planes of anesthesia (depth)
Analgesia - Loss of pain
Excitement - Combative behavior
Medullary paralysis and death
-Gases or volatile liquids
-High lipid solubility
-Very narrow therapeutic index
-Newer agents are non-explosive, non-flammable, and include nitrous oxide and halogenated hydrocarbon ethers
-early agents: nitrous oxide (not potent), diethyl ether (explosive), chloroform (carcinogen), ethylene (explosive), cyclopropane (explosive)
-current: NO, halothane, methyoxflurane, isoflurane, sevoflurane, desflurane
-steady state occurs quickest in richly perfused, low capacity tissue compartments: Brain, heart, liver, kidneys, endocrine glands > skeletal muscle > fat > bone, ligaments, cartilage
minimal alveolar concentration required to eliminate movement in 50% of patients challenged by a standardized skin incision, usually expressed % of agent in the anesthetic mixture
inverse = potency. most potent agents have the smallest MAC
NO has MAC > 100% and can't be used alone
-time required to reach steady state is inversely prop to blood flow, prop to % lipid, prop to tissue volume
-Brain, heart, liver, kidney, endocrine glands > Skeletal muscle > Fat > Bones, ligament, cartilage
-Begins with change in inspired gas to pure oxygen
-Proportional to respiratory rate and volume
-Inversely proportional to residual tidal volume
-Inversely proportional to blood solubility and cardiac output
-Proportional to partial pressure difference
-decreases hepatic and renal blood flow
-Decreases blood pressure
-Sensitizes myocardium to catecholamines
-*Hepatotoxic* - massive hepatic necrosis
-lowest MAC, highest potency, slowest induction
Good muscle relaxation
Stabilizes cardiac output
No increase in intracranial pressure
Does not sensitize myocardium to epinepherine
Must be delivered using special vaporizer
Relaxes bronchial smoth muscle- good for asthmatics
Rapid onset and recovery
Non-irritating, can be used for mask induction in children
Potential renal toxicity at low flow rates
Rapid onset and recovery
Relatively safe, nonirritating
No muscle relaxation
Must be combined with other , more potent anesthetics for surgical anesthesia
IV anesthetic Induction
Drug rapidly moves into heart after IV injection and then 70% goes to brain, liver and kidney, then to CNS
-Elderly and other patients with decreased cardiac output divert more blood to the CNS to compensate for reduced flow -> caution & reduced doses
IV anesthetic Recovery
-redistribution from the brain into the other tissues eventually reaching high levels in adipose.
-slowly diffuses out of these into the blood where the liver and kidney metabolize it
-Recovery slows after repeated doses and metabolism and plasma clearance then become important
-Replaced thiopental as first choice for anesthetic induction
-Water-insoluble sedative hypnotic that is prepared in a peanut-oil or egg-white emulsion for intravenous injection
-Reduces blood pressure and intracranial pressure without affecting myocardium
-for outpatient procedures and sedation in intensive care units.
-Not likely to cause nausea, Rapid onset, Lowers intracranial pressure
-New water-soluble form of propofol approved only for sedation
-slower effects than propofol but much longer duration
-cause sedation in about 4 minutes as opposed to 30 seconds for propofol.
-ultra-short acting agents (thiopental, methohexital) used to induce anesthesia
-effects < 1 min, quick recovery due to tissue redistribution
-may cause hypotension, Causes apnea, coughing, laryngospasm, bronchospasm and chest wall spasm
-Contraindicated in patients with asthma or with acute intermittent or variegate porphyria
-Rapid onset of action, Potent anesthesia
-Poor analgesia, Causes significant nausea, Little muscle relaxation, Causes laryngospasm
-contra: asthma, acute intermittent or variegate porphyria
-Used with other agents to increase sedation and amnesia
-Midazolam is most frequently used but diazepam and lorazepam are also used
-Minimal cardiovascular depression but all can cause respiratory depression
-Amnesia is anterograde resulting in failure to place information in long-term memory.
-Used to reduce amount of anesthetic by producing analgesia
-Fentanyly and its congeners sufentanyl and remifentanyl are most commonly used
-Not good amnesics and all cause respiratory depression
-Effects can be antagonized by naloxone or naltrexone
-Good analgesia, More rapid acting than morphine, Effects can be antagonized by naloxone
-Respiratory depression, Hypotension, Muscle rigidity
-Hypnotic without analgesia used to induce anesthesia
-not water-soluble. is produced in propylene glycol
-Rapid induction and short-acting
-Used for patients in shock and with coronary artery disease because it has little effect on the heart and circulation
-Causes decreased plasma cortisol and aldosterone levels that can persist for 8 hours by inhibiting 11-beta-hydroxylase, should not be continually infused
-Can cause involuntary motions
-Short-acting non-barbiturate anesthetic that causes a dissociated state
-the patient is unconscious but may appear to be awake, does not feel pain.
-works through the NMDA receptor
-stimulates central sympathetic outflow causing increased cardiac output and blood pressure
-Useful in asthmatics, patients in shock but contraindicated in stroke and hypertension
-used for short procedures in children and elderly
-Increases cerebral blood flow and frequently causes post-operative hallucinations (nightmares) in adults
-Emergence phenomena particularly in adults
-rare in its ability to sedate without causing respiratory depression
-alpha-2 agonists in specific regions of brain
-Has sedative, analgesic, anxiolytic, sympatholytic properties which reduce the amount of volatile anesthetic, sedative and analgesic requirements without causing respiratory depression
-Decreases undesirable cardiovascular reflexes
Clinical disorders/other conditions that are a focus of clinical attention - allows for entry of multiple disorders
Personality Disorders, Mental Retardation, habitually used defense mechanisms
Physical Disorders, General Medical Conditions
Psychosocial/Environmental Stressors contributory role - i.e. number, desirability, degree of change
Global Assessment of Function (GAF), current and recent
social, occupational, psychological spheres
-initiating signs usually of focal cerebral dysfunction
-signs progress rostral to caudal
-motor signs often asymmetrical
-history of brainstem dysfunction or sudden onset coma
-oculovestibular features (vertigo/vomiting) often precede or accompany compa
-cranial nerve dysfunction present
-bizarre respiratory patterns at onset
leads to 3rd nerve dysfunction - impaired pupillary light reflex (efferent limb)
-dolls eye response present = normal
-In fully awake patients, this reflex response is under the control by the voluntary control of gaze.
-Afferent - CN 8, Efferent - CN 3, 4, 6 through MLF/PPRF
-brisk rotation of head with eyes held open
-watch for contra-versive movements of eyes
-flexion - eyes deviate up and eyelids open
-extension - eyes deviate downward
-also involves proprioceptive afferents from the neck
-ensure integrity of TM
-elevate the head to 30 deg so that horizontal semicircular canal is vertical
-instill 10-20 cc of ice water into one ear
-if awake - deviation of eyes toward, nystagmus away
-if comatose - deviation toward, no fast phase nystagmus
-wait 5 min, then do other ear
-COWS: cold opposite, warm same
-for vertical eye movements: both ears, cold water - downward gaze; both ears, warm water - upward gaze
-midbrain-hypothalamus -> central reflex hyperpnea
-lower pons -> apneustic, cluster, ataxic
-medulla -> loss of automatic breathing
major depressive disorder
-5-12% in men; 10-25% in women
-50% onset age 20-40
-no relation to socioeconomic status
-occurs w/o history of mania, hypomania, or mixed sx
-2 or more weeks of depressed mood, anhedonia, changes in appetite/sleep, psychomotor agitation/retardation, decreased concentration, thoughts of death/suicide
-must experience at least 4 sx: change in appetite/weight, changes in sleep/activity, lack of energy, feelings of guilt, problems with thinking clearly/decision making, recurrent thoughts of death and suicide
-onset of episode assc w/ death of spouse
-15% eventually commit suicide
-treatable in 70-80%
-Most effective treatment is integrated pharmacotherapy and psychotherapy
-start with SSRIs
-poorer prognosis if long duration of episode, temporal association of mood and psychotic symptoms, poor premorbid social functioning
Bipolar I Disorder
-equal # of men & women - 0.4-1.6%
-onset at age 30
-men usually present w/ mania; women present w/ depression or mixed state with increased rapid cycling
-more common w/ higher socioeconomic status
-hereditary: 1st degree relatives of Bipolar I patients are 8-18 x more likely to have bipolar I
-50% of all Bipolar I d/o patients have at least 1 parent with a mood d/o.
-mania: stages I - III, with stage III the worst
-Distinct period of abnormally and persistently elevated , expansive or irritable mood for at least 1 week
-hypomanic sx last at least 4 days, w/o impairment in social, occupational, or work fxn as in mania. no psychosis
-associated with inflated self esteem, decreased need for sleep, distractibility, great mental/physical activity and over involvement in pleasurable activities with the potential of negative outcome.
-3 or more sx: inflated self esteem, decreased need for sleep, pressured speech, racing thoughts, distractibility, increased goal directed activity, excessive pleasurable activity w/ high risk of painful consequences
-Substance abuse, particularly alcohol, is used to self medicate
-Pathological gambling, exhibitionism, bright clothing, bright makeup
-Loss of attention to detail
-impulsive w/ conviction, hyperreligious, hyperpolitical
-Adolescents often misdiagnosed as antisocial, schizophrenic, chemically dependent, academic problems, multiple suicide attempts
45% of manic episodes recur. Untreated manic episodes last 3-6 months with a recurrence rate, on average, of 10 episodes
Bipolar II Disorder
-lifetime prevalence - 0.5%
-Criteria for hypomania occurs in combination with Major Depressive Disorder
-earlier age of onset than Bipolar I
-assc w/ marital disruption
-greater risk of suicide attempts & completion than bipolar I or MDD
MDD w/ melacholic features
-loss of pleasure in (almost) all pleasurable activity
-lack of reactivity to usually pleasurable stiuli
-3 of these sx: distinct quality of the depressed mood, early morning awakening, marked pscyhomotor retardation or agitation, significant wt loss or anorexia, excessive or inappropriate guilt
MDD w/ atypical features
-2(+) of: significant weight gain or increase in appetite, hypersomnia, leaden paralysis, long history of interpersonal rejection sensitivity
-more common in women
-aka hysterial dysphoria
-may occur in bipolar I or II and dysthymic disorder
MDD w/ catatonia
-2(+) of stupurous/motoric immobility, excessive motor actiivity, extreme negatvism, psychomotor retardation with posturing and waxy flexibility, echolalia or echopraxia
MDD w/ postpartum onset
-severe depression beginning w/i 4 weeks of giving birth
-often in women w/ preexisting mood or other psychiatric conditions
-may include marked insomnia, lability, & fatigue with suicidal thoughts
-homicidal & delusional beliefs about baby
-can be psychiatric emergency
-may apply to manic, mixed state, or brief psychotic d/o
-present for at least 2 yrs
-more common in elderly men, substance & alcohol disorders
-responds poorly to medications
-is 10-15% of those w/ MDD
-can also occur in Bipolar I and II disorders
MDD w/ seasonal pattern
-Depression develops with shortened daylight in winter and fall and disappears during spring and summer
-aka seasonal affective disorder
-hypersomnia, hyperphagia, and psychomotor slowing
-related to abnormal melatonin metabolism
-treated with exposure to bright artificial light for 2-6 hrs/day
-may occur in bipolar I and II
MDD w/ pseudodementia
-presents as cognitive dysfunction resembling dementia
-in elderly and those w/ prior mood disorders
-depressive sx prominent and primary and predate cognitive symptoms
-respond to antidepressant medications or ECT
MDD w/ rapid cycling
-4 episodes in 12 month period
-increased incidence in females with MDD and hypomanic episodes
-less severe than MDD
-more common & chronic in women
-often in those w/ long term stress and sudden losses
-can coexist w/ substance abuse, personality disorders, OCD
-sx worse later in the day
-more common w/ 1st degree relative w/ MDD
-2 of: poor appetite, overeating, sleep roblems, fatigue, low self-esteem, poor conc/difficulty making decisions, feelings of hopelessness, 2 years not without sx for more than 2 months, no MDD episode in 2 years, no manic/mixed/hypomanic history, no chronic psychotic disorder, not substance abuse
-depressed all the time but may not be as depressed as a patient who is experiencing major depression
-20-30% develop major depression, bipolar I, or bipolar II
-alternating periods of hypomania and moderate depression
-chronic & nonpsychotic
-sx present for 2 years
-equally represented in men & women
-onset in late adolescence & early adulthood
-substance abuse common
-MDD and BPI more common in 1st degree relatives
-may respond to lithium
-Major Mood disorder , usually bipolar II, develops in 30%
due to hypothyroidism with fatigue, depression, suicidality. More common in women. May mimic psychosis
mad hatter's syndrome
due to mercury intoxication produces manic symptoms and occasionally depression.
-Baseline of Dysthymia with
intermittent bouts of major
Simple partial seizure
Diverse manifestations determined by region of the brain that is affected. A key feature is preservation of consciousness.
complex partial seizure
Impaired consciousness lasting 30 seconds to two minutes, often associated with purposeless movements such as lip smacking or hand wringing.
Associated with bizarre generalized EEG activity during seizure, but evidence of temporal lobe abnormalities in many cases (temporal lobe or psychomotor seizures).
reflexes abolished, including pain.
stereotopic - starts in same place in homonculus
Secondary generalized - cross corpus callosum to other hemisphere
Can have progressed from simple partial seizures (auras)
partial seizures w/ secondarily generalized tonic-clonic seizure
-simple or complex partial seizure evolves into tonic-clonic seizure w/ loss of consciousness and sustained contractions (tonic) of muscles throughout the body followed by periods of muscle contraction alternating with periods of relaxation (clonic), typically lasting 1-2 minutes
absence (petit mal) seizure
-Brief (usually less than 10 seconds but not more than 45 seconds) and abrupt loss of consciousness associated with high-voltage, bilaterally synchronous, 3-per-second spike-and-wave pattern in the EEG; usually some symmetrical clonic motor activity.
-brief shocklike contraction of muscles that may be restricted to a part of one extremity or may be generalized
Atypical absence seizures; tonic seizures; atonic seizures; clonic and myoclonic seizures
Generalized tonic-clonic (grand mal) seizures
-Major convulsions; usually a sequence of maximal tonic spasm of all body musculature followed by synchronous clonic jerking and prolonged depression of all central functions.
-loss of consciousness
-discharge involves both hemispheres simultaneoulsy
-no distinct aura
-Activated by photic stimulation and hyperventilation
a state in which there are recurring seizures without restoration of consciousness between seizures. if these seizures are tonic-clonic, that is of course a medical emergency which must be treated.
-causes: fever, brain damage in the neonatal period, acute encephalopathies, meningitis, toxic encephalopathy, withdrawal of antiepileptic medication, barbiturate abstinence.
process in which repeated, focal application of initially subconvulsive electrical stimulation to the amygdala that result in intense partial epilepsy. Hypersensitivity persists for the life of the animal.
-women 2x as likely
-high comorbidity w/ major depression
-without agoraphobia: have recurrent unexpected panic attacks, w/ at least 1 of the attacks followed by 1 month (+) of persistent concern of having adtl attacks, worry about the implications of the attack, a significant change of behavior related to the attacks
-treatment: begin with benzodiazepines -> Alprazolam (Xanax) 0.25 - 1 mg TID or QID, Clonazapam (Klonopin) 0.5 - 1 mg BID
-beyond acute phase: SSRIs in higher doses than for depression -> Escitalopram (Lexapro) 10-25 mg once daily, Sertaline (Zoloft) 50-200 mg once daily
Anxiety about being in places or situations from which escape might be difficult (or embarrassing)
-the situates are avoided or else are endured w/ marked distress or w/ anxiety about having a panic attack
-4.4% adults, women 2x more than men
-Marked and persistent fear that is excessive or unreasonable, cued by the presence or anticipation of a specific object or situation.
-person recognizes that fear is excessive or unreasonable
-if <18 persists for at least 6 months
-use exposure-based procedures, especially in vivo exposure
-no pharmacological intervention
-equal among men and women, 3.7% adults
-A marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. The individual fears that he or she will act in a way (or show
anxiety symptoms) that will be humiliating or
-person recognizes that fear is excessive or unreasonable
-if <18 persists for at least 6 months
-treatment: SSRIs in doses higher than for depression -> ParoxetineCR (Paxil CR) 25-37.5 mg once daily, Escitalopram (Lexapro) 20-25 mg once daily, Sertraline (Zoloft) 50-200 mg once daily, or Benzodiazepines
-CBT, approaches that address self esteem
Obsessive Compulsive Disorder
-2.3% adults, equal among men & women
-1/3 adults had their first sx in childhood
-reduction of intrusive, unwanted thoughts and repetitive actions/behaviors that cause distress or impairment.
-person has recognized that the obsessions or compulsions are excessive or unreasonable
-treatment: SSRIs, Clomipramine (Anafranil) titrate 25 mg - 250 mg once daily, Benzodiazepines, or Atypical antipsychotics (Risperidone 0.25-1 mg once-twice daily)
-Behavioral or cognitive behavioral therapy
Posttraumatic Stress Disorder
-women > men
-rape is most likely trigger. childhood sexual abuse
-duration of disturbance > 1 mo
-antidepressants: MAOIs, Tricyclics, SSRIs
Generalized Anxiety Disorder
-women 2x > men
-comorbid w/ other disorders
-risk is highest between childhood & middle age
-for at least 6 mos. subjective anxiety/tension, excessive worry, and a variety of
physiologic complaints (GI, musculoskeletal, neurological)
-start w/ SSRIs @ higher doses than for depression -> Escitalopram (Lexapro) 10-25 mg once daily, Sertraline (Zoloft) 50-150 mg once daily, ParoxetineCR (PaxilCR) 25-37.5 once daily
-SNRIs (6-8 weeks to respond) - VenlafaxineXR (EffexorXR) 75-225 mg daily, Busprione (Buspar) 5-15 mg TID
-Benzodiazepines -> Clonazapam 1-2 mg up to TID
drugs facilitating anesthesia
-benzodiazepenes - anxiolytic
-H2 blockers - inhibit gastric acid secretion
-H1 blockers - prevent allergic reaction
-antiemetics - reduce n/v
-analgesics - reduce pain as anesthesia decreases
-anticholinergics - decrease secretions, prevent bradycardia
-NM blockers - skeletal m relaxation
-replacement of normal lung gases w/ inspired anesthetic mixture
-time required is: directly prop to residual lung capacity, inversely prop to resp volume, inversely prop to resp rate
-independent of physical properties of gas
transfer from lung to circulation begins as partial pressure in alveoli increases
blood/gas partition coefficient
-ratio of amt of anesthetic in blood to amt in the gas phase at equilibrium
-low blood solubility -> more rapid induction & recovery
-high blood solubility -> slower induction & recovery
clouding of consciousness (drowsiness)
minimally reduced awareness to environment
mild to moderate reduction in alterness; a lesser interest in environment
can be aroused only with vigorous and continuous stimulation
can't be aroused to respond appropriately to stimuli even with vigorous stimulation
eye opening: 1 (no response) - 4 (spontaneous, open with blinking at baseline)
Verbal response 1 (no response) - 5 (oriented conversation)
Motor response: 1 (no response) - 6 (obeys commands for movement)
13 of higher - mild brain injury
9-12 - moderate brain injury
<9 - severe brain injury
mood disorder etiology
-dysregulation of biogenic amines - NE, serotonin, DA
-Dysregulation of AA nts like GABA
-dysregulation of neuroactive peptides - endogenous opiates
-dysregulation of neuroendocrine systmes: 50% of depressed pts have elevated cortisol, 5-10% have thyroid disorder, blunted sleep induces increase in GH
-disordered sleep - abnormal EEGs, delayed sleep onset, shortened latency to REM, increased length of 1st REM episode, abnormal delta sleep
-circadian rhythm dysregulation
-limbic system, basal ganglia, hypothalamus
-genetics - more significant in Bipolar I > MDD
-Stressful life events precede onset of the 1st episode of Bipolar I d/o and Major Depressive d/o
-sudden loss in tone. head drop. lasts 1-2 sec.
EEG: slow spike-wave, flattening
-doesn't realize what happened
Neuroleptic Malignant Syndrome
-Fever, diaphoresis, marked muscular rigidity, stupor, respiratory & autonomic dysfunction, leukocytosis
-0.5-1% pts who receive high potency neuroleptics
-Death from respiratory or renal failure, cardiovascular collapse, arrhythmias
-Mechanism relates to sudden decrease in dopaminergic activity
-tx: Bromocriptine, L-dopa, carbidopa, amantidine, dantrolene
-should not be re-exposed to a neuroleptic drug for at least 2 weeks.
-direct correlation of increased risk with advancing paternal age (subject to greater epigenetic change)
-dysfunction in limbic system & basal ganglia. loss of brain volume.
-too much dopaminergic activity. partly due to loss of GABAergic neurons in hippocampus
-anhedonia suggests dysfunction in the norepinephrine reward neural system
-phencyclidine (PCP), a glutamate antagonist, causes psychosis
-decreased muscarinic & nicotinic receptors -> ACh & nicotine
-altered conc of substance P & neurotensin
-decreased size of limbic system, inc amygdala, hippocampus, parahippocampal gyrus, disorganization in hippocampus
-lateral and third ventricle enlargement and reduction in cortical volume
-reduced symmetry that originates in fetal life
-abnormalities of prefrontal cortex
-shrinkage of thalamus
-abnormal EEGs, inability to filter out irrelevant sounds and are extremely sensitive to background noise
-seen w/ complex partial epilepsy, esp left-sided seizure forms, medial temporal location of lesion, early onset of seizures
-P300; a large positive EP wave that occurs about 300msec after a sensory stimulus from limbic system
-eye mvmt dysfunction (frontal lobes)
-dec T cell IL-2 production, reduced #/responsiveness of peripheral lymphocytes, abn cellular & humoral reactivity to neurons, brain-directed Abs
-peak onset 18-25 males, 25-35 females. women have 2nd peak appearing in middle age.late onset >35. equal in men & women. winter & early spring births.
-Higher rates of metabolic syndrome: insulin resistance, hypertension, dyslipidemia, increased waist circumference
-10-15% commit suicide, 50% attempt
-Risk factors: male, young, post-psychotic depression, realistic assessment of deterioration due to illness
-75-90% smoke (abn of nicotinic rec). nicotine may decrease positive sx
-High cannabis use increased risk of developing schizophrenia 6X
-2(+) during 1 month: delusions, hallucinations, disorganized speech (frequent derailment or incoherence), grossly disorganized or catatonic behavior, negative symptoms (affective flattening, alogia, avolition)
-only 1 if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary
-Continuous signs of the disturbance persist for at least 6 months
-Preoccupation with one or more delusions or frequent auditory hallucinations.
-None of the following: disorganized speech, disorganized or catatonic behavior, or flat or inappropriate affect
-delusions of persecution or grandeur, first episode of illness at an older age, ego resources greater, less regression, typically tense, suspicious, guarded, reserved, sometimes hostile or aggressive
-all prominent: disorganized speech, disorganized behavior, flat or inappropriate affect
-criteria are not met for catatonic type
-early onset, usually before 25; marked regression to primitive, disinhibited, unorganized behavior, aimless, non-constructive activity, pronounced thought disorder, poor self-care, inappropriate emotional responses and social interactions
-motoric immobility as evidenced by catalepsy (maintaining body position into which one is placed) or stupor
-excessive motor activity (that is apparently purposeless and not influenced by external stimuli
-extreme negativism (an apparently motiveless resistance to all instructions or maintenance of a rigid posture against attempts to be moved) or mutism
-peculiarities of voluntary movement as evidenced by posturing (voluntary assumption of inappropriate or bizarre postures), stereotyped movements, prominent mannerisms, or prominent grimacing
-echolalia or echopraxia (echoing speech or movement)
-patient may show a rapid alternation between extremes of excitement and stupor; supervision is needed to prevent injury to self or others, medical care may be needed due to malnutrition, exhaustion, hyperpyrexia or self-inflicted injury
-Absence of prominent delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior.
-continuing evidence of the disturbance, as indicated by the presence of negative symptoms or two or more symptoms listed in Criterion A for schizophrenia, present in an attenuated form
a serious and likely permanent movement disorder related to therapy with dopamine blocking drugs. 20-30% of long-term patients on typicals exhibit symptoms, 3-5% of young patients per year on typicals develop TD
Higher incidence in females, older age, organic and affective mental illness
-Similar to schizophrenia but symptoms last between 1 and 6 months
-Typical presentation is rapid onset without a significant prodrome, with return to baseline functioning within 6 months
-good prognosis: onset of psychotic sx w/i 4 weeks of 1st noticeable change in normal behavior, confusion at height of episode, good premorbid social & occupation functioning, absence of blunted or flat affect
-60-80% progress to schizophrenia
-tx: 3-6 month course of antipsychotic medication
-Has features of both schizophrenia and affective (mood) disorders
-Depressive type may be more common in older patients, bipolar in younger
-females > males, age of onset later in women.
-Men may exhibit antisocial behavior and flat or inappropriate affect
-either a major depressive episode, a manic episode, or a mixed episode, concurrent with symptoms that meet Criterion A for schizophrenia. there have been delusions or hallucinations for at least 2 weeks
-Mean age of onset is 40
-Slightly more females than males
-Females likely to have erotomanic delusions. Males likely to have paranoid delusions
-delusions are non-bizarre and present at least 1 mo
-not related to schizophrenia or mood disorders
-premorbid personality - extroverted, dominant, hypersensitive
-IQ lower than average
-good prognosis: high functioning, female, <30, sudden onset, short illness, precipitating factors
-Main defense mechanisms of reaction formation, denial, and projection
Erotomanic type of Delusional Disorder
delusions that another person, usually of higher status, is in love with the individual; more common in females, males may become aggressive
delusions of inflated worth, power, knowledge, identity, or special relationship to a deity or famous person
delusions that the individual's sexual partner is unfaithful; usually affects males
delusions that the person (or someone to whom the person is close) is being malevolently treated in some way. Patient may be litigious or become aggressive.
delusions that the person has some physical defect or general medical condition
post partum psychosis
Occurs in 0.1% of pregnancies
50-60% of patients have just had their first child 50% of children have experienced perinatal omplications
Most cases represent an underlying mood disorder, usually bipolar disorder
2/3 go on to have a mood episode within a year
2-3 weeks after delivery
fatigue, insomnia, restlessness, emotional lability, progressing to suspiciousness, confusion, irrational statements, obsessive concern about the baby's health, delusions and or hallucinations
lack of GnRH secretion as a result of mutation in scaffolding protein - disrupts migration of GnRH and olfactory neurons from the olfactory placode (nose) to the hypothalamus
organizational theory - sex steroids
the sexual phenotype of the body and the CNS is determined by exposure to certain sex steroids during developmental critical periods (pre- and postnatal)
activational theory - sex steroids
actions of sex steroids on the mature CNS stimulate certain behaviors & physiological processes
-transcribed in hypothalamus and in frontal & temporal cortex of adult men.
-also expressed in the ventral striatum and dopaminergic neurons of substantia nigra, areas which are intimately involved in the motor pathways and implicated in motivational aspects of behavior
sexual dimorphic nucleus
structural dimorphism in the size of a small area of the preoptic area; can be influenced by steroids
-3x larger in males
-related to sexual behavior
Freud's theory of psychosexual development
Oral stage (0-1) - nursing, oral examination
Anal stage (2-3) - potty training, control
Phallic stage (3-6) - discovery of genitals, differences (Oedipus & Electra complex)
Latency stage (7-puberty) - sexuality issues subside; same sex friends
Genital stage (puberty-adult) - maturity, love, work, etc..
did not consider pre- and postnatal hormonal effects
third interstitial nucleus of anterior hypothalamus (INAH3)
-3x larger in men > women
-2-3x larger in heterosexual men vs gay men
-heterosexual men had more aromatase - converts testosterone -> estradiol
dimorphism in cognitive function
-Cerebral asymmetry is more pronounced in males than in females (female brains show less functional asymmetry)
-Females better at verbal fluency/interpreting facial expressions
-Males score higher in mathematical reasoning/ understanding spatial relationships
-5alpha-reductase-2 is necessary to convert testosterone to 5alpha-DHT for normal differentiation in external genitalia.
-XY, raised as females until puberty, then become phenotypic males (5a-reductase-1 is expressed at puberty and beyond)
Complete Androgen Insensitivity syndrome (CAIS)
-mutation in the androgen receptor so that the body
cannot respond to testosterone or 5a- DHT
-normal male levels of testosterone -> estradiol peripherally by aromatase.
-gender identity is female
-strong evidence that testosterone is the hormone that masculinizes the CNS in humans
Congenital Adrenal Hyperplasia (CAH)
-most common cause of ambiguous genitalia in newborns
-genetic defect in 21a-hydroxylase that they cannot convert 17a OH-P to 11b-cortisol -> elevated androgens due to lack of cortisol feedback to inhibit ACTH
-Can't make cortisol or aldosterone. Are at risk for salt wasting.
- shunt cortisol pathway to weak androgens - male & female.
-females are anatomically masculinized
-Agonists (codeine, hydromorphone, heroin)- substitutions: at 3, 6, 17 positions.
-The mixed agonist/antagonists or pure antagonists typically have substitutions at the 17 position (or at 14). This tertiary amine is modified, usually with a bulkier alkyl group.
-responsible for spinal and supraspinal analgesia, respiratory depression, miosis, euphoria, reduced GI motility, and physical dependence.
-mu receptor activation turns off tonic inhibition by GABAAR of parasysmpathetic tone
-responsible for spinal and to a lesser extent supraspinal analgesia.
-produces respiratory depression, miosis, dysphoria
produces both spinal and supraspinal analgesia, but spinal analgesia is more robust.
may or may not be a true opiate receptor. It appears to be associated with dysphoria and hallucinations and may be a site of action for PCP. lowers pain threshold in certain cases
-precursor of endorphins
-restricted in CNS. High levels in arcuate nucleus -> projects to brainstem, limbic areas, & SC. Peptides from POMC also found in pituitary and islet cells of pancreas.
-Proenkephalin A = precursor of enkephalins
-Proenkephalin B = precursor of dynorphins
-widespread throughout CNS and are often found together. in areas of CNS involved in pain preception. (laminae I & II, spinal trigeminal n, periaqueductal gray)
-also found in areas that modulate affective behavior, motor control, and autonomic fxn.
also found in nerve plexuses, the adrenal medulla, and exocrine glands of the stomach and intestine
-analgesia: nociceptive pain more responsive than neuropathic pain. Change perception of/response to pain, & raise threshold. Dull pain > sharp pain. Due to activation of postsyn opiate rec of ascending STT & enhanced activity in descending bulbospinal tract.
-Euphoria (mu & delta receptors): DA neurons in the VT are activated by opiates -> turns off inhibition of DA neurons by GABAnergic neurons -> project to n accumbens.
-Dysphoria (kappa receptors) - block firing of DA neurons
-alter hypothalamic heat regulation -> temperature falls
-neuroendocrine (mu) - decrease LH, FSH, ACTH, b-endorphin. increase prolactin, ADH
-miosis - activation of mu & kappa receptors on PS nerves inn the pupil. toxic doses -> pinpoint pupils.
-convulsions (mu & delta) - activate hippocampal pyramidal cells
-antitussive - depression of medullary cough centers
-n/v - stimulation of CTZ in area postrema of medulla, esp in ambulatory pt..
-depressed respiration - concentration dependent. Therapeutic concentrations of morphine reduce rate, minute volume, and tidal exchange.
-suppression of brainstem centes that control rhythm & that sense pCO2. admin of O2 -> apnea.
-block nerve conduction of sensory & motor nerves, completely reversible
-block voltage-dependent Na+ channels. SOA near the intracellular/cytoplasmic end of Na+ channel pore. reduce Na+ influx
-noncompetitive antagonists & pore blockers
-effects are frequency dependent - nerve that is firing more frequently is more susceptible to local anesthetic bllock.
-stabilize inactivated state of Na+ channel
-changes in resting membrane potential alter the prob that the channel will be open - affect sensitivity. depolarized -> increased probability of opening, & vv
-most are weak bases (pka 8-9), poorly water soluble. In tissues exist as iionized cationic form.
-lipophilicity allows LA to cross membrane. charged form binds to Na+ channel
-inhibition: Type C > B > A. pain blocked first, then sensory, then motor fxns. recovery in reverse. peripheral n in bundle > central
-all vasodilators except cocaine
-ester linked: prone to hydrolysis, metabolized rapidly by butyrocholinesterase, more likely to produce hypersensitivity
-amide-linked: metabolized by hepatic microsomal system (impaired liver fxn -> toxicity)
-CV toxicity: excessive absorption, direct suppression of heart (dec cond velocity & inotropic effect), CV & death from arrythmia or suppression of electrical activity.
-CNS toxicity: intravascular injection, suppression of inh pathways. restlessness -> convulsions, coma, cardiorespiratory arrest
-coadministered w/ local anesthetics
-can increase duration of effect of by 50%
-reduce toxicity of LA
-usually epi, also NE, phenylephrine, vasopressin
-overdosage -> hypoxia (avoid extremities)
-cocaine is natural vasoconstrictor
-provided by aqueous salts of many anesthetics (benzocaine, lidocaine)
-formulations for use on all surfaces except eyes
-benzocaine particularly good for burns/conditions of denuded flesh, b/c it isn't absorbed
-the injection of the local anesthetic in a region without regard to the cutaneous route of the nerves
-can be used for superficial tissues or intraabdominal organs
-injection of local anesthetic into/about peripheral nerves or nerve plexuses.
-affects both sensory & motor nerves
-local anesthetic injected into epidural space bounded by ligamentum flavum, dura, & spinal periosteum
-can be injected into sacral hiatus, or in lumbar, thoracic, or cervical regions
-spinal nerve roots chiefly affected
-large doses needed b/c diffusion is required
-injection of anesthetic around nerve roots w/i subarachnoid space in lumbar region.
-can deaden entire lower body
-autonomic nerves extremely sensitive to local anesthetics -> CV fxn depressed.
-headache can occur because of leak of CSF from hole in dura
migraine without aura
-4-72 hr duration
-18% of wmen, ages 30-50. 6% in men
-at least 5 headache attacks
-headache has 2(+): unilateral pain localized to temple/orbital region, pulsating pain, moderate -> severe intesity, aggravated by routine physical activity
-must have 1: n/v, photophobia/phonophonia
-can become chronic: headache occurrence >15 day/mo for > 3 months, menstrual relationship
migraine with aura
-aura: Recurrent disorder manifesting in attacks of reversible focal neurological symptoms that usually develop gradually over 5-20 min and last for less than 60 min.
-visual auras most common - photopsia. also sensory aura. least common - motor weakness & aphasia.
-Can present with + and/or - features and usually mixed
-headache likes migrainous sx or headache is completely absent (less common)
-rare, usually also experience migraines w/o auras
-50% of patients have a first-degree relative with migraine
coritcal spreading depression (CSD)
-wave of complete neuronal & glial depolarization lasting 1(+) min
-wave propagates from medial -> lateral and posterior -> anterior grey matter
-long-lasting suppression of neural activity
-occurs in visual cortex contralateral to visual aura
-observed following subarachnoid hemorrhage or stroke
-unclear if CSD initiates migraine
Familial hemiplegic migraine (FHM)
-Severe auras including hemiparesis/hemiplegia and classic migraine symptoms
-genetic variant in 3 genes coding for cation channels: voltage-gated Ca2+ channel (P/Q), subunit of Na+/K+ ATPase, voltage-gated Na+ channel
-mice with these mutations have increased susceptibility to CSD
-vasodilation of meningeal blood vessels in supratentorial dura activates CN V -> antidromic (opposite to normal direction) release of vasoactive peptides from nerve terminals -> causes more dilation of blood vessels
-any activation of CNV -> antidromic release of vasoactive peptides from nerve terminals (esp calcitonin gene related peptide) -> lowers threshold of nociceptors and causes larger generation potential of receptors -> increased # AP along primary afferent & recruitment of more afferents firing
-transient receptor potential cation channel, subfamily V, member 1, aka capsaicin receptor
-activated by a wide variety of exogenous and endogenous physical and chemical stimuli
-receptors are found mainly in the nociceptive neurons of the PNS
-potential therapeutic targets for migraine headache
-cis isomer of capsaicin
-specific agonist for TRPV-1 receptors on C afferents
-desensitizes receptors - decreases the activation of these receptors -> alleviates firing of primary sensory afferents. blocks voltage-gated Ca2+ channels
-high level of activity from nociceptor afferents (primarily C fibers) -> activity dependent increase in excitability of cell bodies in trigeminal ganglia -> leads to trigeminal nucleus caudalis (TNC) overstimulation
-decreased threshold of somas in TNC with secondary afferents crossing over and forming trigeminothalamic tract. APs generated faster and have increased firing
-> hyperalgesia & allodynia
-increased release of vasoactive peptides (Substance P, glutamate, CGRP) from primary afferent endings onto trigeminovascular system. circulates until it hits peripheral endings -> direct effect on TNC somas
-results in inhibition of periaqueductal gray & nucleus raphe magnus -> more incoming pain afferents from TNC & SC
-greater occipital n is activated (spinal nerve from dorsal rami of cervical spinal nerve 2) -> receives afferents from posterior scalp & neck muscles
-excessive nociceptor afferent stimulation leads to central sensitization at C2 level of SC -> direct connection into TNC via Lissauer's tract and tract running through substantia gelantinosa
-on CN V afferent endings
-agonists of presynaptic receptors
-usually inhibitiory, antidromic release
-cause decreased release of nt
-break vasodilator cycle
-promote normalization of afferent signaling
therapy to block receptor activation of trigeminal nucleus caudalis
-5HT1D and 5HT1F receptors on primary afferent axons synapse on TNC, some 5HT1B
-decrease release of neurotransmitter
-interrupts pain signal transmission
-could prevent development of central sensitization
tension-type headache (TTHA) - infrequent episodic
-10(+) episodes <1 day/mo/yr
-headahce lasts 30 min - 7 days
-has 2(+) - bilateral location, pressing & non-pulsating, mild or moderate intensity, not aggravated by routine physical activity
-may have phonophobia or photophobia
tension-type headache (TTHA) - frequent episodic
-at least 10 episodes > 1 but < 15 days for at least 3 mo/yr
-has 2(+) - bilateral location, pressing & non-pulsating, mild or moderate intensity, not aggravated by routine physical activity
-may have phonophobia or photophobia
-frequently coexits w/ migraine w/o aura
ension-type headache (TTHA) - chronic
-at least 10 episodes > 15 days/month for > 3mo/yr
-has 2(+) - bilateral location, pressing & non-pulsating, mild or moderate intensity, not aggravated by routine physical activity
-can evolve over time from episodic tension-type headache or de novo
-daily and unremitting w/i 3 days of its first onset
-difficult to distinguish from chronic migraine
-dysfunction of pain modulatory systems - peripheral sensitization of nociceptive pathways -> responsible for episodic
-convergence of nociceptor inputs on TNC
-central sensitization: lamina I and V of SC receive afferents from neck & shoulder mm. myofacial afferents from TNC -> mechanism for chronic TTHA
-type of trigeminal autonomic cephalagia
-prominent PS autonomic features
-episodic = 85%; chronic = 15%
-pain starts quickly, no warning. max pain reached w/i 2-15 min, lasting up to 180 min
-excruciating, deep, nonfluctuating pain around eye and temple (distribution of CN V1)
-unilateral & presents on same side
-ipsilateral autonomic sx
-3-4 x males > females. onset @ 20-40
-ipsilateral autonomic sx: conjunctival injection/lacrimation, nasal congestion/rhinorrhea, eyelid edema, forehead & facial sweating, miosis/ptosis, restlessness/agitation
-at least 5 attacks
-severe to very severe unilateral orbital, supraorbital, or temporal pain lasting 15-180 min
-accompanied by at least 1 (all ipsilateral): onjunctival injection/lacrimation, nasal congestion/rhinorrhea, eyelid edema, forehead & facial sweating, miosis/ptosis, restlessness/agitation
-at least 2 cluster periods lasting 7-365 days and separated by pain-free remission periods > 1 mo
-cluster periods last 2 weeks - 3 mos
-attack lasting for > 1 yr w/o remission or with remissions lasting <1 mo
may arise de novo or evolve from episodic
-trigeminal distribution of pain
-ipsilateral cranial autonomic features
-circadian pattern of attacks
cluster headache pathophysiology
-afferent stimulation of TNC via CN V1
-sympathetic projections from hypothalamus -> intermediate horn in SC, upper cervical spinal nn that exit and synapse in SCG -> innervate face. allows convergence of signals via Lissauer's tract & SG with TNC activation
-hypothalamic activation of Superior Salivatory Nulcues -> increase in PS outflow via sphenopalatine ganglion
-vasodilation of internal carotid in cavernous sinus compresses sympathetic innervation -> horner's like sx
-phase-shifting in super chiasmatic nucleus -> periodicity of sx
-CN V not necessary for some chronic forms
-inflammation of cavernous sinus walls
schizophrenia - good prognosis
-obvious precipitating factors
-good premorbid social, sexual, & work histories
-mood disorder sx (esp depressive)
-family history of mood disorders
-good support systems
substance abuse criteria
-never met dependence criteria
-meets 1 of these w/i 12 mos
- Failure to carry out major obligations at work, home or school because of repeated substance use
- Repeated use of substance even when it's physically dangerous to do so.
- Recurrent experience of legal problems
- Continued substance use despite knowing that it has caused or worsened social or interpersonal problems.
substance dependence criteria
-meets 3 within 12 mo
-Amount/duration of use greater than intended.
-Unsuccessful efforts to control or reduce use
-Spending much time using substance, recovering from its effects, or trying to obtain it.
-Reducing or abandoning important work, social or leisure activities because of substance use.
-Continued substance use despite knowing that it has probably caused ongoing physical or psychological problems.
early vs sustained remission
Months 2-12 after the patient last experienced problems with the substance. This period of time was singled out because most patients are especially vulnerable to relapse during the first year of sobriety.
after the first year the patient is said to be in sustained remission
There have been no symptoms of dependence or of abuse. During months 2-12 this would be called early full remission; after the first year is termed sustained full remission
The patient has met at least one criterion for either dependence or abuse, but does not fully qualify for either of these diagnoses. ]
-withdrawal: 2+ of autonomic hyperactivity, increased hand tremor, insomnia, n/v, transient visual/tactile/auditory hallucinations, psychomotor agitation, anxiety, generalized tonic-clonic seizures
-readily absorbed po. 20-30% from stomach, remainder from upper GI. distributes in TBW. readily crosses membranes, crosses placenta, appears in breast milk
-max BAL 30-90 min after dose
-eliminated by first pass metabolism - stomach & liver (portal v). pseudo zero-order kinetics. 2% - 10% excreted unchanged through urine, saliva, sweat and breath. equilibrates in breath at a 2100:1 blood : breath partition coefficient
-at high BAL also metabolized by P450-2E1 enzyme (CYP2E1) - causes induction of enzyme
-causes changed NADH/NAD ratio in liver -> hyperlacticacidemia, hyperuricemia, hypoglycemia, hyperlipidemia, ketosis
-Humans have a 3-4 fold variability in elimination rates
-acute tolerance (Mellanby effect) at high doses
-anxiolysis, inhibition of temp regulation, altered neuroendocrine activity (diuresis, dec steroidogenesis)
-metabolic tolerance (induction of ADH, CYP2E1) & CNS tolerance (major).
-may benefit long-term cognition abilities
-brain shrinkage in prefrontal cortex, ventricular enlargement
-Moderate intake (1-2 drinks/day) associated with reduced risk of coronary heart disease. heavy drinking associated with increased cardiovascular mortality
-low doses increase gastric secretion, high doses dec gastric secretion & motility. Chronic use can lead to gastritis, diarrhea, esophageal dysfunctions, and malabsorption syndromes
Naltrexone blocks opioid receptors involved in the rewarding effects of alcohol and craving for alcohol. It's available in oral (Depade®, ReVia®), and extended-release injectable (Vivitrol®) given as once monthly injections.
used to reduce relapse drinking
acts on the GABA and glutamate neurotransmitter systems and is thought to reduce symptoms of protracted alcohol abstinence such as insomnia, anxiety, restlessness, and dysphoria.
thought to modulate NMDA and GABAA receptors
interferes with metabolism of alcohol, resulting in accumulation of acetaldehyde which, in turn, produces a very unpleasant reaction including flushing, nausea, and palpitations if the patient drinks alcohol.
-Abrupt cessation of nicotine use, or reduction in the amount of nicotine used, followed within 24 hours by four (or more) of the following signs:
-dysphoric or depressed mood
-irritability, frustration, anger
-increased appetite or weight gain
-Verenicline tartrate (Chantix)
-intoxication: 2 or more of the following: tachycardia or bradycardia, pupillary dilation, elevated/lowered BP, perspiration or chills, n/v, evidence of weight loss, psychomotor agitation or retardation, muscular weakness, respiratory depression, chest pain, cardiac arrhythmias, confusion, seizures, dystonia,s dykinesias, or coma
-withdrawal: Dysphoric mood and two (or more) of the following - fatigue, vivid unpleasant dreams, insomnia/hypersomnia, increased appetite
-acute effects: euphoria, increased energy, mental alertness, decreased appetite, increased HR, increased BP, vasoconstriction, hyperthermia, mydriasis
-chronic effects: addiction, irritability, mood disturbances, restlessness, paranoia, auditory hallucinations, disturbances in HR, chest pain, resp failure, strokes, seizures, headaches, adbl pain, nausea
-Clinically significant maladaptive behavioral or psychological changes (e.g., impaired motor coordination, euphoria, anxiety, sensation of slowed time, impaired judgment, social withdrawal) that developed during, or shortly after, cannabis use.
-2 or more of:
MDMA affects the brain by increasing the activity of at least three neurotransmitters: serotonin, dopamine, and norepinephrine. causes them to be released from their storage sites in neurons
-2 or more of:
-tachycardia or bradycardia
-elevated or lowered blood pressure
-perspiration or chills
-evidence of weight loss
-psychomotor agitation or retardation
-muscular weakness, respiratory depression, chest pain, or cardiac arrhythmias
-confusion, seizures, dyskinesias, dystonias, or coma
Dysphoric mood and two (or more) of the following:
-vivid, unpleasant dreams
-insomnia or hypersomnia
-psychomotor retardation or agitation
-Sniffing highly concentrated amounts of the chemicals in solvents or aerosol sprays can directly induce heart failure and death within minutes of a session of repeated inhalations
-particularly associated with the abuse of butane, propane, and chemicals in aerosols
-can result in irreversible effects
-hearing loss - toluene (spray paints, glues, dewaxers) and trichloroethylene (dry-cleaning chemicals, correction fluids)
-peripheral neuropathies, or limb spasms - hexane (glues, gasoline) and nitrous oxide (whipped cream dispensers, gas cylinders)
-CNS or brain damage - toluene
-Bone marrow damage - benzene (gasoline)
-2 or more of: dizziness, nystagmus, incoordination, slurred speech, unsteady gait, lethargy, depressed reflexes, psychomotor retardation, tremor, generalized muscle weakness, blurred vision or diplopia, stupor or coma, euphoria
-Pupillary constriction (or pupillary dilation due to anoxia from severe overdose) and one (or more) of the following signs, developing during, or shortly after, opioid use:
-drowsiness or coma
-impairment in attention or memory
-cessation of (or reduction in) opioid use that has been heavy and prolonged (several weeks or longer)
-administration of an opioid antagonist after a period of opioid use
-3 or more of: dysphoric mood, n/v, muscle aches, lacrimation/rhinorrhea, pupillary dilation/piloerection/sweating, diarrhea, yawning, fever, insomnia
opoid dependence pharmacotherapy
-agonists: methanone, buprenorphine
-antagonist: naltrexone (relapse prevention)
sedative, hypnotic, or anxiolytic
-intoxication: one or more of: slurred speech, incoordination, unsteady gait, nystagmus, impairment in attention or memory, stupor or coma
-withdrawal: 2 (+): autonomic hyperactivity, increased hand tremor, insomnia, n/v, transient visual/tactile/auditory hallucinations/illusions, psychomotor agitation, anxiety, generalized tonic-clonic seizures
-Perceptual changes occurring in a state of full wakefulness and alertness (e.g., subjective intensification of perceptions, depersonalization, derealization, illusions, hallucinations, synesthesias)
-2(+): pupillary dilation, sweating, palpitations, blurring of vision, tremors, incoordination
acute effects: rush: 45 sec - 1 min. -"on the nod" - sedation/tranquility <1 hr. depressed respiration (mu receptors). clouded mental functioning. n/v. analgesia
chronic effects: addiction, collapsed veins, abscesses/bacterial infections, infection of heart lining & valves, rheumatologic problems, adrenal/gonadal homeostasis, mood swings, malnutrition, chronic constipation
mesolimbic system & drug reward
-major neural substrate for the reinforcement produced by opiates, psychostimulants, ethanol, nicotine, and cannabinoids
-Ventral tegmental area -> nucleus accumbens -> prefrontal cortex
-Lesions of the mesolimbic DA neurons attenuate the reinforcing effects of iv cocaine.
-Animals will self-administer amphetamine and dopamine into the nucleus accumbens.
-ethanol and cannabinoids cause increased DA release in the NAc.
-in the presence of opiates & THC DA release is enhanced indirectly by influencing GABA
-D1 rs increase cAMP, D2 rs decrease cAMP. D2 involved in rewards.
-opiate reward -> ventral tegmental area
-stimulant reward -> n accumbens
-brain stimulation reward -> MFB
opiate receptors & psychostimulant reinforcement
-drug self-admin: opiate mu & delta, D1/D2. stimulant reward -> Nucleus accumbens (DA). Opiate reward -> ventral tegmental area (ENK).
-intracranial self-stimulation: mu & delta, D2. brain stimulant reward -> medial forebrain bundle
-conditioned place preference: mu & delta, D2
acute drug state
-Increased activity of mesolimbic dopaminergic system -> increased dopamine -> decreased cAMP
-minutes to hours
cAMP transduction pathway & drug reward
-increased cAMP opposes reinforcement and suggests the involvement of protein kinases, protein phosphatases and phosphoproteins in drug reinforcement
-reduction in function of the cAMP pathway is involved in reinforcement (found using bilateral PKA inhibitor in rats)
-acute reinforcing drug exposure is assc with decreased cAMP activity. Acute inhibition of this system may also contribute to drug craving and relapse in addicted subjects.
-chronic drug exposure produces an up-regulation of the cAMP pathway in the Nucleus accumbens, which could underlie tolerance to reinforcement.
chronic drug state
-tolerance, sensitization, and dependence develop
-up-regulation of cAMP pathway
-increase of ∆FosB
-over days - years
adaptations in VTA Dopamine neurons
Chronic psychostimulants or opiates can produce long-term changes in DA synthesis, release, D2 autoreceptor sensitivity, neurofilament proteins (decreased axonal transport and axon caliber, dendritic shrinkage).
Adaptations in postsynaptic G Protein Receptor Coupling.
Regulatory changes in gene transcription
-Increased activity in locus ceruleus -> increase in glutamate & norepinephrine -responsible for negative feeling
-decrease in dopamine and serotonin
-over hours to days
-craving & stress-induced relapse
-synaptic remodeling (learning & memory)
brain & cocaine
-"Rush": short-duration signals in VTA, basal forebrain, caudate, cingulate, lateral prefrontal cortex
-"Craving": sustained signals in NAc, right parahippocampal gyrus, some regions of lateral prefrontal cortex.
-on PET scan - acute reduction in glucose utilization. cravings are associated with increase in glucose utilization in nucleus accumbens
-gradual accumulation of proteins such as ∆FosB (transcription factor) in nucleus accumbens during chronic treatment with cocaine and other drugs of abuse.
-∆FosB is very stable. may represent molecular switch that gradually converts acute responses into relatively stable adaptations that underlie long-term responses such as craving. once this happens, will always crave the drug
-increases the responsiveness of mice to the rewarding and locomotor-activating effects of cocaine. may be mediated partly by induction of the AMPA receptor in the NAc.
-∆FosB, by altering gene expression, enhances sensitivity to cocaine, and may thereby contribute to cocaine addiction
-Not produced in brain until addicts have used cocaine several times
-ALDH21 is responsible for metabolism of acetaldehyde by liver mitochondria
-a genetically dominant yet inactive allele, ALDH22 gives natural protection from alcoholism because acetaldehyde is aversive. causes an endogenous disulfiram (ANTABUSE) effect
-1 or more of: slurred speech, incoordination, unsteady gait, nystagmus, impairment in attention or memory, stupor or coma
-acute intoxication: involvement of GABAA , NMDA-type glutamate receptors, and protein kinases
-chronic: Dopamine, GABAA and mu opioid receptors involved in rewarding aspects that allow dependence. BK channels may mediate development of tolerance, arg-vasopressin.
calcium channels, altered gene expression in physical dependence/withdrawal reaction
neuroinflammation in brain damage
-used to suppress drinking
-acts by inhibition of ALDH. also may suppress cocaine use via DBH inhibition
-Catabolized by same enzymes as ethanol
-Zero order kinetics also, but slower than ethanol
-ADH forms formaldehyde and ALDH forms formic acid
-poisoning -> acidosis, partial or total blindness, headache, dizziness, delirium, nausea and vomiting
-correct acidosis with bicarbonate
-give ethanol to slow conversion of methanol to formaldehyde, or can dialyze blood
-potent CNS & respiratory depressant
-poisoning -> Extreme abdominal pain, nausea and vomiting
-Giving ethanol will NOT help
-Dialysis only useful treatment for poisoning
-contained in anti-freeze
-Metabolized by ADH, ALDH, etc., and eventually to oxalic acid which reacts with calcium and forms deposits in the kidneys
-Treatment: gastric lavage, bicarbonate for acidosis, methylene blue for methemoglobinemia and ethanol to decrease metabolism by ADH
-decreased frontal lobe volumes, 3-4% smaller brain vol in all regions
-genetics: DA receptor genes, dopamine transporter gene, DA-beta-hydroxylase gene
-inattention, impulsivity, hyperactivity. Inattentive Type is more likely to be missed in childhood.
-persistent sx of inattention, onset before 7, impairment in 2(+) settings (school, work, ome). Evidence of clinically significant impairment in social, academic, or occupational functioning
-comorbidities: anxiety, conduct disorder, ODD, affective disorder, tic disorder, mania/hypomania, learning/academic problems, depressive disorders. In adolescents and adults, substance abuse is seen in >50% of patients
-1:1 redirection improves grades/function, does better when motivated
-assc w/ increased smoking, earlier onset of substance abuse, increased traffic violations/accidents
-stimulants - methylphenidate, amphetamine. change doses over 2-3 days.
-non-stimulants - atomoxetine - SNR1. optimize every 2-4 weeks.
-off-label: antidepressants (tricyclics, buproprion, venlafaxine); alpha2 adrenergic agonists (clonidine, guanfacine)
-long-acting stimulants - concerta, metadate, ritalan LA, Focalin XR, Daytrana patch
-50% have good prognosis, 25% develop antisocial PD, 50% half residual sx into adulthood
-more reuptake, more vesicular release of neurotransmitters.
-avoid in young kids due to mood effects
-Dexedrine 6-8 hour duration
-Mixed Amphetamine Salt = Adderall 4-6 hour duration
-Mixed Amphetamine Salt = Adderall XR 10 hour duration
-Prodrug (lisdexamfetamine)= Vyvanse 12-14 hour duration.
-Selective Norepinephrine Reuptake Inhibitor
-no "on and off"
-effects seen at 2-4 weeks
-SE: appetite, GI, sedation
-can exacerbate moodiness
-Precautions: Prozac and Paxil use with resultant increase in blood levels (increase mood swings).
-Dose based on weight. (Initial 0.5mg/kg/day then titrate to 1.4 mg/kg/day)
-Selective alpha2a adrenergic receptor agonist
-not first line therapy for ADHD
-dosage 1-4 mg daily
-Side effects: hypotension can be severe, sedation, bradycardia and syncope.
-Cannot be used with Clonidine (same medicine)
-MUST RULE OUT DELAYS, Hearing loss, and speech or language impairment. Perform developmental screening.
-Behavioral therapy. Meds have paradoxical effects.
-hyperactivity & impulsivity are most problematic
-at risk: prenatal drug/alcohol use by mom, complications at delivery, inborn errors of metabolism
physical complaints lacking organic basis/physical findings in presence of etiologically significant psychological factors
-a somatoform disorder
-multiple physical complaints, onset before age 30, lasts over years, diminished social/occupational function
-≥ 8 unexplained symptoms with 4 pain, 2 GI, 1 sexual/reproductive, 1 pseudoneurologic
-sx not explained by medical condition or subtance abuse
-not intentionally produced or feigned
-female predominance (10-20:1)
-familial pattern in 1o female relatives, sociopathy/substance abuse in male relatives
-assc w/ histrionic & anti-social PDs, lower socioeconomic group, lower levels of education, patient's concept of disease, repeated surgeries, social instability, co-morbid mood/anxiety/substance use disorders
-a somatoform disorder
-One or more symptoms/deficits affecting voluntary motor/sensory function suggestive of neurological (i.e. psudoseizures) and/or medical condition
-Initiation/worsening of symptoms is related to psychologically meaningful event, stressor
-Symptom is not intentionally produced or feigned
-Not limited to pain/sexual dysfunction, is not better accounted for by other mental disorder
-female predominance (2-5:1)
-Coexistent physical d/o, later dx of neurologic d/o not uncommon (20-60%).
-classical findings - secondary gain, histrionic personality, la belle indifference
-Better prognosis - acute onset, clear precipitant, good pre-morbid adjustment,absence of medical/neurological co-morbidity
-a somatoform disorder
-Psychological factors have important role in onset/severity exacerbation/maintenance of pain
-Pain not intentionally produced or feigned
-Female predominance (2:1), presents in 4th-5th decade
-Depressive sxs often underlie/coexist - also associated with sense of guilt, history of physical/sexual abuse
-a somatoform disorder
-Equal M:F ratio, any age of onset but often later
-Obsessive-compulsive, narcissistic personality traits
-Duration ≥ 6 months - chronic, waxing and waning course
- Possible variant of OCD
Body Dysmorphic Disorder
-a somatoform disorder
-Hypochondriacal subtype with earlier age of onset
-mainly head/face but could be any part of body
-Not of delusional proportions (but could be prodrome to psychosis)
-Possible variant of OCD
-type of factitious disorder. least common, most dramatic
-socially maladjusted males from lower socioeconomic class
-triad of repeated disease simulation, pathologic lying, wandering
-socially conforming young women
-higher socioeconomic class
-intelligent, educated, often employed in medical field
-sxs often intermittent and in response to psychosocial stressors (loss, rejection, criticism)
-Delays in psychosexual development, antisocial/ delinquent behavior.
-Core conflicts related to self-esteem, dependency, mastery, masochism.
-Behavior as "repetition-compulsion"
-Positive prognostic features - other Axis I D/O, some social supports, ability to cope with confrontation, establish rapport.
mechanism of inhaled anesthetics
-no specific receptor
-action on the proteins that form ion channels
-prolonging ion current after GABA -> reducing postsynaptic neuronal excitability
-increased activity of glycine receptors in spinal motor neurons
-blockade of excitatory post-synaptic current of nicotinic receptors
lesions that cause coma
-diffuse hemispheric damage
-damage to paramedian portion of upper midbrain & caudal diencephalon
-high pontine & lower midbrain paramedian pontine injury
-pontine hemorrhage -> compression of surrounding brain stem, can cause dysfunction that extends beyond the area of the tissue loss
psychodynamic theory of depression
1. Disturbance of infant/mother relationship at 10-18 months (oral phase) increases vulnerability
2. Depression linked to real or imagined loss
3. Introjections of departed to deal with loss
4. Views the object of loss with ambivalence of love and hate, turns anger on self
Cognitive theory of depression
-Aaron Beck puts forth chronic, habituated thoughts "depressive schemata"
1. Views of self as negative
2. Views of environment and the world as hostile and demanding
3. Views of the future as suffering and failure
-5 or more sx for at least 2 weeks
-Includes at least depressed mood or loss of interest/pleasure
-weight loss/gain, insomnia/hypersomnia, psychomotor retardation/agitation, failure or loss of energy, guilt or worthless thoughts, decreased concentration, recurrent thoughts of death
-Cannot be a mixed state with mania
-Patient must be clinically distressed and impaired in function
-Symptoms cannot be directly related to substance use or a general medical condition
-Is not bereavement
-Average depressed episode lasts 10 months if untreated
At least 75% have a second episode of depression, usually in the first 6 months after initial episode
Average number of lifetime depressive episodes is 5
comorbitidies with bipolar disorder
-obsessive compulsive disorder
antidepressants & delay of onset
-At the postsynaptic membrane - there is increased adrenergic or serotonerigic receptor density or sensitivity as well as increased G-protein coupling.
-There is increased neurogenesis (and presumably synaptic contacts)
-Downregulation of the transporters for serotonin (SERT) , norepinephrine (NET) etc..and therefore increased neurotransmitter in synapse
neuroimaging & ADHD
-ADHD pts have decreased blood flow to anterior cingulate and increased flow in frontal striatum
-decreased cerebral metabolism in brain areas controlling attention
-increased DAT protein binding - may result in accelerated re-uptake leading to reduced dopamine in the synaptic cleft
-3-4% smaller brain volumes in all regions - frontal lobes, temporal gray matter, caudate, cerebellum
-children that were medicated had increase in brain volumes
-Impaired cognitive function - higher cortical function
-cognitive impairment resulting in inability to carry out activities of daily living (ADLs)
-primarily specific (cortical) neuronal degeneration, unknown causes
-majority due to age
-primary causes: primary neurodegenerative disorders - Alzheimer's,, Pick's (frontotemporal degeneration), Lewy-body dementia, Parkinson's
-secondary causes - reversible. ex - syphilis
-acute confusional state
-impaired and reduced attn, often accompanied by hallucination and delusional thoughts
-often reversible (3-6 months)
-sometimes persistent - beclouded state
-metabolic, infectious, inflammatory, & toxic causes
-due to progressive cerebrovascular events
-preventable - vascular risk factors
-pts who have Alzheimer's can develop cerebrovascular events that account for cognitive impairment -> mixed-type dementia
-can be widespread areas of infarction (strokes, lacunar infarcts)
-diffuse white matter injury (CADASIL)
-strategic infarcts (hippocampus)
-onset after 50, w/ increasing incidence w/ increasing age. Prevalence 2X every 5 years (40% at 85-90)
-early - memory dysfunction (amnesic syndrome). Insidious onset of higher level intellectual impairment, mood and behavior changes followed by progressive memory loss, disorientation, aphasia, eventually mute and immobile
-amyloid plaques (amyloid 1-42 peptides) & neurofibrillary tangles (tau protein - abnormal phosphorylation & aggregation)
-medial temporal lobe/hippocampal formation & basal forebrain cholinergic neurons (Nucleus basalis of Meynert) are most vulnerable. atropy primarily frontal, temporal, & parietal. may have hydrocephalus ex-vacuo
-impaired episodic memory
-neurofibrillary tangles, senile (neuritic) plaques, amyloid angiopathy
-CSF: reduced amyloid beta-1-42, increased tau or phospho-tau
-reduced glucose metabolism in bilateral temporal parietal regions
-amyloid protein on PET/CT
-5-10% cases familial (usually earlier onset)
AD & genetics
-Amyloid precursor protein - chr 21 (Down's syndrome also has overproduced amyloid). cell surface protein w/ single transmembrane domain. If cut correctly, soluble protein is produced. W/ alternative processing (can be gene mutation) it's endocytosed and degraded by β- and γ-secretase, it forms the Aβ peptide - found in plaques, tangles, & CAA
-Presenilin 1: chr 14, young onset, early death. familial type. Presinilin 2: chr 1. mutations increase production of Aβ peptide, causes early onset familial AD
-Apo-E (apolipoprotein E) - chr 19. allelic variants APO-E4, APO-E3, APO-E2.
-APO-E4 carriers - increased risk of developing AD at younger age (10 yrs earlier)
-APO-E2 & APO-E3 carriers have protective effect - AD in later age, reduce a-beta-142
-ACh -> memory & attention. use anticholinesterases
-Dopamine -> psychosis
-Serotonin -> depression
-Norepinephrine -> depression
-Memantidine (NMDA receptor antagonist) for neuroprotection
-Anti-Beta Amyloid deposition: phase I & II & III
-Anti-tau phosphorylation: phase I & II
-Cholinesterase inhibitors: Donepezil, Rivastigmine, Glantamine ER
-for mild disease - no meds, leisure activities
-mild to moderate - CE inhibitors, progress slowly
-moderate to severe - donepezil, memantine, psycho-social support. progress fast
-Aß Vaccination - emerging
-Solanezumab (Eli Lilly)
primary posterior cortical atrophy syndrome
-gradual cortical atrophy of bilateral occipital/parietal lobes
-no secondary causes
-progressively impaired visuospacial function -> Balint's syndrome -> cortical blindness
-Majority due to alzheimer's - rare
Behavioral variant (FTD)
-fronto-temporal lobar degenration
-pts with bizarre behaviors - disinhibited, apathetic
-characteristic lobar atrophy of frontal & temporal lobes bilaterally
-Chr 17 - tau mutations, progranulin mutations
primary progressive aphasia
-fronto-temporal lobar degeneration
-progressive dysfunction of language
-cortical regions surrounding left perisylvian fissure gradually atrophy
-3 subtypes: agrammatic/non-fluent, semantic, logopenic
-can be due to Alzheimer's
-Parkinson's disease with dementia (PDD)
-lewy body disorder
-develops in context of established PD, at least 1-2 yrs after d/o.
-impairment in >1 domain - attention, executive, visuospatial, memory, language
-decline from premorbid level
-deficits severe enough to impair daily life
-tx - Rivastigmine (cholinesterase inhibitor)
-due to autosomal mutation in α-synuclein
Dementia of Lewy Bodies (DLB)
-Parkinsonism - bradyphrenia (slowness in throught process), bradykinesia
-predominant visuospatial dysfunction
-early onset of visual hallucinations
-doesn't respond to dopaminergic treatments
-often mixed with Alzheimer's pathology
-cholinesterase inhibitor treatments
-due to autosomal mutation in α-synuclein
-seen in Alzheimer's disease
-extracellular spherical collections of dilated, tortuous neuritic processes, 20-200 micrometers
-microglia & astrocytes at perimeter
-primary component = Aβ peptide
-most commonly used d/o criteria require counting of plaques & relating to pt age (CERAD criteria)
-black spots on silver stain. Amyloid component is green w/ congo red stain.
-seen in Alzheimer's disease
-bundles of intracytoplasmic filaments that displace or encircle the nucleus ("flame cells")
-remain visible after death of the neuron ("ghost tangles")
-composed of microtuble-associated tau protein & ubiquitin
Cerebral Amyloid Angiopathy (CAA)
-almost always seen in Alzheimer's
-deposition of Aβ peptide in cerebral vessel walls
-toxic to vessels, make them brittle & bleed
-deposits w/ Congo red stain
-seen in AD
-neuronal intracytoplasmic vacuoles containing granules
-seen in AD
-ovoid pink extracellular bodies containing paracrystalline arrays of beaded filaments
-w/i neurofibrillary tangles in AD
-becomes hyperphosphorylated and loses the ability to bind to microtubules
-amount of neurofibrillary tangles correlates best with the degree of dementia (better than neuritic plaques)
-tau is not mutated
-rare disease w/ progressive dementia, behavioral & personality changes, & language disturbances
-severe knife edge atrophy of frontal & temporal lobes
-neuron loss most severe in cortex of these lobes
-surviving neurons have swelling (Pick cells) or cytoplasmic inclusions (Pick bodies)
-Pick bodies stain intensely w/ silver stains. filled with accumulated tau.
Idiopathic Parkinson Disease
-Parkinsonism in the absence of any other known cause
-usually sporadic, but can be AD mutation in gene for α-synuclein
-one stage of Lewy Body progression
-pallor of substantia nigra & locus ceruleus due to loss of pigmented cells
-Lewy bodies - large round eosinophilic inclusions w/ halo in cytoplasm of neurons, contain neurofilaments, α-synuclein, & ubiquitin. Also present in Nucleus Basalis of Meynert, Locus Ceruleus and the Dorsal Motor Nucleus of the Vagus
-10-15% of IPD patients develop dementia, and may have Lewy bodies throughout cortex (diffuse Lewy body disease)
-nigral stage of Lewy Body Spectrum Disorder (also limbic & neocortical stages based on progression)
-autonomic dysfunction - excessive salivation, increased sweating
-30% older patients have dementia
-depression in 30-40% pts
Progressive Supranuclear Palsy
-truncal rigidity, dysequilibrium, abnormal speech, vertical gaze palsy that progresses to difficulty w/ all eye movements, mild progressive dementia
-onset 5th-7th decades. M> F 2:1. lethal w/i 5-7 yrs
-widespread midbrain neuron loss & globose neurofibrillary tangles (Tau+, in locus ceruleus or substantia nigra)
-type of multiple system atrophy
-loss of neurons in both substantia nigra & target neurons in caudate & putamen. w/ gliosis, no lewy bodies.
-clinically similar to Idiopathic Parkinsons, but no response to L-dopa
-affects glia, not neurons
-type of Multiple System Atrophy
-combines features of Idiopathic Parkinson's Disease or striatonigral degeneration with autonomic disturbances due to degeneration of neurons in intermediolateral column of SC
-autonomic features - impotence, orthostatic hypotension, sweat & salivary disturbances, pupillary abnormalities
-type of Multiple System Atrophy
-loss of neurons of pontine nuclei, inferior olives, & Purkinje cells of cerebellum.
-ataxia, eye & somatic movement disorders, rigidity, & dysarthria
-most cases AD, some AR, some sporadic
-progressive movement disorders & dementia
-degeneration of striatal neurons
-jerky, hyperkinetic, dystonic movements involving whole body (chorea)
-may later develop parkinsonism w/ bradykinesia & rigidity (15 years)
-loss of GABAnergic neurons in basal ganglia increases inhibition of subthalamic nucleus - prevents it from regulationg motor output.
-autosomal dominant. HD gene codes for huntingtin protein. trinucleotide rpts of CAG (glutamine). more rpts = earlier onset, increased severity
-atrophy: caudate > putamen > globus pallidus > frontal cortex > parietal cortex
-dilation of lateral & third ventricles (hydrocephalus ex-vacuo)
-severe loss of striatal neurons (esp medium-spiny neurons). most in caudate. aggregates of huntingtin.
-dopamine levels in striatum normal or elevated. reduced enzymes that catalyze synthesis of GABA & ACh.
-resemble sx of excessive dopaminergic activity induced by L-dopa.
-Attempts to treat disease with agents that enhance cholinergic or GABA activity been disappointing.
-tx: dopamine receptor antagonists, phenothiazines, haloperidol, dopamine depleting agents (reserpine or tetrabenazine, produce iatrogenic parkinsonism)
Spinocerebellar Ataxias (SCAs)
-genetically distinct diseases (29)
-signs and symptoms referable to the cerebellum (progressive ataxia), brainstem, spinal cord, and PNS
-3 types of mutations (the 3rd was other, who cares)
-CAG (polyglutamine) repeats, similar to HD
-expansion of non-coding region repeats (in RNA), similar to myotonic dystrophy
-AR progressive disease beginning in childhood w/ ataxia, then hand clumsiness & dysarthria. most DTRs absent, loss of proprioception, vibratory, pain, & temp sensation
-most have pes cavus and kyphoscoliosis, arrhythmias. CHF, DM in 10%
-GAA trinucleotide repeat in gene coding for frataxin.
-atrophy of neurons & axonal loss from SC, brain stem, cerebellum (dentate), and possibly motor cortex. atrophy of DRG, enlarged heart, pericarditits & myocarditis
-AR disease in childhood, usually lethal by 2nd decade
-Recurrent resp tract infections followed by ataxia, dysarthria, & eye movement disorders
-telangiectasias in skin & conjunctivae
-develop lymphomas (most common cause of death), gliomas, or carcinomas
-abnormal ATM gene impairs DNA repair
-heterozygous carriers may be at increased risk for (breast) cancer
-loss of Purkinje & granular cells of cerebellum, degeneration of dorsal columns, spinocerebellar tracts, & anterior horn cells, peripheral neuropahty
-hypoplastic LNs, thymus, goands
Amyotrophic Lateral Sclerosis
-Motor neuron disease. loss of upper & lower motor neurons leads to muscle atrophy, fasciculations, & hyperreflexia. can involve cranial nerve nuclei
-onset in older adults
-10% AD w/ mutations in SOD1 (superoxide dismutase) gene. familial cases have earlier onset
-atrophy of precentral gyrus, anterior spinal roots, & muscles (denervation atrophy). loss of anterior horn cells along entire SC, gliosis, loss of neurons of CN nuclei. demyelination from CST to anterior roots
-causes destruction of substantia nigra pars compacta dopaminergic neurons
-an impurity in an illicit meperidine "designer"drug
-responds to standard dopaminergic therapy
-MPTP (inactive) readily crosses BBB. MAO-B converts MPTP to active, neurotoxic MPP+ outside dopaminergic neurons, in astrocytes or serotonergic neurons. MPP+ taken up by dopamine transporter, causes dopaminergic cell death (inhibits mitochondrial respiration).
-MAO-B inhibitors (segiline) can protect against MPTP-induced toxicity in non-human primates
-Dopamine uptake blockers also protective
-multiple tic disorder. onset 5-7.
-stereotyped & purposeless movements of coordinated muscle groups.
-common tics involve excessive eye blinking, throat clearing, head shaking,& facial grimacing. centered in upper body.
-coprolalia - obscene or socially inappropriate speech.
-All tics aggravated by stressful environmental stimuli or settings.
-comorbid w/ ADHD
-hyperfunctioning of DA systems - haloperidol helpful in 2/3. Also pimozide & risperidone. Clonidine effective if haloperidol-resistant
-ion channel level - defective synaptic transmission. reduced inhibitory synaptic activity or enhanced excitatory
-neurons show paroxysmal depolarizing shifts of membrane potential & assc high frequency firing, loss of IPSP, & synchronous discharge of surrounding cells
-more common in adults than children
-HA, seizures, focal neurologic signs
-Grade I = low-grade focal astrocytoma
-Grade II = low-grade diffuse astrocytoma. infiltrative and destructive, but indolent. survival > 5 yrs. evolve to higher grade.
-low grade blend imperceptibly, more cellular, have gliosis, fibrillary GFAP-positive background, minimal nuclear pleomorphisms/atypia.
-Grade III = high-grade diffuse
-Grade IV = highest-grade diffuse - gliobastoma multiforme (GBM). presence of geographic necrosis or microvascular proliferation
-can occur anywhere in CNS
multiple regions or entire brain affected w/o focal tumor mass. start out grade IV.
-more cellular & atypical than low-grade lesions, are grade III
-mitotic figures present
-called gemistocytic astrocytoma when there are predominantly brightly eosinophilic cells
-gemistocyte = stuffed cell w/ pink
-death w/i 8-10 mos
-pleomorphic gross appearance w/ areas of hemorrhage and necrosis
-often crosses midline through white matter tracts - *"butterfly lesions"* that are *ring enhancing*
-WHO IV - highest grade
-final pathway for all high grade gliomas
-more *cellular* & mitotically active than anaplastic astrocytoma
-*necrosis*, sometimes w/ peripheral *pseudopalisading*, & *vascular (endothelial) proliferation*
-frequent *mitotic figures*
Juvenile Pilocytic Astrocytoma
-benign astrocytoma. WHO grade I
-can occur anywhere in CNS, but most commonly in cerebellum. common in children
-*cystic w/ mural nodule*
-*bipolar cells* w/ long GFAP-positive processes; increased # vessels including idosyncratic endothelial proliferation
-*Rosenthal* fibers - large red extracellular cigar-shaped bodies
-typically biphasic - cell-rich & cell-poor
-benign astrocytoma. WHO grade I
-in superficial temporal lobe in children/young adults w/ history of seizures
-*atypical astrocytes & foamy cells*
-Rosenthal fibers or *eosinophilic granular bodies* (smaller red extracellular globules, probably early Rosenthal fibers)
Subependymal Giant Cell Astrocytoma
-benign astrocytoma. WHO grade I
-very strong assc w/ tuberous sclerosis
-tubers (cerebral hamartomas) probably evolve into SEGA
-in any subependymal location
-*large epitheliod astrocytes* w/o mitotic activity or necrosis
-4th-5th decade, often w/ history of seizures
-in white matter of cerebral hemispheres
-more chemosensitive than astrocytomas, esp if positive for deletions on chr 1p & 19q
-avg survival is 5-10 yrs
-well-circumscribed lesions, w/ hemorrhage and calcification
-sheets of cells w/ uniform round-oval nuclei, perinuclear halos, fine capillary network, calcifications
-partially GFAP positive
arise in periventricular locations. In children usually around 4th ventricle, in adults around SC. Lead to hydrocephalus, disseminate into CSF
avg survival is 4 yrs despite therapy & benign histologic appearance
well-circumscribed. fairly uniform cells w/ round-oval nuclei and fibrillary background. GFAP-positive fibrillary processes surround vessels as *perivascular rosettes*, or form true rosettes.
arises at filum terminale.
cuboidal ependymal-like cells around papillary structures within myxoid background.
recurrence likely if incompletely resected.
solid periventricular tumors that often *protrude into ventricles*. benign, asymptomatic. may cause hydrocephalus if large enough.
clusters of small ependymal-like cells scattered in a fibrillary background
Choroid plexus papiloma
most common in children (in lateral ventricles). also in adults (in 4th ventricle). look like exaggerated normal CP.
cause hydrocephalus due to ventricular obstruction & CSF overproduction.
malignant version = choroid plexus carcinoma, common in children, difficult to differentiate from metastatic lesion
colloid cyst of third ventrilce
cystic lesion containing gelatinous materal that hangs from roof of 3rd ventricle
more common in young adults
hydrocephalus, presents as positional HA
most common in children
slow growing, usually benign. well-circumscribed, often calcified. clumps of large neurons ("ganglion cells") in acellular stroma
similar to gangliocytoma, with astrocytic component. usually slow growing. glial component sometimes transforms to high grade lesion w/ poor prognosis.
usually *intraventricular near foramen of Munro*. *mimics oligodendroglioma*: sheets of uniform cells with perinuclear halos, but positive for neuronal markers and GFAP-negative
most common in young to middle-age adults.
excellent prognosis, especially if completely excised
Dysembroplastic Neuroepithelial Tumor
multinodular lesion, usually in temporal lobe, in children w/ history of seizures. often microcystic w/ neurons floating in pools of myxoid materal and surrounding glial cells without atypia.
good prognosis w/ complete excision
primitive neuroectodermal tumor (PNET)
usually in children.
assc w/ chr 17p - i(17q)
untreated prognosis dismal, but with good excision and radiation 5 yr survival ~75%
usually midline of cerebellum, often lateral cerebellum in adults. very cellular with little cytoplasm, hyperchromatic nuclei, high mitotic rate, can express neuronal and/or glial markers, Homer Wright rosettes.
Propensity for CSF seeding with "drop" metastases
Primary CNS lymphoma
most common CNS tumor in immunosuppressed. also in immunocompetent in ~60 yo.
primary: originally rising in CNS, or metastatic spread of lymphoma from distant primary site (rare)
high grade B cell lymphoma (express B cell antigens like CD20), aggressive, poor response to chemo
In immunosuppressed, cells express EBV genome
often multifocal, well-circumscribed, with central necrosis, periventricular spread. *tumor cells accumulate around vessels*
CNS Germ Cell Tumors
usually in midline in pineal or suprasellar area. most common in adolescents & young adults. must be differentiated from metastasis.
parallel those seen in gonads. CSF spread may complicate tx.
pineal parenchymal tumor
well-differentiated neuronal tumor arising from pineocytes. no necrosis or mitotic activity
pineal parenchymal tumor
resembles medulloblastoma. small cells w/ little cytoplasm, high mitotic rate, necrosis
usually benign tumors, arise from meningothelial cells of arachnoid. usually attached to dura, but can be intraventricular
in adults. F:M = 2:1, but 10:1 in spinal meningiomas.
cells express progesterone receptors - grow rapidly during pregnancy.
increased risk in pts with neurofibromatosis type II
rounded dural-based lesions that compress brain, but easily separated from it. can present as meningeal plaque. can invade adjacent bone and/or brain.
variants - syncytial, fibroblastic, transitional, secretory, psammomatous. usually (+) for epithelial membrane antigen (EMA). Can be WHO I, II, or III.
papillary or clear cell variants have poorer prognosis & more likely to recur.
malignant (aplastic) meningioma
WHO grade III. rare. defined by mitotic activity, nuclear atypia, necrosis. Rhabdoid & clear-cell types
50% of all intracranial tumors.
5 most common primaries - Lung, breast, bowel, cutaneous (melanoma), kidney. It spells Lubbock, kind of.
often multiple, can involve meninges. usually sharply circumscribed, often at gray-white junction
peripheral nerve sheath tumor. Positive for Schwann cell marker S-100 protein.
benign tumors arising from Schwann cells. sx are those of nerve compression.
sporadic or assc w/ neurofibromatosis type II
if extradural, arise from large peripheral nerve trunks.
intracranial lesions usually arise from cerebellopontine angle attached to CN VIII - present w/ tinnitus or hearing loss (acoustic neuroma)
encapsulated, usually attached to the nerve, but can usually be separated from it.
mixture of 2 growth patterns - relatively cellular Antoni A areas w/ palisading nuclei (Verocay bodies) and Antoni B areas of less dense cellularity in myxoid stroma.
degenerative changes - nuclear atypia in ancient schwannomas.
peripheral nerve sheath tumor. Positive for Schwann cell marker S-100 protein.
small benign nodules in skin, subcut fat, or peripheral nerve. spindle cells in fibrotic stroma.
can be assc w/ neurofibromatosis type I
peripheral nerve sheath tumor. Positive for Schwann cell marker S-100 protein.
almost always assc w/ neurofibromatosis type I.
risk of malignant transformation. usually arise at (multiple) large nerve trunks. spindle cells in myxoid stroma closely infiltrate between nerve fibers. can't be separated from nerve.
malignant peripheral nerve sheath tumor
Positive for Schwann cell marker S-100 protein
invasive, malignant tumor arising from nerve trunks. multiple recurrences are usually followed by metastatic disease. arise de novo or from malignant transformation of plexiform neurofibromas.
strongly assc w/ neurofibromatosis type I & history of radiation exposure
primarily spindle cells w/ nuclear atypia, high mitotic rate, necrosis. may have mixture of sarcomatous elements or may be epithelioid.
Neurofibromatosis type I (von Recklinghausen Disease)
-AD. multiple plexiform and cutaneous neurofibromas, optic nerve gliomas, pigmented nodules of the iris ("Lisch nodules,") hyperpigmented macules ("café au lait spots")
mutations in tumor suppressor gene NF1 on chr 17 - codes for neurofibromin.
Neurofibromatosis type II
AD, less common than type I. bilateral acoustic neuromas and *multiple meningiomas*, sometimes glial hamartomas.
mutation in NF2 gene on chr 22 - codes for protein merlin (a cytoskeletal protein)
AD. renal angiomyolipoma, various organ cysts, subungual fibromas. skin lesions - angiofibromas, leathery thickening (shagreen patch), hypopigmented areas (ash-leaf patches)
tubers - cortical hamartomas. firm areas w/ haphazardly arranged neurons and large eosinophilic cells which express both neuronal and glial antigens
Subependymal lesions may *bulge into ventricles* ("candle guttering"); may evolve into SEGA
Von Hippel-Lindau Disease
AD disease with hemangioblastomas of cerebellum & retina, various organ cysts, and greatly increased risk of renal cell carcinoma
Mutations of a tumor suppressor gene on chromosome 3, which codes for pVHL; pVHL is part of the protein degradation pathway (ubiquitin E3 ligase), including HIF-1a (signal of hypoxia)
Benign tumors, typically present as a cyst with a mural nodule. Very vascular with capillary-sized or slightly larger vessels, interstitial cells with lipid-rich vacuolated cytoplasm. Can mimic metastatic renal cell carcinoma
10% have polycythemia due to ectopic erythropoietin production
cluster A PDs
paranoid, schizoid, schizotypal
odd & eccentric
cluster B PDs
antisocial, borderline, histrionic, narcissistic
dramatic, emotional, erratic - require a lot of attention
cluster C PDs
avoidant, dependent, obsessive-compulsive
anxious or fearful
5(+): needs lots of advice for decisions, can't be responsible for big things, can't disagree due to fear of losing support, can't initiate projects due to self-confidence problems, goes to extremes to be accepted, can't be alone, must immediately replace broken relationship, preoccupation with being left along
most common trait. high comorbitiy with depression & anxiety. suffers through degradation. severe version is self-defeating. therapy must focus on independence.
cluster C PD
social inhibition, inadequacy, hypersensitivity to criticism
4(+): avoids jobs or activities due to fear of criticism, only relates to those who like them, can't develop intimacy due to fear, preoccupied with being ridiculed, inhibited in new relationships due to inadequacy, views self as inferior to others, avoids activities that could be embarrassing
sabotages relationships as they get more intimate - fear of rejection.
tx is exposure based therapy. can use anxiolytics.
Cluster C PD
preoccupation with order, perfection, and control at the expense of flexibility and efficiency
4(+): so focused on rules that they lose the point, too perfectionistic to complete task, all work no play, hoards everything, can't delegate, rigid & stubborn
commonly assc w/ eating disorders. have few friends.
therapy, anxiolytics, and SE drugs (????) can help
Cluster B PD
excessively emotional and attention-seeking
5(+): must be center of attention, sexually seductive, rapid & shallow shifting emotions, attention via appearance, speech lacks detail, exaggerated expression of emotions, easily influenced by others, thinks relationships are more intimate than they are
flirts but may not act out sexually. lessens with age. sensation-seeking
In therapy, have to manipulate them to follow orders (CREEPY)
cluster B PD
grandiose, attention-seeking, lacks empathy
5(+): grandiose, preoccupation with fantasies of success, can only associate with special people, requires admiration, entitled, exploitative of others, lacks empathy, mind ruled by thoughts of envy, arrogant
less anxious and chaotic than w/ borderline PD
difficult to treat. Axis-I is generated by narcissistic injury. must be in control.
cluster B PD
unstable relationships, image, or marked impulsivity
5(+): frantic efforts to avoid abandonment, intense love-hate relationships, 2+ areas of dangerous impulsivity, recurrent self-harm threats or gestures, affective instability, chronic emptiness, increase anger displays, transient paranoia or dissociation due to stress
often confused with Bipolar I or II
presents as normal when interviewing
Marsha Linehan's DBT is only effective long-term treatment of self-harm behavior
mood-stabilization is critical
75% of all psychiatric lawsuits
easy to overdose on TCAs and MAOIs
Validate and Set Firm Limits, have others around
cluster B PD
violates rights of others since 15
3(+): behavior is grounds for arrest, lying/conning, impulsivity/poor planning, aggressive/fights, reckless disregard for others' safety, irresponsible with work/money, lack of remorse
at least 18. conduct disorder before 15.
75% of prison pop.
can be charming and normal, don't think they have a problem, survival minded. justification & consequences. need for stimulation. substance/medication abuse.
impulse control meds help. careful with benzos and stimulants. negotiation techniques.
15% of antisocial population
views humans as objects to be used. excessively cruel, remorseless. can be very intelligent.
tx have little chance
4(+): suspects without basis, preoccupation with doubts about loyalty, relunctant to confide, benign remarks = proof, bears grudges, reacts angrily to perceived attacks, suspects infidelity
can present as normal. unemotional, guarded historian. doesn't have fixed delusions or hallucinations. doesn't have over-involved relationships
unemotional therapy best
detached emotions, restricted range of emotions
4(+): no desire for close relationships, solitary activities only, no interest in sex w/ others, anhedonic, no close friends, indifferent to praise or criticism, detached/cold/flat
7.5% of people. solitary history. may be attached to anything not human, have no interest in people, can be creative. no schizophrenia in family, no delusions or hallucinations
Don't push them, reassure no relationship pressure from you
Problems with relationships, cognitive and perceptual distortions, eccentric
5(+): ideas of reference (not delusional), strange/odd/magical beliefs, unusual perceptions and illusions, odd thinking and speech, suspicious, inappropriate or constricted affect, odd appearance and behavior, no friends, social anxiety = paranoia
related to familal schizophrenia. hyperaware of others feeling state. superstitious. decompensate to psychosis.
neuroleptics can help
No full criteria for an Axis-II disorder
Pervasive and causes impairment
Passive-Aggressive - Less extreme affect than Borderline
Depressive - Dysthymia fluctuates more
Sadistic - No gain except to inflict pain
therapeutic uses of ethanol
-solvent for water-insoluble drugs (po & topical)
-Rubbing agent (50-70% v/v) to prevent bedsores
-Sponge baths for fever
-Skin disinfectant (70% v/v)
-Denatured alcohol injected for relief of long-lasting pain of trigeminal neuralgia, inoperable carcinoma
-Antidote for methanol and ethylene glycol poisoning