A DURET HEMORRHAGE?

crushing of the midbrain between herniating temporal lobe and opposite leaf of

tentorium leads to hemorrhage and necrosis of the midbrain and pons

Symptoms:

-Cheyne-Stokes respirations- pattern of breathing where person goes

through cycles of breathing deeply and quickly at first, followed by decline

and then pause in breathing before starting again

-Stupor or coma

-Fixed pupils and gaze alterations

-Bipyramidal signs

WHICH AREAS OF THE ADULT BRAIN ARE

PARTICULARLY VULNERABLE TO HYPOXIA?

CA1 of hippocampus

Purkinje cells of cerebellum

Layers 3 and 5 of cortex

WHICH CRANIAL NERVE IS OFTEN

COMPRESSED WITH AN UNCAL HERNIATION?

CN III – pupillary dilation

PCA may be compressed as well

WHY IS A TONSILLAR HERNIATION LIFE

THREATENING?

Brainstem compression compromises respiratory and cardiac centers in the

medulla

HERNIATIONS

Subfalcine herniation = cingulate herniation is when the cingulate gyrus herniates under the cerebral falx remember that the cingulate gyrus is superior to the corpus callosum this herniation may lead to compression of branches of the anterior cerebral artery

(and therefore I'm guessing deficits along the midline of the brain) Transtentorial herniation = uncal herniation = mesial temporal herniation is when the medial

aspect of the temporal lobe is compressed against the free margin of the tentorium

increased displacement in this area compresses CN III, resulting in pupillary dilation (“blown pupil”) and impairment of ocular movement on the side of the lesion

may also compress the posterior cerebral artery, resulting in ischemic injury to the brain tissue it supplies (including the primary visual cortex)

extreme herniation may compress the contralateral cerebral peduncle, resulting in hemiparesis on the ipsilateral side (Kernohan’s Notch)

uncal herniation is often accompanied by hemorrhagic lesions in the midbrain and pons called secondary brainstem hemorrhages or Duret hemorrhages

Tonsillar herniation is when the cerebellar tonsils are displaced through the foramen magnum this is life threatening! because it causes brainstem compression and compromises vital

respiratory and cardiac centers in the medulla oblongata

DESCRIBE THE ROLE OF SHH GENES IN

PATTERNING THE DORSAL/VENTRAL AXIS OF

THE NERVOUS SYSTEM.

Shh (sonic hedgehog) patterns the dorsal-ventral axis of the spinal cord. It is

expressed first in the notochord and then in the floor plate and induces ventral

differentiation in the neural tube. Shh expressed in the prechordal plate induces

ventral midline structures in the telencephalon as well as midline facial

structures.

Facial midline defect associated with loss of Shh or Shh pathway genes include

cyclopia, nasal, palate, and dental defects.

Mutations in Shh and its signaling pathway can cause human

holoprosencephaly (HPE), which is the failure of hemispheric cleavage.

DESCRIBE THE LOCATION OF NEURAL

PROGENITOR CELLS IN THE DEVELOPING

FOREBRAIN AND IN THE ADULT FOREBRAIN.

In the developing forebrain, neural progenitor cells are found in the ventricular

zone of the neural tube in ALL brain regions (intermediate progenitors also

found in the subventricular zone)

In the adult forebrain, there are much fewer neural progenitor cells. They are

found in a thin subventricular zone and in the dentate gyrus of the

hippocampus.

NPCs in the SVZ make neurons that migrate to the olfactory bulb.

Neurogenesis in the hippocampus can be enhanced by exercise and

antidepressants.

LIST THE TWO MAJOR ROLES OF A RADIAL

GLIAL CELL IN THE CEREBRAL CORTEX.

A radial glial cell is both 1) a progenitor cell, and 2) a guiding scaffold for

migration of its daughters.

The earliest neural progenitor cells are called neuroepithelial cells, or

neuroepithelial stem cells. Later in development, these neuroepithelial cells are

called radial glia. In order for the cortex to grow layers, neurons need to migrate

out of the ventricular zone. This migration is glial guided.

DESCRIBE THE DIFFERENCE IN DAUGHTER

CELLS PRODUCED BY A SYMMETRIC VERSUS

AN ASYMMETRIC DIVISION OF A

NEUROEPITHELIAL PROGENITOR CELL.

Symmetric division of a neuroepithelial cell produces two apical progenitors.

Symmetric division increases area. Too few symmetric divisions may cause

microcephaly

Asymmetric division produces one progenitor and one neuron. Asymmetric

division increases thickness.

DESCRIBE WHAT IS MEANT BY INSIDE-OUT

FORMATION OF THE NEURONAL LAYERS OF THE

CEREBRAL CORTEX.

In normal development, neurons migrate out of the ventricular zone, past their

earlier-born sisters. Therefore, the innermost layer of the cerebral cortex

contains the first-born neurons, and the outermost layer contains the last-born

neurons. This is called inside-out development.

DEFINE EACH OF THE FOLLOWING CLINICAL

TERMS RELATED TO DEVELOPMENTAL

ABNORMALITIES: LISSENCEPHALY, CORPUS

CALLOSUM AGENESIS.

Lissencephaly: agyria; “smooth brain” with no gyri or sulci; can be caused by

defects in neurogenesis as well as neuron migration

Reelin important

Dcx important

Corpus callosum agenesis: defect in axon tract formation of the CC

Netrin important

DESCRIBE THE DEVELOPMENTAL BASIS OF

LISSENCEPHALY.

Can be caused by mutations in reelin gene. Reelin is secreted in the marginal

zone (layer 1 of cortex) and instructs cortical neuron migration and lamination.

(not sure how much of that molecular crap we need to know so will edit if

needed after class)

Mutations in DCX gene can also result in lissencephaly

DESCRIBE THE PROCESS BY WHICH THE

NUMBER OF POSTMITOTIC NEURONS IN THE

DEVELOPING NERVOUS SYSTEM IS REDUCED TO

REACH THE NUMBER IN THE ADULT BRAIN.

This process is similar to what we saw at the NMJ. Once a neuron grows an

axon to its target, it needs neurotrophins from its target to survive and persist.

Multiple neurons at a single target compete for trophic factors. The neurons

that do not receive enough undergo apoptosis, which is a normal part of

development.

DEFINE THE TERM “ACTIVITY DEPENDENT

PRUNING” OF NEURAL CONNECTIONS.

This refers to the refinement of circuits, where axon and dendrite branches are

“pruned” based on electrical activity and competition for space and trophic

factors. Again this is similar to the NMJ. Active synapses will get stronger and

inactive ones will get weaker and will get eliminated.

Neurons that fire together wire together – Hebb’s rule

DESCRIBE WHY THE LOSS OF VISION IN ONE

EYE DURING THE CRITICAL PERIOD FOR

DEVELOPMENT OF VISION CAN LEAD TO

IMPAIRED VISION OR BLINDNESS.

This all depends on the critical periods for any system in the brain. For vision, it

occurs in the first few years of life. Plasticity will allow a certain amount of time

for a behavior to “crystallize,” kind of like putting a stick in cement-- it will move

at first but then will solidify. For binocular vision, it develops in 6 months-2

years.

Recovery of binocular vision after 6 months is difficult and almost impossible

after 2 years. So, a cataract in one eye, or closing one eye any time before 5

years of age can lead to amblyopia or cortical blindness. Prolonged deprivation

of that eye firing signals will cause rewiring in the visual cortex and will lead to

vision loss even if the cataract or blockage is removed later. The sooner you

can repair the eye, the fuller recovery will be because more plasticity is

available.

STATE THE APPROXIMATE AGE AT WHICH THE

CRITICAL PERIOD FOR DEVELOPING

BINOCULAR VISION ENDS.

6 months to 2 years

STATE THE APPROXIMATE AGE AT WHICH THE

CRITICAL PERIOD FOR DEVELOPING LANGUAGE

ENDS.

0-12 years

DISTINGUISH SPINA BIFIDA (OCCULT AND

CYSTIC FORMS) FROM NEURAL TUBE CLOSURE

DEFECTS.

Spina bifida is incomplete formation of the vertebral (neural) arches. Failure of

the neural tube itself to close is known as rachischisis. Spina bifida and

rachischisis are both forms of neural tube defects.

DISTINGUISH MENINGOMYELOCELE,

MENINGOCELE, AND SPINA BIFIDA OCCULTA IN

TERMS OF MORPHOLOGY AND CLINICAL

PRESENTATION AND SYMPTOMS.

Spina bifida is a failure of the bony vertebral arch to form, which normally occurs due to signals from the roof plate. There are two types of spina bifida -spina bifida occulta and spina bifida cystica, which can be subdivided into meningocele and meningomyelocele.

Spina bifida occulta: defect is restricted to laminae of one or two vertebrae. Adjacent skin develops normally. The location is sometimes indicated by a thick tuft of long hair. Patients are usually asymptomatic.

Spina bifida cystica: one or more vertebral arches completely fail to develop. This can lead to a herniation of the meninges through a defect in the skin (meningocele) or herniation of both meninges and spinal cord (meningomyelocele). Patients with severe meningomyelocele usually present with neurological symptoms.

DISTINGUISH BETWEEN CHILDREN AND ADULT

POPULATIONS IN TERMS OF THE INCIDENCE

AND THE LOCATION OF CNS TUMORS.

Adults: Supratentorial

2% of primary tumors

Gliomas, meningiomas

Metastatic more common

Children: Infratentorial

2nd most common malignancy

Pilocytic astrocytoma, medulloblastoma

NAME THE BASIS FOR THE CLASSIFICATION OF

CNS TUMORS ACCORDING TO THE WHO,

NOT staged and the TNM staging system is not applicable Rarely metastasize outside the nervous system No lymphatics in the brain

Location is critical to treatment, prognosis, and outcome. Histological grading is also critical for prognosis

Tumor Nomenclature Classified according to their resemblance to mature and immature cells of the CNS

Histological Grade Grade I: Slow-growing, non-malignant, associated with long-term survival Grade II: Relatively slow-growing but sometimes recur as higher grade tumors. Can

be malignant or non-malignant Grade III: Malignant and often recur as high grade tumors Grade IV: Malignant, aggressive

NAME THE COMMON PATHOPHYSIOLOGIC

EFFECTS OF CNS TUMORS IN THE BRAIN.

Space occupying lesion Increased ICP Hydrocephalus

Altered function of Tissues Seizures Focal neurological defects Paraneoplastic syndrome

Signs and Symptoms headaches vomiting (particularly children) confusion, lethargy, coma papilledema

DESCRIBE THE GROWTH PATTERNS OF

GLIOMAS, MENINGIOMAS, AND METASTATIC

TUMORS.

Gliomas = infiltrative, disseminate

Exclusions (gliomas that do not show infiltrative growth pattern):

Ependymomas, choroid plexus papillomas, circumscribed astrocytomas

Meningiomas = grow by expansion

Metastatic tumors = hematogenous spread or direct invasion from adjacent

tissues

DESCRIBE THE DISSEMINATION PATTERNS OF

GLIOMAS

Spread along white matter tracts (i.e. cross into other hemisphere by corpus

callosum) BUTTERFLY LESIONS

Spread along the pial membrane (i.e. “travel” along subpial surface of brain,

invade into subarachnoid space and diffusely spread through the

leptomeninges)

Spread along perivascular space (i.e. Virchow-Robin space = fluid-filled space

surrounding perforating arteries and veins in the parenchyma of the brain)

Spread across the ependyma and ventricular lining (ventricular and CSF

seeding)

RARELY metastasize outside CNS

EXPLAIN WHY EVEN LOW-GRADE OR BENIGN

CNS TUMORS CAN HAVE A POOR CLINICAL

OUTCOME

Tumor environment

Limited intracranial volume

Important structures

NAME 4 MOST COMMON GENETIC SYNDROMES

ASSOCIATED WITH NS TUMORS AND THE

TUMORS ASSOCIATED

Syndrome Gene Locus Nervous syst. tumors

Neurofibromatosis 1 NF1 17q11 Neurofibroma, optic nerve glioma,

MPNST

Neurofibromatosis 2 NF2 22q12 Bilateral vestibular schwannoma,

peripheral schwannoma,

meningioma, ependymoma

Tuberous Sclerosis TSC1/TSC2 9q34/16p13 Subependymal Giant Cell

Astrocytoma (SEGA)

Von Hippel-Lindau VHL 3p25 Hemangioblastoma

NAME ENVIRONMENTAL FACTORS THAT HAVE

BEEN LINKED TO THE PATHOGENESIS OF

NERVOUS SYSTEM TUMORS.

There is a definitive link between ionizing radiation and nervous system tumors

Radiation-induced tumors:

Meningiomas

Gliomas

Malignant nerve sheath tumors

Uncertain

Electromagnetic Fields

Cell Phones

Diet (e.g. N-nitroso compounds, vitamins, EtOH, tobacco)

Viruses

LIST THE TUMOR TYPES THAT ARE CLASSIFIED

AS NEUROEPITHELIAL TUMORS AND THE

TUMORS THAT ARE USUALLY DESIGNATED

“GLIOMAS.”

Tumors of Neuroepithelial tissue: (red tumors are referred to as gliomas)

Astrocytic Tumors

Oligodendroglial Tumors

Oligoastrocytic Tumors

Ependymal Tumors

Choroid Plexus Tumors

Neuronal and Mixed Neuronal-Glial Tumors

Pineal Tumors

Embryonal Tumors

WHAT FOUR CHARACTERISTICS CAN SUGGEST

POTENTIAL FOR MALIGNANCY OF A TUMOR

Atypia (cytological)

Mitotic activity

Endothelial microvascular proliferation

Necrosis

HISTOPATHOLOGY OF PILOCYTIC

ASTROCYTOMA

Piloid cells with microcystic areas

Rosenthal fibers

WHAT IS THE POPULATION, LOCATION, AND

GRADE OF PILOCYTIC ASTROCYTOMA?

Children

Midline structures

Cerebellum

Optic nerve and chiasm – Optic Nerve Glioma

Third ventricle region/hypothalamus

Brainstem (often dorsal exophytic)

Spinal cord in adults

Grade I

HISTOLOGY OF DIFFUSE ASTROCYTOMAS

Nuclear pleomorphism

Atypia/ Mitotic figures

Geographic Necrosis

Microvascular endothelial proliferation (absence of BBB)

Palisading Necrosis

DESCRIBE THE CLINICAL PRESENTATION AND AGE

GROUP AFFECTED BY OLIGODENDROGLIOMAS.

Long clinical histories

Slow clinical evolution

Seizures in 90% of cases

Location mostly in frontal and temporal lobe (supratentorial areas)

Age group:

Majority of tumors occur in adults, with a peak incidence in the 40s and 50s.

Only 6% of oligodendrogliomas are from pediatric patients. Rare in children

HISTOLOGY OF OLIGODENDROGLIOMA

Fried egg appearance

Chicken wire vessels

Hemorrhagic

Frontal and temporal preference

Calcifications seen on CT

IMPORTANT PROGNOSTIC PARAMETER OF

OLIGODENDROGLIOMA

1p, 19q codeletion

STATE THE LOCATION AND MOST PREVALENT

AGE GROUP IN WHICH MEDULLOBLASTOMAS

ARISE.

Children

Cerebellum

Malignant Grade IV

High CSF dissemination

HISTOLOGY OF EMBRYONAL TUMORS

Small round blue cell

Homer-Wright rosettes

LIST TWO TUMORS ARISING FROM THE NERVE

SHEATH CELLS AND TWO GENETIC SYNDROMES

ASSOCIATED

STATE THE CELL TYPE OF ORIGIN OF

MENINGIOMAS. LIST COMMON LOCATIONS

WHERE MENINGIOMAS ARISE.

Arise from meningioepithelial cells – arachnoid cells mesenchymal origin

Location

Convexity, skull base, spine

Intradural, extra-cerebral and extra-medullary tumors

Intraventricular tumors may occur but are rare

HISTOLOGY OF MENINGIOMA

Meningothelial Fibrous

SyncytialPsommatous

WHAT IS THE MOST COMMON LOCATION OF

CNS METASTASES

Cerebral hemispheres

Gray white matter border

STATE THE 5 MOST COMMON SOURCES OF

METASTATIC TUMORS TO THE CNS

Intracranial

Lung

Breast

Skin

Kidneys/Colon

Unknown

Intraspinal

Breast

Lung

Prostate

Leukemia/lymphoma

WHAT ARE THE THREE MAJOR CLINICAL

PRESENTATIONS OF INFECTION IN THE CNS?

Meningitis – inflammation of leptomeninges

Pia and arachnoid

Acute or Subacute

Abscess

Central necrotic mass and capsule formation

Mass lesion

Few fibroblasts, think immunodeficiency

Encephalitis

Inflammation either diffuse or localized, can involve spinal cord

Regional selectivity due to specific viruses

WHAT ARE THE MOST IMPORTANT MODES OF

TRANSMISSION IN THE CNS

Blood stream

Most common

Direct spread

Bones and sinuses

Direct implantation

Iatrogenic, trauma surgeries

Centripetal spread: retrograde from PNS

Rabies, Herpes

Axonal transport

EXPLAIN THE PATIENT’S CHARACTERISTICS

INCLUDING AGE AND IMMUNOLOGICAL STATUS

AND TYPES OF INFECTION THAT MAY OCCUR.

Age – young and old are at high risk

Adolescents/young adults epidemics

Immunocompromised

Post-transplant, post-chemo, AIDS

Chronic steroid treatment

Time of year

Seasonal infections

WHAT IS THE MOST COMMON ENTRY SITE OF

BACTERIAL MENINGITIS

Upper respiratory

ACUTE BACTERIAL MENINGITIS

Purulent infiltrate in subarachnoid space

PMN infiltrate

Perivascular inflammatory cuffings

Cerebral edema

CSF

PMN

10-10,000 cells/mm3

Glucose – low

Protein – high

Gram - reactive

SUBACUTE BACTERIAL MENINGITIS

Mononuclear infiltrates (lymphocytes, macrophages, plasma cells)

Inflammatory vasculitis: thrombosis/infarcts

Leptomeningeal fibrosis

CSF: low white cell count, predominantly mononuclear cells

WHAT ARE THE COMPLICATIONS OF BACTERIAL

MENINGITIS?

Cerebral infarcts

Hydrocephalus

Abscesses

Hearing loss

Mental retardation

STATE THREE CAUSES OF NON-VIRAL CHRONIC

MENINGITIS

TB

Lyme

Syphilis

ASEPTIC MENINGITIS

Aseptic meningitis is inflammation of the meninges with CSF lymphocytic

pleocytosis and no apparent cause after routine CSF stains and cultures.

Viruses are the most common cause of aseptic meningitis. Other causes may

be infectious or non-infectious.

Headaches, mild fever

CSF – lymphocytic infiltrate, negative gram culture

More benign than bacterial meningitis

VIRAL MENINGITIS

Viral Meningitis Most common viral infection of the CNS More benign condition than bacterial meningitis, self-limited with none or few sequelae Affects frequently children and young adults

CSF profile: – Low cellularity (50 to < 1000 cells/mm3); predominance of lymphocytic cells – Glucose: mostly normal – Protein: mostly normal to slightly elevated – Gram: non-reactive

Histopathology: Mild to moderate lymphocytic infiltration of the leptomeninges Common Viral Meningitis

Enteroviruses – most common cause of meningitis Herpes simplex virus (HSV)-2 Mumps (paramyxovirus) – vaccination has ↓ incidence HIV Lymphochoriomeningits virus, arbovirus, measles, parainfluenza virus, adenovirus

FUNGAL AGENTS OF ASEPTIC MENINGITIS

Candida

Aspergillus

Cryptococcus

Coccidiodes

Blastomyces

WHAT ARE THE PATHOLOGIC SIGNS OF

TUBERCULOSIS MENINGITIS

Base of brain and cranial nerves are affected

Granulomas

Gelatinous exudate

Hydrocephalus early

COMPLICATIONS OF TB MENINGITIS

Infarcts: occlusive endarteritis

Abscesses: tuberculomas

Hydrocephalus

Severe leptomeningeal fibrosis

OSTEOMYELITIS

FUNGAL MENINGITIS

Major concern in immunocompromise

Most are SECONDARY infections

FIND PRIMARY

Blood stream spread and sinuses!

Involvement of base of brain and cranial nerves

Granulomatous reaction less prominent

Immunocompetent

Blastomyces (SE)

Coccidiodes (SW)

WHAT ARE THE THREE TYPES OF FUNGAL

INFECTION IN THE CNS?

1) Chronic Meningitis: inflammatory process of leptomeninges & CSF within the subarachnoid space

usually tuberculous, spirochetal, or cryptococcal

2) Vasculitis: direct fungal invasion of blood vessel walls => causing vascular thrombosis => producing infarction (potential to be hemorrhagic & become septic)

mucormycosis and aspergillosis (most common); candidiasis (sometimes)

3) Parenchymal Invasions:

Candida: (hematogenous dissemination) produces multiple microabscesses+/- granular formation)

Cryptococcus: (hematogenous dissemination)

Mucormycosis: (direct extension invasion) commonly in diabetics with ketoacidosis

DEFINE CEREBRITIS AND ABSCESS.

Abscess:

Space-occupying infectious lesion

Well-defined lesion with necrotic center and capsule formation

Ring-enhancing at neuroimaging

Results from the ‘maturation’ of cerebritis

Cerebritis:

Poorly-defined lesion with acute inflammatory reaction

necrotic (“soupy-like”) appearance

surrounded by high degree of edema

Progresses to abscess

WHAT ARE THE CHARACTERISTICS OF

ASPERGILLUS ABSCESS

Poorly defined hemorrhagic lesions

Vascular invasion infectious vasculisit

Seen in immunocompromised

COMPLICATIONS OF ABSCESS

Cerebral Edema

Mass effect

Herniations

Rupture into ventricles

Secondary abscess

STATE THE MOST COMMON ROUTE OF ENTRY OF

ABSCESSES.

Usually the consequence of a secondary infection.

Blood stream dissemination from an extra-cerebral primary source

Adults: lungs, teeth, pelvic or abdominal sources

Children: congenital cardiac lesions

Contiguous spread from adjacent structures

Examples: Otitis media, sinusitis, osteomyelitis

Iatrogenic causes

Examples: Trauma, post-surgical procedures

Cryptogenic abscess

Note: Obligatory workup for ruling out cardiac shunts

VIRAL ENCEPHALITIS ROUTES OF INFECTION

Hematogenous

Centripetal

HSV, Rabies, maybe arbovirus

WHAT ARE THE FOUR COMMON PATHOLOGICAL

FEATURES OF VIRAL ENCEPHALITIS

Mononuclear infiltrates

Microglial activation

Rod and gitter cells, nodules, neuronophagia

Inclusion bodies

Specific for viruses

Intranuclear or intracytoplasmic

Necrosis

Variable amongst ages

Infants get microcephaly

MICROGLIAL ACTIVATION

COWDRY, NEGRI, JC VIRUS INCLUSION

STATE THE MOST COMMON GROSS AND

MICROSCOPIC FEATURES SEEN IN HERPES

(HSV) ENCEPHALITIS

Temporo-frontal and limbic distribution

Hemorrhagic/necrotic lesions with edema

Dense inflammatory infiltrates

Parenchymal and perivascular cuffings

Neuronal inclusions

Intranuclear – Cowdry A

Intracytoplasmic may be seen

Chronic lesions – infarct like lesions

WHICH RESPECTIVE GANGLION DO HSV1 AND

HSV2 INHABIT?

HSV1 – trigeminal

HSV2 – dorsal root ganglion

WHY ARE RED BLOOD CELLS COMMON IN

HERPES SIMPLEX ENCEPHALITIS.

It is a hemorrhagic encephalitis

WHAT IS THE CORTICAL DISTRIBUTION OF

HERPES ENCEPHALITIS?

Frontotemporal

STATE THE CAUSATIVE AGENT OF PML, THE

LOCATION OF THE LESIONS AND THE

PREFERENTIAL CELL INFECTED

JC Virus

Oligodendrocyte

White matter of CNS

Reactive astrocytosis and macrophagic infiltration (gitter cells)

DESCRIBE WHY CORTICOSTEROIDS MAY BE

IMPORTANT IN THE TREATMENT OF BACTERIAL

MENINGITIS.

Dexamethasone

To dampen immune response which can cause much of the damage of the

disease

MENINGITIS VACCINES

H. Influenzae

BEST

Has almost eradicated meningitis of this cause

N. Meningitidis

S. pneumoniae

NAME THE CRITERIA FOR DEFINING A

NEUROLOGICAL EMERGENCY.

In the nervous system

TREATABLE

EXPLAIN WHY ADDITIONAL ANTIBIOTICS MAY

BE NECESSARY TO TREAT BACTERIAL

MENINGITIS.

Drug resistance

DESCRIBE THE SIGNS AND SYMPTOMS OF

HERPES SIMPLEX ENCEPHALITIS AND HOW IT

IS DIAGNOSED AND TREATED AS WELL AS THE

PROGNOSIS. Sx: Change in personality, altered mentation and decreased level of consciousness,

fever, cortical focal neurologic findings, headache, papilledema, nausea and

vomiting and focal and generalized seizures

Lumbar puncture - CSF WBC 10s, 100s to 1000-2000 /mm3, predominantly

lymphocytes, may contain 10s to 1000s of RBCs, opening pressure may be

elevated, PCR of cerebral spinal fluid test of choice (96% sensitivity, 99%

specificity)

CT – Rarely may show hypodensities in the region of the temporal or frontal lobes

MRI – Hyperintensities onT2 and gadolinium enhancement around lesion

Rx: Acyclovir (10 mg/kg every 8 hrs for 21 days)

Prognosis:

Mortality rates: 19% at 6 months, 28% at 18 months, 70% for placebo treated

patients

Poor outcomes: >30 yo, comatose or semi-comatose with a GCS<6 (70% mortality)

WHAT IS XANTHOCHROMIA AND ITS CAUSE

Yellow CSF

Bilirubin released from ruptured RBCs

WHAT IS VIEWED ON AN MRI OF HERPES

ENCEPHALITIS?

The MRI is well regarded as a test for diagnosing herpes encephalitis. It is

common to see hyperintensities on T2 and gadolinium enhancement around

the lesion in the lobe that is infected. As the temporal lobe is the most common

cortical structure to be infected by herpes this is frequently well delineated with

gadolinium enhancement.

WHAT IS THE TEST OF CHOICE FOR HERPES

ENCEPHALITIS?

The CSF PCR for herpes simplex is now the test of choice for diagnosis.

DISTINGUISH HSV 1 AND HSV 2 IN TERMS OF

ENCEPHALITIS

HSV 1 – most common, most grave form of acute encephalitis

HSV 2 – neonatal encephalitis

TORCH

ARE THERE RISK FACTORS FOR HERPES

ENCEPHALITIS?

NO

Anyone can get it

No seasonal variation either

CHRONIC VIRAL ENCEPHALITIS

Long incubation period

Many end in death

Rubella – progressive rubella panencephalitis

Measles – SSPE

JC virus – PML

All rare

WHICH IMMUNOSUPPRESSIVE DRUG IS HIGHLY

ASSOCIATED WITH PML

Natalizumab

WHAT IS THE CELL INFECTED IN PML?

Oligodendrocyte

STATE THREE PATTERNS OF DISEASES CAUSED

DIRECTLY BY HIV-1.

Aseptic meningitis

AIDS dementia – subacute encephalitis

AIDS acute encephalitis

TORCH

Toxoplasmosis

Other (syphilis)

Rubella

Cytomegalovirus

Herpes and HIV

Chorioretinitis****

Microcephaly

Calcification

TRANSMISSION

Tranplacental vs. transvaginal – (HSV-2) and breast feeding

CEREBRAL MALARIA

DEFINE MENINGISMUS.

Meningismus: Marked signs of meningeal irritation

Meningismus is present in all of the following conditions:

Infectious meningitis

Subarachnoid hemorrhage

Carcinomatous meningitis

Chemical meningitis

LIST 5 SYMPTOMS OF MENINGEAL IRRITATION.

Headache

Lethargy

Sensitivity to light (photophobia) and noise (phonophobia)

Fever

Nuchal rigidity (stiff neck, unable to touch chin to chest)

MENINGOCOCCAL NON-BLANCHING PURPURA

Due to Coagulopathy

Can be positive for organism

EXPLAIN WHY A HEAD CT SHOULD BE DONE

PRIOR TO AN LP IN BACTERIAL MENINGITIS

Performing a head CT allows the clinician to determine whether a mass lesion

is present. If a mass lesion is present, lumbar puncture is contraindicated.

Mass lesions may produce increased ICP. In conditions of increased ICP,

removal of CSF may precipitate herniation.

LP PARAMETERS

WHEN SHOULD ANTIBIOTICS BE STARTED?

IMMEDIATELY – BEFORE LP

Empiric therapy

Ampicillin + Ceftriaxone unless 3-7 yrs old

WHAT ARE THE SPECIFIC THERAPIES FOR

BACTERIAL MENINGITIS

S. pneumonia – vanc + ceftriaxone

N. meningitidis – ceftriaxone

WHAT IS THE PROPHYLACTIC RX FOR

EXPOSURE TO BACTERIAL MENINGITIS?

Cipro

Rifampin (for children)

LIST THE COMMON CAUSES OF BACTERIAL

MENINGITIS AND THEIR EMPIRIC TREATMENTS

IN NEONATES, OLDER CHILDREN, AND ADULTS.

DESCRIBE THE STRUCTURE, GROWTH

PROPERTIES, AND VIRULENCE FACTORS OF S.

PNEUMONIAE.

Gram-positive cocci in short chains or pairs (lancet-shaped diplococcic)

Fastidious facultative anaerobes, Microaerophilic (lack catalase)

Grow on agar, alpha-hemolytic

Fermentive metabolism – produce acids like lactic acid

Optochin-sensitive and produce peroxide.

Anti-phagocytic capsule, pneumolysin, cell wall

DESCRIBE THE MECHANISMS OF

PATHOGENESIS FOR S. PNEUMONIAE FOR THE

CNS DISEASE IT CAUSES.

Meningitis is acquired as a result of bacteremia, typically through the

respiratory tract or other sometimes at other sites.

Can happen as a primary disease following head trauma or Eustachian tube

obstruction.

IF A CT FOR MENINGITIS IS ALMOST ALWAYS

NORMAL WHY IS IT DONE?

To look for a mass lesion that may be mimicking the symptoms of bacterial

meningtis

CAN INCREASED ICP BE SEEN ON A CT/MRI

SCAN? **

NO

WHAT IS THE GOLD STANDARD FOR CNS

INFECTION?

Lumbar puncture

Safe with generalized icp but not mass lesio/hydrocephalus

Bacterial meningitis

Almost all have increased opening pressure

Elevated WBC 100-1000 - PMNs

Low glucose

High protein

PATHOGENESIS OF RABIES

1. Inoculation with saliva of infected animal

2. Slow replication in muscles and/or skin

3. Binding and entry into peripheral motor nerve

4. Retrograde transport

5. Replication in motor neurons of spinal cord and dorsal root ganglia

6. CNS infection (concentrated in brainstem)

Negri bodies

BH4 deficiency leads to neurotransmission failure

7. Anterograde transport to organs, salivary glands

DESCRIBE THE STRUCTURE AND TAXONOMIC

CLASSIFICATION OF RABIES VIRUS

Rabies virus structure:

-Bullet-shaped, negative-sense, single-stranded, helical enveloped RNA virus

N protein coats the RNA with M protein at the tip to attach to membrane, G,L, P

-Negri bodies, prominent cytoplasmic inclusion bodies, are seen at autopsy of

human and animal victims

NO NUCLEAR INVOLVEMENT, RNA dependend RNA polymerase present in

virion

Taxonomic classification:

-Family Rhabdoviridae, genus Lyssavirus

-There are 7 Lyssavirus genotypes, all of which have been known to transmit

rabies in humans, but type 1 accounts for the majority of cases

-Within genotype 1 genetic variants have been defined

AT WHAT POINT IS THE VACCINE NO LONGER

ABLE TO AID THE PATIENT?

As soon as the virus reaches the peripheral nervous system, the virus cannot

be stopped.

WHAT IS THE TEMPORAL COURSE OF RABIES?

Clinical rabies develops after incubation period of 1 month to 1 year

a. Prodromal period (2-10 d)

Nonspecific symptoms

Specific early symptoms

b. Acute neurological phase (“furious”, paralytic)

Hydrophobia

c. Coma

d. Death

SX

Nonspecific Fever Malaise Sore throat Nausea/ vomiting/ weakness

Severe encephalitis Agitation Depressed mentation Seizures Hydrophobia/aerophobia Drooling

Coma Death

WHAT IS THE MOST SENSITIVE DIAGNOSTIC

TEST FOR RABIES?

RT-PCR

ONCE RABIES ENCEPHALITIS

DEVELOPS, NO THERAPY HAS

PROVEN EFFECTIVE

POST EXPOSURE PROPHYLAXIS

Postexposure prophylaxis (PEP)

Effective only when given promptly.

PEP includes wound cleansing

HRIG (human-rabies Ig)

Immunization with killed vaccine virus produced in cell culture

(HDCV=human diploid cell vaccine)

WHAT ARE THE TWO MOST IMPORTANT

VECTORS IN THE U.S. CURRENTLY?

Bats

Racoons

Dogs used to be a threat, still exists in other countries

WHAT IS THE MILWAUKEE PROTOCOL

Induced coma + antiviral treatment

WHAT ARE THE TWO ENTITIES FOR

PREVENTION OF RABIES?

Rabies immunoglobulin

Rabies killed vaccine

IDENTIFY WHICH GENDER HAS LESS

FUNCTIONAL BRAIN ASYMMETRY. IDENTIFY

WHETHER RIGHT-HANDERS OR LEFT-HANDERS

HAVE LESS FUNCTIONAL BRAIN ASYMMETRY.

Females and left-handers have less functional asymmetry

More diffusely distributed

EXPLAIN TWO REASONS WHY LATERALIZATION

OF BRAIN FUNCTION IS ASSESSED IN ADVANCE

OF BRAIN SURGERY.

To preserve patients ability to speak and comprehend language, surgery is

limited in the language dominant hemisphere.

The hippocampus is assessed to ensure that an adequate amount will be

preserved to support memory. If an inadequate amount is preserved then the

patient may develop dense anterograde amnesia

DESCRIBE HOW THE WADA TEST IS

PERFORMED AND INTERPRETED.

The Wada test is used to lateralize speech processes so that surgery can be planned to minimize post-op aphasia.

Procedure: Inject sodium amytal (barbiturate with sedative-hypnotic properties, wiki) into R carotid,

sodium amytal essentiatlly deactivates the entire hemisphere, mimicking the post-op effects of excision

Assess expressive functions have patient name objects, count, recite days of the week

Additional assessments Naming - whole and parts Repeating familiar and unfamiliar phrases Reading Following complex commands - inverted syntax

Repeat assessment after injection into L carotid

NAME THE TYPICAL OUTCOME OF THE WADA

TEST ON THE LANGUAGE DOMINANT AND

NONDOMINANT HEMISPHERES.

Speech disruption/aphasia after L injection

One patient had disruption after R injection

NAME THE TYPICAL OUTCOME OF THE WADA

TEST ON MOTOR FUNCTION.

Contralateral flaccid hemiparesis

STATE THE DEGREE TO WHICH SPEECH IS

LATERALIZED IN RIGHT-HANDERS.

96% Left

4% Right

0% bilateral

Left handers

70% left

15% right

15% bilateral

DESCRIBE THE MEMORY DEFICITS IN PATIENT

HM WHO UNDERWENT BILATERAL TEMPORAL

LOBE SURGERY.

Patient HM suffered from severe epilepsy without a clearly localized epileptic

focus. The patient underwent bilateral temporal ressections. The patient

developed dense anterograde memory deficit (aka dense anterograde

amnesia), but retained normal intellectual functioning postoperatively.

DESCRIBE THE PROCEDURE FOR IAP MEMORY

TESTING. EXPLAIN HOW THIS TEST

DISSOCIATES FOR ANOMIA AND AMNESIA.

Inject sodium amytal (barbiturate with sedative-hypnotic properties, wiki) into R carotid, sodium amytal essentiatlly deactivates the entire hemisphere, mimicking the post-op effects of excision

Present items during period of drug effect

Patient is asked to recall and recognize these items after recovery

Assessment of new learning

Anomia vs. amnesia

Anomia = inability to recall or recognize the names of objects

Amnesia = inability to recall past events or form new memories

When memory is tested by this method patients are able to recognize items they were shown during the confusional period. Thus they retained the ability to recall the objects name (no anomia) even if they didn’t remember being shown the item (amnesia).

DISTINGUISH BETWEEN THE TWO

HEMISPHERES IN TERMS OF WHICH PRIMARILY

CODES FOR EACH OF THE FOLLOWING: WORDS,

SHAPES, FACES, LETTERS, FAMILIAR MATERIAL,

NOVEL MATERIAL.

Left Hemisphere: words, letters, familiar material (Left = Language)

Right Hemisphere: shapes, faces, novel material

NAME THE MOST COMMON ANESTHETIC

INDUCTION AND A3 CLINICALLY USED INHALED

ANESTHETICS.

The most commonly used drug for the induction of anesthesia: Propofol (IV)

- Works on GABAa R which are chloride channels to increase inhibition –

increasing chloride ion flux

- Antiemetic

- Pain on injection (not understood, some pt pain is severe) and can cause

hypotension

Inhaled anesthetics:

-Volatile: halothane, enflurane, isoflurane, desflurane, sevoflurane

-Gaseous: nitrous oxide, xenon

DESCRIBE THE MAIN RECEPTOR TARGET FOR

ANESTHETIC DRUGS

-Chloride channels (GABAa and glycine receptors) and potassium channels

(K2P, possibly Kv, and Katp channels) remain the primary inhibitory ion

channels for anesthetic action. Anesthetics are agonists at these receptors (net

inhibitory effect)

-Excitatory ion channels targets include those activated by acetylcholine

(nicotinic and muscarinic receptors), by excitatory AAs (AMPA, kainate, and

NMDA receptors), or by serotonin (5-HT2 and 5-HT3 receptors). Anesthetics

are antagonists at these receptors (net inhibitory effects)

GABAa is the main mechanism!

N2O and ketamine are antagonists at NMDA receptors!

EXPLAIN THE CONCEPT OF MINIMAL ALVEOLAR

CONCENTRATION AND WHY IT IS USEFUL IN

ADMINISTERING INHALED ANESTHETICS.

The concentration of gas at which 50% of individuals are immobile upon cutting

Increased tissue solubility leads to lower MAC

Expressed in % atm

High MAC – faster kinetics

MAC is lowered by CNS depressants

MAC is lower in the elderly (higher potency)

WHICH INHALANT IS USED MOST COMMONLY IN

CHILDREN

Sevoflurane (if they won’t tolerate IV)

WHAT CLASS OF DRUGS ARE MOST COMMONLY

USED FOR “PREMEDICATION”

Benzodiazepines (GABAa Receptor)

Midazolam

Anxiolytic

Sedation

Anterograde amnesia

Painless IV injection

Rapid brief action and can be reversed with flumazenil

Modest respiratory depression

WHAT IS THE MINIMUM RISK OF POSTOP

NAUSEA AND VOMITING?

40%

RISK FACTORS

Female gender

Non-smoker

History of PONV

Post-op opiods

0-10%

1-20%

2- 40%

3-4 – 60-80%

HOW CAN WE PREVENT PONV?

Propofol

Limit inhaled anesthetics

Don’t use nitrous oxide

Limit opiate requirement

Ketorolac

Nerve blocks

Anti-emetic drug

Odansetron

WHICH INHALED ANESTHETIC IS NO LONGER

USED IN THE US

Halothane – no longer availability

Also Isoflurane is decreasing

The difference is mainly speed of onset and offset.

We want drugs that are very fast and very controllable

Also big Pharma

HUGE PRICING DIFFERENCE

CHARACTERISTICS AND SIDE EFFECTS OF

NITROUS OXIDE, DESFLURANE AND

SEVOFLURANE

Nitrous Oxide (gas)

Colorless, odorless tasteless

MAC 100%

Minimum CV effects

Desflurane

Least soluble volatile, MAC 6%

Pungent

Hypotension

Bronchoconstrictor

Malignant Hyperthermia

Sevoflurane

MAC 2.0%

Hypotension

Bronchodilator

Slightly pungent

Useful for induction

Malignant Hyperthermia

Delivered through vaporizers,

ET tube

Contribute to postop nausea

BALANCED ANESTHESIA

Limit side effects by combining drugs

Nitrous Oxide – short acting, no hypotension ,may cause nausea

Opiates – short acting, fentanyl, remifentanil

Local anesthetics

DESCRIBE THE MAJOR PERIOPERATIVE

INDICATIONS FOR BENZODIAZEPINES, OPIATES,

AND MUSCLE RELAXANTS.

Analgesia

Sedation

Amnesia

Relaxation – easier to cut and operate, prevent reflex responses

NAME THE MAIN CLASSES OF DRUGS USED TO

TREAT POSTOP PAIN, AND THEIR MOAS.

Opioid analgesics: Activate opioid receptors in the CNS, leads to analgesia SE: respiratory suppression (can cause death with apnea), hypoxia, sedation, nausea,

decreased blood pressure, urinary retention, itching, flaccid skeletal muscles, constipation

Ketamine: Partially water-soluble and highly lipid-soluble; differs from most other IV anesthetics in

that it produces significant analgesia Also has significant amnestic effects (“dissociative” anesthetic) Preserves muscle tone - can maintain protective airway reflexes and spontaneous

respiration Produced through inhibition of the NMDA receptor complex SE: increases in BP, HR, and cardiac output, increased ICP, unpleasant emergence

reactions after administration (vivid colorful dreams, hallucinations, out-of-body experiences, increased and distorted visual, tactile, and auditory sensitivity) – pair with benzodiazepines

Also - Tylenol

WHAT DRUG CAN YOU USE TO TREAT

MALIGNANT HYPERTHERMIA?

Dantrolene – inhibits ryanodine receptor

WHAT IS THE IMPORTANT ADVANTAGE OF IV

ADMINISTRATION?

Increases bioavailability of drug

WHY CAN’T THE PATIENT WITH A LUMBAR

LAMINECTOMY GET SPINAL OR EPIDURAL

ANESTHESIA

Not able to do neurologic exam after surgery

Confusion about etiology of neurological complication

DEFINE THE FOLLOWING TERMS: STROKE, TIA,

ISCHEMIA.

Stroke: is a focal neurologic deficit occurring in a vascular distribution, typically

lasting greater than 24 hours and producing infarction. It is a cardiovascular

disease that affects the blood vessels supplying the brain.

Transient Ischemic Attack (TIA): is a transient episode of neurological

dysfunction caused by focal brain, spinal cord, or retinal ischemia that does not

produce acute infarction.

Ischemia: is an insufficiency of cerebral blood flow that results in oxygen and

glucose deficits to neural tissue. Neurons are particularly susceptible to

ischemia due to their high rates of metabolism.

DEFINE THE MAJOR TYPES OF STROKE AND

THEIR PREVALENCE.

Ischemic (Intraluminal Occlusive) Stroke

Thrombotic stroke: occurs when a blood clot (thrombus) forms and blocks blood flow in a cerebral artery. Blood clots usually form in arteries damaged by atherosclerosis. Prevalence of 53%.

Embolic Stroke: results when a detached blood clot (or a particle) flows into and clogs a cerebral artery. An embolus typically forms in the heart or large artery and is carried in the blood supply to the brain where it encounters progressively smaller vessels, and eventually becomes lodged. Prevalence of 31%.

Hemorrhagic Stroke

Intracerebral hemorrhage: occurs when a parenchymal artery bursts, flooding the surrounding tissue (parenchyma) of the brain. Common causes of intracerebral hemorrhage are severe hypertension and the rupture of an aneurysm. Prevalence of 10%.

Subarachnoid hemorrhage (SAH): occurs when a blood vessel on the surface of the brain ruptures and bleeds into the subarachnoid space. Prevalence of 6%.

DISTINGUISH BETWEEN THE SUBTYPES OF

ISCHEMIC (OCCLUSIVE) AND HEMORRHAGIC

STROKES.

Ischemic (occlusive) stroke: occurs when there is some type of blood clot

(thrombus) that forms and blocks/clogs blood flow in a cerebral artery. Ischemic

challenge to the brain tissue is created downstream from the occlusion.

Hemorrhagic stroke: results from an artery in the brain rupturing/bursting which

leads to increased intracranial pressure, accumulation of blood in the

parenchyma, and ischemia downstream from the rupture.

NAME THREE KEY FEATURES OF ISCHEMIC

STROKE THAT DETERMINE THE PROGNOSIS

FOR THE PATIENT.

Duration

Intensity

Location

DISTINGUISH BETWEEN THE ISCHEMIC CORE

AND THE ISCHEMIC PENUMBRA IN TERMS OF

THE FOLLOWING: DEGREE OF ISCHEMIA,

PROGNOSIS FOR RECOVERY, POTENTIAL FOR

THERAPY.

Ischemic core (area at center of crisis): dense ischemia, poor prognosis, and

undergoes infarction if reflow is delayed.

Ischemic penumbra (area surrounding core): partial blood flow, prognosis

improves with early intervention, and can exhibit infarction or selective neuronal

loss.

Ischemia INJURY CASCADE

DISTINGUISH BETWEEN THE GENERAL

VULNERABILITY AND SELECTIVE

VULNERABILITY OF NEURONS TO ISCHEMIA

Neuron vulnerability General vulnerability : neurons are very vulnerable to ischemia most can only survive short periods of deep ischemia infarction = generalized cell death necrotic cell death is common in cerebral infarction pannecrosis: neurons, glial cells, and vascular cells are all affected penumbral zone is what enables many neurons to survive longer ischemic

periods Selective vulnerability some neurons are especially vulnerable to ischemia they can have delayed death after ischemic events of less than 3 min. CA1 of hippocampus Purkinje cells of cerebellum Layers 3 and 5 of cortex loss of neurons is delayed since it involves apoptotic mechanisms (not

necrosis)

WHY DO NEURONS DIE?

High metabolic demands

ATP runs down with ischemia

Injury mechanisms

Excitotoxicity

DESCRIBE THE EXCITOTOXICITY HYPOTHESIS

FOR CELL LOSS DURING ISCHEMIC INJURY.

Dying neurons release high amounts of glutamate

too much glutamate (excitatory NT) activates both ionotropic (AMPA, NMDA)

and metabotropic (GluR) receptors

activation of these neurons leads to elevated intracellular Ca2+

too much intracellular Ca2+ leads to deleterious calcium cascades, like

proteolytic + lipolytic enzyme systems

EXPLAIN HOW CEREBRAL EDEMA CAN BE A

POTENTIALLY LETHAL COMPLICATION OF

STROKE.

Normally peaks between 3-5 days after onset of stroke and leads to mass

effect

increase ICP

restrict blood flow

compress ventricles

shift midline structures

intracellular cytotoxic edema (more brain volume from swollen cells)

cells fail to maintain normal osmotic gradient cellular swelling

extracellular vasogenic edema (more brain volume from more space between

cells)

increase in fluids in interstitial space that originates from leaky vasculature

EXPLAIN WHY STROKE IS A MEDICAL

EMERGENCY.

Prompt treatment is crucial

Early action can minimize brain damage and potential complications

WHY IS IT IMPORTANT TO DISTINGUISH

BETWEEN ISCHEMIC AND HEMORRHAGIC

STROKE AND HOW IS THE DX MADE?

It is important to distinguish between ischemic and hemorrhagic stroke

because optimal treatment modalities differ in different types of strokes. Rapid

diagnosis is critical to survival chances.

Major goals in treating strokes include:

Re-establishing/maintaining blood flow for occlusive (ischemic) strokes

Limiting progression of cellular injuries

Remove blood around arteries (avoid delayed deficits)

Computerized tomography is typically used to distinguish between ischemic

and hemorrhagic stroke

DEFINE THE PURPOSE OF T-PA TREATMENT AND

STATE THE TIME COURSE OVER WHICH IT CAN

BE USED.

TPA (tissue plasminogen activator) is a clot dissolving drug used for the

treatment of ischemic stroke.

t-PA works by converting inactive plasminogen into plasmin which is a serine

protease that dissolves fibrin clots

Treatment with t-PA should be initiated within 3 to 4.5 hours of stroke onset.

DEFINE “TRIPLE H” THERAPY FOR SAH AND

DESCRIBE HOW IT WORKS.

SAH (subarachnoid hemorrhage) can be treated using the “Triple H” therapy.

The three H’s stand for

Hypertension: involves increasing the blood pressure to force blood through

the narrowed arteries

Hypervolemia: involves increasing IV fluids to increase blood volume

Hemodilution: involves making the blood thin and watery in order for it to flow

more easily through the narrowed arteries.

LIST 3 NON-MODIFIABLE RISK FACTORS FOR

STROKE.

Age: older population at higher risk (according to CDC and AHA according to

comments)

Sex: males are more likely to suffer from stroke (CDC and AHA) but women are

more likely to die of stroke (CDC)

Race: African Americans at higher risk (CDC and AHA)

LIST 3 MODIFIABLE RISK FACTORS FOR STROKE

Hypertension

Heart disease

Diabetes mellitus

WHAT ARE STRATEGIES FOR REPERFUSION

Thrombolytic agents

Mechanical disruption

Bypassing obstruction

IPSP

100 ms

20 pA

100 ms

20 pA

100 ms

20 pA

+ Benzodiazepine

Sedative, anxiolytic, analgesic

DISTINGUISH BETWEEN THE TWO MAIN

CLASSES OF GABA RECEPTORS.

: Two main classes

GABA-A – ionotropic, chlorine channels

GABA-B - metabotropic – 2nd messengers K/Ca channels

GABA-A and nicotinic cholinergic receptors = ionotropic pentamers; GABA-A

conducts Cl-, nicotinic nonspecifically conducts Na+, Ca++, K+

GABA-B inhibits adenylate cyclase (PKA pathway), activates post-synaptic K+

channels, inhibits pre-synaptic Ca++ conductance

IDENTIFY THE MEDICAL USE OF THE GABA-B

RECEPTOR AGONIST BACLOFEN IN NEUROLOGY

Alcohol Dependence

DESCRIBE THE EFFECT THAT BDZ BINDING TO

GABA-A CHANNELS HAS ON THE ACTIVITY OF

CNS NEURONS.

The binding site for GABA is between the alpha and beta units

The binding site for BDZ is between the beta and gamma units

This induces conformational change and increases affinity for GABA

ALLOSTERIC MODULATION

DEFINE ALLOSTERIC MODULATION. PROVIDE

EXAMPLES OF DIFFERENT TYPES OF

ALLOSTERIC MODULATION.

Allosteric modification: modulation achieved by binding of a drug to a site

distinct from the site required for activation

Positive (agonism): benzodiazapines

Negative (inverse agonism): CCE (reduces effect of positive agonism)

Antagonist (blocker): Flumazenil

GABAGABA

+ pos modGABA

+ neg modGABA

+ antag

Re

lative

GA

BA

-

induced c

urr

ent

2.0

0

0.5

1.0

- Rudolph & Knoflach, 2011

DEFINE WHAT A BDZ RECEPTOR ANTAGONIST IS

AND GIVE AN EXAMPLE OF ONE.

Flumenazil

DISTINGUISH BETWEEN A GABA-A RECEPTOR

ANTAGONIST AND A BDZ RECEPTOR

ANTAGONIST

GABA-A antagonists block (or compete for) the binding of GABA to the GABA-A

receptor, and therefore prevents activation of the receptor (opening of the Cl-

channel).

The BDZ receptor antagonist binds to the BDZ binding site, which is at an

allosteric site on the GABA receptor. It therefore does not inhibit GABA binding.

BDZs work by increasing the probability of activation of the GABA-A receptor in

response to GABA.

LIST IN ORDER, FROM MILD TO MOST SEVERE,

THE PROGRESSIVE DOSE-DEPENDENT EFFECTS

OF BDZS ON THE BRAIN.

Side effects from Mild to Severe

Anxiolysis= reduction in anxiety

Sedation= decreases activity, moderates excitement, calms

Hypnosis= drowsiness, facilitates onset & maintenance of sleep

Even at high doses, will not cause death (unlike barbiturates)

Can however reduce fatal dose of other substances (alcohol)

EFFECT SELECTIVITY

NAME TWO FACTORS THAT CAN INFLUENCE

DOSING OF BENZODIAZEPINES

Age

Sex

SIDE EFFECTS OF BENZODIAZEPINES

Sedation

Tolerance

Dependence

Respiratory depression

Coma (less risk than with barbiturates)

Additive CNS depression effects with alcohol

DESCRIBE WHY DIFFERENT ALPHA SUBUNITS

ARE ASSOCIATED WITH DIFFERENT BEHAVIORS

They are expressed in different parts of the brain

Alpha1 – hypnosis

Alpha2 - anxiety

Alpha3 and Alpha5 – muscle relaxation

Z compounds – alpha 1 selective agents

SEDATION – sleep aids

Technically not benzodiazepines

Imidazopyridine - zolpidam

STRUCTURE OF BENZODIAZEPINES

Benzene ring fused to a diazepine ring

Diazepam

Clonazepam

Cl

CH3 O

diazepam

O2N

Cl

H O

clonazepam

IDENTIFY THE VARIOUS CLASSES OF BDZS AND

DESCRIBE THEIR MAIN CLINICAL USES.

Sedation-Hypnosis

True Benzodiazepines

Triazolam (closest to ‘ideal hypnotic’)

Flurazepam (less ‘early morning insomnia’)

Z Compounds

Zolpidem (Ambien)

Zaleplon (Sonata)

Eszopiclone (Lunesta)

Anxiolysis

Most benzodiazepines, with medium to long T1/2

Low doses often used

Alpha-2 selective benzodiazepines are actively being developed

Severe Anxiety:

Associated with prominent autonomic signs (e.g. panic disorders)

High-potency benzodiazepines are used:

Alprazolam (Xanax)

Clonazepam (Klonopin): absence seizures

Lorazepam (Ativan): status epilepticus

Anticonvulsant

Only a few used

e.g. lorazepam (status epilepticus), clonazepam (absence seizures), clorozepate

EXPLAIN THE CHARACTERISTICS OF

TOLERANCE/DEPENDENCE TO BDZS.

Tolerance: primarily observed with anticonvulsant actions limited tolerance observed with sedative-hypnotic and anxiolytic effects

Dependence/Addiction: physical dependence is usually mild follows general rules of drug dependence: higher dosage = more severe withdrawal longer t1/2 = less severe withdrawal

estimated 0.1-0.2% of adult population abuse or are dependent on BDZs (300K -600K in the U.S.)

GABA receptors are located in the VTA (ventral tegmental area) modulating GABA receptor activity in the VTA hypothesized to increased

dopamine release (reward system)

IDENTIFY THE MEDICAL USES OF FLUMAZENIL.

It is used to reverse conscious sedation, general anesthesia and

benzodiazepine overdose aka stupor. However, there is a potential risk of

seizures.

WHY DO BARBITUATES HAVE MORE SERIOUS

SIDE EFFECTS?

Bind to GABA site open Cl conductance channel

High doses are fata

DESCRIBE THE MOLECULAR AND SYNAPTIC

EFFECTS OF AMPHETAMINES. HOW DO THEY

INFLUENCE CNS NORADRENALINE AND

SEROTONIN NEURONS THAT MEDIATE WAKING.

Amphetamine structures mimic catecholamines, so they can bind to the same transporters as catecholamines and also induce concentration-dependent effects.

1. Amphetamines are taken up by the same transporter (Norepinephrine transporter) and increases concentration of catecholamine within the cells. When the concentration is high enough, NET reverse transports NE out of the cell, enabling post-synaptic binding and effects.

Indirect release of NE into synapse

2. Amphetamines are transported into vesicles by vesicular monoamine transporter VMAT2, increasing the intravesicular pH.

The increase in pH inhibits VMAT2, causing a further buildup of intracellular catecholamine and causing more reverse transport and more catecholamine effects.

Dopamine - reward + psychosis/addiction

NE - fight or flight effects, increased BP/HR/stroke risk (+vigilance and anorexia)

5HT (Serotonin) - increased vigilance and anorexia

DESCRIBE SOME COMMON PROBLEMS AND

SIDE EFFECTS THAT ARE ASSOCIATED WITH

PROLONGED USE OF

Restlessness, dizziness, insomnia (Basically an extension of its clinical effects!)

Addiction/Dependency

CV/GI effects

Neurotoxicity and neuronal degeneration

Psychosis

EXPLAIN WHY MODAFINIL REPRESENTS A NEW

APPROACH TO THE TREATMENT OF

HYPERSOMNIA.

Modafinil is a psychostimulant but doesn’t have the same side effects

(jitteriness, anxiety, or excess locomotor activity or rebound effect) as

amphetamine or the same addiction tendencies. The mechanism isn’t fully

understood but it does increase glutamine release and diminish GABA release.

It’s new because it was approved in 2004 for use in hypersomnia?

Also doesn’t have cardiovascular side effects